Immunosuppressive Sirolimus Research Articles

Notes From the European Society of Cardiology Congress XXIII

The results of the Randomized Study with the Sirolimus Eluting Velocity Balloon Expandable Stent (RAVEL) were thought by many in Stockholm to launch a new era in cardiology. A total of 238 patients with stable or unstable angina due to single-vessel disease and a mean age of 63 years were randomized to receive either a bare-metal Bx Velocity stent or a similar stent coated with the immunosuppressive antibiotic sirolimus. Sirolimus is released from the stent over ≈45 days. Both groups were treated for 2 months with either clopidogrel or ticlopidine. The results after 210 days of follow-up were reported by M.C. Morice …

Sirolimus, but not the structurally related RAD (everolimus), enhances the negative effects of cyclosporine on mitochondrial metabolism in the rat brain.

Clinical studies have shown enhancement of cyclosporine toxicity when co-administered with the immunosuppressant sirolimus. We evaluated the biochemical mechanisms underlying the sirolimus/cyclosporine interaction on rat brain metabolism using magnetic resonance spectroscopy (MRS) and compared the effects of sirolimus with those of the structurally related RAD. Two-week-old rats (25 g) were allocated to the following treatment groups (all n=6): I. control, II. cyclosporine (10 mg kg(-1) d(-1)), III. sirolimus (3 mg kg(-1) d(-1)), IV. RAD (3 mg kg(-1) d(-1)), V. cyclosporine+sirolimus and VI. cyclosporine+RAD. Drugs were administered by oral gavage for 6 days. Twelve hours after the last dose, metabolic changes were assessed in brain tissue extracts using multinuclear MRS. Cyclosporine significantly inhibited mitochondrial glucose metabolism (glutamate: 78+/-6% of control; GABA: 67+/-12%; NAD(+): 76+/-3%; P<0.05), but increased lactate production. Sirolimus and RAD inhibited cytosolic glucose metabolism via lactate production (sirolimus: 81+/-3% of control, RAD: 69+/-2%; P<0.02). Sirolimus enhanced cyclosporine-induced inhibition of mitochondrial glucose metabolism (glutamate: 60+/-4%; GABA: 59+/-8%; NAD(+): 45+/-5%; P<0.02 versus cyclosporine alone). Lactate production was significantly reduced. In contrast, RAD antagonized the effects of cyclosporine (glutamate, GABA, and NAD(+), not significantly different from controls). The results can partially be explained by pharmacokinetic interactions: co-administration increased the distribution of cyclosporine and sirolimus into brain tissue, while co-administration with RAD decreased cyclosporine brain tissue concentrations. In addition RAD, but not sirolimus, distributed into brain mitochondria. The combination of cyclosporine/RAD compares favourably to cyclosporine/sirolimus in regards to their effects on brain high-energy metabolism and tissue distribution in the rat.

SIROLIMUS-ASSOCIATED EYELID EDEMA IN KIDNEY TRANSPLANT RECIPIENTS

The immunosuppressant sirolimus is effective in preventing acute rejection episodes. So far, unusual edema formation has not been reported as a side effect. Two groups of patients with renal transplants, consisting of 11 patients each, were followed for up to 29 months. The immunosuppressive regimen was either sirolimus and prednisone with or without cyclosporine or azathioprine/mycophenolate and prednisone with cyclosporine. Routine follow-up included a thorough clinical investigation. Edema formation was documented photographically. In 5 of the 11 patients treated with sirolimus uni- or bilateral, non-itching, eyelid edema was observed. After discontinuation of sirolimus, lid edema disappeared. The duration until recovery varied from weeks to months. No cause of edema formation other than the treatment with sirolimus was detected. Severe eyelid edema formation seems to be associated with sirolimus treatment. The underlying mechanism is unknown.

Simultaneous simple and fast quantification of three major immunosuppressants by liquid chromatography—tandem mass-spectrometry

Objectives: The aim of the current study was to develop a simple, fast and universal method for quantification of any combination of the three major immunosuppressants sirolimus, tacrolimus and cyclosporin in whole blood, using a LC-tandem mass spectrometer (API-2000, SCIEX, Toronto, Canada). Methods: 250 μL whole blood was spiked with internal standard (ritonavir), and protein precipitated with 350 μL acetonitrile. The sample was centrifuged and 30 μL aliquot was injected onto the HPLC column, where it underwent an online extraction with ammonium acetate. After that the automatic switching valve was activated, changing the mobile phase to methanol and thereby eluting the analytes into the tandem mass spectrometer. The high selectivity of a tandem mass analyzer allows determination of any combination of the three drugs within a 5 min run. Results: Between-day precision was between 2.4% and 9.7% for all analytes at the concentrations tested. Accuracy ranged between 98.8% and 103.2% ( n = 20). The method was linear over the measuring ranges of all analytes. Within-run precision was below %CV = 6% for all analytes. Good correlation with other analytical methods was observed. Conclusions: The simplicity, universality and high throughput of the method make it suitable for application in a clinical laboratory. The method has been implemented in our laboratory for a routine use.

Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD

Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD

Therapeutic drug monitoring of the immunosuppressant sirolimus (rapamycin) and its major metabolites

Therapeutic drug monitoring of the immunosuppressant sirolimus (rapamycin) and its major metabolites

CONVERSION FROM LIQUID TO SOLID SIROLIMUS FORMULATIONS IN STABLE RENAL ALLOGRAFT TRANSPLANT RECIPIENTS.

236 Purpose: Clinical trials investigating the immunosuppressant sirolimus (SRL) have thus far utilized an oil-based liquid drug formulation. In this study, we converted stable renal allograft recipients from the liquid SRL formulation (L-SRL) to a solid pill formulation (S-SRL).Methods: 12 renal transplant recipients who had received L-SRL for more than 1 year were converted to S-SRL on a milligram-to-milligram basis. Twelve-hour pharmacokinetic (PK) profiles of SRL and concurrent 12-hour cyclosporine (CsA) PK profiles were conducted with the last L-SRL dose and again at 2, 4, and 8 weeks post-conversion to S-SRL. Whole blood samples were drawn immediately prior to and at 0.5, 1, 2, 3, 5, 8, and 12 hours after dosing. SRL concentrations were determined by HPLC, CsA concentrations by TDx. Additionally, the repetitive PK profiles for S-SRL were compared with previous repetitive PK profiles on L-SRL. Comparisons were by ANOVA, while comparisons between S-SRL PK profiles and the previously obtained L-SRL PK profiles were made using t-tests. Results: There were no differences between PK profiles of S-SRL post-conversion and L-SRL immediately pre-conversion or L-SRL repetitive PK profiles for SRL AUC0-12, dose-corrected SRL trough concentration (C0), time to maximum SRL concentration (tmax), relative bioavailability of the solid formulation, or CsA AUC0-12. The only significant differences in the PK parameters were between the maximum SRL concentration (Cmax) measured during the last L-SRL PK profile vs. 4 weeks post-conversion to S-SRL and between Cmax for all L-SRL PK profiles vs. S-SRL (both p<0.02). Table,TableThere were no episodes of acute rejection, nor were there any observed changes in creatinine, white blood counts, platelets, AST, ALT, triglycerides, or cholesterol. Conclusions: Conversion to the solid SRL formulation from the liquid formulation results in similar PK profiles and appears to be safe and well-tolerated in renal transplant recipients.

Structural identification of three metabolites and a degradation product of the macrolide immunosuppressant sirolimus (rapamycin) by electrospray-MS/MS after incubation with human liver microsomes.

Structural identification of three metabolites and a degradation product of the macrolide immunosuppressant sirolimus (rapamycin) by electrospray-MS/MS after incubation with human liver microsomes.