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Transplantation Proceedings May 2003Sirolimus is the USAN-assigned generic name for the natural product rapamycin. Sirolimus is produced by a strain of Streptomyces hygroscopicus, isolated from a soil... (Review)
Review
Sirolimus is the USAN-assigned generic name for the natural product rapamycin. Sirolimus is produced by a strain of Streptomyces hygroscopicus, isolated from a soil sample collected from Rapa Nui commonly known as Easter Island. Although sirolimus was isolated as an antifungal agent with potent anticandida activity, subsequent studies revealed impressive antitumor and immunosuppressive activities. Sirolimus demonstrates activity against several murine tumors, such as B16 43 melanocarcinoma, Colon 26 tumor, EM ependymoblastoma, and mammary and colon 38 solid tumors. Sirolimus is a potent inhibitor of antigen-induced proliferation of T cells, B cells, and antibody production. Demonstration of the potent immunosuppressive activity of sirolimus in animal models of organ transplantation led to clinical trials and subsequent approval by regulatory authorities for prophylaxis of renal graft rejection. Interest in sirolimus as an immunosuppressive therapy in organ transplantation derives from its unique mechanism of action, its unique side-effect profile, and its ability to synergize with other immunosuppressive agents. The molecular mechanism underlying the antifungal, antiproliferative, and immunosuppressive activities of sirolimus is the same. Sirolimus forms an immunosuppressive complex with intracellular protein, FKBP12. This complex blocks the activation of the cell-cycle-specific kinase, TOR. The downstream events that follow the inactivation of TOR result in the blockage of cell-cycle progression at the juncture of G1 and S phase.
Topics: Animals; Humans; Immunosuppressive Agents; Models, Animal; Models, Biological; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 12742462
DOI: 10.1016/s0041-1345(03)00211-2 -
Nephrology, Dialysis, Transplantation :... Sep 2007Acute rejection episodes are now as low as 5-20% in the first year after renal transplantation; however, graft half-life has remained almost unchanged in the last... (Review)
Review
Acute rejection episodes are now as low as 5-20% in the first year after renal transplantation; however, graft half-life has remained almost unchanged in the last decade. This statistic is mainly attributable to the side effects of immunosuppression, with loss of allografts due to the chronic allograft nephropathy that is a consequence of calcineurin inhibitor toxicity or hypertension. Patient death due to cardiovascular events, infections and malignancy also contribute to allograft loss. The introduction of the inhibitors of the mammalian target of rapamycin sirolimus and everolimus in renal transplantation has increased the repertoire of immunosuppressive protocols substantially. They have a different mode of action and a different side effect profile (i.e. lower nephrotoxicity, less hypertension and less neoplastic potential) than the calcineurin inhibitors. The inhibitors of the mammalian target of rapamycin therefore provide an especially promising alternative for the maintenance immunosuppression after renal transplantation. This overview provides a summary of the current literature on inhibitors of the mammalian target of rapamycin, with a special focus on sirolimus.
Topics: Antineoplastic Agents; Everolimus; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Transplantation Immunology; Transplantation Tolerance; Treatment Outcome
PubMed: 17890266
DOI: 10.1093/ndt/gfm652 -
Blood Jan 2023
Topics: Sirolimus; Immunosuppressive Agents; Tacrolimus; TOR Serine-Threonine Kinases; T-Lymphocytes
PubMed: 36656615
DOI: 10.1182/blood.2022018568 -
Nephrology (Carlton, Vic.) Dec 2005Sirolimus (Rapamycin, Wyeth Pharmaceuticals Australia Pty Ltd, Baulkham Hills, NSW, Australia) (SRL) has received increasing attention as an immunosuppressant in renal... (Review)
Review
Sirolimus (Rapamycin, Wyeth Pharmaceuticals Australia Pty Ltd, Baulkham Hills, NSW, Australia) (SRL) has received increasing attention as an immunosuppressant in renal and other solid organ transplantation. Sirolimus is the first marketed agent in a new class of drugs with a novel mechanism of action. Sirolimus binds, like tacrolimus, to a member of the FK binding protein (FKBP) family. The SRL/FKBP complex binds to the protein kinase mTOR. Binding to mTOR blocks activation of signal transduction pathways causing arrest of the cell cycle in the G1 phase. It is now known that mTOR is a central regulator of cell growth and proliferation. The immunosuppressive properties of SRL are due primarily to blockade of interleukin-2 (IL-2)-induced proliferation of T cells. There is still much to be learnt about how best to use the drug. The key advantage over the current choice of immunosuppressive agents is the ability to preserve renal function and pathology while producing excellent rejection-free, graft survival rates. Thus, SRL may find its pivotal role as a calcineurin inhibitors replacement in patients whose grafts are affected by chronic allograft nephropathy. A second major driver for use may prove to be the impact of SRL on cancer incidence and prognosis. Studies still need to be performed to evaluate the best timing for commencement of SRL and the optimal dosage to minimize side-effects.
Topics: Animals; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Pregnancy; Sirolimus
PubMed: 16354246
DOI: 10.1111/j.1440-1797.2005.00493.x -
American Journal of Therapeutics 2004Despite major technological advances in the practice of percutaneous coronary intervention, restenosis of the treated arteries remains a challenge for many... (Review)
Review
Despite major technological advances in the practice of percutaneous coronary intervention, restenosis of the treated arteries remains a challenge for many interventional cardiologists. Sirolimus is a macrolide antibiotic with potent antifungal, immunosuppressive, and antimitotic activities. Sirolimus inhibits in-stent restenosis via 2 major mechanisms of action: by blocking the process of neointimal hyperplasia by inhibiting smooth muscle cell proliferation and by inhibiting inflammatory cell activity. In pivotal clinical trials, the sirolimus-eluting stent has demonstrated significant improvements in angiographic and clinical outcomes compared with bare metal stents in patients with de novo lesions in native coronary arteries. Since the systemic exposure of sirolimus in patients who received the drug-eluting stent is minimal, adverse effects resulting from systemic exposure of sirolimus are unlikely to occur. Further studies are needed to determine the safety and effectiveness of sirolimus-eluting stents in patients with more complex coronary artery lesions. In addition, the long-term safety, efficacy, and cost-effectiveness of this novel drug-eluting device will need to be established in ongoing clinical trials. This review article focuses on the pharmacology as well as clinical studies of the sirolimus-eluting stent.
Topics: Anti-Bacterial Agents; Coronary Disease; Drug Administration Schedule; Humans; Randomized Controlled Trials as Topic; Sirolimus; Stents; Treatment Outcome
PubMed: 15133538
DOI: 10.1097/00045391-200405000-00011 -
Current Opinion in Nephrology and... Nov 2002There has been a necessary change in attitude to transplantation; there is much less concern with short-term outcome and more concern with long-term kidney function,... (Review)
Review
There has been a necessary change in attitude to transplantation; there is much less concern with short-term outcome and more concern with long-term kidney function, overall health and quality of life. Nephrotoxicity is an invariable consequence of long-term treatment with calcineurin antagonists and it is one of the most underestimated causes of late graft loss; it has been reported as a serious threat to both patient and graft survival following heart, liver and bone marrow transplantation. Sirolimus has been shown in many recent studies to be of great value in allowing patients to be weaned from cyclosporine with excellent patient and graft survival at 24 months a significant improvement in renal function with resolution of hirsutism and gum hyperplasia. Patients maintained on the combined regime of cyclosporine and sirolimus had significantly higher blood pressure, much more cyclosporine nephrotoxicity and hyperuricaemia at 12 months. The experimental studies have found cyclosporine and sirolimus potentiate with each other's good and adverse effects. Cyclosporine therefore augments hyperlipidaemia caused by sirolimus, and sirolimus augments nephrotoxicity caused by cyclosporine. The results of these studies indicate that sirolimus is a suitable replacement for cyclosporine or tacrolimus for long-term maintenance therapy. By contrast the use of sirolimus in combination with cyclosporine results in potentiation of side effects. The principal disadvantages being increased cyclosporine associated nephrotoxicity and sirolimus associated hyperlipidaemia
Topics: Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus
PubMed: 12394605
DOI: 10.1097/00041552-200211000-00006 -
Clinical Pharmacokinetics 2004Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which... (Review)
Review
Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxyethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects. For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed. Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3-1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children. The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients. The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia. Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 microg/L in combination therapy with ciclosporin (trough concentration 100-300 microg/L) and prednisone.
Topics: Adult; Animals; Area Under Curve; Biological Availability; Child; Chromatography, High Pressure Liquid; Clinical Trials as Topic; Enzyme-Linked Immunosorbent Assay; Everolimus; Humans; Immunosuppressive Agents; Metabolic Clearance Rate; Sirolimus; Tissue Distribution
PubMed: 14748618
DOI: 10.2165/00003088-200443020-00002 -
The Journal of the Association of... Oct 2005Though organ transplantation has evolved in many a ways over the years, it is not without the disadvantage of causing rejections. Cyclosporin, azathioprine and... (Review)
Review
Though organ transplantation has evolved in many a ways over the years, it is not without the disadvantage of causing rejections. Cyclosporin, azathioprine and corticosteroids are time tested and efficacious; however each is accompanied with its own array of disadvantages. Sirolimus is a relatively new immunosuppressant isolated from a macrolide antibiotic. It may have a beneficial role in prophylaxis of rejection as well as treatment of refractory rejection. It also has antifungal, antitumor and anti-smooth muscle proliferative roles.
Topics: Humans; Immunosuppressive Agents; Molecular Structure; Sirolimus
PubMed: 16459533
DOI: No ID Found -
The Annals of Pharmacotherapy Sep 2000To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and economic issues associated with sirolimus, the most recent immunosuppressive agent... (Review)
Review
OBJECTIVE
To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and economic issues associated with sirolimus, the most recent immunosuppressive agent approved for kidney transplantation.
DATA SOURCES
A MEDLINE search (1966-June 2000) was completed to identify primary and review articles. In addition, abstracts from recent meetings on transplantation were reviewed for information and research on sirolimus.
STUDY SELECTION AND DATA EXTRACTION
Blinded, randomized, controlled studies were the goal, but, as with most newly approved immunosuppressive agents, a significant amount of information on sirolimus is not available in this optimal form. All articles were assessed and all pertinent information was incorporated in this review.
DATA SYNTHESIS
Sirolimus is structurally related to the immunosuppressive agent tacrolimus, and retains a pharmacokinetic and drug interaction profile similar to that of the calcineurin inhibitors, cyclosporine and tacrolimus. However, the novel mechanism of action of sirolimus differs significantly from these agents, as does its adverse effect profile. The most significant adverse reaction is hyperlipidemia. Clinical experience with sirolimus has allowed transplant centers to expand its use into other areas of transplantation as well as certain autoimmune disorders.
CONCLUSIONS
The definitive role of sirolimus will continue to be determined; however, sirolimus offers an excellent addition to the transplant immunosuppression armamentarium.
Topics: Adrenal Cortex Hormones; Clinical Trials as Topic; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Organ Transplantation; Retrospective Studies; Sirolimus
PubMed: 10981252
DOI: 10.1345/aph.19380 -
Expert Opinion on Pharmacotherapy Mar 2005This review of immunosuppression in renal transplantation has allowed us to highlight the deleterious effect of calcineurin inhibitor nephrotoxicity and to emphasise the... (Review)
Review
This review of immunosuppression in renal transplantation has allowed us to highlight the deleterious effect of calcineurin inhibitor nephrotoxicity and to emphasise the importance of sirolimus. Now, a whole new set of possibilities has opened up in immunosuppression: sirolimus-based immunosuppression without calcineurin inhibitors; sirolimus in combination with calcineurin inhibitors in reduced doses; early calcineurin inhibitor withdrawal from a regimen that combines sirolimus, calcineurin inhibitors and steroids; and calcineurin inhibitor conversion to sirolimus when the first signs of graft nephrotoxicity appear. These new strategies in immunosuppression in renal transplantation are associated with good results in graft and patient survival in year 1, and with better renal function. Therefore, we can hope for better long-term results in transplantation, with a significant increase in the graft half-life and in the patient survival.
Topics: Calcineurin Inhibitors; Cyclosporine; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Sirolimus; Tacrolimus
PubMed: 15794738
DOI: 10.1517/14656566.6.3.479