Fletcher C V, Englund J A, Edelman C K, Gross C R, Dunn D L, Balfour H H
Department of Pharmacy Practice, University of Minnesota Health Sciences Center, Minneapolis 55455.
Antimicrob Agents Chemother. 1991 May;35(5):938-43. doi: 10.1128/AAC.35.5.938.
The incidence of cytomegalovirus disease, the most important infectious complication of renal transplantation, was reduced in renal allograft recipients by a regimen of prophylactic high-dose oral acyclovir. To analyze the pharmacologic aspects of our prophylactic approach, we evaluated safety, pharmacodynamics, and in vitro susceptibility data. One hundred four recipients of cadaveric renal allografts received either oral acyclovir (n = 53) in doses of up to 3,200 mg/day or a placebo (n = 51) for 12 weeks posttransplant. Leukocyte count and serum creatinine were selected as markers of laboratory safety and were evaluated pretransplant, at study midpoint (creatinine only), and at study completion. Concentrations of acyclovir in plasma were determined to verify the ability of the dosing strategy to achieve predicted values. Viral resistance was assessed by calculation of in vitro 50% inhibitory concentrations (IC50s) of acyclovir for the cytomegalovirus strains collected from the subjects. Our results showed no difference in leukocyte count or serum creatinine between the acyclovir and placebo recipients. Plasma acyclovir concentrations were maintained within the expected limits and did not differ between patients who developed cytomegalovirus disease and those who did not. The mean acyclovir IC50s for cytomegalovirus isolates were 42.6 mumol/liter in the acyclovir recipients and 48 mumol/liter in the placebo recipients. We conclude that the clinical benefit of high-dose oral acyclovir therapy occurred despite plasma drug concentrations below the mean IC50 for the patient viral isolates. Furthermore, the use of the regimen did not produce leukopenia, adversely affect renal function, or alter the susceptibility of cytomegalovirus strains to acyclovir. This approach and dose adjustment scheme may be appropriate for other immunocompromised patients at risk for cytomegalovirus infection and disease.
巨细胞病毒疾病是肾移植最重要的感染性并发症，在肾移植受者中，通过高剂量口服阿昔洛韦预防方案，其发病率有所降低。为分析我们预防方法的药理学方面，我们评估了安全性、药效学及体外药敏数据。104例尸体肾移植受者在移植后12周接受了每日剂量高达3200mg的口服阿昔洛韦（n = 53）或安慰剂（n = 51）。选择白细胞计数和血清肌酐作为实验室安全性指标，并在移植前、研究中点（仅肌酐）和研究结束时进行评估。测定血浆中阿昔洛韦浓度，以验证给药策略达到预测值的能力。通过计算从受试者收集的巨细胞病毒株对阿昔洛韦的体外50%抑制浓度（IC50）来评估病毒耐药性。我们的结果显示，阿昔洛韦组和安慰剂组在白细胞计数或血清肌酐方面无差异。血浆阿昔洛韦浓度维持在预期范围内，发生巨细胞病毒疾病的患者与未发生者之间无差异。阿昔洛韦组巨细胞病毒分离株的平均阿昔洛韦IC50为42.6μmol/L，安慰剂组为48μmol/L。我们得出结论，尽管血浆药物浓度低于患者病毒分离株的平均IC50，但高剂量口服阿昔洛韦治疗仍具有临床益处。此外，该方案的使用未产生白细胞减少，未对肾功能产生不利影响，也未改变巨细胞病毒株对阿昔洛韦的敏感性。这种方法和剂量调整方案可能适用于其他有巨细胞病毒感染和疾病风险的免疫受损患者。
