Sirolimus
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Sirolimus
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| Systematic (IUPAC) name | |
| [3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,
19S*,26aR*]]-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3- [2-(4-hydroxy-3-methoxycyclohexyl) -1-methylethenyl]-14, 16-dimethoxy-4,10,12, 18-tetramethyl-8-(2-propenyl)-15, 19-epoxy-3H-pyrido[2,1-c] [1,4] oxaazacyclotricosine-1,7,20, 21(4H,23H)-tetrone, monohydrate. |
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| Identifiers | |
| CAS number | 53123-88-9 |
| ATC code | L04AA10 |
| PubChem | 6436030 |
| DrugBank | APRD00178 |
| Chemical data | |
| Formula | C51H79NO13 |
| Mol. weight | 914.172 g/mol |
| Pharmacokinetic data | |
| Bioavailability | 20%, less after eating food rich in fat |
| Protein binding | 92% |
| Metabolism | Hepatic |
| Half life | 57-63 hours |
| Excretion | Mostly faecal |
| Therapeutic considerations | |
| Pregnancy cat. |
C |
| Legal status | |
| Routes | Intravenous, oral, cutaneously |
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, better known as Easter Island. It is marketed as Rapamune® by Wyeth.
Interestingly, rapamycin originally was developed as an antifungal agent. However, this was abandoned when it was discovered that rapamycin had potent immunosuppressive and antiproliferative properties.
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[edit] Mechanism of action
Despite its similar name, it is not a calcineurin inhibitor like tacrolimus or cyclosporin. However, it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to IL-2 and thereby blocks activation of T- and B-cells. In contrast, tacrolimus and cyclosporine inhibit the production of IL-2.
The mode of action of sirolimus is that it binds to the cytosolic protein FK-binding protein 12 (FKBP12), in a similar way to tacrolimus. However, unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) pathway through direct binding to the mTOR Complex1 (mTORC1).
[edit] Use in transplant
The chief advantage sirolimus has over calcineurin inhibitors is that it is not toxic to kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure, and this can be prevented by use of sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used.
Sirolimus can also be used alone or in conjunction with calcineurin inhibitors and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimes. As impaired wound healing is a possible side effect of sirolimus, some transplant centres prefer not to use it immediately after the transplant operation, and start to give it after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined and is the subject of a number of ongoing clinical trials.
[edit] Anti-proliferative effects
The anti-proliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus eluting stents when compared to bare metal stents, resulting in fewer repeat procedures. A sirolimus eluting coronary stent is marketed by Cordis, a division of Johnson & Johnson, under the tradename Cypher. According to an editorial in the Nov 9 2006 issue of the New England Journal of Medicine (335;19), however, such stents may increase the risk of vascular thrombosis.
[edit] 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. Other mTOR inhibitors such as temsirolimus (CCI-779) or everolimus (RAD001) are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma.
Combination therapy of doxorubicin and rapamycin (Sirolimus) has been shown to drive AKT-positive lymphomas into remission in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs like doxorubicin or cyclophosphamide. Rapamycin blocks Akt signalling and the cells lose their resistance to the chemotherapy. Bcl-2-positive lymphomas were completely resistant to the therapy; Nor are eIF4E expressing lymphomas sensitive to Rapamycin*. Rapamycin showed no effect on its own.[1] ,[2] ,[3] ,[4] , *http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list uids=16103051&dopt=Citation
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. Patients on immunosuppressive medications have a 10-100 x increased risk of cancer compared to the general population. Furthermore, patients currently have or have already been treated for cancer have a higher rate of tumor progression and recurrence than patients with an intact immune system.
[edit] References
- ^ http://www.nature.com/bjc/journal/v91/n8/full/6602162a.html
- ^ http://www.sciencedaily.com/releases/2004/03/040318073757.htm
- ^ http://www.cshl.edu/public/releases/combotherapy.html
- ^ http://www.signaling-gateway.org/update/updates/200405/nrc1349.html
- ↑ Pritchard, David I. (2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discovery Today 10: 688–691.
[edit] See also
[edit] External links
- Rapamune website
- Cypher coronary stent website
- Rapamycin, from Fermentek, a vendor's product page
- Link page to external chemical sources.
| Immunosuppressants (L04) edit | ||
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Abetimus, Adalimumab, Afelimomab , Anakinra, Alefacept, Antilymphocyte immunoglobulin (horse), Antithymocyte immunoglobulin (rabbit) , Azathioprine, Basiliximab, Ciclosporin, Daclizumab, Efalizumab, Etanercept, Everolimus, Gusperimus , Infliximab, Leflunomide, Methotrexate , Muromonab-CD3 , Mycophenolic acid, Natalizumab, Pimecrolimus, Tacrolimus, Thalidomide, Sirolimus |
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