Oral Valganciclovir Is Noninferior to Intravenous Ganciclovir for the Treatment of Cytomegalovirus Disease in Solid Organ Transplant Recipients

Intravenous ganciclovir is the standard treatment for cytomegalovirus disease in solid organ transplant recipients. Oral valganciclovir is a more convenient alternative. In a randomized, international trial, recipients with cytomegalovirus disease were treated with either 900 mg oral valganciclovir or 5 mg/kg i.v. ganciclovir twice daily for 21 days, followed by 900 mg daily valganciclovir for 28 days. A total of 321 patients were evaluated (valganciclovir [n = 164]; i.v. ganciclovir [n = 157]). The success rate of viremia eradication at Day 21 was 45.1% for valganciclovir and 48.4% for ganciclovir (95% CI -14.0% to +8.0%), and at Day 49; 67.1% and 70.1%, respectively (p = NS). Treatment success, as assessed by investigators, was 77.4% versus 80.3% at Day 21 and 85.4% versus 84.1% at Day 49 (p = NS). Baseline viral loads were not different between groups and decreased exponentially with similar half-lives and median time to eradication (21 vs. 19 days, p = 0.076). Side-effects and discontinuations of assigned treatment (18 of 321 patients) were comparable. Oral valganciclovir shows comparable safety and is not inferior to i.v. ganciclovir for treatment of cytomegalovirus disease in organ transplant recipients and provides a simpler treatment strategy, but care should be taken in extrapolating to organ transplant recipients not properly represented in the present study.     

更昔洛韦治疗婴幼儿手足口病的疗效观察

目的 探讨更昔洛韦对婴幼儿手足口病（HFMD）的临床疗效。方法 将65例婴幼儿HFMD患儿随机分为治疗组和对照组，治疗组加用更昔洛韦，观察临床有效率及不良反应率，并对结果进行统计学分析。结果 临床有效率治疗组为90．91地，对照组56．25％，引起白细胞下降，血小板下降治疗组为33．33％、27．27％，对照组为9．38％、3．13％，差异均有显著性。结论 治疗组疗效优于对照组，但须随访对白细胞和血小板的影响。     

Cytomegalovirus Disease in High-Risk Transplant Recipients Despite Ganciclovir or Valganciclovir Prophylaxis

The clinical patterns and predictors of cytomegalovirus (CMV) disease in kidney and/or pancreas transplant patients on ganciclovir (1.0 g po t.i.d.) or valganciclovir (450 mg po q.d.) prophylaxis were studied. This is a retrospective analysis of 129 transplant recipients. Median follow up was 12 months (range, 6-18 months). The overall incidence of CMV disease at 1-year post-transplant was 14% (4% tissue-invasive, 10% noninvasive). Seventeen of 18 patients were diagnosed with CMV after completion of 3 months' prophylaxis (median 8 weeks, range, 2-28 weeks). Induction treatment with thymoglobulin, and Donor +/Recipient - CMV status were the strongest predictors for the development of CMV disease. Cytomegalovirus incidence was not different between patients treated with ganciclovir or valganciclovir (15 vs. 17%, respectively). Valganciclovir (450 mg q.d.) is as effective as oral ganciclovir in CMV prophylaxis. High-risk individuals might require higher doses or longer duration of valganciclovir treatment.     

腺病毒介导的HSV-tk基因治疗人膀胱癌的动物实验研究

目的　探讨带有HSV -tk基因的重组腺病毒 (Ad -tk)结合GCV对人膀胱癌的治疗作用。方法　建立人膀胱癌裸鼠移植瘤模型 2 1只 ,采用肿瘤原位注射Ad -tk结合GCV治疗。结果　 5× 10 8PFU的Ad -tk肿瘤原位注射结合GCV治疗 ,能明显抑制肿瘤生长 ,肿瘤平均重量为 0 .2 1g ,病理检查表明肿瘤组织坏死、出血伴纤维组织增生 ;而 3个对照组Ad -tk/PBS组、PBS/GCV组、PBS组肿瘤平均重量分别为 1.6 0、1.5 2、1.71g。与对照组比较 ,肿瘤生长抑制率分别为 86 .9%、86 .2 %、87.7% ,有显著性差异 (均P <0 .0 1)。结论　Ad -tk/GCV系统对人膀胱癌的敏感性较高 ,疗效显著。     

Differences in CMV-Specific T-Cell Levels and Long-Term Susceptibility to CMV Infection after Kidney, Heart and Lung Transplantation

Patients after kidney, heart and lung transplantation differ in their immunosuppressive drug regimens and in susceptibility to infectious complications with cytomegalovirus (CMV). In this study, CMV-specific T-cell responses were characterized in long-term transplant recipients and associated with the frequency of infectious complications. CMV-reactive CD4 T cells from 50 healthy controls, 68 renal, 14 heart and 24 lung transplant recipients were flow cytometrically quantified by the induction of cytokines after specific stimulation. Moreover, the immunosuppressive effect of calcineurin inhibitors on specific T-cell reactivity was quantified in vitro and compared with responses in vivo. Median CMV-specific T-cell frequencies in long-term renal (1.48%; range 0.06-17.26%) and heart transplant recipients (0.90%; 0.13-12.49%) did not differ from controls (1.82%; 0.26-21.00%). In contrast, CMV-specific T-cell levels were significantly lower in lung transplant recipients (0.50%; <0.05-4.98%) and showed a significant correlation with the frequency of infectious episodes (r =-0.57, p = 0.005). The differences within the groups were associated with increasing dosages of immunosuppressive drugs, as exemplified for calcineurin inhibitors that dose dependently reduced specific T-cell reactivity in vitro. In conclusion, monitoring CMV-specific CD4 T cells may serve as a measure for long-term disease susceptibility and may contribute to an improved management of CMV complications after lung transplantation.     

Valganciclovir Dosing According to Body Surface Area and Renal Function in Pediatric Solid Organ Transplant Recipients

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients ≤2 years old. Patients received up to 100 days' valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 × body surface area × creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 ± 11.9 μg * h/mL; liver 61.7 ± 29.5 μg * h/mL; heart 58.0 ± 21.8 μg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment-related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir-dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults     

Gene therapy of malignant brain tumors: a rat glioma line bearing the herpes simplex virus type 1-thymidine kinase gene and wild type retrovirus kills other tumor cells.

Tumor cells infected with a retrovirus vector (VIK) containing the herpes simplex virus thymidine kinase (HSV-TK) gene can be selectively killed by treatment with nucleoside analogues, such as ganciclovir. To mediate delivery of the HSV-TK gene to "recipient" tumor cells, "donor" C6 rat glioma cells infected with the VIK vector (C6VIK) were superinfected with wild type Moloney murine leukemia virus (WT Mo-MLV). These modified donor cells (C6VIKWT) produced both wild type retrovirus and the VIK vector. In culture, C6VIKWT cells were 300-fold more sensitive to the toxicity of ganciclovir than were C6VIK cells, suggesting that the presence of wild type retrovirus contributed to the toxicity. Co-culture of C6VIKWT cells with the C6 subline, C6BAG, sensitized the latter to ganciclovir treatment. Nude mice inoculated subcutaneously with a mixture of C6VIKWT and C6BAG cells showed regression of subsequent tumors when treated with ganciclovir. The observations show that tumor cells modified in culture by infection with a retrovirus bearing the HSV-TK gene and wild type retrovirus are not only sensitive to ganciclovir, but can transfer this sensitivity to neighboring "naive" tumor cells in culture and in vivo.     

HSV1-TK/GCV系统对人肺腺癌细胞A549生物学特性的影响

目的　观察转TK基因肺癌细胞对丙氧鸟苷 (GCV)的敏感性及TK GCV系统杀灭肿瘤细胞机制。方法　观察转TK基因、转空载体A5 49细胞 (下分别简称A5 49 TK、A5 49 pLXSN)和A5 49细胞形态学改变、生长增殖特性。GCV对 3种细胞生长抑制 (MTT法 )。电镜、流式细胞仪观察A5 49 TK、A5 49细胞经 5 0μmol LGCV作用 3d后细胞凋亡。 结果　转基因细胞变为不规则 ,呈多角型 ,透亮度下降 ,体外增殖能力下降 ,A5 49 TK ,A5 49 pLXSN ,A5 493种细胞倍增时间分别为 42 .3 5、41.75、3 6.18h。依据IC5 0 ,A5 49 TK细胞对GCV敏感性比A5 49细胞提高 46倍 ,电镜发现A5 49 TK细胞有凋亡小体 ,核呈半月征等 ,流式细胞仪发现A5 49 TK、A5 49细胞亚G0 G1 期分别为 ( 12 .2 1± 1.76) %、( 1.3 2± 0 .47) % ,两者比较P <0 .0 1。结论　A5 49 TK细胞获得了对GCV敏感性 ,TK GCV杀灭肿瘤细胞与诱导凋亡有关。     

高效液相色谱法测定更昔洛韦滴眼液的含量

目的 :建立测定更昔洛韦滴眼液含量的高效液相色谱法。方法 :以HypersilC18为色谱柱 ,甲醇 水 (10∶90 )为流动相 ,检测波长 2 5 2nm。结果 :更昔洛韦在 2 .5～ 4 0mg·L-1浓度范围内线性关系良好 (r =0 .9998) ,平均回收率为 10 0 .7% ,RSD为0 .33%。结论 :本方法简便、快速、灵敏 ,可作为该滴眼液的质量控制。