Inhibitors of the Hepatitis C Virus Polymerase; Mode of Action and Resistance

The hepatitis C virus (HCV) is a pandemic human pathogen posing a substantial health and economic burden in both developing and developed countries. Controlling the spread of HCV through behavioural prevention strategies has met with limited success and vaccine development remains slow. The development of antiviral therapeutic agents has also been challenging, primarily due to the lack of efficient cell culture and animal models for all HCV genotypes, as well as the large genetic diversity between HCV strains. On the other hand, the use of interferon-α-based treatments in combination with the guanosine analogue, ribavirin, achieved limited success, and widespread use of these therapies has been hampered by prevalent side effects. For more than a decade, the HCV RNA-dependent RNA polymerase (RdRp) has been targeted for antiviral development. Direct acting antivirals (DAA) have been identified which bind to one of at least six RdRp inhibitor-binding sites, and are now becoming a mainstay of highly effective and well tolerated antiviral treatment for HCV infection. Here we review the different classes of RdRp inhibitors and their mode of action against HCV. Furthermore, the mechanism of antiviral resistance to each class is described, including naturally occurring resistance-associated variants (RAVs) in different viral strains and genotypes. Finally, we review the impact of these RAVs on treatment outcomes with the newly developed regimens.     

非胰岛素依赖型糖尿病患者血清唾液酸的改变

测定20例NIDDM伴有心脑血管病变的患者、20例单纯NIDDM患者的血清唾液酸（SA）水平，并与20例正常人进行比较。结果发现所有NIDDM患者的血清SA水平均显著增高（P＜0．01），其中伴有心脑血管疾病患者的血清SA水平显著高于单纯NIDDM患者（P＜0．05），同时血清SA水平与血清胰岛素及C肽水平、收好压之间存在相关。提示血清SA水平与NIDDM患者的心脑血管疾病关系密切，可能是心脑血管并发症发生的一个危险因素。     

Responses of CDKs and p53 in Delayed Ischemic Neuronal Death

Stroke is a debilitating disease that affects millions each year.While in many cases cerebral ischemic in jury can be limited by effectivw resuscitation or thrombolytic treatment,the injured neurons wither in a process known as delayed neuronal death(DND).Mounting evidence indicates that DND is not simply necrosis played out in slow motion but apoptosis is triggered.Of particular interest are two groups of signal proteins that participate in apoptosis-cyclin dependent kinases(CDKs) and p53-among a myriad of signaling events after an ischemic insult.Recent investigations have shown that CDKs,a family of enzymes initially known for their role in cell cycle regulation,are activated in injured neurons in DND.As for p53,new reports suggest that its up-regulation may represent a failed attempt to rescue in jured neurons,although its up-regulation was previously considered an indication of apoptosis.These observations thus rekindle an old quest to identify new neuroprotective targets to minimize the stroke damage.In this review,the author will examine the evidence that indicates the participation of CDKs and p53 in DND and then introduce pre-clinical data to explore CDK inhibition as a potential neuroprotective target.Finally,using CDK inhibition as an example,this paper will discuss the pertinent criteria for a viable neuroprotective strategy for ischemic in jury.     

CLINICAL OBSERVATION ON THERAPEUTIC EFFECTS OF COMBINED TREATMENT OF NONINSULIN DEPENDENT DIABETES

Thetherapeuticeffectofacupuncturefordia betesmellitus(DM)hasbeenconfirmedbyalarge numberofclinicalinvestigations.Itisasubjectfor acupuncturiststoconsiderandsearchforatherapy providingbettertherapeuticeffectsbywayofproper differentiationofsyndromesandcombinationofacu points.Basedonclinicalexperiencegainedformore than30years,theauthorsofthepresentpaperhave graduallyformedaneffectivecombinedtherapyfor treatingtypeⅡDM(noninsulindependentDM)and itsvariouscomplications.Thereportisasfollows.1CLI…     

非依赖型糖尿病全血低切变率粘度值的临床意义

目的:为了探讨非依赖型糖尿病全血低切变率粘度值测定的临床意义。方法:对91例非依赖型糖尿病血液流变学低切率粘度值进行了检测,并对其结果及形成机制进行了分析讨论。结果:91例非依赖型糖尿病低切变率粘度值和对照组相比有显著性差异,p<0．01。结论:非依赖型糖尿病全血低切变率粘度增高,可造成微血管循环障碍,是非依赖型糖尿病易形成心梗、脑梗及其他微血管病的一种重要因素。     

Intravenous cyclophosphamide is the drug of choice for steroid dependent nephrotic syndrome

BACKGROUND: Steroid dependency is a major problem seen after therapy for idiopathic nephrotic syndrome in childhood. Although there is consensus about the usage of cyclophosphamide (CYC) in frequent relapsers, there is still a controversy concerning its usage in steroid-dependent nephrotic syndrome (SDNS). METHODS: In the present study, nineteen children with SDNS were treated with CYC: ten via the intravenous (i.v.) route, and nine via the oral route. Remission was then maintained with prednisolone. Oral CYC therapy consisted of CYC at a dose of 2 mg/kg per day for 12 weeks. Intravenous (i.v.) CYC therapy consisted of CYC 500 mg/m2 per month (with intravenous 3500 cc/m2 per 24 h one-third saline hydration) for 6 months. RESULTS: The cumulative dose of CYC was 168 mg/kg in the oral group and 132 mg/kg in the IV group. Daily oral CYC dose was 1.96~0.31 mg/kg, whereas i.v. CYC dose was 0.73~0.03 mg/kg. Long-term complications and side-effects such as alopecia, infection and hemorrhagic cystitis were not observed in the i.v. CYC treated group. In the long term, the dosage of prednisolone that held remission after CYC, the annualized relapse rates and the subsequent relapse time were significantly better in the i.v. CYC group, and the number of patients in remission for 2 years was significantly higher in the i.v. treated group (P<0.05). CONCLUSIONS: In SDNS, i.v. CYC has a long lasting effect with lower annualized relapse rates and longer subsequent relapse time with a lower steroid dosage required to maintain remission than oral CYC. The results of the present study showed the safety of the i.v. route, and it is the preferable treatment in noncompliant patients for its long lasting remission and simple and inexpensive follow up.     

起搏器高度依赖性患者起搏器置换方法与疗效探讨

目的 :探讨起搏器高度依赖性患者起搏器置换方法与疗效。　方法 :对 8例起搏器高度依赖性患者 ,在起搏器与电极的接口松解前 ,应用在体起搏器间断接触法 ,使自身逸搏心律得已恢复 ,然后再行松解接口以及必要的起搏参数测试。　结果 :起搏器离体次数为 3～ 7(5± 2 )次 ,最长逸搏间期为 3.38～ 6 .2 0 (4.5 1± 1.11)s,自身逸搏心率为 30～ 4 3(38± 5 )次 /min ,均顺利完成起搏器置换。　结论 :在体起搏器间断接触法切实可行 ,能够明显提高起搏器高度依赖性患者起搏器置换的安全性     

关附甲素对豚鼠乳头肌动作电位最大除极速度的频率依赖性抑制作用

应用标准微电极技术，研究了关附甲素对豚鼠右心室乳头肌动作电位最大除极速率(V_max)的频率依赖性抑制作用(RDB)，并与美西律，奎尼丁，劳卡尼进行了比较. 在相同刺激间隔(300 ms)，产生50%左右RDB的药物浓度下，美西律的RDB开始最快，其第2个V_max所产生的抑制已占RDB的64%，奎尼丁，劳卡尼和关附甲素的RDB开始速率常数分别为每个动作电位0.165, 0.076和0.136. 美西律，奎尼丁，劳卡尼和关附甲素产生RDB的恢复时间常数分别为1.4, 9.0, 18.2和44.0 s，而且它们的恢复时间常数是不依赖于药物浓度而变化的，结果提示，关附甲素是一个慢动力学钠通道阻滞剂.