Başkent Üniversitesi Yayınları

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search.filters.applied.f.language: search.filters.language.en_USSubject: search.filters.subject.Mycophenolate mofetil

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    Pharmacokinetics of Mycophenolic Acid During the Early Period After Renal Transplant
    (Başkent Üniversitesi, 2007-12) Nazemian, Fatemeh; Mohammadpur, Amir-Houshang; Abtahi, Bahareh; Naghibi, Massih
    Objectives: Mycophenolic acid, the active metabolite of mycophenolate mofetil, is administered with cyclosporine and oral steroids to prevent acute rejection after renal transplant. The aim of this study was to investigate correlations among time after transplant, subjects’ demo­graphics, and myco­phenolate mofetil dosage according to body weight with mycophenolic acid pharmacokinetics during the early posttransplant period. Patients and Methods: Mycophenolic acid plasma levels of 19 patients were determined by a validated high-performance liquid chromatographic method at the steady state soon after transplant when graft function was good (glomerular filtration rate ≥ 70 mL/min). All patients received a fixed dosage of mycophenolate mofetil (1 g b.i.d.) in combination with cyclosporine and steroids. The area under the time-concentration curve (AUC) and mycophenolic acid plasma clearance were measured for each patient. Results: The AUC from zero to 12 hours and trough levels increased as the time after transplant increased (P < .05), but mycophenolic acid plasma clearance decreased over time (P = .02). There was a correlation between total body weight and the AUC (P = .01, r2 = –0.627) as well as between total body weight and mycophenolic acid clearance (P = .04, r2 = 0.555). No statistically significant differences were found regarding mycophenolic acid plasma level, AUC, and mycophenolic acid plasma clearance with regard to sex or age of the subjects (P > .05). The mycophenolate mofetil dosage according to body weight correlated positively with the AUC (P = .01, r2 = 0.628), but there was a negative cor­relation between total body weight and myco­phenolic acid plasma clearance (P = .02, r2 = –0.604). Conclusions: Our results demonstrate that total body weight, time after transplant, and myco­phenolate mofetil dosage according to body weight affect mycophenolic acid pharmacokinetics. We suggest that mycophenolic acid pharma­cokinetics monitoring is necessary to individualize myco­phenolate mofetil dosing during the early post­transplant period.
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    The Cairo Kidney Center Protocol for Rapamycin-based Sequential Immunosuppression in Kidney Transplant Recipients: 2-Year Outcomes
    (Başkent Üniversitesi, 2007-12) Barsoum S. , Rashad; Morsy, A. Ahmed; Iskander, Irene R.; Morgan, Manal M.; Fayad, Tarek M. F.; Atalla, Nasr T.; Wafik, Hani; Grace, Renne A.; Adel, Noha; Khalil, Soha S.
    Objective: This study examines the outcomes of de novo kidney transplants treated by a sequential protocol, designed to target the succession of immunologic events following engraftment. Subjects: A total of 113 sequential live-donor recipients were randomized into 2 arms. Patients in arm A received prednisolone, cyclosporine, and sirolimus for 3 months (phase 1), followed by replacement of cyclosporine with mycophenolate mofetil (phase 2). Those in arm B (controls) received prednisolone/cyclosporine/mycophenolate mofetil throughout the study. The primary endpoints were patient and graft survival rates at 2 years. Secondary endpoints included biopsy-proven acute rejection, early and late graft function, hypertension, and adverse reactions. Results: The 2-year intent-to-treat patient and graft survival rates (95.8% vs 91.4% and 94.6% vs 90.2%) were numerically but not significantly higher in arm A. The overall incidence of biopsy-proven acute rejection was numerically lower (13.5% vs 18.9%), yet it occurred exclusively with cyclosporine C2 levels below 770 ng/mL (P = .28). Mean time for serum creatinine to reach 132 µmol/L was significantly longer in arm A (7.3 vs 2.9 days). Graft function at 2 years (eGFR, 70.2 vs 55.9 mL/min) and number of drugs needed to control blood pressure (mean 1.7 vs 2.25) were significantly more favorable in group A. Significant adverse effects for patients in arm A included proteinuria (36.8% vs 18.6%), hyper­lipidemia (peak cholesterol > 7.75 mmol/L in 32.9% vs 23.7% of patients) and thrombocytopenia (platelet count < 100 × 109/L in 32.9% vs 13.5 % of patients). Conclusions: The described protocol reduced the incidence of biopsy-proven acute rejection in patients after kidney transplant, particularly in those with adequate cyclosporine blood levels. Despite the significantly higher incidence of certain adverse effects (ie, delayed graft function, proteinuria, hyperlipidemia, and transient thrombocytopenia), patient and graft survival rates at 2 years were numerically, though not statistically, improved in patients in arm A. At 2-year analysis, compared with patients in the control arm (arm B), graft function significantly improved in patients in arm A, and the number of drugs needed to control blood pressure was significantly lower.
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    Renal Function and Histology in Kidney Transplant Patients Receiving Tacrolimus and Sirolimus or Mycophenolate Mofetil
    (Başkent Üniversitesi, 2006-12) Kamar, Nassim; Van, Tuan Tran; Ribes, David; Modesto, Anne; Cointault, Olivier; Lavayssière, Laurence; Ader, Jean Louis; Durand, Dominique; Rostaing, Lionel
    Objective: The aim of this study was to assess the effects of tacrolimus in combination with either sirolimus (n = 10) or mycophenolate mofetil (n = 7) on renal function and renal histopathologic factors 6 and 12 months after kidney transplantation. Materials and Methods: Renal function was assessed by the glomerular filtration rate (as measured by the inulin clearance rate) and by determining renal functional reserve. A renal allograft biopsy was performed at the time of transplantation and 6 and 12 months later. Results: Serum creatinine levels tended to be higher in the sirolimus group 12 months after transplantation. In contrast, inulin clearance and renal functional reserve were similar in both groups 6 and 12 months after transplantation. With respect to histopathologic findings, only mononuclear-cell interstitial inflammation was significantly higher in the sirolimus group than in the mycophenolate mofetil group 12 months after transplantation. However, the progression of tubular atrophy, interstitial fibrosis, and vascular fibrous intimal thickening within the first postoperative year was significantly greater in the sirolimus group. Conclusions: In the long term, the addition of sirolimus to treatment with tacrolimus in de novo renal transplant patients might more adversely affect renal allograft survival than might the addition of mycophenolate mofetil to tacrolimus therapy.
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    Impact of Mycophenolic Acid Dose Modifications on Renal Function After Kidney Transplantation
    (Başkent Üniversitesi, 2006-12) Kamar, Nassim; Oufroukhi, Loubna; Sallusto, Federico; Cointault, Olivier; Lavayssière, Laurence; Mouzin, Marc; Guitard, Joelle; Durand, Dominique; Rostaing, Lionel
    Objective: Mycophenolic acid dose modifications after renal transplantation seem to adversely affect renal allograft outcome. The aim of this retrospective study was to examine the effect of mycophenolic acid dose modifications on renal function 1 year after transplantation and to determine the factors predictive of those dose modifications within the first year after renal transplantation. Patients and Methods: All 130 patients at our institution who were treated de novo between January 2002 and April 2003 with either a mycophenolate mofetil-based or an enteric-coated mycophenolate sodium-based therapy and who had a functioning renal allograft 1 month after transplantation were included in this study. Results: Fifty-seven patients (43.8%) underwent a dose modification during the first year after transplantation. One, 3, 6, and 12 months after transplantation, renal function was significantly improved in the patients who did not receive a dose modification. A mycophenolic acid dose that 1 year after transplantation was less than the initial dose received just after transplantation was an independent factor associated with deteriorating renal function. Sirolimus immunosuppression, Cytomegalovirus infection, and pretransplant lymphocyte counts were independent factors associated with mycophenolic acid dose modifications within the first year after kidney transplantation. Conclusions: Modification of the mycophenolic acid dose may adversely affect renal function 1 year after transplantation.
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    Mutagenic and Cytotoxic Effects of Immunosuppressive Drugs on Human Lymphocyte Cultures
    (Başkent Üniversitesi, 2004-12) Oliveira, Vilma Duarte; Zankl, Heinrich; Rath, Thomas
    Objectives: Immunosuppressive drugs such as cyclosporine A, mycophenolate mofetil, tacrolimus, and the immunosuppressive agent sirolimus are used effectively to prevent immunologic rejection after solid organ transplantation. The most serious complication among patients undergoing immunosuppressive therapy is the risk developing cancer. The question is whether the drugs used have mutagenic properties and so contribute to increased cancer risk. Materials and Methods: We evaluated the mutagenic and cytotoxic effects of the above-mentioned drugs in human lymphocyte cultures with special consideration given to clinically relevant blood-drug concentrations. Mutagenicity was tested by analyzing micronuclei using the well-established cytokinesis-block micronucleus assay with cytochalasin B. To evaluate cytotoxicity, the cytokinesis-block proliferation index was calculated. Concentrations used ranged from 0.1-2 µg/mL for cyclosporine A, 1-20 µg/mL for mycophenolate mofetil, 5-40 ng/mL for tacrolimus, and 2.5-50 ng/mL for sirolimus. We also estimated mutagenicity and cytotoxicity in the blood of kidney transplanted patients using the above-mentioned techniques. Results: Cultures supplemented with mycophenolate mofetil or tacrolimus showed higher amounts of micronuclei when compared with solvent controls in all concentrations tested. Addition of cyclosporine A to cultures also led to a rise in the number of micronuclei at concentrations of 0.2 µg/mL and 0.4 µg/mL. In contrast with the other immunosuppressive drugs, sirolimus induced only weak mutagenic activity in the micronuclei test at its highest concentration (50 ng/mL). Cytotoxic effects were seen only in mycophenolate-mofetil–supplemented cultures at all concentrations tested (P < 0.01). In comparison with healthy persons, those with kidney transplants under immunosuppression displayed a broad reduction in the cytokinesis-block proliferation index (P < 0.001) and a significant increase in the frequency of micronuclei (P < 0.001). Conclusions: Our results indicate that mycophenolate mofetil and tacrolimus display more mutagenic effects in vitro than do cyclosporine A or sirolimus, and that transplanted patients exhibit higher amounts of micronuclei and a noteworthy reduction in the cytokinesis-block proliferation index compared with healthy persons.