Correlation between the negative inotropic potency and binding parameters of 1,4-dihydropyridine and phenylalkylamine calcium channel blockers in cat heart

Summary Partially purified plasma membranes were prepared from cat ventricle. The purification factors for the calcium channel ligands (+)-³H-PN 200-110, ³H-nimodipine (1,4-dihydropyridines) and (–)-³-H-desmethoxyverapamil (a phenylalkylamine) were 3.1-, 3.4- and 2.9-fold, respectively, whilst -adrenoceptors labelled with (–)-³H-dihydroalprenolol were purified 3.0-fold.(+)-³H-PN 200-110 bound to 930±140 fmol/mg of membrane protein with a dissociation constant of 70 pmol/l at 25°C. Under the same conditions ³H-nimodipine bound to 490±24 fmol/mg of sites with a K _D of 120 pmol/l. (–)-³-H-desmethoxyverapamil bound to 530±55 fmol/mg of sites with a K _D of 2.47 nmol/l.Twelve 1,4-dihydropyridines were evaluated for binding inhibition constants (K _i) with (+)-³H-PN 200-110 and 13 phenylalkylamines with (–)-³-H-desmethoxyverapamil in radioligand binding assays. Of the twelve 1,4-dihydropyridines evaluated (±)-nitrendipine was the most potent with a K _i-value of 280 pmol/l, nifedipine had a K _i-value of 500 pmol/l and the weakest drug tested, (±)-Bay b4328, had a K _i-value of 14.3 nmol/l. The EC₅₀-values of the same 1,4-dihydropyridines to inhibit the electrically driven cat papillary muscle were 77- to 3,450-fold higher and little correlation existed between K _i and EC₅₀-values.Thirteen phenylakylamines were tested for their potency to inhibit (–)-³-H-desmethoxyverapamil binding. The most potent phenylalkylamine with respect to negative inotropy was (±)-D 595 with an EC₅₀-value of 794 nmol/l, the least potent substance was (±)-Sz 45 with an EC₅₀-value of 39.8 mol/l. The binding inhibition constants for the phenylalkylamines were 13-to 322-fold lower than the values for negative inotropy, but a significant positive correlation between the K _i and EC₅₀-values (n=12, r=0.84) was observed. The absolute differences may reflect the state-dependent binding of phenylalkylamines to the channel.QSAR analysis revealed nearly identical correlations between physicochemical substituent properties on the one hand and binding affinities or functional potency on the other hand. In both cases the electronic properties (F-constant) of ring substituents mainly determine the variance in potency.     

The effect of the β-carboline FG 7142 on the behaviour of male rats in a living cage: An ethological analysis of social and nonsocial behaviour

The effects of FG 7142, a -carboline benzodiazepine receptor partial inverse agonist, on the social behavior of pair-housed rats were investigated. Four 6-min dyadic social encounters in a living cage were observed in a paradigm in which one member of a pair of rats was injected. The four injection groups (n=8) were vehicle control, and FG 7142 at 2.5, 5.0 and 10.0 mg/kg, respectively. All injections were administered 2 min before the start of the first observation trial. Compared to the effects of vehicle alone, FG 7142 decreased aggressive behaviour but did not change the level of total social interaction. Thus there were compensating increases in approaching and avoiding behaviours following the administration of FG 7142. Locomotion declined marginally and immobility increased in FG 7142-injected rats. FG 7142 decreased the incidence of self-grooming. The evidence is consistent with a relatively selective reduction in intraspecies aggression in male rats after the injection of the -carboline inverse agonist.     

Terpene hydrocarbons in Pimpinella anisum L.

The essential oil of anise (fruits and shoots) was investigated focusing on the composition of the hydrocarbon fraction. Several sesquiterpenes were identified by GC-MS and the relative composition of the fractions was established by GC analysis. -Himachalene and the diterpene neophytadiene were isolated by TLC and column chromatography at low temperatures. Their structures were determined by MS and NMR including¹H-¹H correlated COSY and NOE experiments.     

Chlorhexidine-induced degeneration of adrenergic nerves

Summary Possible toxic effects of chlorhexidine (CHX) on the sympathetic adrenergic ground plexus were studied in whole mounts of albino rat irides using Falck-Hillarp fluorescence histochemistry. CHX dissolved in an isotone, buffered sodium-acetate solution or in 70% alcohol was injected into the anterior chamber of eye. CHX caused a marked and dose-dependent degeneration of adrenergic nerves. Two days after the lowest dose, 0,25 g (5 l of a 0.05% CHX solution), approximately 30% of the nerves had disappeared. Almost complete degeneration was observed after the same time with higher doses (2.5 g, 5.0 g, and 7.5 g corresponding to 0.5, 1.0, and 1.5% CHX respectively). Two weeks after the lowest dose, the nerves had regenerated almost completely. With the highest dose used, only some 40% of the normal adrenergic nerve plexus had reformed after 51 days. Alcohol as a solvent did not have an additive effect on the neurotoxic action caused by CHX. The results demonstrate yet another aspect of chlorhexidine neurotoxicity, degeneration of peripheral adrenergic nerve terminals. This suggests that neurotoxic actions on thin unmyelinated fiber systems should be looked for also in the central nervous system (CNS).Supported by the Swedisch Council for Planning and Coordination of Research (Project: Chemical Hazards in the Environment), The Swedish Medical Research Council (14X-03185; 14P-5867; 04P-6889), Magnus Bergvalls Stiftelse, and Karolinska Institute Fonder     

Genetic Analysis Workshop II: combined segregation, linkage, and association analysis

A combined segregation, linkage, and association analysis using the program COMBIN was performed on the simulated pedigree data prepared for the Second Genetic Analysis Workshop. The model used in COMBIN is described and the presented results illustrate its effectiveness in the analysis of such data. Linkage analysis was performed and maps for each linkage group are presented.     

Enrichment techniques and trace analysis with microbore columns in liquid chromatography

The advantages of microbore columns for trace analysis by liquid chromatography are identified, with reference to on-column enrichment techniques performed on analytical micro-columns. The selectivity and high sensitivity of the amperometric detector are utilized in combination with a microbore column for a number of pharmaceutical and bioanalytical analyses, including phenothiazines, parabens, sulphonamides, catecholamines, tetracyclines, vitamins, amino acids and dipeptides.     

2015—2020年四川省手足口病流行病学特征分析

目的 分析2015—2020年四川省手足口病流行病学及病原学特征,为手足口病的防控提供科学依据。 方法 利用描述流行病学方法对2015—2020年四川省手足口病监测资料进行统计分析。 结果 2015—2020年四川省累计报告手足口病520 147例,重症1 759例,死亡38例,2015—2020年四川省手足口病发病率呈波动状,年均发病率为104.82/10万,2015—2017和2019年呈现明显的双峰(4—7月和10—12月),2018、2020年呈单峰,发病高峰分别在7—11月和10—12月;年龄以 5 岁及以下儿童为主,男女性别比为1.38∶1;发病率居前五位的地区是成都市(221.25/10万)、眉山市(145.51/10万)、德阳市(115.52/10万)、雅安市(108.02/10万)和遂宁市(100.56/10);共报告实验室确诊病例44 410例,其中其他肠道病毒、CoxA16、EV71分别占65.53%、22.35%、12.12% 。 结论 2015—2020年四川省手足口病发病水平呈上升趋势,防控压力逐渐加大。四川省手足口病发病以5岁以下儿童为主,成都及周边,川东北发病率较高,优势病原分型构成发生变化,其他肠道病毒比重逐渐提高,病原学监测工作需要调整。     

2010—2020年云南省学校食源性疾病暴发事件流行病学分析

目的 了解云南省学校食源性疾病暴发事件流行病学特征和趋势。 方法 收集2010—2020年云南省各地报告的学校食源性疾病暴发资料,并进行描述性流行病学分析。 结果 2010—2020年共发生学校食源性疾病暴发260起,发病6 600人,死亡2人,总体呈下降趋势。学校食源性疾病暴发高峰期为第二、四季度,占总起数的66.54%(173/260);暴发场所多发生在小学,占总起数的58.08%(151/260)。报告明确或可疑致病因子的185起事件中由微生物或可疑微生物引起的占40.00%(74/185),毒素引起的占46.49%(86/185);明确致病因子的118起暴发事件中,60.17%(71/118)是由4种致病因子引起的,其中蓖麻毒素导致的最多,达22起(18.64%),发病人数428人,其次是蜡样芽孢杆菌20起(16.95%),原因食品被归因为一类食品植物类,主要是大米、三明治、面包。导致暴发污染环节最多的是生产加工环节(50.77%,132/260)。 结论 关注学校食源性疾病暴发事件流行特征,在学生开学季时,加强对小学食堂植物类食品的生产加工环节管理和监督。微生物、毒素感染是学校食源性疾病主要的致病因素,且原因查明率低,进一步强化医疗机构食源性疾病微生物、毒素检测能力,提高原因查明率,最大限度地降低学校食源性疾病的发病率。     

2005-2019年理塘县法定传染病疫情分析

目的了解理塘县近15年法定传染病疫情形势及流行特征,为政府制定防控措施提供科学依据。方法对2005—2019年理塘县法定传染病疫情进行描述性流行病学分析。采用ArcGIS 10.3软件绘制各乡镇发病情况分布图,SPSS 21.0软件进行χ²检验、趋势性χ²检验。结果2005—2019年理塘县共计报告甲乙丙类传染病21种6154例,年均发病率为644.33/10万,发病呈上升趋势。死亡37例,年均死亡率3.87/10万,病死率0.60%。呼吸道传染病发病最高(341.12/10万);发病前3位的病种为肺结核(271.91/10万)、乙肝(103.24/10万)及包虫病(67.22/10万);肺结核、其他感染性腹泻病、艾滋病/HIV、梅毒发病呈上升趋势。3月、9月分别出现1次发病高峰;20~29岁、30~39岁和10~19岁组发病居前3位;男女性别比为1.24∶1;发病以农民、牧民及学生为主。结论2005-2019年理塘县法定传染病发病率较高且呈上升趋势,应针对高发传染病、上升趋势明显的传染病、重点人群进行分析研究,采取针对性措施控制疫情。