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PubMed2000

A practical guide to the analysis of sirolimus using high-performance liquid chromatography with ultraviolet detection.

BACKGROUND: Sirolimus, a new immunosuppressive agent, has recently been approved in the United States for use in combination with cyclosporine and corticosteroids in renal allograft transplantation. Therapeutic drug monitoring (TDM) of sirolimus is advocated by the drug's manufacturer in certain patient populations. Given the known pharmacokinetic interaction of sirolimus with cyclosporine and the requirement for patient compliance, physicians may wish to monitor steady-state trough levels of this agent. Several types of analytical methods have been investigated for use in TDM of sirolimus: immunoassay, high-performance liquid chromatography with ultraviolet detection (HPLC-UV), and HPLC with mass-spectrometric detection (HPLC-MS or HPLC/MS/MS). OBJECTIVE: This review identifies analytical parameters that are critical to clinical TDM of sirolimus when HPLC-UV is used. METHODS: Extraction of sirolimus from whole blood was performed using either liquid-liquid or solid phase techniques, whereas liquid chromatography was performed on reverse-phase analytical columns. The drug was detected at its UV extinction maximum. Calculated analytical parameters were evaluated according to current industry standards. RESULTS: HPLC-UV methods for the quantification of sirolimus meet or exceed industry standards of performance for clinical TDM. Comparison of the sirolimus levels in clinical samples analyzed by both HPLC-UV and HPLC/MS/MS indicated that the methods provided similar results. CONCLUSION: HPLC-UV methods, although they use a less-sophisticated mode of detection than HPLC-MS or HPLC/MS/MS methods, provide an alternative means of performing TDM without sacrificing the analytical performance required for clinical monitoring of sirolimus.

Calibration↗
PubMed2000

Toxicity and efficacy of sirolimus: relationship to whole-blood concentrations.

BACKGROUND: Sirolimus is a novel macrolide immunosuppressive drug with a mechanism of action distinct from that of both cyclosporine and tacrolimus. Recent clinical studies have demonstrated a decrease in acute rejection episodes in renal transplant patients receiving sirolimus compared with controls. The major toxicities associated with sirolimus treatment are thrombocytopenia and hyperlipidemia. In addition, concern has been raised by the higher serum creatinine levels noted in patients receiving sirolimus and cyclosporine compared with controls receiving cyclosporine and azathioprine. OBJECTIVE: The objective of the present review is to summarize the efficacy and toxicity data for sirolimus. Special consideration is given to evidence that links these effects to dose or whole-blood concentrations of sirolimus. RESULTS: The literature indicates that trough concentrations of sirolimus >15 ng/mL appear to be associated with a greater risk of both thrombocytopenia and hyperlipidemia, whereas trough sirolimus concentrations <6 ng/mL have been associated with an increased incidence of acute rejection. CONCLUSION: The evidence to date supports target trough sirolimus concentrations of 6 to 15 ng/mL in most patients. In higher-risk groups and patients receiving cyclosporine-sparing regimens, higher concentrations may be necessary to achieve similar efficacy.

Humans↗
PubMed2000

Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus.

BACKGROUND: Sirolimus is a novel macrocyclic antibiotic that has an immunosuppressive mechanism of action distinct from that of cyclosporine and tacrolimus. OBJECTIVE: The objective of this report is to provide an overview of the clinical development of sirolimus with emphasis on the mechanism of immunosuppressive activity, prevention of acute renal allograft rejection, clinical pharmacokinetics, concentration-effect relationships, and therapeutic drug monitoring (TDM). RESULTS: Pharmacokinetic studies in adult renal transplant patients have shown that sirolimus may be characterized as a drug with rapid absorption (t(max) = 1 to 2 hours), low systemic availability (F = 14%), linear dose proportionality (2 to 24 mg), extensive partitioning into formed blood elements (B/P = 36), large apparent volume of distribution (1.7 L/kg), prolonged terminal half-life (62 hours), and large intersubject (CV = 52%) and intrasubject (CV = 26%) variability in oral-dose clearance. Results from phase 111 pivotal trials showed that sirolimus (2 or 5 mg/d) reduced acute renal graft rejection (generally, P < 0.01) without TDM. Although TDM may not be required for a regimen consisting of full-dose cyclosporine and corticosteroids with sirolimus 2 mg/d (4 hours after cyclosporine), it may be warranted in patients (1) with hepatic impairment, (2) who are young children, (3) who are receiving concurrent doses of strong CYP3A/p-glycoprotein inhibitors or inducers, (4) in whom cyclosporine dosing is markedly reduced or discontinued, and (5) who are at a high risk for rejection. A whole-blood sirolimus therapeutic window of 5 to 15 ng/mL (measured by microparticle enzyme immunoassay) is recommended for patients at standard risk of rejection. The large intrapatient variability observed in trough sirolimus concentrations indicates that dose adjustments should be optimally based on more than a single trough sample. Because of the time required to reach steady state, sirolimus dose adjustments would optimally be based on trough levels obtained >5 to 7 days after a dose change. CONCLUSIONS: The effective use of sirolimus in an immunosuppressive regimen for the prevention of acute renal allograft rejection requires an understanding of the drug's clinical pharmacokinetics, concentration/adverse-effect relationship, concentration-efficacy relationship, and TDM.

Animals↗
PubMed1996

The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients.

A 14-day ascending dose course of sirolimus (rapamycin, RAPA) was administered to quiescent renal transplant patients receiving a double-drug cyclosporine (CsA)/corticosteroid regimen in a double-blinded randomized study. Oral sirolimus or placebo was delivered twice daily in divided doses for 13 days and a final dose was administered on the morning of study day 14. In addition, patients in the sirolimus- and placebo-treated groups were compared with a demographically matched, concurrently treated control cohort of 30 patients who received the same concentration-controlled CsA/corticosteroid regimen. The study cohort was partitioned into four sirolimus dose level groups: placebo (0 mg/m2/day, N = 10), low dose (1 to 3 mg/m2/day, N = 9), medium dose (5 to 6 mg/m2/day, N = 9), and high dose (7 to 13 mg/m2/day, N = 12). the primary side effect of sirolimus was a reversible decrease in platelet (PLT) and white blood cell (WBC) counts. Cholesterol values increased statistically significantly in the sirolimus-treated patients when compared with those of the placebo patients, but not when compared with those of the control group patients. There were no statistically significant differences in the steady-state average concentrations of CsA among sirolimus dose groups (including placebo). No differences were observed between the pre- and post-sirolimus treatment values of systolic and diastolic blood pressure values, glomerular filtration rates (GFR), serum creatinine values (SCr), and serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) or triglyceride levels. Because the principal side effects of sirolimus are distinct from the principal nephrotoxic properties of CsA, this drug combination may display potent immunosuppression without exacerbated toxicity.

Adult↗
PubMed2001

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.

Animals↗
PubMed2006

Proteinuria following conversion from azathioprine to sirolimus in renal transplant recipients.

Recent studies have reported a significant increase of proteinuria in kidney transplant recipients who were switched from a calcineurin inhibitor (CI) to sirolimus. This has (partly) been ascribed to the hemodynamic renal effects of CI withdrawal. We have evaluated the evolution of proteinuria in renal transplant recipients who underwent conversion from azathioprine to sirolimus. In a randomized, prospective, multicenter study called RESCUE (Recurrent cutanEous Squamous cell Carcinoma Under RapamunE) the efficacy and safety is investigated of conversion to sirolimus in stable renal transplant recipients with a cutaneus squamous cell carcinoma (SCC). In our center 25 patients have been included in this study of which 13 patients were randomized to continue their current immunosuppressive treatment and 12 to conversion to sirolimus. After a mean follow-up of 360 days mean proteinuria increased from 0.37+/-0.34 to 1.81+/-1.73 g/24 h after conversion to sirolimus (P<0.005). In the control group there was no change in proteinuria. A significant increase of proteinuria was observed in all seven patients with proteinuria before conversion, whereas proteinuria remained absent in all patients without previous proteinuria. Two of the patients with proteinuria were converted from cyclosporine and five were converted from azathioprine to sirolimus. Sirolimus was discontinued in five patients with proteinuria, and in all of them proteinuria declined to baseline values. Our study demonstrates that conversion from azathioprine to sirolimus after kidney transplantation may cause a reversible increase of proteinuria. Sirolimus-induced proteinuria therefore cannot be ascribed to the hemodynamic renal effects of withdrawal of CI.

Aged↗
PubMed2002

Nelfinavir, a protease inhibitor, increases sirolimus levels in a liver transplantation patient: a case report.

With the increasing success of liver transplantation and the proven effectiveness of highly active retroviral therapy in HIV-positive patients, liver transplantation has been performed successfully in selected HIV-positive recipients with CD4 and an HIV viral load response to highly active antiretroviral therapy. In these patients, an interaction between a protease inhibitor (nelfinavir) and tacrolimus has been shown. The effect of nelfinavir on the pharmacokinetics of sirolimus, a newer immunosuppressive drug, is currently not known. The goal of the present case report is to document the interaction between sirolimus and nelfinavir in a liver transplantation patient. A 40-year-old woman who was HIV positive underwent a cadaveric liver transplantation for acute fulminant liver failure secondary to nevirapine (a nonnucleoside reverse transcriptase inhibitor). Postoperatively, she was treated with tacrolimus and steroids. She experienced steroid-resistant rejection and was started on sirolimus on the 17th postoperative day. Kinetic parameters were determined after a 2-mg oral dose of sirolimus and 250 mg of nelfinavir by collecting multiple peripheral venous blood samples before and after sirolimus administration. The kinetic parameters were compared with parameters from three liver transplantation patients on sirolimus who were not on nelfinavir. After normalizing the kinetic parameters to sirolimus dose of 1 mg/d, 0-hour and 24-hour trough sirolimus concentrations were nine-fold and five-fold higher for the patient who was on nelfinavir, compared with those who were not on nelfinavir. The maximum concentration was 3.2 times higher, the area under the concentration curve was 1.6 times higher, and the terminal disposition half-life was prolonged by 60%. The time to reach the peak concentration was 1 hour in all patients. Increase in trough concentration, peak concentration area under the curve concentration, and prolongation of half-life of sirolimus has been shown in a patient who was on a low dose (one fifth the recommended dose) of nelfinavir.

Adult↗
PubMed2003

Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications.

Sirolimus is a new immunosuppressive agent increasingly being used in liver transplant recipients. There is concern that sirolimus may be associated with wound complications and hepatic artery thrombosis (HAT). We have used sirolimus as primary immunosuppression in 170 liver transplant recipients and therefore reviewed our experience with wound complications and HAT in our cohort of patients. Records of all 170 patients administered sirolimus as primary immunosuppression and 180 historic controls were reviewed. Numbers of wound and hepatic artery complications were recorded, as well as the prevalence of obesity, reoperation, diabetes, and OKT3 use, all of which are risk factors for wound complications. The prevalence of wound complications was 12.4% in sirolimus-treated patients compared with 13.9% in historic controls (P = not significant [NS]). The prevalence of hepatic artery complications was 5.3% in sirolimus-treated patients compared with 8.3% in historic controls (P = NS). The prevalence of obesity and OKT3 administration was significantly lower in sirolimus-treated patients. Multivariate analysis failed to show an association between sirolimus therapy and hepatic artery or wound complications. The prevalence of wound and hepatic artery complications is not different in liver transplant recipients administered sirolimus as part of a primary immunosuppressive regimen compared with historic controls.

Cohort Studies↗
PubMed2000

Sirolimus: a new agent for prevention of renal allograft rejection.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of sirolimus are reviewed. Sirolimus can be used as an adjunct to cyclosporine and corticosteroids for preventing organ rejection in renal allograft recipients. It appears to block cell-cycle progression in the mid-to-late G1 phase; it also inhibits interleukin-2-dependent and independent proliferation of B-lymphocytes and production of immunoglobulins A, M, and G. Sirolimus is extensively metabolized by the liver and undergoes O-demethylation and hydroxylation. The mean oral clearance is 208 +/- 95 mL/hr/kg with an elimination half-life of 57 to 63 hours in kidney transplant recipients. Sirolimus is poorly absorbed from the gastrointestinal tract; its apparent oral bioavailability is about 15%. Two pivotal Phase III, multicenter, randomized, double-blind trials evaluating the efficacy of sirolimus in the prophylaxis of acute renal allograft rejection after transplantation have been conducted. A significant reduction in the occurrence of acute rejection was noted in both trials compared with azathioprine- or placebo-treated patients. Also, both sirolimus groups required significantly less antibody therapy for treatment of rejection. The primary adverse effects associated with sirolimus therapy include hypercholesterolemia and hypertriglyceridemia. Hypertension, diarrhea, increased creatinine, hypokalemia, arthralgia, rash, acne, leukopenia, and thrombocytopenia have also been observed. The labeled recommendations are a 6-mg loading dose as soon as possible after transplantation and a maintenance dose of 2 mg per day. Sirolimus is a potent novel immunosuppressive agent with proven efficacy in the prevention of acute rejection after renal transplantation. Use of sirolimus may lead to effective therapeutic strategies for sparing the use of cyclosporine and corticosteroids.

Animals↗
PubMed2003

Long-term pharmacokinetic study of the novel combination of tacrolimus and sirolimus in de novo renal allograft recipients.

It was recently shown in two randomized studies that combining sirolimus (rapamycin) and tacrolimus is very efficient in renal transplantation. However, little is known about the long-term pharmacokinetics of this combination. We performed simultaneous AUC measurements (area under the concentration curves) of sirolimus and tacrolimus at 1, 3, and 12 months posttransplantation in nine de novo recipients treated with this drug combination to characterize the evolution of the pharmacokinetics of both drugs and to investigate possible interactions between the two compounds. Patients were treated with a standard-dose tacrolimus or with a reduced-dose tacrolimus in combination with sirolimus and corticosteroids. This long-term pharmacokinetic study has shown that when sirolimus is combined with tacrolimus, dose changes of sirolimus are reflected by pharmacokinetic exposure parameters. Patients taking a low dose of sirolimus in combination with a standard dose tacrolimus might require sirolimus dose increments over time to maintain constant exposure to sirolimus. Further prospective dose-controlled studies are necessary to investigate a possible effect of a standard-dose tacrolimus on long-term sirolimus bioavailability and/or metabolism. Dose reductions of tacrolimus in both study groups were reflected by concordant decreasing pharmacokinetic exposure parameters, which illustrates the common clinical practice of reducing the dose of calcineurin inhibitor as time elapses after transplantation.

Dose-Response Relationship, Drug↗
PubMed2001

Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients.

BACKGROUND: Sirolimus, a promising new immunosuppressive drug for organ transplantation, is currently associated with side effects, such as thrombocytopenia and hyperlipidemia. METHODS: Eight renal transplant recipients, who developed unexplained interstitial pneumonitis during sirolimus therapy, were extensively re-screened for all causes of pneumonitis. RESULTS: Interstitial pneumonitis was constantly characterized by bilateral interstitial infiltrates on chest x-rays and lung computed tomography scans, with marked general symptoms in all patients but one. Bronchoalveolar lavage (BAL) disclosed lymphocytic alveolitis (mainly of the CD4 type) in seven patients and alveolar hemorrhage in one. Transbronchial lung biopsies, performed in two patients, showed bronchiolitis obliterans with organizing pneumonia combined with lymphocytic interstitial pneumonitis. Pulmonary infections were ruled out by specific stainings and cultures of BAL, bronchial aspirates, and blood cultures. After the elimination of all possible causes, sirolimus-induced pneumonitis was considered probable. Discontinuation of sirolimus in seven cases and dose reduction in the remaining case dramatically improved clinical and radiological status within a few weeks and led to complete resolution within 3 months. CONCLUSIONS: Sirolimus is very probably responsible for interstitial pneumonitis on the following grounds: (a) occurrence of pneumonitis during sirolimus therapy; (b) absence of any other causes; and (c) resolution within 3 months of sirolimus discontinuation or dose reduction. Sirolimus should now be added to the list of possible causes of pulmonary complications after renal transplantation. Discontinuation or dose reduction of sirolimus led to complete and lasting resolution of symptoms.

Aged↗
PubMed2002

Intestinal transplantation before and after the introduction of sirolimus.

INTRODUCTION: Small bowel transplantation has been limited by high rates of rejection and graft loss. In June 2000, we began using sirolimus, an immunosuppression agent with proven efficacy in kidney transplantation. We reviewed results among intestinal transplant recipients before and after the introduction of sirolimus. METHODS: Thirty-one intestinal transplants were performed in 29 patients at our center between July 1998 and April 2001. All patients were followed for at least 30 days posttransplant. In the first 19 transplants (group 1), patients received tacrolimus, steroids, and antibody induction therapy (either daclizumab or OKT3). In the next 12 consecutive transplants (group 2), patients received tacrolimus, steroids, basiliximab, and sirolimus. RESULTS: Eighteen children (7 males and 11 females, mean age 2.1+/-2.2 years) and 11 adults (9 males and 2 females, mean age 38.1+/-12.4 years) underwent transplantation. All patients survived transplantation. The overall reoperation rate was 1.7 procedures per patient in group 1 and 1.1 procedures per patient in group 2. The most common indications were abscess (n=7), planned second look (n=7), leaks/fistulas (n=6), dehiscence (n=6), obstruction (n=4), ischemic bowel (n=3), perforations (n=3), stomal complications (n=3), and graft removal (n=3). The incidence of biopsy-proven rejection in the first 30 days was 73.7% in group 1 and 16.7% in group 2 (P<0.002). Sirolimus was temporarily held or discontinued in 66.7% of patients. Actuarial 1-year graft survival was 91.7% with sirolimus and 57.9% without sirolimus (P<0.04). Actuarial 1-year patient survival was 91.7% with sirolimus and 79% without sirolimus (P=0.12). CONCLUSIONS: An immunosuppressive regimen that includes sirolimus has improved graft survival. Furthermore, this regimen has significantly decreased the incidence of early rejection and has eliminated early graft loss caused by fulminant rejection.

Adult↗
PubMed2006

Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose.

The pharmacokinetics and metabolic disposition of sirolimus (rapamycin, Rapamune), a macrocyclic immunosuppressive agent for the prevention of allograft rejection in organ transplantation, were investigated in 6 healthy male volunteers after a single nominal 40-mg oral dose of the C-radiolabeled drug, with the added aim of assessing the potential role of sirolimus metabolites in the clinical pharmacology of the parent drug. The absorption of parent drug and derived materials was rapid (tmax 1.3 +/- 0.5 hours, mean +/- SD), and the elimination of sirolimus was slow (t(1/2) 60 +/- 10 hours, mean +/- SD) in whole blood. The high whole blood to plasma (B/P) concentration ratio of sirolimus (142 +/- 39) was consistent with its extensive partitioning into formed blood elements. The markedly lower B/P value based on radioactivity (2.7 +/- 0.4) suggested that drug-derived products partitioned into formed blood elements to a much lesser extent. Based on AUC0-144h values, unchanged sirolimus represented an average 35% of total radioactivity in whole blood. Drug-derived products in whole blood were characterized by HPLC, LC/MS, and LC/MS/MS as 41-O-demethyl, 7-O-demethyl, and several hydroxy, dihydroxy, hydroxy-demethyl and didemethyl sirolimus metabolites. The percentage distribution of sirolimus metabolites in whole blood ranged from 3%-10% at 1 hour to 6%-17% at 24 hours after drug administration. Based on their low immunosuppressive activities and relative abundance in whole blood of humans after sirolimus administration, metabolites of sirolimus do not appear to play a major role in the clinical pharmacology of the parent drug. A majority of the administered radioactivity (91.0 +/- 8.0%) was recovered from feces, and only 2.2% +/- 0.9% was renally excreted.

Administration, Oral↗
PubMed2005

Treatment of psoriasis with topical sirolimus: preclinical development and a randomized, double-blind trial.

BACKGROUND: Systemically administered sirolimus has demonstrated efficacy in psoriasis in a multicentre European study. OBJECTIVES: To determine the efficacy and safety of topically applied sirolimus in treating psoriasis. METHODS: In vitro studies were followed by a pilot study designed to determine if sirolimus penetrates human skin, and by a randomized, double-blind, left-right comparative, dose-ranging study consisting of treatment with 2.2% sirolimus for 6 weeks and 8% sirolimus for an additional 6 weeks in 24 patients with stable, chronic plaque psoriasis. The primary outcome measure was clinical score. Secondary measures were ultrasound plaque thickness, plaque erythema, and computerized image analysis of immunohistochemical stains for immunocytes and proliferating cells. Pharmacokinetics and blood chemistry monitoring for safety were also performed. RESULTS: A significant reduction in the clinical score (P = 0.03) (mean score 9.1 following sirolimus vs. 11.2 in control) was achieved with topical sirolimus. Measurements of plaque thickness and erythema did not show significant improvement with treatment. Computerized image analysis of biopsies showed a significant reduction in CD4+ cells (P = 0.0054) and proliferating cells (stained by Ki-67) in the epidermis (P = 0.0153) with sirolimus treatment compared with control. CONCLUSIONS: Topically applied sirolimus penetrates normal skin and may have some antipsoriatic and immunosuppressive activity.

Administration, Topical↗
PubMed2006

Amiodarone-sirolimus/tacrolimus interaction in a pediatric heart transplant patient.

A two year-old female who had underwent ABO-incompatible heart transplantation at four months of age was admitted with unexplained anemia and renal dysfunction. The patient also had evidence of moderate liver dysfunction. Maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil and prednisolone. Tacrolimus was held on day 2 for five days because of an elevated trough blood concentration. The patient required one fourth of her maintenance dose to keep trough concentrations within the target range. Nadolol and amiodarone were prescribed on day 7 to control ventricular arrhythmias. Sirolimus was prescribed on day 11. A precautionary (non-steady-state) sirolimus trough concentration was grossly elevated. Sirolimus was held and tacrolimus was discontinued. Sirolimus blood concentrations remained above the target range for fourteen days despite successive dose manipulations. The patient succumbed from complications of ECMO on day 42. Amiodarone and cyclosporine interactions in the solid organ transplant population have been previously described. To our knowledge, there are no cases of amiodarone and sirolimus or tacrolimus interactions reported in English literature. Both tacrolimus and sirolimus are metabolized through the same enzyme system as cyclosporine, and the chance of a similar interaction occurring is high. Sirolimus is also a substrate of p-glycoprotein and thus may be significantly affected by amiodarone. We have described a potential interaction with sirolimus, tacrolimus and amiodarone. If amiodarone is deemed the most appropriate choice for the patient, clinicians should consider prospectively decreasing sirolimus and tacrolimus doses. Blood concentrations should also be monitored more frequently in order to minimize prolonged periods of supratherapeutic concentrations and related toxicities.

Amiodarone↗
PubMed2004

Comparison of late luminal loss response pattern after sirolimus-eluting stent implantation or conventional stenting.

BACKGROUND: We investigated the pattern of late luminal loss after sirolimus-eluting or bare stent implantation. METHODS AND RESULTS: The study population comprised 238 patients treated with sirolimus-eluting stents and 526 patients treated with conventional stents. The distribution of late loss of sirolimus stents was largely skewed to the right and differed from the distribution for bare stents. When divided according to the presence of binary restenosis (diameter stenosis >50%), restenotic lesions in the bare stent group (26.0%) had a late loss of 1.40+/-0.64 mm and in the sirolimus group (7.9%) of 1.16+/-0.76 mm. Nonrestenotic lesions in the bare stent group had a late loss of 0.58+/-0.44 mm, whereas the late loss of nonrestenotic lesions in the sirolimus group remained close to zero (-0.05+/-0.33 mm). Differences between poststenting and follow-up measurements in the sirolimus group (late loss) resembled variations observed in repeated angiographic measurements, as assessed from a random sample of 30 segments measured repeatedly. After multivariate adjustment, stent type did not influence the degree of late loss in restenotic lesions. However, nonrestenotic bare stents had a significantly larger estimated luminal loss (0.58 mm; 95% CI, 0.52 to 0.65) than sirolimus-eluting stents, for which the predicted late loss was almost 0 (-0.04 mm; 95% CI, -0.10 to 0.02). CONCLUSIONS: The pattern of late loss after sirolimus-eluting stent implantation follows a peculiar behavior, different from lesions treated with conventional stents. Whether this is explained by an unusual statistical distribution or a biological all-or-none response of restenosis after sirolimus-eluting stenting remains to be investigated.

Aged↗
PubMed2005

Potent inhibitory effect of sirolimus on circulating vascular progenitor cells.

BACKGROUND: Neointimal hyperplasia is the major cause of in-stent restenosis (ISR). The sirolimus-eluting stent (SES) has emerged as a promising therapy to prevent ISR; however, the exact mechanism by which locally delivered sirolimus, an immunosuppressive agent, prevents ISR remains unknown. Recent evidence suggests that circulating progenitor cells may contribute to neointimal formation. METHODS AND RESULTS: Mononuclear cells (MNCs) were isolated from peripheral blood of healthy human volunteers. Smooth muscle (SM)-like cells outgrew from the culture of MNCs (1x10(6)) in the presence of platelet-derived growth factor-BB and basic fibroblast growth factor, whereas endothelial cell-like cells were obtained in the presence of vascular endothelial growth factor. Sirolimus potently inhibited SM-like cell outgrowth. The number of SM-like cells was significantly reduced at a concentration as low as 0.1 ng/mL (15.9+/-5.8% of control, P<0.001). Sirolimus also exerted an inhibitory effect on endothelial cell-like cells that originated from MNCs. Wire-mediated vascular injury was induced in femoral arteries of bone marrow chimeric mice. Either vehicle or sirolimus was administered locally to the perivascular area of the injured arteries. Sirolimus significantly reduced neointima hyperplasia at 4 weeks (intima/media ratio 2.0+/-0.3 versus 1.0+/-0.2, P<0.05) with a decreased number of bone marrow-derived SM-like cells and hematopoietic cells in the lesion. Reendothelialization was retarded in the arteries treated with sirolimus. CONCLUSIONS: The potent inhibitory effects of sirolimus on circulating smooth muscle progenitor cells may mediate the clinical efficacy of SES, at least in part. Sirolimus potentially may affect reendothelialization after stent implantation.

Animals↗
PubMed2002

Delayed wound healing with sirolimus after liver transplant.

OBJECTIVE: To report 3 separate cases of wound dehiscence in liver transplant recipients receiving sirolimus for immunosuppressive therapy. CASE SUMMARIES: Three patients who had received liver transplants experienced a delay in wound granulation and healing after being placed on an immunosuppressive regimen containing sirolimus and steroids. Each patient was admitted and treated for wound dehiscence, at which time sirolimus was discontinued. When other immunosuppressive agents were substituted for sirolimus, each incisional wound granulated and closed without complication. DISCUSSION: Sirolimus is an important adjunctive immunosuppressant used to prevent acute rejection episodes in patients who have undergone transplant, particularly when nephrotoxic effects from first-line calcineurin inhibitors become problematic. The unique ability of sirolimus to inhibit smooth muscle cell proliferation and intimal thickening by blocking important growth factors may subsequently become a significant feature to prevent the development of chronic rejection. Theoretically, by this same mechanism, sirolimus may play a role in forestalling wound healing and may even promote dehiscence. CONCLUSIONS: These case reports describe patients who underwent liver transplant who developed wound dehiscence possibly secondary to sirolimus therapy. Although the cases were complicated by acute rejection, wound infections, and comorbidities, wound granulation and healing began after discontinuation of sirolimus. Substitution with another immunosuppressant may be necessary for patients who experience wound dehiscence after transplant.

Adult↗