No abstract

Since its approval in 1983 for immunosuppressive therapy in patients undergoing organ and bone marrow transplants, cyclosporin has had a major impact on organ transplantation. It has significantly improved 1-year and 2-year graft survival rates, and decreased morbidity in kidney, liver, heart, heart-lung and pancreas transplantation. Several studies have supported the efficacy of cyclosporin in preventing graft-versus-host disease in bone marrow transplantation. Cyclosporin is also possibly effective in treating diseases of autoimmune origin and as an antineoplastic agent. The introduction of therapeutic drug monitoring of cyclosporin was extremely useful because of the wide inter- and intraindividual variability in the pharmacokinetics of cyclosporin after oral or intravenous administration. Optimal long term use of cyclosporin requires careful monitoring of the blood (or plasma) concentrations. Sustained and clinically significant drug-drug interactions can occur during long term therapy with cyclosporin. The coadministration of multiple drugs with cyclosporin could result in graft rejection, renal dysfunction or other undesirable effects. Any interaction that leads to modified cyclosporin concentrations is of potential clinical importance. Cyclosporin itself may have significant effects on the pharmacokinetics and/or pharmacodynamics of coadministered drugs, such as digoxin, HMG-CoA reductase inhibitors and antineoplastic drugs affected by multidrug resistance. Many drugs have been shown to affect the pharmacokinetics and/or pharmacodynamics of cyclosporin. Interactions between cyclosporin and danazol, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, metoclopramide, nicardipine, verapamil, carbamazepine, phenobarbital (phenobarbitone), phenytoin, rifampicin (rifampin) and cotrimoxazole (trimethoprim/sulfamethoxazole) are well documented in a large number of patients. Other interactions (such as those with aciclovir, estradiol and imipenem) are documented only in isolated case studies.

Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m 2 intravenously) as add-on therapy. The mean age was 8 years (range, 2-16 years). Rituximab did not reduce proteinuria at 3 months (change, 212% [95% confidence interval, 273% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.