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sirolimus
Sirolimus is a relatively new immunosuppressant
drug used to prevent rejection in organ
transplantation, and is especially useful in kidney
transplants. It is also known as rapamycin.
Sirolimus is a macrolide antibiotic ("-mycin") first
discovered as a product of the bacterium
Streptomyces hygroscopicus in a soil sample from
an island called Rapa Nui. Rapamycin originally
was developed as an antifungal agent.
However,when it was discovered rapamycin had
potent immunosuppressive.
Chemical structure:
Formula C51 C79 NO31
Physical properties:
Names:
Rapamycin , sirolimus , rapamune
Melting point 183-185 C
Mol. Wt. 914.18
Mechanism of Action:
RAPA blocks T lymphocyte proliferation . RAPA’s effects are not limited
to IL-2- or IL-4 mediated growth of T cells, as it has been found to
inhibit IL-12 , IL-7, and IL-15 driven proliferation of activated T cells
RAPA blocks cell cycle progression in mid-to-late G1 phase , RAPA
blocks lymphocyte proliferation . RAPA inhibits IL-2 dependent and
independent proliferation of purified normal human B lymphocytes
stimulated with Staphylococcus aureus (SA) . It also prevents SA and
IL-2 or IL-6 dependent differentiation into antibody-producing cells,
thereby decreasing IgM, IgG and IgA production .
SRL binding to specific cytosolic binding proteins called immunophilins
(FKBPs).
This complex inhipits isomerase activity (PPlase).
FKBP 12 is the most relevant binding protein for the
immunosuppressive effects of RAPA.
Pharmacokinetics:
1-Adminstration:
Oral solution or tablets.
2-Absorption:
SRL reaches maximum concentration in the blood in 2 h with the
solution, compared to 6 h with the tablet formulation.
Oral bioavailability is low (around 15% when administered with
cyclosporine A (CsA)).
3-distribution:
Due to its lipophilic nature, SRL is extensively distributed to fatty
tissues and so has a large volume of distribution (5.6–16.7 L/kg).
Within plasma, SRL is extensively bound to plasma proteins. SRL has a
long half-life (60 h) so, when
commencing SRL, a loading dose is necessary.
4-metabolism:
The metabolites of SRL are inactive .Sirolimus is metabolized by the
cytochrome P450–3A4 Isoenzyme so its effected by enzyme inducers
&inhibitor. The clearance of SRL approximates that of liver blood flow,
so dose reductions may be needed in patients with hepatic impairment.
5-excretion:
SRL is excreted by the liver.
Pharmacological Action:
*Sirolimus does not block IL production by activated T cells but
instead blocks the response of T cells to cytokines.
*It is a potent inhibitor of B cell proliferation &immunoglobulin
Production.
*Sirolimus also inhibits the mononuclear cell proliferative response to
colony stimulation factors &suppresses hematopoietic recovery after
myelotoxic treatment in mice .
* sirolimus displayed comparatively lower platelet and white blood cell
counts .
* SRL increases total cholesterol, LDL, triglycerides, apoB- 100, and
apoC-III; these effects are repeatable, dose-dependent and
reversible.
* Sirolimus causes anaemia, thrombocytopaenia and leukopaenia due
to bone marrow suppression.
Sirolimus in CVS:
SRL has not been shown so far to increase
cardiovascular morbidity or mortality but SRL may
improve the cardiovascular risk of patients posttransplantation. In cardiac allograft recipients
treated with CsA and steroids, SRL was found to
be superior to azathioprine in preventing cardiac
transplant vasculopathy. SRL is associated with
less hypertension compared to CNI-based regimes
and may be less diabetogenic, but does increase
lipid levels .
Therapeutic Uses:
A- In Adult:
1- Kidney :
sirolimus as a primary agent with cyclosporine and
prednisone reduced the overall incidence of acute allograft
rejection episodes from 32 to 7.5%.
2-Islet:
In a widely heralded initial experience, reported the
successful use of sirolimus as a primary
immunosuppressive agent in seven patients with type 1
diabetes who underwent islet cell transplantation. This
glucocorticoid-free regimen combined sirolimus, tacrolimus,
and daclizumab.
3-liver:
Sirolimus has been used in combination with tacrolimus
after liver transplantation to allow the subtherapeutic use
of tacrolimus.
B-In Children:
Pharmacokinetics different in children compared with
adults.
Half-life (h) of sirolimus is shorter in children because of
rapid metabolism and some children may need twice a day
dosing .
1-Kidney:
Studies in children using sirolimus for primary
immunosuppression are still limited.
2-Liver:
Sirolimus was used as primary immunosuppression in
combination with subtherapeutic tacrolimus.
3- Intestine:
Addition of sirolimus to a tacrolimus decreased early
rejection and improved graft survival in children and adults
receiving intestinal transplants compared with control.
C- In Cancer:
The anti-proliferative effects of sirolimus
may have a role in treating cancer. Recently,
it was shown that sirolimus inhibited the
progression of dermal Kaposi's sarcoma in
patients with renal transplants.
As with all immunosuppressive medications,
rapamycin decreases the body's inherent
anti-cancer activity and allows some cancers
which would have been naturally destroyed
to proliferate .
Adverse Effect:
A- Major Adverse Effect:
1- Hyperlipidaemia:
A major effect on lipid metabolism.
SRL increases total cholesterol, LDL, triglycerides, apoB100, and apoC-III; these effects are repeatable, dosedependent and reversible.
2-Wound Complications:
Sirolimus is associated with a high wound complication in
the early stages post-transplantation, with rates varying
between 6–15% due to its anti-proliferative properties
Wound complications include delayed wound healing,
lymphocoele, haematoma, incisional hernia and
relaparotomy for wound complication.
3- Haematological:
Sirolimus causes anaemia, thrombocytopaenia and
leukopaenia due to bone marrow suppression, but rarely
leads to discontinuation of therapy.
4- Thrombosis:
SRL was not associated with an increased risk of deep vein
thrombosis (DVT), but the DVT that did develop were
preceded by lymphocoele in threequartersof cases.
5-Oral Ulcers:
Initially, it was assumed that these aphthous ulcers were
due to herpes simplex infection but this has not been
confirmed and it is now assumed that they result from a
direct toxic effect of SRL.
6- Lung Toxicity:
In a phase II trial of SRL, an increased incidence of
Pneumocystis carinii pneumonia (PCP) was reported in a
single centre that did not use routine PCP prophylaxis .
Drug – Drug Interaction:
Sirolimus and CNI are both metabolized by the cytochrome
p450 3A4 isoenzyme.
SRL blood concentration is 30% higher with CsA
To minimize this interaction, SRLshould be given 4 h after
CsA.
SRL does not appear to have a pharmacokinetic interaction
with tacrolimus.
Mycophenolic acid AUC is higher when SRL and
mycophenolate mofetil (MMF) does not affect SRL
exposure.
compared to co-administration of SRL and CsA.
Enzymes inhibitor increase its concentration .
Enzymes inducer decrease its concentration.
Dosage:
The maintenance sirolimus doses ranged from 0.5 to 15
mg once daily .
The dose was only reduced in the presence of drug –
indused toxicity.
Missed Dose:
Do not double doses.
If you miss a dose of sirolimus and remember it within 12
hours, take the missed dose as soon as you remember.
However, if it is almost time for the next dose, skip the
missed dose, go back to your regular dosing schedule, and
check with your doctor.
Sirolimus Monotherapy:
Monotherapy to 29 primary renal transplant
patients show acute rejection developed in
eightout of 29 (five of which were antibodymediated). One graft was lost to rejection. All
other patients tolerated therapy well.
Combination Therapy:
A-with CsA:
show reduction in the incidence of acute allograft
rejection episodes to 7.5% over3 years.
B-with tacrolimus:
SRL and TRL might compete for FK-binding
proteins (FKBP), producing antagonistic effects ,
the large amount of cytosolic FKBP seems to
obviate this possibility.