CorticosteroidiSTORIA
1563 Eustachio scopre lrsquoesistenza delle ghiandole surrenali 1849 Addison attribuisce la ldquopelle bronzeardquo a malfunzionamento delle ghiandole surrenali 1856 Brown-Sequard rimuove le ghiandole surrenali di gatti e cani i quali poi moriranno nellrsquoarco di qualche giorno dimostrando cosirsquo lrsquoimportanza vitale di queste ghiandole 1894 Viene scoperta la suddivisione delle surrenali (corteccia e midollare) Lrsquoadrenalina viene secreta dalla midollare1938 Reichstein isola 29 nuove sostanze dalla corteccia surrenale e tutte sono steroidi1948 Kendall isola il cortisone1950 Kendall Reichstein ed Hench riceveranno il premio Nobel per la medicina
ldquoFor a long period I had from time to time met with a very remarkable form of general anaemia occurring without any discoverable cause whatever The disease presented in every instance the same general character pursued a similar course and with scarcely a single exception was followed after a variable period by the same fatal result The appetite is impaired or entirely lost the whites of the eyes become pearly the pulse small and feeble The body wastes slight pain or uneasiness is from time to time referred to the region of the stomach and there is occasionally actual vomiting which in one instance was both urgent and distressing Neither the most diligent inquiry nor the most careful physical examination tends to throw the slightest gleam of light upon the precise nature of the patientrsquos malady But with a more or less manifestation of the symptoms already enumerated we discover a most remarkable and sofar as I know characteristic discoloration taking place in the skinrdquo
Thomas Addison 1855
Rev Endocr Metab Disord 2010 Jun11(2)147-53
The diagnosis of Cushings syndromeCarroll TB Findling JWEndocrinology Center (TBC JWF) Medical College of Wisconsin W129 N7055 Northfield Drive Building A Suite 203 Menomonee Falls WI 53051 USA tcarrollmcweduAbstractSpontaneous Cushings syndrome is well known but unusual clinical disorder Many of the clinical features (central weight gain glucose intolerance hypertension muscle weakness) are seen in other common conditions Recognition of patients with multiple features features unusual for their age (ie early onset osteoporosis or hypertension) patients with features more specific to Cushings syndrome (ie easy bruising facial plethora and violaceous striae) and patients with incidental adrenal mass or polycystic ovary syndrome should prompt an evaluation for cortisol excess Late-night salivary cortisol 1 mg overnight dexamethasone suppression testing or 24 h urine free cortisol determination have excellent diagnostic characteristics and should be obtain in patients with suspected Cushing syndrome If this initial testing is abnormal further evaluation should be directed by an endocrinologist experienced in the diagnosis and differential diagnosis of Cushing syndrome
Cushingrsquos Support amp Research Foundation
Abdominal weight gainRed round lsquomoonrsquo faceThinning extremitieslsquoBuffalo humprsquo
High blood pressureHigh blood sugarMuscle weaknessOsteoporosisFracturesInfectionsBlood clotsVisual field defects
Easy bruisingThinning skinPoor wound healingAcnePurple striaeHirsutismFemale baldingMenstrual irregularity
Sleep disordersExcessive hungerExcessive thirstFrequent urinationSweating
AnxietyConfusionConcentration lossMemory lossDepressionSuicidal thoughtsPanic attacksIllustration from Mayo Clinic Family Health Book 2d ed 1996
Symptoms VaryAnd may include any number of these
Courtesy of wwwCSRFcom
HPA
Ipotalamo
Ipofisi
Surrenali
I glucocorticoidi sono degli ormoni rilasciati dale ghiandole surrenali sotto lo stimolo ipofisario dellrsquoACTH e ancor prima dallo stimolo ipotalamico rappresentato dal CRH Il glucocorticoide per eccellenza egrave il cortisolo Molti glucocorticoidi di sintesi sono altamente efficaci nel trattare malattie infiammatorie quali asma reazioni autoimmuni e allergie I loro effetti terapeutici sono generalmente ascrivibili alla forte azione inibitoria sulla produzione di cellule T cosigrave come sulla inibizione del rilascio di interleuchina 2 e del suo recettore Anche le interleuchine proinfiammatorie 1 6 e 12 vengono inibite nel loro rilascio cosigrave come per il Tumor necrosis factor alfa presente nei monociti e macrofagi Questi effetti sono mediati dai recettori per i glucocorticoidi presenti nel citoplasma Una volta legati al suo recettore i glucocorticoidi traslocano nel nucleo e regolano lrsquoespressione genica legandosi specificativamente a sequenze di DNA con geni detti elementi dei recettori dei glucocorticoidi Il recettore dei glucocorticoidi altera anche lrsquoespressione genica attraverso lrsquointerazione diretta con proteine non recettoriali legate al promotore presente sul geneA queste azioni antiinfiammatorie perograve sono legati effetti collaterali quali aumento di peso corporeo diabete ipertensione osteoporosi cambiamenti comportamentali e alterazione del sonno
Livelli di cortisolo durante la giornata e durante I giorni della settimana
The measurement of late-night salivary cortisol usually at 2300 to 2400 h has proven to be a very useful approach to the diagnosis of Cushingrsquos syndrome
Lrsquoinspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantitagrave elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo egrave stato finalmente chiarito in anni recenti Paradossalmente il composto E (cortisone) che Kendall usava egrave una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivitagrave antinfiammatoria La conversione sistemica del cortisone a cortisolo egrave principalmente per via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il cortisone a cortisolo La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte il cortisolo in cortisone ed egrave generalmente espressa nel tessuto e dipende dallrsquoattivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene Poichegrave sia lrsquoaldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei lrsquoattivitagrave della 11betaHSD2 egrave richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire lrsquooccupazione dei recettori mineralocorticoidei
CortisoloCortisone
11betaHSD1
11betaHSD2
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
ldquoFor a long period I had from time to time met with a very remarkable form of general anaemia occurring without any discoverable cause whatever The disease presented in every instance the same general character pursued a similar course and with scarcely a single exception was followed after a variable period by the same fatal result The appetite is impaired or entirely lost the whites of the eyes become pearly the pulse small and feeble The body wastes slight pain or uneasiness is from time to time referred to the region of the stomach and there is occasionally actual vomiting which in one instance was both urgent and distressing Neither the most diligent inquiry nor the most careful physical examination tends to throw the slightest gleam of light upon the precise nature of the patientrsquos malady But with a more or less manifestation of the symptoms already enumerated we discover a most remarkable and sofar as I know characteristic discoloration taking place in the skinrdquo
Thomas Addison 1855
Rev Endocr Metab Disord 2010 Jun11(2)147-53
The diagnosis of Cushings syndromeCarroll TB Findling JWEndocrinology Center (TBC JWF) Medical College of Wisconsin W129 N7055 Northfield Drive Building A Suite 203 Menomonee Falls WI 53051 USA tcarrollmcweduAbstractSpontaneous Cushings syndrome is well known but unusual clinical disorder Many of the clinical features (central weight gain glucose intolerance hypertension muscle weakness) are seen in other common conditions Recognition of patients with multiple features features unusual for their age (ie early onset osteoporosis or hypertension) patients with features more specific to Cushings syndrome (ie easy bruising facial plethora and violaceous striae) and patients with incidental adrenal mass or polycystic ovary syndrome should prompt an evaluation for cortisol excess Late-night salivary cortisol 1 mg overnight dexamethasone suppression testing or 24 h urine free cortisol determination have excellent diagnostic characteristics and should be obtain in patients with suspected Cushing syndrome If this initial testing is abnormal further evaluation should be directed by an endocrinologist experienced in the diagnosis and differential diagnosis of Cushing syndrome
Cushingrsquos Support amp Research Foundation
Abdominal weight gainRed round lsquomoonrsquo faceThinning extremitieslsquoBuffalo humprsquo
High blood pressureHigh blood sugarMuscle weaknessOsteoporosisFracturesInfectionsBlood clotsVisual field defects
Easy bruisingThinning skinPoor wound healingAcnePurple striaeHirsutismFemale baldingMenstrual irregularity
Sleep disordersExcessive hungerExcessive thirstFrequent urinationSweating
AnxietyConfusionConcentration lossMemory lossDepressionSuicidal thoughtsPanic attacksIllustration from Mayo Clinic Family Health Book 2d ed 1996
Symptoms VaryAnd may include any number of these
Courtesy of wwwCSRFcom
HPA
Ipotalamo
Ipofisi
Surrenali
I glucocorticoidi sono degli ormoni rilasciati dale ghiandole surrenali sotto lo stimolo ipofisario dellrsquoACTH e ancor prima dallo stimolo ipotalamico rappresentato dal CRH Il glucocorticoide per eccellenza egrave il cortisolo Molti glucocorticoidi di sintesi sono altamente efficaci nel trattare malattie infiammatorie quali asma reazioni autoimmuni e allergie I loro effetti terapeutici sono generalmente ascrivibili alla forte azione inibitoria sulla produzione di cellule T cosigrave come sulla inibizione del rilascio di interleuchina 2 e del suo recettore Anche le interleuchine proinfiammatorie 1 6 e 12 vengono inibite nel loro rilascio cosigrave come per il Tumor necrosis factor alfa presente nei monociti e macrofagi Questi effetti sono mediati dai recettori per i glucocorticoidi presenti nel citoplasma Una volta legati al suo recettore i glucocorticoidi traslocano nel nucleo e regolano lrsquoespressione genica legandosi specificativamente a sequenze di DNA con geni detti elementi dei recettori dei glucocorticoidi Il recettore dei glucocorticoidi altera anche lrsquoespressione genica attraverso lrsquointerazione diretta con proteine non recettoriali legate al promotore presente sul geneA queste azioni antiinfiammatorie perograve sono legati effetti collaterali quali aumento di peso corporeo diabete ipertensione osteoporosi cambiamenti comportamentali e alterazione del sonno
Livelli di cortisolo durante la giornata e durante I giorni della settimana
The measurement of late-night salivary cortisol usually at 2300 to 2400 h has proven to be a very useful approach to the diagnosis of Cushingrsquos syndrome
Lrsquoinspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantitagrave elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo egrave stato finalmente chiarito in anni recenti Paradossalmente il composto E (cortisone) che Kendall usava egrave una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivitagrave antinfiammatoria La conversione sistemica del cortisone a cortisolo egrave principalmente per via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il cortisone a cortisolo La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte il cortisolo in cortisone ed egrave generalmente espressa nel tessuto e dipende dallrsquoattivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene Poichegrave sia lrsquoaldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei lrsquoattivitagrave della 11betaHSD2 egrave richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire lrsquooccupazione dei recettori mineralocorticoidei
CortisoloCortisone
11betaHSD1
11betaHSD2
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Rev Endocr Metab Disord 2010 Jun11(2)147-53
The diagnosis of Cushings syndromeCarroll TB Findling JWEndocrinology Center (TBC JWF) Medical College of Wisconsin W129 N7055 Northfield Drive Building A Suite 203 Menomonee Falls WI 53051 USA tcarrollmcweduAbstractSpontaneous Cushings syndrome is well known but unusual clinical disorder Many of the clinical features (central weight gain glucose intolerance hypertension muscle weakness) are seen in other common conditions Recognition of patients with multiple features features unusual for their age (ie early onset osteoporosis or hypertension) patients with features more specific to Cushings syndrome (ie easy bruising facial plethora and violaceous striae) and patients with incidental adrenal mass or polycystic ovary syndrome should prompt an evaluation for cortisol excess Late-night salivary cortisol 1 mg overnight dexamethasone suppression testing or 24 h urine free cortisol determination have excellent diagnostic characteristics and should be obtain in patients with suspected Cushing syndrome If this initial testing is abnormal further evaluation should be directed by an endocrinologist experienced in the diagnosis and differential diagnosis of Cushing syndrome
Cushingrsquos Support amp Research Foundation
Abdominal weight gainRed round lsquomoonrsquo faceThinning extremitieslsquoBuffalo humprsquo
High blood pressureHigh blood sugarMuscle weaknessOsteoporosisFracturesInfectionsBlood clotsVisual field defects
Easy bruisingThinning skinPoor wound healingAcnePurple striaeHirsutismFemale baldingMenstrual irregularity
Sleep disordersExcessive hungerExcessive thirstFrequent urinationSweating
AnxietyConfusionConcentration lossMemory lossDepressionSuicidal thoughtsPanic attacksIllustration from Mayo Clinic Family Health Book 2d ed 1996
Symptoms VaryAnd may include any number of these
Courtesy of wwwCSRFcom
HPA
Ipotalamo
Ipofisi
Surrenali
I glucocorticoidi sono degli ormoni rilasciati dale ghiandole surrenali sotto lo stimolo ipofisario dellrsquoACTH e ancor prima dallo stimolo ipotalamico rappresentato dal CRH Il glucocorticoide per eccellenza egrave il cortisolo Molti glucocorticoidi di sintesi sono altamente efficaci nel trattare malattie infiammatorie quali asma reazioni autoimmuni e allergie I loro effetti terapeutici sono generalmente ascrivibili alla forte azione inibitoria sulla produzione di cellule T cosigrave come sulla inibizione del rilascio di interleuchina 2 e del suo recettore Anche le interleuchine proinfiammatorie 1 6 e 12 vengono inibite nel loro rilascio cosigrave come per il Tumor necrosis factor alfa presente nei monociti e macrofagi Questi effetti sono mediati dai recettori per i glucocorticoidi presenti nel citoplasma Una volta legati al suo recettore i glucocorticoidi traslocano nel nucleo e regolano lrsquoespressione genica legandosi specificativamente a sequenze di DNA con geni detti elementi dei recettori dei glucocorticoidi Il recettore dei glucocorticoidi altera anche lrsquoespressione genica attraverso lrsquointerazione diretta con proteine non recettoriali legate al promotore presente sul geneA queste azioni antiinfiammatorie perograve sono legati effetti collaterali quali aumento di peso corporeo diabete ipertensione osteoporosi cambiamenti comportamentali e alterazione del sonno
Livelli di cortisolo durante la giornata e durante I giorni della settimana
The measurement of late-night salivary cortisol usually at 2300 to 2400 h has proven to be a very useful approach to the diagnosis of Cushingrsquos syndrome
Lrsquoinspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantitagrave elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo egrave stato finalmente chiarito in anni recenti Paradossalmente il composto E (cortisone) che Kendall usava egrave una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivitagrave antinfiammatoria La conversione sistemica del cortisone a cortisolo egrave principalmente per via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il cortisone a cortisolo La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte il cortisolo in cortisone ed egrave generalmente espressa nel tessuto e dipende dallrsquoattivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene Poichegrave sia lrsquoaldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei lrsquoattivitagrave della 11betaHSD2 egrave richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire lrsquooccupazione dei recettori mineralocorticoidei
CortisoloCortisone
11betaHSD1
11betaHSD2
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Cushingrsquos Support amp Research Foundation
Abdominal weight gainRed round lsquomoonrsquo faceThinning extremitieslsquoBuffalo humprsquo
High blood pressureHigh blood sugarMuscle weaknessOsteoporosisFracturesInfectionsBlood clotsVisual field defects
Easy bruisingThinning skinPoor wound healingAcnePurple striaeHirsutismFemale baldingMenstrual irregularity
Sleep disordersExcessive hungerExcessive thirstFrequent urinationSweating
AnxietyConfusionConcentration lossMemory lossDepressionSuicidal thoughtsPanic attacksIllustration from Mayo Clinic Family Health Book 2d ed 1996
Symptoms VaryAnd may include any number of these
Courtesy of wwwCSRFcom
HPA
Ipotalamo
Ipofisi
Surrenali
I glucocorticoidi sono degli ormoni rilasciati dale ghiandole surrenali sotto lo stimolo ipofisario dellrsquoACTH e ancor prima dallo stimolo ipotalamico rappresentato dal CRH Il glucocorticoide per eccellenza egrave il cortisolo Molti glucocorticoidi di sintesi sono altamente efficaci nel trattare malattie infiammatorie quali asma reazioni autoimmuni e allergie I loro effetti terapeutici sono generalmente ascrivibili alla forte azione inibitoria sulla produzione di cellule T cosigrave come sulla inibizione del rilascio di interleuchina 2 e del suo recettore Anche le interleuchine proinfiammatorie 1 6 e 12 vengono inibite nel loro rilascio cosigrave come per il Tumor necrosis factor alfa presente nei monociti e macrofagi Questi effetti sono mediati dai recettori per i glucocorticoidi presenti nel citoplasma Una volta legati al suo recettore i glucocorticoidi traslocano nel nucleo e regolano lrsquoespressione genica legandosi specificativamente a sequenze di DNA con geni detti elementi dei recettori dei glucocorticoidi Il recettore dei glucocorticoidi altera anche lrsquoespressione genica attraverso lrsquointerazione diretta con proteine non recettoriali legate al promotore presente sul geneA queste azioni antiinfiammatorie perograve sono legati effetti collaterali quali aumento di peso corporeo diabete ipertensione osteoporosi cambiamenti comportamentali e alterazione del sonno
Livelli di cortisolo durante la giornata e durante I giorni della settimana
The measurement of late-night salivary cortisol usually at 2300 to 2400 h has proven to be a very useful approach to the diagnosis of Cushingrsquos syndrome
Lrsquoinspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantitagrave elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo egrave stato finalmente chiarito in anni recenti Paradossalmente il composto E (cortisone) che Kendall usava egrave una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivitagrave antinfiammatoria La conversione sistemica del cortisone a cortisolo egrave principalmente per via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il cortisone a cortisolo La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte il cortisolo in cortisone ed egrave generalmente espressa nel tessuto e dipende dallrsquoattivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene Poichegrave sia lrsquoaldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei lrsquoattivitagrave della 11betaHSD2 egrave richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire lrsquooccupazione dei recettori mineralocorticoidei
CortisoloCortisone
11betaHSD1
11betaHSD2
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
HPA
Ipotalamo
Ipofisi
Surrenali
I glucocorticoidi sono degli ormoni rilasciati dale ghiandole surrenali sotto lo stimolo ipofisario dellrsquoACTH e ancor prima dallo stimolo ipotalamico rappresentato dal CRH Il glucocorticoide per eccellenza egrave il cortisolo Molti glucocorticoidi di sintesi sono altamente efficaci nel trattare malattie infiammatorie quali asma reazioni autoimmuni e allergie I loro effetti terapeutici sono generalmente ascrivibili alla forte azione inibitoria sulla produzione di cellule T cosigrave come sulla inibizione del rilascio di interleuchina 2 e del suo recettore Anche le interleuchine proinfiammatorie 1 6 e 12 vengono inibite nel loro rilascio cosigrave come per il Tumor necrosis factor alfa presente nei monociti e macrofagi Questi effetti sono mediati dai recettori per i glucocorticoidi presenti nel citoplasma Una volta legati al suo recettore i glucocorticoidi traslocano nel nucleo e regolano lrsquoespressione genica legandosi specificativamente a sequenze di DNA con geni detti elementi dei recettori dei glucocorticoidi Il recettore dei glucocorticoidi altera anche lrsquoespressione genica attraverso lrsquointerazione diretta con proteine non recettoriali legate al promotore presente sul geneA queste azioni antiinfiammatorie perograve sono legati effetti collaterali quali aumento di peso corporeo diabete ipertensione osteoporosi cambiamenti comportamentali e alterazione del sonno
Livelli di cortisolo durante la giornata e durante I giorni della settimana
The measurement of late-night salivary cortisol usually at 2300 to 2400 h has proven to be a very useful approach to the diagnosis of Cushingrsquos syndrome
Lrsquoinspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantitagrave elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo egrave stato finalmente chiarito in anni recenti Paradossalmente il composto E (cortisone) che Kendall usava egrave una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivitagrave antinfiammatoria La conversione sistemica del cortisone a cortisolo egrave principalmente per via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il cortisone a cortisolo La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte il cortisolo in cortisone ed egrave generalmente espressa nel tessuto e dipende dallrsquoattivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene Poichegrave sia lrsquoaldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei lrsquoattivitagrave della 11betaHSD2 egrave richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire lrsquooccupazione dei recettori mineralocorticoidei
CortisoloCortisone
11betaHSD1
11betaHSD2
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
I glucocorticoidi sono degli ormoni rilasciati dale ghiandole surrenali sotto lo stimolo ipofisario dellrsquoACTH e ancor prima dallo stimolo ipotalamico rappresentato dal CRH Il glucocorticoide per eccellenza egrave il cortisolo Molti glucocorticoidi di sintesi sono altamente efficaci nel trattare malattie infiammatorie quali asma reazioni autoimmuni e allergie I loro effetti terapeutici sono generalmente ascrivibili alla forte azione inibitoria sulla produzione di cellule T cosigrave come sulla inibizione del rilascio di interleuchina 2 e del suo recettore Anche le interleuchine proinfiammatorie 1 6 e 12 vengono inibite nel loro rilascio cosigrave come per il Tumor necrosis factor alfa presente nei monociti e macrofagi Questi effetti sono mediati dai recettori per i glucocorticoidi presenti nel citoplasma Una volta legati al suo recettore i glucocorticoidi traslocano nel nucleo e regolano lrsquoespressione genica legandosi specificativamente a sequenze di DNA con geni detti elementi dei recettori dei glucocorticoidi Il recettore dei glucocorticoidi altera anche lrsquoespressione genica attraverso lrsquointerazione diretta con proteine non recettoriali legate al promotore presente sul geneA queste azioni antiinfiammatorie perograve sono legati effetti collaterali quali aumento di peso corporeo diabete ipertensione osteoporosi cambiamenti comportamentali e alterazione del sonno
Livelli di cortisolo durante la giornata e durante I giorni della settimana
The measurement of late-night salivary cortisol usually at 2300 to 2400 h has proven to be a very useful approach to the diagnosis of Cushingrsquos syndrome
Lrsquoinspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantitagrave elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo egrave stato finalmente chiarito in anni recenti Paradossalmente il composto E (cortisone) che Kendall usava egrave una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivitagrave antinfiammatoria La conversione sistemica del cortisone a cortisolo egrave principalmente per via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il cortisone a cortisolo La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte il cortisolo in cortisone ed egrave generalmente espressa nel tessuto e dipende dallrsquoattivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene Poichegrave sia lrsquoaldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei lrsquoattivitagrave della 11betaHSD2 egrave richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire lrsquooccupazione dei recettori mineralocorticoidei
CortisoloCortisone
11betaHSD1
11betaHSD2
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Livelli di cortisolo durante la giornata e durante I giorni della settimana
The measurement of late-night salivary cortisol usually at 2300 to 2400 h has proven to be a very useful approach to the diagnosis of Cushingrsquos syndrome
Lrsquoinspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantitagrave elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo egrave stato finalmente chiarito in anni recenti Paradossalmente il composto E (cortisone) che Kendall usava egrave una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivitagrave antinfiammatoria La conversione sistemica del cortisone a cortisolo egrave principalmente per via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il cortisone a cortisolo La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte il cortisolo in cortisone ed egrave generalmente espressa nel tessuto e dipende dallrsquoattivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene Poichegrave sia lrsquoaldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei lrsquoattivitagrave della 11betaHSD2 egrave richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire lrsquooccupazione dei recettori mineralocorticoidei
CortisoloCortisone
11betaHSD1
11betaHSD2
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Lrsquoinspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantitagrave elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo egrave stato finalmente chiarito in anni recenti Paradossalmente il composto E (cortisone) che Kendall usava egrave una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivitagrave antinfiammatoria La conversione sistemica del cortisone a cortisolo egrave principalmente per via epatica attraverso la 11 beta idrossisteroidedeidrogenasi 1 (11betaHSD1) che riduce il cortisone a cortisolo La 11 beta idrossisteroidedeidrogenasi 2 (11betaHSD2) riconverte il cortisolo in cortisone ed egrave generalmente espressa nel tessuto e dipende dallrsquoattivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene Poichegrave sia lrsquoaldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei lrsquoattivitagrave della 11betaHSD2 egrave richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire lrsquooccupazione dei recettori mineralocorticoidei
CortisoloCortisone
11betaHSD1
11betaHSD2
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Farmaci glucocorticoidei
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Beclometasone
BDP is actually a pro-drug with weak glucocorticoid receptor binding affinity that is hydrolysed via esterase enzymes to an active metabolite beclomethasone 17-monopropionate (B-17-MP)
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Beclomethasone 1721-dipropionate (BDP) is a topically active corticosteroid used in the treatment of asthma and rhinitis It was first available in 1972 in a pressurized metered-dose inhaler (MDI) and later in a dry powder inhaler and an aqueous nasal spray
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Numerazione degli atomi di carbonio nello scheletro degli steroidi
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Milestones included the discovery that whereas 9a-fluorination increased anti-inflammatory potency it also caused excessive protein loss potassium losssodium retention and oedema
On the other hand introduction of a 12 double bond in the A ring (to create prednisone from cortisone and prednisolone from cortisol) created derivatives with improved anti-inflammatory properties and reduced undesirable side effects
16a-Hydroxylated compounds retained glucocorticoid activity without concomitant salt and fluid retention while 16a-methylation further increased anti-inflammatory activity Combining 9a-fluorination 1-dehydrogenation and 16a-methylation yielded dexamethasone which was the most potent nonsalt retaining anti-inflammatory of its time
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Inibizione della PLA2 da parte dei glucocorticoidi
MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Vie di formazione dei macrofagi
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Effetti dei glucocorticoidi sulle cellule immunitarie
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Trasferimento nucleo-citoplasmatico e regolazione trascrizionale del recettore per i glucocorticoidi GR alfa Una volta che il ligando si lega al Gralfa questo si dissocia dalla proteina heat-shock proteins (HSPs) e trasloca nel nucleo dove si lega come omodimero al GREs nelle regioni promotrici di particolari geni del DNA o interagisce come monomero con unrsquoaltro fattore di trascrizione (TF) (REs response elements RNPII RNA polymerase II GRE glucocorticoid response element)
Meccanismi molecolari di trascrizione del segnale da glucocorticoidi
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide
I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per lrsquoaldosterone cui necessita lrsquoenzima 11beta HSD2 Per questo motivo i glucocorticoidi circolano a piugrave alte concentrazioni del mineralocorticoide aldosterone ed in condizioni normali i recettori per i mirelalocorticoidi dovrebbero essere occupati dal cortisolo In contrasto le cellule endoteliali contengono lrsquoenzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dallrsquoaldosterone
Gli enzimi 11beta-Idrossisteroide deidrogenasi Gli enzimi della 11betaHSD catalizzano la interconversione dei glucocorticoidi dalla forma attiva a quella inattiva I due isoenzimi sono chiamati 11bHSD1 e 11bHSD2
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Attivazione classica e alternativa dei macrofagi I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente I macrofagi attivati classicamente rispondono allrsquointerferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dellrsquoinfiammazione nella distruzione del tessuto nellrsquouccisione di parassiti intracellulari e nella resistenza ai tumori In contrasto i macrofagi attivati alternativamente rispondono a fattori come lrsquointerleuchina 4 o 3 o 10 ai complessi immunitari al TGF beta e ai glucocorticoidi e contribuiscono allrsquoinfiammazione di tipo 2 alla rimodellazione del tessuto allrsquoangiogenesi alla incapsulazione dei parassiti e alla progressione del tumore
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Effetti dei Glucocorticoidi sullrsquoosso
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Journal of Endocrinology (2009) 201 309ndash320
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Tipico dosaggio dei cortisonici per prevenire la soppressione dellrsquoasse ipotalamo-ipofisi-surrene
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Medical management of adrenal disease a narrative reviewMichalakis K Ilias IDepartment of Endocrinology E Venizelou Hospital 2 Athens GR-11521 Greece
Adrenal diseases comprise for a variety of medical endocrine issues ranging from partial or complete gland insufficiency to several kinds of adrenal hyperfunction either of congenital or neoplastic etiology For hypofunction of the adrenals (partial or complete) the treatment of choice is medical the mainstay of treatment is hydrocortisone Patients with congenital adrenal hyperplasia caused by 21-hydroxylase deficiency are treated with glucocorticoids to control androgen excess Most benign neoplastic adrenal diseases that cause hyperfunction of the gland are surgically treated however this may not be always feasible or effective For Cushings syndrome ketoconazole controls cortisols hypersecretion whereas in case of bilateral idiopathic hyperaldosteronism spironolactone controls hypokalemia and hypertension For neoplastic adrenomedullary disease surgery is the treatment of choice medical treatment is used preoperatively (mainly alpha blockers) and in case of disease persistence and or recurrence (mainly metyrosine) For malignant adrenocortical disease surgical removal remains the indicated treatment but if the potential for surgical intervention is limited due to tumor extension medical treatment can alleviate symptoms of hormone hypersecretion mitotane in selected patients has good results
Endocr Regul 2009 Jul43(3)127-35
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Eventi avversi da cortisonici
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Psychiatry Clin Neurosci 2009 Oct63(5)613-22
Central nervous system effects of natural and synthetic glucocorticoidsFietta P Fietta P Delsante GPsychiatry Department Hospital of Lodi Lodi Italy pierluigifiettaaolodiit
AbstractNatural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress involving almost all organs and tissues including brain Since their therapeutic availability synthetic GC (SGC) have been successfully prescribed for a variety of diseases Mounting evidence however demonstrated pleiotropic adverse effects (AE) including central nervous system (CNS) disturbances which are often misdiagnosed or underestimated The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database Cortisolemia plays a crucial role in control of behavior cognition mood and early life programming of stress reactivity Hypercortisolemia or SGC treatments may induce behavioral psychic and cognitive disturbances due to functional and over time structural alterations in specific brain target areas These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses lt20 mgday) and usually reversible Pediatric patients are particularly susceptible Behavioral changes including feeding and sleeping modifications are common Psychic AE are unpredictable and heterogeneous usually mildmoderate severe in 5-10 of cases Manic symptoms have been mostly associated with short SGC courses and depressive disorder with long-term treatments Suicidality has been reported Cognitive AE peculiarly affect declarative memory performance Physiologic levels of NGC are essential for efficient brain functions Otherwise hypercortisolemia and SGC treatments may cause dose-time-dependent neuropsychic AE and over time structural alterations in brain target areas Clinicians should carefully monitor patients especially children andor when administering high doses SGCPMID 19788629 [PubMed - indexed for MEDLINE]
Effetti dei cortisonici sul sistema nervoso centrale
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Cardiovasc J Afr 2009 Jul-Aug20(4)233-6Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence a meta-analysis and systematic review of the literatureAthappan G Gale S Ponniah TCaritas St Elizabeth Medical Centre Tufts School of Medicine Boston USA ganeshathappangmailcom
OBJECTIVE Corticosteroids are the treatment of choice in most forms of vasculitis However their role in the primary treatment of Kawasaki disease (KD) is controversial Our aim was to conduct a meta-analysis to assess the clinical course and coronary artery outcome of adding corticosteroids to standard therapy [intravenous immunoglobulin (IVIG) + aspirin] in patients with acute KD METHODS We included randomised trials comparing the addition of corticosteroids to conventional primary therapy for Kawasaki disease RESULTS A total of four studies were identified which included 447 patients The meta-analysis revealed a significant reduction in re-treatments with IVIG in patients receiving corticosteroid plus standard therapy compared with standard therapy alone [odds ratio (OR) 048 95 confidence interval (CI) 024- 095] There was however no significant reduction in the incidence of coronary artery aneurysms among patients who received corticosteroid therapy plus standard therapy compared with standard therapy alone for either up to a month (OR 074 95 CI 023-240) or over one month ([OR 074 95 CI 037-151) Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 081 95 CI 005-088) CONCLUSION The inclusion of corticosteroids in regimens for the initial treatment of Kawasaki disease decreased rates of re-treatment with intravenous immunoglobulin However the addition of corticosteroids to standard therapy did not decrease the incidence of coronary aneurysms or adverse events
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Duchenne muscular dystrophy (DMD) is a disease linked to the X-chromosome which affects 1 in 3600-6000 newborn males It is manifested by the absence of the dystrophin protein in muscle fibres which causes progressive damage leading to death in the third decade of life The only medication so far shown to beeffective in delaying the progression of this illness are corticosteroidswhich have been shown to increase muscle strength in randomised controlled studies long-term studies have demonstrated that they prolong walking time and retard the progression of respiratory dysfunction dilated cardiomyopathy and scoliosisSeveral potential drugs are now being investigated Genetic therapy involving the insertion of a dystrophin gene through a vector has proven effective in animals but not humans Currently under clinical study is Ataluren a molecule that binds withribosomes and may allow the insertion of an aminoacid in the premature termination codon and exon-skipping which binds with RNA and excludes specific sites of RNA splicing producing a dystrophin that is smaller but functional There are alsostudies attempting to modulate other muscular proteins such as myostatin and utrophin to reduce symptoms This paper does not address cardiomyopathy treatment in DMD patients
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Endogenous Cushingrsquos syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitaryndashadrenal axis It is traditionally divided into ACTHdependent and ACTH-independent Cushingrsquos syndrome In the majority of cases it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushingrsquos disease)
The medical therapy of hypercortisolaemia in Cushingrsquos syndrome is predominantly based on the inhibition of adrenal steroidogenesis at one or more enzymatic sites or alternatively by antagonism of the glucocorticoid receptor or the suppression of ACTH
Oral therapy with ketoconazole and metyrapone are the most frequent steroidogenic enzyme inhibitors currently in use
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Kawasaki disease
Vascoliti
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
Br J Haematol 2010 Jun149(5)638-52 Epub 2010 Apr 12
The optimal use of steroids in paediatric acute lymphoblastic leukaemia no easy answersMcNeer JL Nachman JBSection of Paediatric HaematologyOncology University of Chicago Comer Childrens Hospital Chicago IL USAAbstractGlucocorticoids are an integral component of therapy for acute lymphoblastic leukaemia (ALL) but usage differs between cooperative group protocols All groups use glucocorticoids during induction but vary on whether to use dexamethasone or prednisone Issues to consider in the choice of induction steroid include impact on event-free and overall survival acute morbidity such as infection risk diabetes and behavioural disturbances and long-term complications such as avascular necrosis It is generally agreed that dexamethasone is the steroid of choice for groups using a delayed intensification phase but dosing schedules (intermittent versus continuous) vary There is no consensus on the potential benefit of steroid administration during maintenance therapy
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
I glucocorticoidi sono farmaci molto efficaci contro la
leucemia perograve ad essi sono associati eventi tossici
importanti
- Le tossicitagrave a breve termine sono mialgia miopatia
infezioni iperglicemia problemi comportamentali
soppressione dellrsquoasse ipotalamo-ipofisi-ghiandole surrenali
possono terminare alla sospensione del trattamento
- La necrosi avascolare dellrsquoosso egrave di particolare gravitagrave
perchegrave ha un grande impatto nella qualitagrave della vita per il
resto della vita del paziente
Tossicitagrave da corticosteroidi
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI
bullMETIRAPONE (inibitore della 11-idrossilazione)bullTRILOSTANO (inibitore della 3 -idrossisteroide deidrogenasi)bullKETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo)
Il metirapone blocca la sintesi del cortisolo attraverso lrsquoinibizione della steroid 11β-hydroxylase Questo fatto stimola lrsquoipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels Quando un eccesso di ACTH egrave la causa di ipercortisolismo il test del metirapone aiuta a vedere se la causa egrave lrsquoACTH ipofisaria o egrave di natura ectopica ovvero non-ipofisaria
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