sirolimus in hyperinsulnisim Journal club
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Transcript of sirolimus in hyperinsulnisim Journal club
Journal clubYassin M Alsaleh
Introduction
• Hyperinsulinemic hypoglycemia, a
major cause of severe hypoglycemia
during the neonatal period.
• is characterized by inappropriate
insulin secretion.
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.
• 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.
Introduction
Introduction
• However, some patients who have
undergone surgery continue to have
recurrent hyperinsulinemic
hypoglycemia.
• whereas diabetes mellitus and
exocrine pancreatic insufficiency
develop in others..
• 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
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...
Introduction
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
• 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
Introduction
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.
The adverse effects of mTOR
inhibitors• increased risk of infection,
immunosuppression,
• abnormalities in renal function
• Fatigue.
• pneumonitis.
• Stomatitis.
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.
• 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.
Methods
• Approval for the study was obtained
from the drugs and therapeutics
committee at the hospital.
• written informed consent was taken
from parents.
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
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.
Methods
Critical
appraisal
PICO• Population: patients with
diffuse hyperinsulinemichypoglycemia that had been unresponsive to diazoxideand octreotide
• Intervention: sirolimus
• Control:
• Out come: glycemic response
Relevance1. 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
Validity1. Was the assignment of patients
to treatment randomized?
NO
2- Was the assignment concealed?
NO
29
Validity3- 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
Validity3. 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
Validity5. Aside from the experimental
intervention, were the groups treated
equally?
• Co-intervention?
• Contamination?
• Compliance?
yes
32
Validity6. Were all clinically important
outcomes considered?
NO,
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Results clinical significance
• Precision of the effect:
• Confidence intervals?
• NO
34
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
Assuming that the study conclusion is true ,would it lead to a change in your practice?
YES
• 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.
Conclusion