Preclinical Drug Metabolism in the Age of High-Throughput Screening: An Industrial Perspective

With the advent of genomics, combinatorial paradigms and high-throughput screen (HTS)-based pharmacological testing, the number of compounds flowing through the discovery pipeline is likely to escalate. At the same time, with increased knowledge of the human drug-metabolizing enzymes and the availability of in vitro absorption-metabolism (AM) models, Preclinical Drug Metabolism is poised to meet the challenges of HTS. In order to be successful, however, a rational HTS strategy (vs. serendipitous HTS) has to be employed. Such a strategy is based on automation, validation and integration of in vitroAM models and database management (AVID). A generalized strategy for rational (AVID-based) HTS in Preclinical Drug Metabolism is described briefly.     

103例角膜溃疡的病因和病原及药物敏感试验的统计分析

对１９９５年１—１２月间我院门诊１０３例角膜溃疡的病因、病原和药物敏感试验进行统计分析。病因：外伤５９例（５７．２８％），继发感染３４例（３３．０１％），原因不明８例（７．７７％），戴接触镜２例（１．９４％）。病原：真菌３５例（３３．９８％），绿脓杆菌１８例（１７．４８％），金黄色葡萄球菌１５例（１４．５６％），表皮葡萄球菌９例（８．７４％），淋球菌２例（１．９４％）。对１９例真菌性角膜溃疡同时进行细菌培养，有７例为混合感染，占３６．８４％。对几种主要检出菌的药物敏感试验表明：它们对普通抗菌素均可产生一定的耐药性     

猕猴对不同极化方向微波辐射能量吸收的研究

为提供微波辐射安全标准必要的数据，研究了不同极化方向微波辐射能量对猕猴的影响。实验在医学微波无反射室中进行，分为电场，磁场和微波传输方向极化组，辐射频率１ＧＨｚ，用红外热图技术，对暴露在三种极化方向电磁场中猕猴面部各解剖特片部位及胸部在辐射前后进行温度变化的定量分析。     

Dermal absorption of niclosamide in rats and minipigs

The dermal absorption of niclosamide, a drug shown to prevent Schistosomiasis by blocking the dermal penetration of cercariae, has been examined in Sinclair minipigs and rats. Radioactivity in the urine and feces collected daily for 7 days after application of 14C-niclosamide accounted for less than 2 per cent and 10 per cent of the labelled compound applied to pig and rat skin, respectively. Approximately 20 per cent of the radioactivity from the dose solution was recovered on the skin excised from the area of application in both minipigs and rats. No radioactivity was detected in organs removed from the pig 7 days after application of radiolabelled drug while less than 6 per cent of the dose could be accounted for in the rat organs/carcass. Radioactivity in swine blood, removed 0.5, 1, 2, 4 and at 24 h intervals after dosing, was at or below three times background in all of the samples. Total recovery of the applied radioactivity was 78 per cent in pigs and 57 per cent in rats. These studies indicate that niclosamide is very poorly absorbed after dermal application. The results are consistent with earlier comparative studies showing that dermal penetration of xenobiotics in rats is generally higher than in swine.     

Buffering the stomach content enhances the absorption of diflunisal in man

Diflunisal, a lipophilic salicylate, is absorbed more slowly in healthy volunteers than aspirin. In this paper we report on attempts to influence diflunisal absorption by buffering the gastric milieu. Sodium bicarbonate given together and 30 min after diflunisal tablets significantly (p less than 0.05) shortened the time to reach peak plasma concentration (tmax greater than 15 per cent), raised maximum plasma concentration slightly (Cmax 6 per cent) and increased the area under the plasma concentration-time curve (AUC greater than 8 per cent). Other pharmacokinetic parameters, including terminal half-life and renal elimination of the compound, were not considerably influenced. These findings indicate that the absorption of diflunisal was enhanced by increased gastric pH, presumably a result of an increased solubility of diflunisal in the stomach together with faster transport into the small intestine. In one volunteer, after intravenous administration diflunisal plasma concentrations declined in a triphasic manner with a terminal half-life of 12.8 h. The volume of distribution was approximately 10 per cent of body weight. Based on the ratio of AUC after equivalent i.v. and oral diflunisal doses, the absolute bioavailability was 89.5 per cent.     

Repeated testing attenuates conditioned place preference with cocaine

Cocaine-treated rats acquired a preference for cocaine-associated contextual stimuli (CS) relative to saline-injected control rats. However, when animals were given repeated tests for conditioned place preference intermittent between conditioning trials, they displayed an attenuation in strength of conditioning. This attenuation was not due to pharmacologic tolerance (Experiment 1), but rather reflected a disruption in learning due to exposure to the CS alone (Experiment 2). Like other examples of classical conditioning, the strength of the conditioned response (CR) as assessed by the conditioned place preference model may be influenced by partial reinforcement.     

天津医科大学第三医院抗生素类药物的利用分析

目的：对抗生素类药物利用状况进行分析，以考察应用情况，促进用药合理性，方法：查阅药库2000年药品购入目录，采用药物利用状况分析法，对抗生素用药频度和药物费用等进行分析。结果：该院应用的抗生素主要为头孢菌素，喹诺酮类；DDDs排序靠前的是诺氟沙星，羟氨苄青霉素和复方新诺明等。结论：该院用药基本合理，但水平较低。     

铁制剂治疗缺铁性贫血的随机对照临床研究

目的 了解硫酸铁控释片、琥珀酸亚铁、多糖铁复合物治疗缺铁性贫血的疗效及不良反应。方法 将105例不诊于血液科门诊的缺铁性贫血患者，按照入选标准，以随机区组的方法随机分入3个治疗组，分别予以硫酸业铁控释片（福乃得，500mg，每日1次）、琥珀酸业铁（速力菲,，0．1g，每日3次）、多糖铁复合物（力蜚能，0．15g，每日2次）治疗8周，每1－2周随访1次，随访血常规、网织红细胞计数及药物的不良反尖。治疗前及治疗结束检查血清铁、总铁结合力、血清铁蛋白等有关铁参数。结果与结论 以血红蛋白和血清铁蛋白恢复正常作为完全缓解的标准，硫酸亚铁控释片、琥珀酸亚铁、多糖铁复合物3种药治疗8周，缺铁性贫血的完全缓解率分别为74％、76％、40％（P＝0．004），总的有效率分别为81％、89％、76％（P＞0．05）。主要的不良反应为胃肠道反应，3种药中以多糖铁复合物的不良反应最少，其次为琥珀酸亚铁，硫酸铁控释片的不良反应最常见，但大多数能够耐受。     

吉西他滨联合顺铂治疗晚期非小细胞肺癌的临床研究

目的 观察吉西他滨（gemcitabine，GEM）联合顺铂方案治疗晚期非小细胞肺癌的疗效及不良反应。方法 对经病理组织学或细胞学诊断证实的56例晚期非小细胞肺癌患者采用GP方案行静脉化疗：GEM1000mg／m^2，静脉滴注，d1，d8；DDP30mg／m^2，静脉滴注，d1～d3；21天重复，至少治疗2个周期。结果 可评价疗效56例，完全缓解（CR）5．3％（3／56），部分缓解（PR）42．9％（24／56），稳定（SD）33．9％（19／56），进展（PD）17．9％（10／56），总有效率（RR）48．2％（27／56）；肿瘤控制率（CR＋PR＋SD）为82．1％（46／56）；中位缓解期7．4个月，中位生存期11．3个月；不良反应以白细胞及血小板减少，消化道反应，乏力为常见，患者均可耐受，无化疗相关死亡。结论 吉西他滨联合顺铂对晚期非小细胞肺癌有较好疗效，不良反应可为患者所耐受，值得临床应用。     

可手术的Ⅲ期贲门癌术前选择性动脉灌注化疗

目的探讨可手术的Ⅲ期贲门癌术前选择性动脉灌注化疗的疗效。方法可手术的Ⅲ期贲门癌选择性胃左动脉灌注化疗一次。结果76例经胃肠双重造影、腹部CT和B超检查均有不同程度的改善,临床症状明显好转,参照全国胃癌协作组第二次会议制定的进展期胃癌全身化疗判定标准,完全缓解(CR)4%(3/76),部分缓解(PR)86%(65/76),稳定(S)11%(8/76)。结论可手术的Ⅲ期贲门癌术前接受选择性动脉介入化疗近期疗效明显。