Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Sirolimus”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 127 records · Page 7Linked to original sources
PubMed2005

Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus.

Cyclosporine A (CsA) and tacrolimus have been associated with an increased risk for diabetes after transplantation, whereas sirolimus is deemed to be devoid of any effect on glucose metabolism. This study was performed to investigate the effect of the withdrawal of calcineurin inhibitors and the switch to sirolimus on peripheral insulin resistance and pancreatic beta cell response. Twenty-six patients who received a kidney transplant and discontinued CsA and were converted to sirolimus and 15 recipients of suboptimal kidneys who were treated with tacrolimus plus sirolimus for the first 3 mo after grafting and thereafter with sirolimus alone were enrolled. All patients underwent an oral glucose tolerance test and intravenous insulin tolerance test before and 6 mo after the conversion to sirolimus-alone therapy. The withdrawal of CsA or tacrolimus was associated with a significant fall of insulin sensitivity (both P = 0.01) and with a defect in the compensatory beta cell response, as measured by the disposition index (P = 0.004 and P = 0.02, respectively). The increase of insulin resistance and the decrease of disposition index significantly correlated with the change of serum triglyceride concentration after the conversion to sirolimus-based therapy (R(2) = 0.30, P = 0.0002; and R(2) = 0.19, P = 0.004, respectively). Clinically, the switch to sirolimus was associated with a 30% increase of incidence of impaired glucose tolerance and with four patients' developing new-onset diabetes. In conclusion, the discontinuation of calcineurin inhibitors and their replacement by sirolimus fail to ameliorate the glycometabolic profile of kidney transplant recipients. Rather, it is associated with a worsening of insulin resistance and an inappropriately low insulin response.

Adult↗
PubMed2001

Clinical pharmacokinetics of sirolimus.

Sirolimus (previously known as rapamycin), a macrocyclic lactone, is a potent immunosuppressive agent. Sirolimus was recently approved by the US Food and Drug Administration, on the basis of 2 large, double-blind, prospective clinical trials, for use in kidney transplant recipients at a fixed dosage of 2 or 5 mg/day in addition to full dosages of cyclosporin and prednisone. However, despite the fixed dosage regimens used in these pivotal trials, pharmacokinetic and clinical data show that sirolimus is a critical-dose drug requiring therapeutic drug monitoring to minimise drug-related toxicities and maximise efficacy. Assays using high performance liquid chromatography coupled to mass spectrometry, although cumbersome, are the gold standard for evaluating other commonly used assays, such as liquid chromatography with ultraviolet detection, radioreceptor assay and microparticle enzyme immunoassay. Sirolimus is available in oral solution and tablet form. It has poor oral absorption and distributes widely in tissues, displaying not only a wide inter- and intrapatient variability in drug clearance, but also less than optimal correlations between whole blood concentrations and drug dose, demographic features or patient characteristics. Furthermore, the critical role of the cytochrome P450 3A4 system for sirolimus biotransformation leads to extensive drug-drug interactions, among which are increases in cyclosporin concentrations. Thus, sirolimus is now being used to reduce or eliminate exposure to cyclosporin or corticosteroids. The long elimination half-life of sirolimus necessitates a loading dose but allows once daily administration, which is more convenient and thereby could help to improve patient compliance. This review emphasises the importance of blood concentration monitoring in optimising the use of sirolimus. The excellent correlation between steady-state trough concentration (at least 4 days after inception of, or change in, therapy) and area under the concentration-time curve makes the former a simple and reliable index for monitoring sirolimus exposure. Target trough concentration ranges depend on the concomitant immunosuppressive regimen, but a range of 5 to 15 microg/L is appropriate if cyclosporin is being used at trough concentrations of 75 to 150 microg/L. Weekly monitoring is recommended for the first month and bi-weekly for the next month; thereafter,concentration measurements are necessary only if warranted clinically.

Area Under Curve↗
PubMed2002

Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice.

Sirolimus is an immunosuppressant that inhibits interleukin (IL)-2 signaling of T-cell proliferation but not IL-2-induced T-cell apoptosis. Therefore, we hypothesized that administration of IL-2, together with sirolimus, might shift T-cell proliferation to apoptosis and prevent autoimmune destruction of islet beta-cells. We found that sirolimus and IL-2 therapy of female NOD mice, beginning at age 10 weeks, was synergistic in preventing diabetes development, and disease prevention continued for 13 weeks after stopping sirolimus and IL-2 therapy. Similarly, sirolimus and IL-2 were synergistic in protecting syngeneic islet grafts from recurrent autoimmune destruction after transplantation in diabetic NOD mice, and diabetes did not recur after stopping sirolimus and IL-2 combination therapy. Immunocytochemical examination of islet grafts revealed significantly decreased numbers of leukocytes together with increased apoptosis of these cells in mice treated with sirolimus and IL-2, whereas beta-cells were more numerous, and significantly fewer were apoptotic. In addition, Th1-type cells (gamma-interferon-positive and IL-2(+)) were decreased the most, and Th2-type cells (IL-4(+) and IL-10(+)) and Th3-type cells (transforming growth factor-beta1(+)) were increased the most in islet grafts of sirolimus and IL-2-treated mice. We conclude that 1) combination therapy with sirolimus and IL-2 is synergistic in protecting islet beta-cells from autoimmune destruction; 2) diabetes prevention continues after withdrawal of therapy; and 3) the mechanism of protection involves a shift from Th1- to Th2- and Th3-type cytokine-producing cells, possibly due to deletion of autoreactive Th1 cells.

Animals↗
PubMed2004

Comparative effects of sirolimus and mycophenolate mofetil on erythropoiesis in kidney transplant patients.

Anemia and erythrocytosis (PTE) are common after kidney transplantation. We sought to determine the influence of sirolimus compared to mycophenolate mofetil (MMF) on post-transplant erythropoiesis. A total of 214 patients with recent kidney or kidney-pancreas transplants were treated with either sirolimus-based (n = 87) or MMF-based (n = 127) therapy. At 12 months, the prevalence of anemia was 31% with MMF and 57% with sirolimus (p < 0.001). Linear regression was used to examine the independent influence of sirolimus on hemoglobin at 12 months, controlling for multiple factors including gender and renal function. Sirolimus remained a significant correlate of lower hemoglobin in all patients (slope =-1.060, 95% CI: -1.76 to -0.362, p = 0.003), and in patients without PTE (slope =-0.671, 95% CI: -1.32 to -0.028, p = 0.041). PTE, defined as a persistent hematocrit above 51%, occurred in 19% with MMF and 7% with sirolimus (p = 0.013). PTE was examined using logistic regression analysis. Sirolimus use correlated negatively with PTE (odds ratio with sirolimus = 0.33, 95% CI: 0.12 to 0.89, p = 0.028). Our results indicate that, compared to treatment with MMF, treatment of kidney or kidney-pancreas recipients with sirolimus is associated with a higher prevalence of anemia, lower hemoglobin levels and lower incidence of PTE.

Anemia↗
PubMed2006

Intramural delivery of Sirolimus prevents vascular remodeling following balloon injury.

OBJECTIVE: Several studies have demonstrated that Sirolimus-eluting stents reduce restenosis in patients with coronary artery disease. Here, we tested whether direct delivery of Sirolimus into the vessel wall during balloon angioplasty can modify vascular remodeling over several weeks. METHODS AND RESULTS: During angioplasty of the rabbit iliac artery we administered an intramural infusion of Sirolimus or its vehicle directly through a balloon catheter into the vessel wall. After 3 weeks neointimal formation was decreased (0.71+/-0.1 vs. 1.4+/-0.12 intima/media ratio), and this process was attributed to the inhibitory properties of Sirolimus on ECM deposition and smooth muscle cell proliferation. Sirolimus also significantly reduced the deposition of elastin, collagen III and fibronectin within the vascular wall. In parallel, proteomic profiles of arterial wall segments were obtained and 485 protein spots were consistently matched between non-dilated and dilated vessels. Differential expression of 12 proteins were observed between the groups and direct sequencing of digested peptides was performed. Local delivery of sirolimus during angioplasty attenuated the expression of structural proteins that included lamin A, vimentin, alpha-1-antitrypsin, and alpha-actin. CONCLUSIONS: Local administration of Sirolimus during angioplasty prevents smooth muscle cell proliferation associated with vascular remodeling as well as the expression of extracellular matrix and structural proteins. Therefore, local injection of Sirolimus during balloon inflation may be an alternative therapeutic approach for preventing restenosis in small stenotic vessels (i.e., <2.5 mm).

Actins↗
PubMed2006

CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients.

BACKGROUND: The low and highly variable oral bioavailability of the immunosuppressant sirolimus is thought to result partly from genetic polymorphism of the CYP3A5 gene. METHODS: This study aimed to evaluate the contribution of the CYP3A5 single-nucleotide polymorphism A6986G to the interindividual variability of sirolimus pharmacokinetics in 47 renal transplant patients at steady state, 21 of whom were also followed up for the first 3 months after transplantation. The patients were administered sirolimus, mycophenolate mofetil, and corticosteroids but no calcineurin inhibitor. They were genotyped for CYP3A5*3 by use of real-time quantitative polymerase chain reaction based on the 5'-nuclease allelic discrimination assay. Full sirolimus blood concentration profiles were measured at steady state (3 months after transplantation or more) in all patients, as well as at weeks 1 and 2 and month 1 in 21 of these patients, by use of liquid chromatography-tandem mass spectrometry. The sirolimus area under the concentration-time curve (AUC) was calculated via the standard noncompartmental approach. Maximal concentration (C(max)) and trough level (C(0)) values were measured. RESULTS: Significantly lower AUC/dose, C(max)/dose, and C(0)/dose values were found at steady state (n = 47) in individuals carrying at least 1 CYP3A5*1 allele (n = 6) than in *3/*3 patients (26.6 +/- 15.7 versus 51.1 +/- 21.1 [P = .008], 4.8 +/- 3.3 versus 7.7 +/- 3.3 [P = .02], and 1.5 +/- 0.8 versus 3.0 +/- 1.5 [P = .01], respectively), as well as during all posttransplant periods in the subgroup of 21 patients who were followed up for the first 3 months after transplantation (n = 21) (P < .05 always). Patients with the CYP3A5*1/*1 and *1/*3 genotypes required a significantly higher sirolimus daily dose to achieve the same blood concentration at steady state as *3/*3 patients. In patients followed up for the first 3 months after transplantation, C(0) levels within the target range were only achieved after 1 to 3 months of repeated dosing and dose adjustment in both genotypic groups. CONCLUSION: These results confirm that sirolimus metabolic activity and oral clearance are significantly decreased in patients who are homozygous for the CYP3A5*3 single-nucleotide polymorphism and suggest that the determination of this polymorphism could be useful for a priori dose adjustment of sirolimus, given the long half-life of this drug.

Adult↗
PubMed2004

Is sirolimus a safe alternative to reduce or eliminate calcineurin inhibitors in chronic allograft nephropathy in kidney transplantation?

PURPOSE: We evaluate whether cyclosporine (CsA) or tacrolimus (FK) could be reduced or eliminated after sirolimus was added in chronic allograft nephropathy (CAN). By reducing doses of CsA or FK, we expected that renal function would improve. METHOD AND MATERIAL: Twenty-one patients with CAN had sirolimus added as an immunosuppressive agent. We evaluated the creatinine (Cr) level 3 months after addition. The doses of CsA and FK were decreased gradually and then eliminated over a course of 4 to 6 weeks. If the Cr level rose rapidly or other prominent signs of rejection occurred; low-dose CsA or FK would be added per protocol. We evaluated the duration of engraftment before sirolimus and the Cr level when it was added. RESULTS: Renal function improved in 13 of 21 cases. The improvement in Cr ranged from 12.5% maximally to 1.84% minimally. Seven of 13 cases still required low-dose CsA. The average duration of engraftment before sirolimus was 13.66 +/- 10.80 months. The average Cr level before sirolimus was 1.65 +/- 0.56 mg/dL. In the other eight cases, the Cr level kept rising from 5.1% to 20.4%. The average duration of engraftment was 88.38 +/- 42.21 months. The average Cr level before sirolimus was 2.85 +/- 0.54 mg/dL. Hyperuricemia was noted in 31.3% and hyperlipidemia in 68.8%. CONCLUSION: Sirolimus is a safe alternative to reduce or eliminate CsA or FK in CAN. In cases with a long duration of engraftment and high Cr level, sirolimus might have some effect as a substitute for CNI and thus prevent further nephrotoxicity.

Chronic Disease↗
PubMed2005

Sirolimus delays recovery from posttransplant renal failure in kidney graft recipients.

The aim of this study was to evaluate the impact of sirolimus and cyclosporine (CsA) combined therapy on the incidence and duration of delayed graft function (DGF), and the impact of the latter on 1-year graft function. The study entailed 23 cadaveric renal recipients treated with sirolimus-CsA-prednisone regimen (sirolimus group). The reference group entailed 23 patients treated with CsA-azathioprine-prednisone. In the sirolimus group the frequency of DGF was 39% and was essentially the same as in reference group (34.8%). The duration of DGF was significantly longer in SRL group and lasted 21.2 +/- 12.2 days versus 6.8 +/- 2.5 in reference group (P = .004). Serum creatinine level decreased below 3.0 mg/dL after 36 +/- 22 days in sirolimus group versus 16.8 +/- 6 days in reference group (P < .04). Cold ischemia was slightly longer and donors were older in DGF patients in both groups. Sirolimus dose during first month was higher in DGF patients (3.5 versus 2.6 mg), whereas level of CsA was lower (230 versus 310 ng/mL). Biopsy-proven acute rejection (AR) occurred in most of DGF patients and during the DGF period. Serum creatinine level at the 12th month posttransplant was higher in DGF versus non-DGF patients (2.0 +/- 0.5 versus 1.5 +/- 0.4 mg/dL). One-year patient and graft survival was 100% in sirolimus group and 100% and 95% in reference group. In conclusion, sirolimus significantly retards the recovery from posttransplant renal failure; however, it does not increase the incidence of DGF. Patients who suffered from posttransplant acute renal failure had worse renal function at 1 year after transplantation, independent of the treatment protocol.

Adult↗
PubMed2005

Sirolimus as primary immunosuppression agent in kidney transplant recipients: Akdeniz University experience.

OBJECTIVES: Recently usage of sirolimus as the primary immunosuppressant is widening among kidney transplant recipients. We reviewed the clinical follow-up of patients transplanted at our center using sirolimus protocols. METHODS: Sirolimus including primary immunosuppressive treatment protocols were begun in February 2002. Among the 21 patients (15 men, six women) who received sirolimus, six patients were prescribed sirolimus + prednisolone; seven, sirolimus + mycophenolate mofetil + prednisolone; and eight, sirolimus + cyclosporine + prednisolone. The mean age of the patients was 32.9 +/- 7.3 years and the mean posttransplantation follow-up, 13.2 +/- 4.5 months. RESULTS: Three patients experienced acute rejection episodes, which were treated successfully with steroids. None of the patients had either hematologic or wound healing problems. Lymphoceles developed in eight patients. Serum creatinine level was 1.4 +/- 0.5 mg/dL at 12 months. There was a serious increase in serum cholesterol and triglyceride levels starting from the first month posttransplant (total cholesterol levels pretransplant and at 1 month, respectively: 159.3 +/- 29.5 and 255.7 +/- 52.3 mg/dL, P = .0001; triglycerides pretransplant and at 1 month, respectively: 146.9 +/- 89.5 and 215.1 +/- 102.5 mg/dL, P = .001). Despite routine antihyperlipemic treatment those high levels were maintained for 12 months. CONCLUSIONS: We achieved 100% graft and patient survival rates for 1 year among patients who were using sirolimus. But the most important role in defining the morbidity and mortality in this group of patients is cardiovascular events; for this reason the abnormalities in the lipid profile must be taken seriously.

Cyclosporine↗
PubMed2003

Safety and efficacy of sirolimus in kidney transplant patients and in patients with coronary artery disease undergoing angioplasty.

UNLABELLED: We show the key results of our 4-year experience with sirolimus in kidney transplant patients and in nontransplanted patients undergoing coronary angioplasty. METHODS: Recipients of one-haplotype living-related kidney allografts were randomized to receive sirolimus (2 mg/d, n = 35) or azathioprine (2 mg/kg per day, n = 35). Recipients of fully mismatched living kidney allografts (n = 55) received sirolimus (2 mg/day). High-risk recipients of black ethnicity (n = 68) were randomized to target whole-blood trough sirolimus concentrations between 8 and 12 ng/mL or 15 to 20 ng/mL. All kidney transplant patients received cyclosporine and prednisone. Sirolimus/cyclosporine pharmacokinetic studies were performed in 40 patients receiving 2 mg (n = 20) or 5 mg (n = 20) of sirolimus 7 days after transplantation. In the coronary intervention study, 12 patients at high risk for in-stent restenosis received sirolimus for 28 days after angioplasty. RESULTS: The incidence of biopsy-confirmed acute rejection was 11.4% in recipients of one-haplotype living-related kidney allografts, 16.4% in recipients of fully mismatched living kidney allografts, and 15% (8 to 12 ng/mL) and 4% (15 to 20 ng/mL) in high-risk recipients of black ethnicity. Cyclosporine exposure was higher after morning administration compared to evening administration. There were poor correlations between sirolimus and cyclosporine exposures. The 4-month follow-up angiography revealed no restenosis (stenosis diameter > 50%), a late loss of 0.56 +/- 0.40 mm, and a loss index of 0.33 +/- 0.30. The follow-up 3D-intravascular ultrasound restudy showed an in-stent relative volumetric obstruction of 9.9 +/- 5.5%. Sirolimus in highly effective in preventing kidney allograft acute rejection and in-stent coronary restenosis.

Adult↗
PubMed2003

Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: double-blind, randomised controlled trial (E-SIRIUS).

BACKGROUND: Sirolimus-eluting stents have been developed to prevent restenosis in the treatment of coronary artery disease. We investigated the risk of restenosis with use of sirolimus-eluting stents compared with bare-metal stents to assess possible differences. METHODS: We enrolled 352 patients in whom one coronary artery required treatment, with diameter 2.5-3.0 mm and lesion length 15-32 mm. We randomly assigned patients sirolimus-eluting stents (n=175) or bare-metal stents (control, n=177). At 8 months we assessed differences in minimum lumen diameter and binary restenosis within the lesion (restenosis of > or =50% diameter, including 5 mm vessel segments proximal and distal to stented segment). Patients were also followed up for 9 months for major adverse cardiac events. Analysis was by intention to treat. FINDINGS: Stent implantation was successful in 100% of sirolimus-stent patients and 99.4% of controls. The mean diameter of treated coronary arteries was 2.55 mm (SD 0.37) and mean lesion length was 15.0 mm (6.0). Multiple stents were implanted in 170 (48%) patients. At 8 months, minimum lumen diameter was significantly higher with sirolimus-eluting stents than with control stents (2.22 vs 1.33 mm, p<0.0001). The rate of binary restenosis was significantly reduced with sirolimus-eluting stents compared with control stents (5.9 vs 42.3%, p=0.0001). Significantly fewer patients with sirolimus-eluting stents had major adverse cardiac events at 9 months than did controls (8.0 vs 22.6%, p=0.0002), due mainly to a lower need for target-lesion revascularisations (4.0 vs 20.9%, p<0.0001). INTERPRETATION: Sirolimus-eluting stents are better than bare-metal stents for treatment of single long atherosclerotic lesions in a coronary vessel smaller than 3 mm in diameter.

Angioplasty, Balloon↗
PubMed2003

Tacrolimus and sirolimus decrease oxidative phosphorylation of isolated rat kidney mitochondria.

1. Tacrolimus and sirolimus are potent immunosuppressors used in transplantation. Tacrolimus has been suspected to alter mitochondrial respiration of different tissues but sirolimus has not been evaluated. 2. We evaluated the in vitro effect of tacrolimus and sirolimus on oxidative phosphorylation of isolated rat kidney mitochondria. 3. Oxygen consumption was measured with a Clark-type electrode. Tacrolimus and sirolimus increased the resting rate (state 4) and had no significant effect on ADP-stimulated respiration (state 3). The decrease of respiratory control ratio was concentration-dependent with a biphasic curve for tacrolimus. The EC(50)s were 3.4 x 10(-11) M and 2.3 x 10(-8) M for tacrolimus and 4.4 x 10(-10) M for sirolimus. The maximal inhibition was 20 and 14% for tacrolimus and sirolimus, respectively. 4. Tacrolimus and sirolimus had an uncoupling effect on oxidative phosphorylation related to a decrease of the inner membrane fluidity. At the opposite of cyclosporin A, no effect on swelling or Ca(2+) fluxes was observed. 5. All events occurred at therapeutic concentrations and then could appear during long-term treatment. Cellular consequences such as chronic nephrotoxicity with tacrolimus are suggested. The risk of cyclosporin A nephrotoxicity potentiation by sirolimus is discussed.

Animals↗
PubMed2003

A retrospective review of sirolimus (Rapamune) therapy in orthotopic liver transplant recipients diagnosed with chronic rejection.

Treatment options are limited for orthotopic liver transplant (OLT) recipients suffering from chronic rejection (CR). We performed a retrospective review of OLT recipients diagnosed with CR and treated with sirolimus. The medical records of all OLT recipients treated with sirolimus between October, 1998 and October, 2000 were retrospectively reviewed. The diagnosis of CR was made by both clinical and histologic criteria: bile duct to hepatic artery ratio less than 0.7, histologic activity index, hepatic arterial wall thickening, and chronic elevation of liver chemistries. Two groups were defined in regard to sirolimus response: sirolimus responders (SR) and sirolimus nonresponders (SNR). Response to treatment was granted only when patients were found to have resolution of abnormal liver transaminases and an improvement in hepatic artery to bile duct ratio. Serum collections for liver chemistries were collected on days 1, 30, 60, and 90. Liver biopsies were reviewed in blinded fashion from day 1 and at least 180 days on therapy by double-blinded pathologists. Sirolimus-related complications were recorded and include drug toxicity, anemia with and without treatment, hospitalizations, infections, immunosuppression complications, lipid profile disorders, edema, muscle aches, and gastrointestinal complaints. Twenty-one patients were diagnosed with CR. The SR group included 13 of 21, and 8 of 21 were in the SNR group. Anemia was diagnosed in 12 of 21 patients: SR, 7 of 13; SNR, 5 of 8; with 5 patients requiring red blood cell transfusions (2 SR, 3 SNR). Recombinant erythropoietin was started in 5 of 21 patients. Sirolimus serum levels were found to be greater than 20 ng/dL in 12 patients. Sirolimus was discontinued in 9 patients,

Adolescent↗
PubMed2006

Randomized trial of paclitaxel- and sirolimus-eluting stents in small coronary vessels.

AIMS: Sirolimus- and paclitaxel-eluting stents effectively reduce restenosis in small coronary vessels. The relative efficacy of these drug-eluting stents in this high-risk subset is not known. METHODS AND RESULTS: A total of 360 patients undergoing percutaneous coronary intervention for de novo lesions in native coronary vessels with a diameter of <2.80 mm received randomly paclitaxel-eluting stents (n=180) or sirolimus-eluting stents (n=180). The primary endpoint was in-stent late luminal loss. Secondary endpoints were angiographic restenosis and need of target lesion revascularization. The study intended to show that the paclitaxel-eluting stent is not inferior to the sirolimus-eluting stent with respect to the primary endpoint. The non-inferiority margin was set at 0.16 mm. Follow-up angiography was performed in 87% of the patients. In-stent late luminal loss in the paclitaxel-eluting stent group was 0.32 mm (upper 95% boundary, 0.42 mm), which was greater than that in the sirolimus-eluting stent group, failing to show the non-inferiority of the paclitaxel-eluting stent to the sirolimus-eluting stent (P>0.99). Angiographic restenosis was found in 19.0% of the lesions in the paclitaxel-eluting stent group and 11.4% of the lesions in the sirolimus-eluting stent group (P=0.047). Target lesion revascularization was performed in 14.7% of the lesions treated with paclitaxel-eluting stents and 6.6% of the lesions treated with sirolimus-eluting stents (P=0.008). CONCLUSION: The paclitaxel-eluting stent is associated with a greater late luminal loss and is less effective in reducing restenosis in small coronary vessels than the sirolimus-eluting stent.

Aged↗
PubMed1999

Correlation between pretransplantation test dose cyclosporine pharmacokinetic profiles and posttransplantation sirolimus blood levels in renal transplant recipients.

We sought to determine whether pretransplantation test dose pharmacokinetic measurements of cyclosporine (CsA) concentrations would forecast the posttransplantation blood concentrations of sirolimus in renal transplant patients treated de novo with CsA, sirolimus, and prednisone. All 44 renal transplant recipients enrolled in Phase I/II studies of de novo posttransplantation therapy with sirolimus, CsA, and prednisone underwent pretransplantation pharmacokinetic profiling after having received paired intravenous (i.v.) and oral test doses of CsA. After transplantation, all patients were treated with CsA on a once- or twice-daily schedule (according to a concentration-controlled regimen), with tapering doses of prednisone, and with fixed doses of sirolimus on a once-daily schedule. Patients were divided into four cohorts based on the deviation of their pretransplantation CsA clearance or bioavailability values from the mean. Patients with high pretransplantation CsA clearance rates displayed a significantly lower mean posttransplantation value of sirolimus trough concentrations than patients with low pretransplantation CsA clearance rates. In contrast, values for pretransplantation absolute oral CsA bioavailability failed to correlate with the mean posttransplantation concentration of sirolimus but did predict posttransplantation CsA bioavailability. Therefore, pretransplantation CsA clearance rate estimates may forecast posttransplantation sirolimus concentrations, possibly guiding use of sirolimus therapy to achieve an optimal ratio of concentration-dependent immunosuppressive versus toxic effects.

Biological Availability↗
PubMed2000

Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates.

BACKGROUND: Current immunosuppressive protocols fail to prevent chronic rejection often manifested as graft vascular disease (GVD) in solid organ transplant recipients. Several new immunosuppressants including sirolimus, a dual function growth factor antagonist, have been discovered, but studies of drug efficacy have been hampered by the lack of a model of GVD in primates, as a prelude to clinical trials. As described earlier, we have developed a novel non-human primate model of GVD where progression of GVD is quantified by intravascular ultrasound (IVUS). METHODS: Twelve cynomolgus monkeys underwent aortic transplantation from blood group compatible but mixed lymphocyte reaction-mismatched donors. To allow the development of GVD in the allograft, no treatment was administered for the first 6 weeks. Six monkeys were treated orally with sirolimus from day 45 after transplantation to day 105. RESULTS: Progression of GVD measured as change in intimal area from day 42 to 105 was halted in sirolimus-treated monkeys compared to untreated monkeys (P<0.001, general linear model). On day 105, the intimal area +/- SEM was 3.7+/-1.0 and 6.4+/-0.5 mm2, respectively (P<0.05, t test). The magnitude of allograft intimal area on day 105 correlated inversely with sirolimus trough levels (R2=0.67, P<0.05). Regression of the intimal area was seen in four of six sirolimus-treated monkeys, which was significantly different from the untreated monkeys (P<0.05). CONCLUSIONS: Our results in the first non-human primate model of GVD showed that treatment with sirolimus not only halted the progression of preexisting GVD but also was associated with partial regression. Sirolimus trough blood levels were correlated with efficacy. Therefore, sirolimus has the potential to control clinical chronic allograft rejection.

Actins↗
PubMed2001

Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease.

BACKGROUND: In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m2) of oral sirolimus on day 1 followed by 5 mg/m2/day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m2/day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days. RESULTS: Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant. CONCLUSION: These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.

Acute Disease↗
PubMed2002

Twenty-eight-day efficacy and phamacokinetics of the sirolimus-eluting stent.

BACKGROUND: In-stent restenosis is caused by neointimal hyperplasia. Sirolimus (rapamycin; Wyeth Research, Radnor, Pennsylvania, USA) inhibits vascular smooth muscle cell proliferation and we evaluated the efficacy of sirolimus in reducing neointimal formation in a rabbit iliac model and in-vivo pharmacokinetics in the porcine coronary model. DESIGN: Randomized, blinded, prospective animal study. METHODS: Bilateral rabbit iliac artery stent implantation was performed using crossflex stents (Cordis Corporation, Warren, New Jersey, USA) coated with sirolimus incorporated in a nonerodable polymer. Arteries were randomized to one of four stent groups: uncoated stents (n = 8); polymer control stents (n = 10); low-dose sirolimus-eluting stents (n = 9); and high-dose sirolimus-eluting stents (n = 10). Histomorphometry was performed at 28 days. Arterial tissue and stents were retrieved at 8, 14 and 28 days and blood samples were obtained daily during the first week. RESULTS: Treatment with low-dose sirolimus was associated with a 23% (P = NS) reduction in neointimal area and treatment with high-dose sirolimus with a 45% (P < 0.05) reduction. Sustained drug release from the stent and prolonged intramural arterial deposition were confirmed for up to 28 days. No detectable sirolimus was found in the blood after 2 days. CONCLUSION: Controlled-release local delivery of a cell-cycle inhibitor from a nonerodable polymer-coated stent reduced neointimal formation in rabbit iliac arteries in a dose-dependent manner and represents a promising strategy for preventing restenosis.

Animals↗