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Corticosteroidi STORIA 1563 Eustachio scopre l’esistenza delle ghiandole surrenali 1849 Addison attribuisce la “pelle bronzea” a malfunzionamento delle.

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Presentazione sul tema: "Corticosteroidi STORIA 1563 Eustachio scopre l’esistenza delle ghiandole surrenali 1849 Addison attribuisce la “pelle bronzea” a malfunzionamento delle."— Transcript della presentazione:

1 Corticosteroidi STORIA 1563 Eustachio scopre l’esistenza delle ghiandole surrenali 1849 Addison attribuisce la “pelle bronzea” a malfunzionamento delle ghiandole surrenali 1856 Brown-Sequard rimuove le ghiandole surrenali di gatti e cani i quali poi moriranno nell’arco di qualche giorno dimostrando cosi’ l’importanza vitale di queste ghiandole Viene scoperta la suddivisione delle surrenali (corteccia e midollare). L’adrenalina viene secreta dalla midollare Reichstein isola 29 nuove sostanze dalla corteccia surrenale e tutte sono steroidi Kendall isola il cortisone 1950 Kendall, Reichstein ed Hench riceveranno il premio Nobel per la medicina

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3 “For 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 patient’s malady; But with a more or less manifestation of the symptoms already enumerated, we discover a most remarkable, and, so far as I know, characteristic discoloration taking place in the skin.” Thomas Addison, 1855

4 Rev Endocr Metab Disord Jun;11(2): The diagnosis of Cushing's syndrome. Carroll TBCarroll TB, Findling JW.Findling JW Endocrinology Center (TBC, JWF), Medical College of Wisconsin, W129 N7055 Northfield Drive Building A, Suite 203, Menomonee Falls, WI 53051, USA. Abstract Spontaneous Cushing's 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 (i.e. early onset osteoporosis or hypertension), patients with features more specific to Cushing's syndrome (i.e. 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.

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6 Cushing’s Support & Research Foundation Abdominal weight gain Red, round ‘moon’ face Thinning extremities ‘Buffalo hump’ High blood pressure High blood sugar Muscle weakness Osteoporosis/Fractures Infections Blood clots Visual field defects Easy bruising Thinning skin Poor wound healing Acne Purple striae Hirsutism Female balding Menstrual irregularity Sleep disorders Excessive hunger Excessive thirst Frequent urination Sweating Anxiety Confusion Concentration loss Memory loss Depression Suicidal thoughts Panic attacks Illustration from Mayo Clinic Family Health Book, 2d. ed, 1996 Symptoms Vary And may include any number of these: Courtesy of

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8 HPA Ipotalamo Ipofisi Surrenali

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10 I glucocorticoidi sono degli ormoni rilasciati dale ghiandole surrenali sotto lo stimolo ipofisario dell’ACTH e ancor prima dallo stimolo ipotalamico rappresentato dal CRH. Il glucocorticoide per eccellenza è 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 così 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 così 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 l’espressione genica legandosi specificativamente a sequenze di DNA con geni detti elementi dei recettori dei glucocorticoidi. Il recettore dei glucocorticoidi altera anche l’espressione genica attraverso l’interazione diretta con proteine non recettoriali legate al promotore presente sul gene. A queste azioni antiinfiammatorie però sono legati effetti collaterali quali aumento di peso corporeo, diabete, ipertensione, osteoporosi, cambiamenti comportamentali e alterazione del sonno.

11 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 Cushing’s syndrome.

12 L ’ inspiegabile osservazione che ricercatori negli anni cinquanta vedevano in pazienti a cui venivano date quantit à elevate di cortisone per os ma avevano piccole concentrazioni di cortisone nel plasma con un alto livello di cortisolo è stato finalmente chiarito in anni recenti. Paradossalmente il composto E (cortisone) che Kendall usava è una molecola inattiva che richiede la trasformazione metabolica in cortisolo per svolgere la sua attivit à antinfiammatoria. La conversione sistemica del cortisone a cortisolo è 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 è generalmente espressa nel tessuto e dipende dall ’ attivazione del recettore mineralocorticoideo per attivazione dei mineralocorticoidi nel rene. Poich è sia l ’ aldosterone che il cortisolo sono entrambi potenti agonisti mineralocoricoidei l ’ attivit à della 11betaHSD2 è richiesta in quei siti dove il cortisolo deve essere disattivato e quidi prevenire l ’ occupazione dei recettori mineralocorticoidei. Cortisolo Cortisone 11betaHSD1 11betaHSD2

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14 Farmaci glucocorticoidei

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17 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)

18 Beclomethasone 17,21-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.

19 Numerazione degli atomi di carbonio nello scheletro degli steroidi

20 Milestones included the discovery that whereas 9a-fluorination increased anti- inflammatory potency, it also caused excessive protein loss, potassium loss, sodium retention and oedema. On the other hand, introduction of a 1,2 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

21 Inibizione della PLA 2 da parte dei glucocorticoidi MECCANISMO DI AZIONE ANTINFIAMMATORIO DEI CORTISONICI

22 Vie di formazione dei macrofagi

23 Effetti dei glucocorticoidi sulle cellule immunitarie

24 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 un’altro fattore di trascrizione (TF). (REs response elements, RNPII RNA polymerase II, GRE glucocorticoid response element). Meccanismi molecolari di trascrizione del segnale da glucocorticoidi

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28 Trasmissione del segnale del recettore mineralocorticoide e glucocorticoide. I macrofagi contengono recettori per i mineralocortocidi e i glucocorticoidi ma non per l’aldosterone cui necessita l’enzima 11beta HSD2. Per questo motivo i glucocorticoidi circolano a più 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 l’enzima 11bHSD2 e di conseguenza I recettori per I mineralocorticoidi sono normalmente attivati dall’aldosterone. 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

29 Attivazione classica e alternativa dei macrofagi. I fenotipi polarizzati di macrofagi sono largamente definiti come classici e attivati alternativamente. I macrofagi attivati classicamente rispondono all’interferone gamma e lipopolisaccaridi e giocano un ruolo importante nel tipo 1 dell’infiammazione, nella distruzione del tessuto, nell’uccisione di parassiti intracellulari e nella resistenza ai tumori. In contrasto, i macrofagi attivati alternativamente rispondono a fattori come l’interleuchina 4 o 3 o 10, ai complessi immunitari, al TGF beta e ai glucocorticoidi e contribuiscono all’infiammazione di tipo 2, alla rimodellazione del tessuto, all’angiogenesi, alla incapsulazione dei parassiti e alla progressione del tumore.

30 Effetti dei Glucocorticoidi sull’osso

31 Journal of Endocrinology (2009) 201, 309–320

32 Tipico dosaggio dei cortisonici per prevenire la soppressione dell’asse ipotalamo-ipofisi-surrene

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34 Medical management of adrenal disease: a narrative review. Michalakis KMichalakis K, Ilias I.Ilias I Department 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 Cushing's syndrome ketoconazole controls cortisol's 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 Jul;43(3):

35 Eventi avversi da cortisonici

36 Psychiatry Clin Neurosci Oct;63(5): Central nervous system effects of natural and synthetic glucocorticoids. Fietta PFietta P, Fietta P, Delsante G.Fietta PDelsante G Psychiatry Department, Hospital of Lodi, Lodi, Italy. Abstract Natural 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 <20 mg/day) and usually reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually mild/moderate, 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 and/or when administering high doses SGC. PMID: [PubMed - indexed for MEDLINE] Effetti dei cortisonici sul sistema nervoso centrale

37 Cardiovasc J Afr Jul-Aug;20(4): Corticosteroid therapy for primary treatment of Kawasaki disease - weight of evidence: a meta- analysis and systematic review of the literature. Athappan GAthappan G, Gale S, Ponniah T.Gale SPonniah T Caritas St Elizabeth Medical Centre, Tufts School of Medicine, Boston, USA. 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) 0.48; 95% confidence interval (CI): ]. 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 0.74; 95% CI: ) or over one month ([OR 0.74; 95% CI: ). Similarly no significant differences between treatment groups were noted in incidence of adverse events (OR 0.81; 95% CI: ). 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.

38 Duchenne muscular dystrophy (DMD) is a disease linked to the X- chromosome which affects 1 in 3,600-6,000 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 be effective in delaying the progression of this illness are corticosteroids, which 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 scoliosis. Several 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 with ribosomes 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 also studies attempting to modulate other muscular proteins, such as myostatin and utrophin, to reduce symptoms. This paper does not address cardiomyopathy treatment in DMD patients.

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40 Endogenous Cushing’s syndrome results from excessive glucocorticoid production with a failure of the normal negative feedback effect on the hypothalamo-pituitary–adrenal axis. It is traditionally divided into ACTHdependent and ACTH-independent Cushing’s syndrome. In the majority of cases, it is caused by an adenoma in the pituitary gland secreting ACTH hormone (Cushing’s disease), The medical therapy of hypercortisolaemia in Cushing’s 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.

41 Kawasaki disease Vascoliti

42 Br J Haematol Jun;149(5): Epub 2010 Apr 12. The optimal use of steroids in paediatric acute lymphoblastic leukaemia: no easy answers. McNeer JLMcNeer JL, Nachman JB.Nachman JB Section of Paediatric Haematology/Oncology, University of Chicago Comer Children's Hospital, Chicago, IL, USA. Abstract Glucocorticoids 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.

43 I glucocorticoidi sono farmaci molto efficaci contro la leucemia però ad essi sono associati eventi tossici importanti. - Le tossicità a breve termine sono mialgia, miopatia, infezioni, iperglicemia, problemi comportamentali, soppressione dell’asse ipotalamo-ipofisi-ghiandole surrenali possono terminare alla sospensione del trattamento. - La necrosi avascolare dell’osso è di particolare gravità perchè ha un grande impatto nella qualità della vita per il resto della vita del paziente. Tossicità da corticosteroidi

44 INIBITORI DELLA BIOSINTESI DEI CORTICOSTREROIDI METIRAPONE (inibitore della 11  -idrossilazione) TRILOSTANO (inibitore della 3  -idrossisteroide deidrogenasi) KETOCONAZOLO (Blocca la rottura della catena laterale del colesterolo) Il metirapone blocca la sintesi del cortisolo attraverso l’inibizione della steroid 11β- hydroxylase. Questo fatto stimola l’ipofisi a produrre ACTH la quale aumenta nel plasma i livelli di 11-deoxycortisol levels. Quando un eccesso di ACTH è la causa di ipercortisolismo, il test del metirapone aiuta a vedere se la causa è l’ACTH ipofisaria o è di natura ectopica ovvero non-ipofisaria.steroid 11β- hydroxylaseACTH


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