The number of patients undergoing the organ transplant treatment has significantly increased the need and use of immunosuppressive drugs.
Immunosuppressant Sirolimus is also known as rapamycin, discovered as a product of Streptomyces hygroscopicus bacterium obtained from the soil. Streptomyces hygroscopicus belong to of actinomycetes. Sirolimus originally used as antifungal agent, has got properties like Lipophilic macrocyclic lactone, immunosuppressive, anti-fungal activity, anti tumor or anti proliferative activity and also marked activity against Gram positive bacteria.
Other Drugs used as Immunosuppressant's are
• Glucocorticoids and their analogues such as predisone
• 6 mercaptopurine
• Monoclonal antibodies like OKT3
• Mycophenolic acid
1. The soil taken from Easter Island (Rapa Nui) was analyzed by Dr. Seghal at Ayerst's research laboratories, Montreal (now Wyeth research laboratories Inc).
2. Dr. Seghal identified a new chemical compound and this new compound showed antifungal properties.
3. Further clinical studies showed that the new compound (drug) was not only a good antifungal agent but it also suppressed immune system, indicating that this can be used as an immunosuppressant agent.
4. After which new chemical compound (drug) was extensively studied to know the mechanism of action and it was also found to be effective against solid tumors.
1. For Industrial production of Sirolimus Streptomyces hygroscopicus NRRL 5491 strain is used.
2. Sirolimus production is a stepwise fermentation process.
a. Inoculums preparation.
b. Culturing the Broth to get the culture
c. Isolation of the Antibiotic from the broth
d. Purification of the crude antibiotic.
Mechanism of Action of Sirolimus:
Sirolimus is an effective immunosuppressive agent, but it is not a calcineurin inhibitor. Sirolimus acts as immunosuppressant by inhibiting the immune response to interleukin-2 (IL-2), by doing this it blocks the activation of both immune cells. That is both T-cells and B-cells.
Sirolimus binds to the protein known as FK-binding protein 12 (FKBP12), which are present in the cytosol of a cell, thus inhibits the activation of both T-cells and B-cells. The Sirolimus and FKBP12 (FK-binding protein 12) complex inhibits the signal transduction by mTOR (mammalian target of rapamycin) via by binding to the mTOR complex1. Mammalian target of rapamycin or mTOR is also known as FRAP (FK-binding protein-rapamycin associated protein) or it is also called as RAFT (rapamycin and FK-binding protein target). Among all these targets mTOR (mammalian target of rapamycin) is most widely used in the biology field.
Interaction between Sirolimus, Tacrolimus & Cyclosporine
1. In vitro studies have confirmed that Sirolimus and CsA act synergistically in the inhibition of T & B cell proliferation.
2. In vitro use of tacrolimus and Sirolimus in excess concentration exhibited selective reciprocal antagonism.
3. In vivo use showed synergism between tacrolimus and Sirolimus.
Side effects associated with Sirolimus
1. Renal effects of Sirolimus in rats (1.5mg/kg for 10 days) showed neither significant renal impairment nor renal histopathology while CsA showed increase in plasma urea, creatinine and reduced glomerular filtration rate and histologic alterations. Also produces renal lesions.
2. Studies for renal parameters in rabbit (50-100 fold increased dose) showed minor increase in blood urea and depressed body weight. While CsA treated mice died of neurotoxicity. Suggesting Sirolimus is less neurotoxic.
3. Studies in monkey (2mg/kg for 90-105 days) suggested that long term use of Sirolimus is associated with increased levels of triglycerides.
4. Studies published in J. of American Society of Nephrology clearly indicated the high risk of diabetes in patients on Sirolimus.
1. Initially Sirolimus as used as antifungal agent but later its immunosuppression properties were discovered.
2. Off label uses- used to clean and disinfect laboratory equipments, surgical equipments, locker rooms, shower rooms for sensitive fungus strains like Candida albicans, Microsporum gypseum.
3. Sirolimus coated stents are used in heart patients to prevent arterial blockage.
Sirolimus have achieved many clinical milestones since its first use started 17 years ago. Sirolimus has been approved for the prophylaxis of organ transplantation is several countries. It has a unique mode of action. Use of Sirolimus resulted in the reduction in the dose of calcineurin inhibitors such as Cyclosporine and Tacrolimus. Use of Sirolimus coated stent in patients resulted in inhibition of restenosis.
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