PHARMACOKINETICS OF THE ENANTIOMERS OF VERAPAMIL AFTER INTRAVENOUS AND ORAL ADMINISTRATION OF RACEMIC VERAPAMIL IN A RAT MODEL

Verapamil is a chiral calcium channel blocking drug which is useful clinically as the racemate in treating hypertension and arrhythmia. The published pharmacokinetic data for verapamil enantiomers in the rat model are limited. Utilizing a stereospecific high-performance liquid chromatographic (HPLC) assay, the enantiomeric disposition of verapamil is reported after intravenous (1·0 mg kg⁻¹) and oral (10 mg kg⁻¹) administration of racemic verapamil to the rat model. After intravenous administration the systemic clearance of R-verapamil was significantly greater than that of S-verapamil; 34·9 ± 7 against 2·7 ± 3·7 mL min⁻¹ kg⁻¹ (mean ± SD), respectively. After oral administration, the clearance of R-verapamil was significantly greater than that of S-verapamil, 889 ± 294 against 351 ± 109 mL min⁻¹ kg⁻¹, respectively. The apparent oral bioavailability of S-verapamil was greater than that of R-verapamil, 0·074 ± 0·031 against 0·041 ± 0·011, respectively. These data suggest that the disposition of verapamil in the rat is stereoselective; verapamil undergoes extensive stereoselective first-pass clearance after oral administration and the direction of stereoselectivity in plasma is opposite to that observed in the human. © 1997 John Wiley & Sons, Ltd.     

Effect of Transfer Factor on Tumor-Associated Immunity and Tumor Growth of the Dunning R-3327G Rat Prostate Adenocarcinoma

ABSTRACT: Of importance in the design and application of improved or new modalities of treatment are their evaluation on relevant animal models. In the case of prostate cancer (PCa) the Dunning R-3327 rat prostate adenocarcinoma (PCa), and its variant sublines, is one such experimental tumor model of its human counterpart. In a preliminary study, the effect of transfer factor (TF), one form of passive immunotherapy, on tumor-associated immunity (TAD and tumour growth and histology of the G subline (a poorly differentiated, fast-growing, androgen sensitive, and poorly metastatic tumour of the Dunning R-3327 rat PCa) has been evaluated. TF prepared from the leukocytes of tumor-bearing animals and nontumor-bearing animals referred to as sensitized (STF) and unsensitized (UTF), respectively, had no significant effect on TAI or tumor size. The only noticeable effect of TF in this study was the presence of variable and moderate lymphocytic infiltrates, necrosis, and degenerative-type cells in tumors of animal recipients of STF. The failure to observe significant differences in TAI among tumor bearing and nontumor bearing animals raises doubt in part, of the immunogenicity of the G subline tumor and its appropriateness, at least for subsequent immunological studies. Further factors considered in this regard, are questions of tumor load, including the possible need for the use of adjuvant, and the parameters and sensitivity of immune responsiveness selected for evaluation and immunocompetency. Subsequent evaluation of the effect of TF on other more immunogenic variant sublines of the Dunning R-3327 rat tumor may yet provide further and more useful information.     

Effect of STS-557 (17α-cyanomethyl 17β-hydroxy-estra-4, 9(10)-dien-3-one) on blood hormone levels, the testis, accessory sex organs and fertility of rats

Treatment with STS-557 (17 alpha-cyanomethyl 17 beta-hydroxy-estra-4,9(10)-dien-3-one; 10 mg kg-1 daily s.c.) for 4 weeks induced atrophy of the seminiferous tubules in adult rats with a reduction in tubule diameter and in the number of round spermatids at stage VII. Elongated spermatids were not detected. Leydig cells were atrophied from the second week of treatment with a concomitant decrease in blood levels of testosterone. The blood levels of FSH and LH were reduced from the third week of treatment. The weight of the reproductive organs was reduced after STS-557 treatment. The treatment induced sterility in 50% of rats after 2 weeks of treatment but after 4 weeks none of the treated males mated. Normal fertility and normal levels of testosterone and FSH were restored after 6 weeks and LH after 4 weeks of withdrawal of treatment. All other parameters studied recovered to pretreatment levels 6 weeks after withdrawal of treatment. STS-557 could act on the pituitary-gonadal axis (reducing gonadotrophin secretion) as well as directly affecting the Leydig cells. The consequent reduction in the blood levels of testosterone in combination with reduced gonadotrophins was presumably responsible for the suppression of spermatogenesis.     

103例不明原因发热回顾性分析

目的:关于不明原因发热(fever of unknown origin,FUO)的病因及确诊方式分析,为FUO的治疗提供依据.方法:回顾性分析2015年5月-2016年11月因“发热查因”在本院感染科住院并符合FUO诊断标准的103例患者的临床资料,分析其主要病因及诊断方法.结果:103例FUO患者住院期间经过血细菌学、影像学、组织病理活检等检查后明确诊断的有93例,确诊率90.3％.感染性疾病55例(53.4％),自身免疫性疾病19例(18.5％),肿瘤性疾病13例(12.6％),其他类疾病6例(5.8％),诊断不明疾病10例(9.7％).结论:感染性疾病是FUO的最主要病因,在非感染性疾病中,自身免疫性疾病及肿瘤性疾病为主要病因;大多数的不明原因发热通过详细、全面的病史采集、体查并结合相关的辅助检查和(或)特殊检查及诊断性治疗可以明确诊断.     

DC-CTL细胞对卵巢癌小鼠不同输注途径的治疗效果比较

目的:探讨DC-CTL细胞采用两种不同的输注方式对卵巢癌小鼠的治疗效果的比较.方法:取健康人的外周血制备DC-CTL细胞,分为抗原负载DC既A1组,未进行抗原负载为A2组,采用酶标法检测A1和A2对卵巢癌细胞的杀伤作用.同时6周龄的雌性SPF小鼠60只,在超净工作台内将SKOV3细胞液接种于裸鼠颈背部皮下建立移植瘤模型,第15天模型建立,选择移植瘤模型建立成功的小鼠48只,随机分为四组,分别为皮下注射组及其对照组,尾静脉注射组及其对照组.两组实验组第21天分别采用皮下注射和尾静脉注射法注入5*103的DC-CTL细胞,对照组注射相同剂量的生理盐水作为安慰剂.第35天处死小鼠,分离瘤组织称重并统计数据.结果:抗原负载的DC-CTL细胞对卵巢癌细胞有更好的杀伤效果.小鼠经颈背部皮肤下注射SKOV3细胞在15天左右成瘤,两组实验组瘤重都明显低于相应的对照组(P＜0.05),而两组实验组之间,尾静脉皮下注射组小鼠的瘤重量明显低于皮下注射组(P＜0.05).结论:DC-CTL细胞能有效的抑制小鼠卵巢癌的发展,DC-CTL细胞经尾静脉注入卵巢癌小鼠体内比皮下注射对小鼠有更好的治疗效果,本实验结果为临床使用DC-CTL细胞治疗卵巢癌输注方式的选择提供了一定的依据.     

The effects of terfenadine with and without alcohol on an aspect of car driving performance

Twelve healthy female volunteers received acute doses of terfenadine, 60 mg, 120 mg, 240 mg or placebo, followed by a 'social' dose of alcohol equivalent to 0.5 g absolute alcohol/kg body weight. Performance was assessed on laboratory analogues of car driving both before and after alcohol administration. Terfenadine (240 mg) was found to significantly impair performance alone and following alcohol. The results demonstrate the importance of establishing the behavioural effects of drugs over a range of doses.     

Endotoxin-like reaction following once-daily gentamicin

An endotoxin-like reaction is a host response to an agent that induces the release of endogenous pyrogens, including cytokines. The typical reaction that is associated with gentamicin is fever and chills, rigor, shivering, tachycardia with hypertension or hypotension, respiratory symptoms and muscle cramps. We report a case of a 92-year-old patient who developed an endotoxin-like reaction in the post-operative recovery unit following 200 mg of gentamicin. The reported side effect is not included in the drug sheet or in the British National Formulary. No similar incidents were reported in the UK. We discuss the clinical picture of this rare event, along with a review of the literature and recommendations.