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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Clotrimazole troches are commonly used as prophylaxis for thrush that may develop in immunocompromised patients. • Conflicting data suggest that clotrimazole may induce or inhibit cytochrome P450 (CYP) 3A4. WHAT THIS STUDY ADDS? • We have demonstrated that clotrimazole increased the area under the concentration–time curve and decreased the apparent oral clearance of midazolam following oral administration without affecting the pharmacokinetic properties of midazolam after intravenous administration. • These data permit the suggestion that clotrimazole may cause clinically relevant changes in the pharmacokinetics or pharmacodynamics of concurrently administered oral CYP3A substrates that undergo significant first-pass metabolism in this patient population. AIMS The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma. METHODS We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg−1 with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters. RESULTS Ten healthy volunteers aged 21–26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 ± 13 l h−1[95% confidence interval 48, 66] to 36 ± 9.8 l h−1 (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration–time curve (mean difference 22 µg h−1 l−1, P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches. CONCLUSIONS Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.

The purpose of this pharmacokinetic study was to determine whether the relative oral bioavailability of tacrolimus is increased with concomitant administration of clotrimazole. Pharmacokinetic studies were conducted in 6 adult kidney transplant patients receiving tacrolimus therapy. Pharmacokinetic profiling was performed by blood sampling over 12 hours before and after the administration of a 5-day course of clotrimazole. Tacrolimus whole-blood concentrations were determined by microparticle enzyme immunoassay. Noncompartmental pharmacokinetic analysis was conducted using WinNonLin, Standard Edition, Version 1.1. Concomitant administration of clotrimazole more than doubled the relative oral bioavailability of tacrolimus. The mean AUC0-12 of tacrolimus was increased 250% with clotrimazole (467.0 +/- 170.0 ng.h/mL versus 188.7 +/- 50.2 ng.h/mL; P = 0.002). Tacrolimus blood trough concentrations also more than doubled with coadministration of clotrimazole (27.7 +/- 10.4 ng/mL versus 11.6 +/- 4.0 ng/mL; P = 0.003). Mean Cmax was significantly increased with clotrimazole (70.7 +/- 34.7 ng/mL versus 27.4 +/- 11.1 ng/mL, P = 0.01). Tmax decreased from 3.2 +/- 1.6 hours to 1.9 +/- 1.0 hours (P = NS). In addition, the apparent oral clearance decreased 60% with coadministration of clotrimazole (median oral clearance 0.16 L/h/kg versus 0.40 L/h/kg; P = 0.03). Thus, clotrimazole causes a significant increase in the relative oral bioavailability, Tmax, and trough concentration of tacrolimus. Tacrolimus levels should be monitored following initiation or discontinuation of clotrimazole to minimize toxicity or precipitation of an acute rejection episode due to subtherapeutic levels.

Erythropoietin (EPO) is widely used among patients with end-stage renal disease awaiting transplantation. Data suggest that EPO therapy may be immunomodulatory. The purpose of this study was to assess the effects of pretransplant EPO therapy on renal allograft outcome. We evaluated 120 consecutive renal transplant recipients to assess the effect of EPO on graft outcome following renal transplantation. Among the study population, 58 patients were receiving EPO before transplantation (EPO group) and 62 patients were not treated with EPO (non-EPO group). Twenty-four of 58 EPO-treated patients (41%) experienced delayed graft function after transplantation, compared with 11 of 62 (18%) non-EPO-treated patients (P

Limited in vitro data suggest that African-Americans exhibit greater resistance to corticosteroids than do non-African-American transplant recipients. However, ethnic differences in clinical response to corticosteroids for treatment of acute rejection have not been investigated previously. The purpose of this study was to evaluate the clinical response to corticosteroid treatment for acute rejection in both African-American and non-African-American renal allograft recipients.We retrospectively reviewed the medical records of 497 consecutive renal allograft recipients to identify patients who had received corticosteroids as initial treatment of acute rejection. One hundred and twenty patients who received corticosteroids for treatment of acute rejection were evaluated in this analysis. The study population was divided into two groups: the African-American group (n=73) and non-African-American group (n=47). All acute rejection episodes were documented by biopsy and were classified as mild-moderate histologically. Corticosteroid therapy consisted of either methylprednisolone, 500 mg intravenously for 3 days, or oral prednisone, 2 mg/kg/day rapidly tapered over 3 weeks.Twenty-six percent (26%) of African-Americans were considered corticosteroid treatment failures compared to an 8.0% failure rate among non-African-Americans (P0.05). One-year graft survival was 78% in African-American versus 96% in non-African-American (P0.05). Among African-American and non-African-American recipients, 1-year patient survival rates were 97% and 100, respectively (P=NS).African-American patients exhibit higher failure rates with corticosteroid treatment of acute rejection. Alternative anti-rejection therapies may need to be considered for this "high-risk" patient population to improve long-term graft survival.

Background: Technical failures continue to plague clinical pancreas transplantation. The somastatin analogue octreotide has been shown able to decrease morbidity after pancreatic resection. We studied the effect of perioperative treatment with octreotide on technical complications after pancreas transplant. patients and methods: %Seventeen recipients of bladder-drained transplant were randomized to receive either octreotide, 100 μg TID SQ for 5 days after transplant (n = 10) or no additional treatment (n = 7). We compared the two groups in terms of patient and graft survival and incidence of graft pancreatitis, intra-abdominal infections, and anastomotic leaks. Results: In the untreated group, 1 patient developed a bladder leak and 2 had intra-abdominal infections, while no complications occurred in the octreotide-treated patients ( P = 0.05). Six-month patient and pancreas survival was 100% and 90%, respectively, in octreotide-treated patients versus 86% and 86% in the control group ( P = NS). Conclusion: Perioperative treatment with octreotide seems able to reduce the incidence of technical complications after pancreas transplantation.

Background Black recipients of kidney transplants have been shown to have lower graft survival than other racial groups. There is ongoing controversy about the optimal immunosuppressive protocol for blacks after kidney transplantation. Patients and Methods Five hundred-eighty-two recipients of kidney transplants performed between 1985 and 1994 were divided into three groups: (1) nonblacks who received cyclosporine and prednisone (N = 292); (2) blacks who received “quadruple” cyclosporine based immunosuppression with OKT3 induction (N = 98); and (3) blacks who received cyclosporine and prednisone only (N = 192). Patient and graft survival and incidence of acute rejection episodes were compared among the groups. Results Blacks had lower graft survival when compared with nonblacks. However, in the subgroup of black recipients who received quadruple immunosuppression, graft survival at 1 year was higher and the incidence of acute rejection episodes was significantly decreased compared with blacks without induction. Graft survival and the incidence of acute rejection in blacks on quadruple therapy was comparable with nonblacks. Conclusions Our data support the principle that quadruple immunosuppression should be used routinely for black recipients of kidney transplants.