From Beach to Bedside: History of the Development of Sirolimus

Napoli, Kimberly L.; Taylor, Paul J.

doi:10.1097/00007691-200110000-00012

Cited by 110 publications

(80 citation statements)

References 174 publications

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“…SRL increases the bioavailability of cyclosporine, thereby potentially increasing its nephrotoxic effect (33). The impact of SRL on Tac in renal transplant recipients is less consistent (32,(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

Chhabra

Skaro

Leventhal

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives The optimal maintenance immunosuppressive regimen to improve long-term renal allograft function and graft survival is yet to be determined.Design, setting, participants, & measurements This observational study prospectively compared tacrolimus/ sirolimus with tacrolimus/mycophenolate mofetil in renal transplant recipients using a prednisone-free regimen with over 8.5 years of follow-up. Patients received methylprednisonlone and anti-IL2 receptor antagonist (Basiliximab) induction and were blindly randomized to either the tacrolimus/mycophenolate mofetil (n=45) or tacrolimus/sirolimus (n=37) groups. Outcome measures included patient and renal allograft survival, incidence of acute rejection, and estimated GFR.Results The tacrolimus/mycophenolate mofetil group compared with the tacrolimus/sirolimus group had overall better renal allograft survival (91% versus 70%, P=0.02); 13 patients (35.1%) in the tacrolimus/sirolimus group and 8 patients (17.8%) in the tacrolimus/mycophenolate mofetil group experienced biopsy-proven acute cellular rejection (P=0.07). By 3 months post-transplant, estimated GFR was significantly lower in the tacrolimus/ sirolimus group compared with the tacrolimus/mycophenolate mofetil group (47.7 versus 59.6 ml/min per 1.73 m 2 , P=0.0002), and this trend persisted throughout the follow-up period. Also, the slope of decline in the tacrolimus/ sirolimus group was significantly steeper than in the tacrolimus/mycophenolate mofetil group.Conclusions This study shows that, in a prednisone-free immunosuppressive regimen, long-term renal graft survival and function are significantly worse in the tacrolimus/sirolimus group than the tacrolimus/ mycophenolate mofetil group. The synergistic nephrotoxic effect and higher acute rejection rates in the tacrolimus/sirolimus compared with the tacrolimus/mycophenolate mofetil group adversely affect graft survival.

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Section: Discussionmentioning

confidence: 99%

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

Chhabra

Skaro

Leventhal

et al. 2012

Clinical Journal of the American Society of Nephrology

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“…A large volume of distribution (approximately 12 L/kg) is seen with sirolimus, the majority of which is distributed into red blood cells (approximately 95%) [18, 30]. Sirolimus is mainly metabolized via hepatic CYP3A enzymes, is primarily excreted via the fecal route, has a clearance that ranges from 1.45 to 6.93 mL/min/kg), and a half-life of approximately 62 hours [18, 27]. …”

Section: Pharmacological Aspects Of Mtor Inhibitorsmentioning

confidence: 99%

mTOR Inhibitors in Tuberous Sclerosis Complex

Curatolo

Moavero

2012

Current Neuropharmacology

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Tuberous sclerosis complex (TSC) is a genetic multiple organ system disorder that is characterized by the development of tumor-like lesions (hamartomas) and neurodevelopmental disorders. Mutations in the TSC1 and TSC2 tumor suppressor genes occur in the majority of patients with TSC, resulting in hyperactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for patients with TSC. Everolimus is the first mTOR inhibitor approved as a treatment option in the USA and in Europe for patients with subependymal giant-cell astrocytomas (SEGAs) associated with TSC. The clinical evidence to date supports the use of mTOR inhibitors in a variety of TSC-associated disease manifestations, including SEGAs, renal angiomyolipoma, skin manifestations, and epilepsy. Furthermore, ongoing clinical trials evaluating mTOR inhibitors in TSC are underway, and the results of these studies are expected to provide further evidence that will firmly establish their role in this setting. This article will discuss the role of the mTOR pathway in TSC and review the pharmacokinetics, pharmacodynamics, clinical efficacy, and tolerability of mTOR inhibitors, along with their current place in clinical practice.

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“…11,12 The rapamycin-FKBP complex associates with and inhibits the activity of a protein with phophatidyl-inositol kinase activity. 13,14 known as the mammalian target of rapamycin (mTOR). mTOR inhibition prevents phosphorylation of proteins involved in regulation of the cell cycle leading to arrest at the G1/S interface 15,16 and inhibition of intracellular signaling pathways associated with growth factor stimulation.…”

Section: Introductionmentioning

confidence: 99%

Dose-dependent Inhibition of Myointimal Hyperplasia by Orally Administered Rapamycin

Uchimura

Perera

Fujitani

et al. 2004

Annals of Vascular Surgery

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Myointimal hyperplasia (MIH) after vascular intervention is a major problem. Recent reports describing elimination of within-stent restenosis by means of rapamycin-eluting stents prompted us to examine the effect of systemic oral rapamycin on MIH induced by arterial trauma. We studied the effect of oral rapamycin on MIH after rabbit aorta balloon injury. Thirty-five New Zealand white rabbits (2.5-3 kg) had aortic injury and were given either no rapamycin (control), 0.1 (low dose) rapamycin mg/kg/day, or 0.4 mg/kg/day (high dose). Rapamycin was started 1 week before injury and continued for 3 (4 weeks total) or 6 weeks (7 weeks total) post-injury. Sections were analyzed to measure aortic intima/media area ratios (I:M) at either 3 or 6 weeks. At 3 weeks, the I:M (mean ± SD) for controls was 0.53 ± 0.1; for low dose, 0.17 ± 0.13; and for high dose, 0.24 ± 0.07 (p < 0.001 vs. control). At 6 weeks, the I:M for controls was 0.52 ± 0.12; for low dose-4 weeks, 0.29 ± 0.15; low dose-7 weeks, 0.33 ± 0.07; and high dose-4 weeks, 0.47 ± 0.16. At 6 weeks only the difference between the low dose-4 weeks and control I:M ratios was significant (p = 0.018). The results confirm earlier studies showing that systemic rapamycin inhibits MIH after arterial injury when drug therapy is started before injury. Therapy for 3 or 6 weeks after injury yields similar inhibition, indicating that exposure to the drug early in the response to injury is more important than prolonged exposure. We observed a paradoxical relation between dose and degree of MIH inhibition, with the low dose being more effective than the high dose at both time intervals studied. Overall, the results suggest that oral rapamycin therapy might be a useful adjunct to clinical interventions at risk for development of MIH.

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From Beach to Bedside: History of the Development of Sirolimus

Cited by 110 publications

References 174 publications

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

mTOR Inhibitors in Tuberous Sclerosis Complex

Dose-dependent Inhibition of Myointimal Hyperplasia by Orally Administered Rapamycin

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