An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk

Owing to its association with Torsades de Pointes, drug-induced QT interval prolongation has been and remains a significant hurdle to the development of safe, effective medicines. Genetic and pharmacological evidence highlighting the pivotal role the human ether-a-go-go-related gene (hERG) channel was a critical step in understanding how to start addressing this issue. It led to the development of hERG assays with the rapid throughput needed for the short timescales required in early drug discovery. The resulting volume of hERG data has fostered in silico models to help chemists design compounds with reduced hERG potency. In early drug discovery, a pragmatic approach based on exceeding a given potency value has been required to decide when a compound is likely to carry a low QT risk, to support its progression to late-stage discovery. At this point, the in vivo efficacy and metabolism characteristics of the potential drug are generally defined, as well its safety profile, which includes usually a dog study to assess QT interval prolongation risk. The hERG and in vivo QT data, combined with the likely indication and the estimated free drug level for efficacy, are put together to assess the risk that the potential drug will prolong QT in man. Further data may be required to refine the risk assessment before making the major investment decisions for full development. The non-clinical data are essential to inform decisions about compound progression and to optimize the design of clinical QT studies.This article is commented on by Guth and Rast, pp. 22–24 of this issue and is part of a themed section on QT safety. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2010     

Vasodilation through levodopa for Parkinson's disease may require high left ventricular assist device flow

We report implantation of a left ventricular assist device (LVAD) in a patient with Parkinson's disease. Postoperative fluid overload together with insufficient LVAD output in the setting of vasodilation through levodopa likely caused renal hypoperfusion and acute kidney injury. A patient like ours, therefore, requires the highest possible increase of HM3 RPM and LVAD flow early after surgery.     

支气管内膜结核36例

1 临床资料自2002年以来,经纤维支气管镜活检或刷检确诊为支气管内膜结核的患者36(男15,女21)例,年龄18～81(平均28.9)岁,病程2 mo～20 a. 临床表现:咳嗽36例,咳痰30例,发热、乏力、盗汗20例,胸痛6例,胸闷、气急5例,喘鸣4例. 肺部听诊局限性哮鸣音10例,局限性呼吸音减低7例,两肺喘鸣音2例,肺部无阳性体征者17例. 胸片或CT提示肺不张11例,阻塞性肺炎6例,肺门阴影增大4例,局限性肺气肿4例,肺部弥漫性病变3例,毁损肺2例,胸腔积液2例,空洞2例,胸片未见异常者3例. 纤支镜检查所见:侵犯右侧17例,左侧16例,双侧同时受累3例. 具体部位为右主支气管2例,上叶4例,中间支3例,中叶3例,下叶2例,多处3例. 左主支气管4例,上叶6例,下叶4例,多处2例,两侧病变共3例. 镜下特点见表1. 参照中华结核和呼吸杂志编委会分型方法[1]. 7例经痰涂片行抗酸染色阳性;32例行纤支镜刷检找抗酸杆菌26例阳性,活检28例,11例证实为结核.     

The subcellular particulate NADPH-dependent O2.(-)-generating oxidase from human blood monocytes: comparison to the neutrophil system

Highly purified preparations of normal human monocytes obtained from peripheral blood were shown to contain a subcellular particulate O2.(-)- generating oxidase system. This O2.(-)-generating activity was present in particulate preparations from monocytes that had been previously stimulated with phorbol myristate acetate but was low or absent in control preparations from unstimulated monocytes or stimulated monocytes from a patient with chronic granulomatous disease. In the stimulated preparations from normal monocytes, O2.(-)-generation was linearly proportional to cell protein concentration, insensitive to inhibition by azide, and dependent on NADPH as substrate. These characteristics are similar to the O2.(-)-generating oxidase system from human neutrophils. A significant difference in the apparent Km for NADPH was shown between preparations from stimulated monocytes and neutrophils (monocyte 83 +/- 16 microM, neutrophil 31 +/- 5 microM, mean +/- SE). Additionally, affinity of the stimulated monocyte particulate preparation for NADH was unmeasurably low.     

Regional infusion of urokinase into occluded lower-extremity bypass grafts: long-term clinical results

The initial outcome, long-term patency rate, and rate of limb salvage were studied in patients after regional urokinase infusion for treatment of thrombosed lower-extremity grafts. Seventy-one infusions were performed in 53 patients. Complete clot lysis occurred in 75% of grafts, with establishment of antegrade blood flow in 66%. Variables that favorably influenced clot lysis and the reestablishment of antegrade blood flow through the graft were a short duration of occlusion and a suprainguinal graft position. The median duration of patency after infusion and adjunctive therapy was 162 days, with 75% limb salvage at 301 days. No statistically significant variables that influenced the length of patency were identified. These long-term patency results are inferior to the reported results in suprainguinal grafts after reoperation. They appear similar to reported results for occluded infrainguinal grafts treated with thrombectomy and patch grafting.     

Infant feeding, wheezing, and allergy: a prospective study

The determinants of wheezing and allergy were investigated in 453 children with a family history of allergic disease. A randomised controlled trial examined the effects of withholding cows' milk protein during the first three months of life and replacing cows' milk with soya milk. The children were followed up to the age of 7 years. Withholding cows' milk did not reduce the incidence of allergy or wheezing. Children who had ever been breast fed had a lower incidence of wheeze than those who had not (59% and 74% respectively). The effect persisted to age 7 years in the non-atopics only, the risk of wheeze being halved in the breast fed children after allowing for employment status, sex passive smoking, and overcrowding. Allergic disease was not associated with exposure to tobacco smoke, house dust mite antigen, or cats. Breast feeding may confer long term protection against respiratory infection.