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sirolimus in hyperinsulnisim Journal club

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sirolimus in hyperinsulnisim Journal club

Publié dans : Santé & Médecine
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sirolimus in hyperinsulnisim Journal club

  1. 1. Journal club Yassin M Alsaleh
  2. 2. Introduction • Hyperinsulinemic hypoglycemia, a major cause of severe hypoglycemia during the neonatal period. • is characterized by inappropriate insulin secretion.
  3. 3. Introduction • The condition may result from defects in many genes including : • ABCC8, KCNJ11, GLUD1, GCK,HADH, SLC16A1, HNF4A, HNF1A, and UCP2. • Two major histologic subtypes have been described: diffuse and focal.
  4. 4. Introduction • Mutations in ABCC8 and KCNJ11 are associated with severe hyperinsulinemic hypoglycemia that is unresponsive to medical treatment with diazoxide and octreotide. • The only alternative treatment currently available for patients with medically unresponsive forms of diffuse hyperinsulinemic hypoglycemia is a subtotal pancreatectomy.
  5. 5. Introduction • However, some patients who have undergone surgery continue to have recurrent hyperinsulinemic hypoglycemia. • whereas diabetes mellitus and exocrine pancreatic insufficiency develop in others..
  6. 6. Introduction • A possible mechanism of diffuse hyperinsulinemic hypoglycemia involves the constitutive activation of the mammalian target of rapamycin mTOR pathway. • The serine–threonine protein kinase mTOR has been implicated in the cellular response to nutrients and growth factor signaling
  7. 7. Introduction • The mTOR pathway is abnormally activated in several neoplasms, including insulinoma. • inhibitors of mTOR have been increasingly recognized as a treatment option in patients with cancer...
  8. 8. Introduction • Long-term treatment with sirolimus in recipients of renal transplants has been noted to induce peripheral insulin resistance by impairing the activation and signaling of protein kinase B through the insulin-receptor substrate pathway
  9. 9. Introduction • potential role for mTOR inhibitors include: • the reduction of beta-cell proliferation. • induce the apoptosis of Beta cells. • the inhibition of insulin production. • induce peripheral insulin resistance. • up-regulating hepatic gluconeogenesis
  10. 10. PHARMACOLOGY • Sirolimus also known as rapamycin. • is a macrolide produced by the bacteria streptomyces hygroscopicus . • It has potent immunosuppressive and antiproliferative properties • USES: • Post renal transplant, insulinoma. • Coronary artery stent coating. • ? TS,SLE,Alzhimer,Porgeria.
  11. 11. The adverse effects of mTOR inhibitors • increased risk of infection, immunosuppression, • abnormalities in renal function • Fatigue. • pneumonitis. • Stomatitis.
  12. 12. Methods • AIM: • To study the glycemic response to sirolimus in four consecutive patients with diffuse hyperinsulinemic hypoglycemia that had been unresponsive to diazoxide and octreotide.
  13. 13. Methods • INCLUSION criteria: • patients with severe hyperinsulinemic hypoglycemia that was unresponsive to maximal doses of diazoxide (20 mg per kilogram per day) and octreotide (35 μg per kilogram per day) were recruited to participate in the study.
  14. 14. Methods • Approval for the study was obtained from the drugs and therapeutics committee at the hospital. • written informed consent was taken from parents.
  15. 15. Methods • All the patients received sirolimus at an initial dose of 0.5 mg/m2/day. • The dose was gradually increased with the goal of reaching a serum trough level of 5 to 15 ng per milliliter. • The serum trough level was measured every 5 days. • Once the desired serum drug level had been reached and blood glucose levels were stable, intravenous glucose and glucagon infusions were gradually tapered
  16. 16. Methods • Regular monitoring was performed including : • CBC,lipid levels, renal and liver function. • After discharge,patients were followed up regularly for assessment of glycemic control and measurement of serum sirolimus levels.
  17. 17. Critical appraisal
  18. 18. PICO • Population: patients with diffuse hyperinsulinemic hypoglycemia that had been unresponsive to diazoxide and octreotide • Intervention: sirolimus • Control: • Out come: glycemic response
  19. 19. Relevance 1. Does the study address a common problem in your practice? YES 2. Does the study address an important outcome to you or to your patient? (DOE vs. POEM). YES
  20. 20. Validity 1. Was the assignment of patients to treatment randomized? NO 2- Was the assignment concealed? NO 29
  21. 21. Validity 3- Were patients analyzed in the groups to which they were randomized (intention to treat analysis)? NA • Was follow-up complete& long enough? complete but long enough ?? 30
  22. 22. Validity 3. Were the groups similar at the start of the trial? Baseline prognostic factors (demographics, co-morditity, disease severity, other known confounders) balanced? NA 4. Were patients, their clinicians, and study personnel 'blind' to treatment? • NO 31
  23. 23. Validity 5. Aside from the experimental intervention, were the groups treated equally? • Co-intervention? • Contamination? • Compliance? yes 32
  24. 24. Validity 6. Were all clinically important outcomes considered? NO, 33
  25. 25. Results clinical significance • Precision of the effect: • Confidence intervals? • NO 34
  26. 26. Applicability 1. Can you do the Intervention exactly as it is described in the paper YES 2. Is your Patient is similar to the population of the study? YES 3. Are the likely treatment benefits worth the potential harms and costs? yes 35
  27. 27. Assuming that the study conclusion is true ,would it lead to a change in your practice? YES
  28. 28. Conclusion • Treatment with mTOR inhibitors, alone or in combination with somatostatin analogues, may be a feasible option for selected patients with no contraindication, although the longterm adverse effects and efficacy of such treatment require further study.

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