Bornhäuser M, Schuler U, Pörksen G, Naumann R, Geissler G, Thiede C, Schwerdtfeger R, Ehninger G, Thiede H M
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus, Dresden, Germany.
Transplantation. 1999 Feb 27;67(4):499-504. doi: 10.1097/00007890-199902270-00001.
Mycophenolate mofetil (MMF) is an inhibitor of purine nucleotide de novo synthesis leading to impaired proliferation of activated lymphocytes. Studies in animals show a synergistic effect of MMF and cyclosporine (CsA) in preventing acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. We performed a pilot study evaluating the feasibility of the combined application of MMF and CsA as GVHD prophylaxis after allogeneic blood stem cell transplantation. Toxicity and the bioavailability of MMF in this setting were investigated.
Fourteen patients who had received grafts from HLA-compatible siblings received 2 g of oral MMF from day 1 to 14 combined with intravenous CsA at 4 mg/kg starting at day-1. Plasma levels of mycophenolic acid (MPA) and its glucoronide were measured by high-performance liquid chromatography. Fifteen patients treated with a combination of CsA and methotrexate at the same institution were referred to as the control group.
Trilineage engraftment was achieved in all study and control patients. Acute GVHD > or = grade II was observed in 46.5% and 60% of the study and control patients, respectively. No major differences in the rate of acute toxicities were detectable. The mean trough blood level of MPA in 10 patients was 0.28 microg/ml, and 5.7 microg/ml for MPA glucoronide. Reduced peak levels of MPA indicate a reduced absorption rate of MMF in the early posttransplant phase.
The combined administration of MMF and CsA was shown to be feasible in patients after allogeneic blood stem cell transplantation. Because of the decreased bioavailability of MMF, dose-finding studies for an intravenous formulation are warranted.
霉酚酸酯（MMF）是嘌呤核苷酸从头合成的抑制剂，可导致活化淋巴细胞的增殖受损。动物研究表明，MMF与环孢素（CsA）在预防异基因骨髓移植后的急性移植物抗宿主病（GVHD）方面具有协同作用。我们进行了一项初步研究，评估MMF与CsA联合应用作为异基因造血干细胞移植后GVHD预防措施的可行性。研究了MMF在此情况下的毒性和生物利用度。
14例接受HLA相合同胞供体移植的患者从第1天至第14天口服2g MMF，并从第-1天开始静脉注射4mg/kg CsA。通过高效液相色谱法测量血浆中霉酚酸（MPA）及其葡糖醛酸化物的水平。15例在同一机构接受CsA和甲氨蝶呤联合治疗的患者作为对照组。
所有研究患者和对照患者均实现了三系造血重建。研究组和对照组分别有46.5%和60%的患者发生急性GVHD≥II级。急性毒性发生率未发现重大差异。10例患者MPA的平均谷血浓度为0.28μg/ml，MPA葡糖醛酸化物为5.7μg/ml。MPA峰值水平降低表明移植后早期MMF的吸收率降低。
MMF与CsA联合给药在异基因造血干细胞移植患者中显示出可行性。由于MMF的生物利用度降低，有必要对静脉制剂进行剂量探索研究。
