Stavudine extended release (once-daily,Bristol-Myers Squibb) for the treatment of HIV/AIDS

Exenatide is a glucagon-like peptide 1 receptor agonist, which has recently received FDA approval in the US for the treatment of Type 2 diabetes. Exenatide is an incretin mimetic that improves glycaemic control in patients with diabetes through acute mechanisms, such as glucose-dependent stimulation of insulin secretion, suppression of inappropriate glucagon secretion and slowing of gastric emptying, as well as chronic mechanisms that include enhancement of β-cell mass in rodent studies and weight loss and inhibition of food intake in humans. This article reviews the mechanisms of exenatide action, as well as its efficacy in the treatment of Type 2 diabetes.     

司他夫定衍生物的合成及抗肿瘤活性评价

目的设计合成一系列司他夫定类衍生物,并评价其抗肿瘤活性。方法以司他夫定为原料,经磺酸酯化后与叠氮化钠反应生成5'-叠氮基司他夫定,再通过Huisgen 1,3-偶极环加成反应得到目标化合物。采用MTT法分别以人肝癌细胞(BEL-7402)、人胃癌细胞(BGC-823)、肺癌细胞(A549)为测试细胞株对目标化合物进行体外抗肿瘤活性评价。结果与结论合成了14个5'-脱氧司他夫定衍生物,目标化合物的结构经核磁共振氢谱和碳谱确证。其中化合物4k对人肝癌细胞(BEL-7402)、人胃癌细胞(BGC-823)、肺癌细胞(A549)具有中等的抑制作用。     

Mitochondrial DNA assessment in adipocytes and peripheral blood mononuclear cells of HIV-infected patients with lipodystrophy according to a validated case definition

BACKGROUND: Several studies have compared mitochondrial DNA (mtDNA) content in tissue from HIV-1-infected patients on highly active antiretroviral therapy with and without evidence of lipodystrophy, the diagnosis of which was based on subjective clinical assessment. OBJECTIVES: The aim of this study was to assess the utility of mtDNA quantification as a marker of HIV-associated lipodystrophy as diagnosed using a published validated case definition. METHODS: We assessed mtDNA content in adipocytes from both thigh and lumbar subcutaneous adipose tissue (n=19), and in peripheral blood mononuclear cells (PBMC) (n=26), obtained from 26 HIV-1-infected patients classified as having lipodystrophy (n=17) or not having lipodystrophy (n=9) according to the validated definition derived from the Lipodystrophy Case Definition Study. RESULTS: The adipocyte and PBMC mtDNA contents did not significantly differ between patients with and without lipodystrophy. Lipodystrophy patients had been treated for significantly longer times, especially with dideoxynucleoside analogues. In both groups, the thigh adipocyte mtDNA content was significantly greater than that of the lumbar region. When all patients were considered together, a statistically significant negative correlation was found between thigh adipocyte mtDNA content and stavudine treatment duration. CONCLUSIONS: Longer exposure to dideoxynucleoside analogues was associated with lipodystrophy, and longer exposure to stavudine was correlated with lower mtDNA content in thigh adipocytes. However, a single measurement of adipocyte mtDNA content in this limited sample of patients could not distinguish between patients with and without clinical lipodystrophy. The observed variation in mtDNA content between different subcutaneous adipose tissue depots argues for harmonization of future studies regarding which depot to biopsy.     

Changes in Body Fat Measured by DEXA in Patients Taking Different Formulations of Stavudine

Abstract

Background: Lipoatrophy is a frequent complication of chronic stavudine therapy. Stavudine extended release formulation (stavudine ER) gives lower peak and higher trough levels than the immediate release formulation (stavudine IR), and we hypothesized that the lower peak might result in less lipoatrophy. Objective: To compare the rate of peripheral lipoatrophy between patients taking stavudine ER and stavudine IR. Method: Body composition was measured by dual energy X-ray absorptiometry (DEXA) every 6 months for 18 months in 29 patients taking either stavudine ER or IR as part of a randomized controlled clinical trial. Results: DEXA fat measurements did not differ between the ER and IR groups at baseline, after a median of 32 months on stavudine-containing treatment. Over the 18 months of follow-up in the whole cohort limb fat decreased by a mean of 0.29 ± 0.50 kg (p = .01) and leg fat percent decreased by a mean of 1.23% ± 1.92% (p = .001), whereas trunk fat and trunk-to-limb fat percent ratio did not change significantly. There was no significant difference between the ER and IR groups in the rate of change of any of the fat parameters. At study completion, the proportion of patients with clinical lipodystrophy was similar in the stavudine ER and stavudine IR groups (67% and 64%, respectively; p = .893). Conclusion: Stavudine ER does not appear to cause less peripheral lipoatrophy.     

Efficacy and safety of stavudine plus didanosine in asymptomatic HIV-infected children with plasma HIV RNA below 50,000 copies per milliliter

Abstract

BACKGROUND: Simple antiretroviral drug combinations might provide a comparable benefit to standard triple regimens in patients with mild HIV disease, because poor adherence and toxicities often compromise the sustained benefit of the latest triple regimens, especially when protease inhibitors are used. Bad adherence is the main cause of virological failure in HIV-positive children. The activity and safety of a double combination of nucleosides with high genetic barrier for resistance (stavudine plus didanosine) was assessed in children with nonadvanced HIV disease. METHOD: From February 1998 to March 1999, 16 children were enrolled in six Spanish hospitals in a trial in which didanosine (180 mg/m²/day) and stavudine (2 mg/Kg/day) were administered for 48 weeks to asymptomatic naive children with plasma HIV RNA below 50,000 copies/mL and CD4 counts above 15%. Genotypic resistance to nucleoside analogues was examined at baseline and at the end of the study. RESULTS: At baseline, median age was 6.5 years (range, 2-14). The absolute and percentage mean CD4 counts were 864 and 32%, respectively (z score: -0.48 and -1.1). Mean plasma viral load was 4.05 log. No clinical events occurred during the 1-year study period. Minor side effects were recorded in two thirds of children, although none led to drug discontinuation. Lipoatrophy was not recognized in any of the participants. Plasma HIV RNA below 400 copies/mL was reached by 43% and 44% of patients at 24 and 48 weeks, respectively. The z score for absolute and percentage CD4 count increased significantly at 48 weeks (+0.63 and +0.97, respectively) in respect to baseline (p < .05). Resistance mutations linked to didanosine (L74V or M184V) or stavudine (V75T) were not recognized and neither were multinucleoside resistant genotypes (151 complex or 69 inserts). However, four children developed AZT-like mutations T215Y and/or M41L. CONCLUSION: Treatment with a dual combination of didanosine plus stavudine in naive children with nonadvanced HIV disease is safe and provides a satisfactory virological outcome at 1 year. Toxicity and drug resistance seem to occur rarely when this combination is used, which allows good adherence and spares other future treatment options.     

高效液相色谱法同时测定人血浆中拉米夫定、地丹诺辛和司他夫定浓度

 目的 建立人血浆中拉米夫定（3TC）、地丹诺辛(ddI)和司他夫定(d4T)的HPLC测定方法。方法 取血浆250 μL，加入内标替加氟和醋酸胺缓冲液混匀，乙腈沉淀蛋白，取上清液常温下氮气吹干，残渣以流动相溶解进样。色谱柱采用Shim-pack CLC-ODS (6 mm×150 mm，5 μm) 柱，流动相为：乙腈-磷酸盐缓冲液(6∶94)。0~9 min紫外检测波长为260 nm， 9~11 min紫外检测波长240 nm， 11~22 min 紫外检测波长为260 nm。柱温为35 ℃。结果 在本试验条件下，3TC在0.02~5 mg·L^-1内线性良好（r=0.999 6，n=6）。ddI在0.05~5 mg·L^-1内线性良好（r=0.999 7，n=6）。d4T在0.02~5 mg·L^-1内线性良好（r=0.999 6， n=6）。高、中、低3个浓度质控样品中，批内误差（RSD）为1.03%～2.70%，批间（RSD）为1.50%～6.77%。结论 本方法操作简便，结果准确可靠，重现性好，为药动学和临床药物研究提供了方法学基础。
     

Weight loss after the first year of stavudine-containing antiretroviral therapy and its association with lipoatrophy, virological failure, adherence and CD4 counts at primary health care level in Kigali, Rwanda

This study was conducted among 609 adults on stavudine-based antiretroviral treatment (ART) for at least one year at health center level in Kigali, Rwanda to (a) determine the proportion who manifest weight loss after one year of ART (b) examine the association between such weight loss and a number of variables, namely: lipoatrophy, virological failure, adherence and on-treatment CD4 count and (c) assess the validity and predictive values of weight loss to identify patients with lipoatrophy. Weight loss after the first year of ART was seen in 62% of all patients (median weight loss 3.1 kg/year). In multivariate analysis, weight loss was significantly associated with treatment-limiting lipoatrophy (adjusted effect/kg/year -2.0 kg, 95% confidence interval -0.6;-3.4 kg; P<0.01). No significant association was found with virological failure or adherence. Higher on-treatment CD4 cell counts were protective against weight loss. Weight loss that was persistent, progressive and/or chronic was predictive of lipoatrophy, with a sensitivity and specificity of 72% and 77%, and positive and negative predictive values of 30% and 95%. In low-income countries, measuring weight is a routine clinical procedure that could be used to filter out individuals with lipoatrophy on stavudine-based ART, after alternative causes of weight loss have been ruled out.     

司他夫定片在人体药动学和相对生物利用度研究

 目的研究司他夫定片剂的健康人体药动学和相对生物利用度。方法采用高效液相色谱法测定20名健康志愿者自身交叉、单剂量口服司他夫定胶囊和片剂各40mg后血浆司他夫定浓度。用3P97药动学软件进行药动学参数计算及生物等效性评价。结果两种司他夫定的药-时曲线均符合一房室模型,参比制剂、被试制剂的主要药动学参数如下:ρ_max分别为(1.01±0.24)和(0.95±0.30)mg·L^-1;t_max分别为(0.78±0.22)和(0.70±0.21)h;t_1/2ke分别为(1.47±0.22)和(1.47±0.23)h;AUC_0～t分别为(2.21±0.46)和(2.08±0.53)mg·h·L^-1;AUC_0～∞分别为(2.33±0.53)和(2.16±0.58)mg·h·L^-1。与标准参比制剂相比,被试制别的相对生物利用度F_0～t为(97.02±27.71)%,F_0～∞为(96.33±29.51)%。对两制剂间的AUC_0～t、AUC_0～∞和ρ_max进行双向单侧t检验,表明两种制剂具有生物等效性。结论司他夫定胶囊和片剂具有生物等效性。