Bases sémantiques et pharmacologiques d’une nouvelle classification des antipsychotiques

The main stages involved in the development of drugs effective against psychotic manifestations are presented, as well as their mechanisms of action. Justification is given for the terms antipsychotic drugs, neuroleptic antipsychotic drugs, non-neuroleptic antipsychotic drugs, and non neuroleptic antipsychotic drugs, effective against negative expressions of schizophrenia. These constitute the basis of the new classification of antipsychotic drugs suggested. Finally, the term “atypical neuroleptic drugs”, frequently used in France, is described as badly constructed and unfortunate and should therefore be abandoned.     

当前我国畜牧业抗菌药应用与耐药性应对趋势

抗菌药在现代农业和医学中发挥了举足轻重的作用,然而,随着民众对食品安全和生态环保意识的逐渐增强,抗菌药物的使用愈发受关注。如何科学合理使用抗菌药,确保动物安全健康,防止药物残留超标,进而实现畜牧业绿色发展是当前研究的重要课题。本文结合当前畜牧业抗菌药使用现状,从四个方面分析了滥用抗菌药的危害,并归纳总结了耐药机制研究进展,最后提出抗菌药替代策略,旨在为畜牧业抗菌药安全使用和抗菌药替代技术研发提供参考。     

Blood pressure and heart rate and withdrawal of antihypertensive drugs.

The immediate effects on heart rate and blood pressure of withdrawing antihypertensive drugs were studied over three-day periods in 26 patients. Four groups of drugs were studied. After withdrawal all patients taking clonidine showed a considerable increase in heart rate and blood pressure with intense ectopic activity. Patients taking postganglionic neurone-blocking drugs showed a similar but less pronounced reaction with increased ventricular ectopic activity. No alarming reactions were seen after withdrawal of methyldopa or beta-blocking drugs. Methyldopa and, especially, beta-blocking drugs are less likely to produce withdrawal reactions than clonidine or the postganglionic neurone-blocking drugs, and patients taking these drugs are therefore less likely to suffer violent reactions if they forget to take their tablets.     

Molecular dynamics simulation as a tool for assessment of drug binding property of human serum albumin

Human serum albumin (HSA) is a major plasma protein and binding of drugs with this plasma protein has a great importance. It possess esterase activity which can cleave the drugs containing ester bond and thus, can regulate the effect of drugs. Till date no systematic study has been done to analyse binding of such drugs and to compare the results with the drugs which do not have ester bond. Therefore, in the present study two different categories—ester and non-ester drugs have been considered to analyse their interaction with HSA at two principle drug binding sites using molecular modelling tools. It is observed that the drugs irrespective of ester or non-ester nature prefer either Sudlow site I or II by hydrogen bond and hydrophobic interactions. The information obtained from the study can assist to study pharmacokinetics of the drugs and that in turn will help in noval drug discoveries.     

Current status and perspectives of biopharmaceutical drugs

Since the first approval of recombinant human insulin three decades ago, more than 150 biopharmaceutical drugs have been marketed, and some of them became blockbuster drugs in market size. The patent expiration of the oldest biopharmaceutical drugs resulted in the development of biosimilar drugs. However the short serum half-life of biopharmaceutical drugs incurs a frequent injection to maintain a target clinical outcome in patients. The other major critical concern of biopharmaceutical drugs is immunogenicity producing anti-drug antibodies. These antibodies may reduce clinical efficacy by neutralizing biological activity, and may not only cause a severe allergic reaction but also other serious adverse reactions by blocking endogenous proteins. In order to improve pharmaceutical properties and reduce immunogenicity, the next generation biobetter drugs were achieved by glycoengineering technology, pegylation technology and protein engineering technology. Other biobetter drugs having optimized binding sites were also generated by in vitro display technology. Many of those biobetter drugs have been developed and/or are under development, and come into the clinical field in the near future.     

Dopaminergic and serotonergic drug use: a nationwide register-based study of over 1,300,000 older people

Objective

To investigate the use of dopaminergic and serotonergic drugs in elderly people.

Methods

We analyzed data on age, sex and dispensed drugs for individuals aged ≥65 years registered in the Swedish Prescribed Drug Register from July to September 2008 (n = 1 347 564; 81% of the total population aged ≥65 years in Sweden). Main outcome measures were dopaminergic (enhancing and/or lowering) and serotonergic (enhancing and/or lowering) drugs and combinations of these.

Results

Dopaminergic and serotonergic drugs were used by 5.6% and 13.2% the participants, respectively. Female gender was related to use of both dopaminergic and, particularly, serotonergic drugs. Higher age was associated with use of dopamine lowering drugs and serotonergic drugs, whereas the association with use of dopamine enhancing drugs declined in the oldest old. The occurrence of combinations of dopaminergic and serotonergic drugs was generally low, with dopamine lowering + serotonin lowering drug the most common combination (1.6%). Female gender was associated with all of the combinations of dopaminergic and serotonergic drugs, whereas age showed a mixed pattern.

Conclusion

Approximately one out of ten older patients uses serotonergic drugs and one out of twenty dopaminergic drugs. The frequent use of dopaminergic and serotonergic drugs in the elderly patients is a potential problem due to the fact that aging is associated with a down-regulation of both these monoaminergic systems. Future studies are needed for evaluation of the impact of these drugs on different cognitive and emotional functions in old age.     

甲胎蛋白携带药物靶向治疗肿瘤

甲胎蛋白（alpha fetoprotein, AFP）是一种在胎儿发育时期高表达的蛋白质,它又是一种穿梭蛋白质,能够将营养物质输送给胚胎细胞。相似的是,在肝癌等恶性肿瘤发展时期,肿瘤细胞也高表达AFP及其受体,它们通过AFP受体摄取AFP及其运载的物质。因此,可以将AFP与抗癌药物结合,选择性攻击肿瘤细胞。AFP与药物的结合方式有多种,它可以和药物非共价结合,药物被包裹在AFP的疏水袋中;也可以通过共价键与药物结合,或者利用AFP与纳米颗粒和脂质体连接来提高输送药物的效果,肿瘤细胞的酸性环境能促使结合的药物有效释放。为了避免AFP致癌的风险,还可以通过改造AFP或利用AFP片段来输送药物。由于AFP介导的肿瘤靶向治疗主要是攻击具有AFP受体的癌细胞,因此对正常细胞影响并不大。AFP携带药物不仅能促进肿瘤细胞对药物的吸收、提高药物的抗肿瘤活性,还能克服多重耐药（multidrug resistance, MDR）问题。另外,AFP携带药物还具有免疫治疗的效果。AFP携带药物不仅能激活T细胞受体,消除免疫耐受,抑制肿瘤的生长,还能利用改造好的AFP靶向抑制髓源性抑制细胞（myeloid-derived suppressor cells, MDSCs）,激活NK细胞和T细胞,从而破坏癌细胞以及阻止癌干细胞的转移。因此,AFP携带药物治疗是免疫治疗与靶向化疗相结合的新疗法,它将成为治疗癌症的一种策略。     

N-acetylcysteine and captopril protect DNA and cells against radiolysis by fast neutrons

N-Acetylcysteine and captopril, respectively mucolytic and antihypertensive drugs, contain free sulfhydryl groups. Since in general thiols have well-established radioprotective abilities, we sought putative radioprotective effects of these drugs against therapeutic fast neutrons. We show that pBR322 plasmid DNA is indeed protected against radiolytic strand breakage by both drugs. The oxygen independent protection is consistent with a hydroxyl radical scavenging mechanism. A clonogenicity assay reveals an increase of the survival of SCL-1 cultured keratinocytes irradiated in the presence of the drugs compared with cells irradiated without drugs. Our results suggest possible interferences between treatment with drugs bearing-SH groups and radiotherapy.     

A systematic analysis of FDA-approved anticancer drugs

Background

The discovery of novel anticancer drugs is critical for the pharmaceutical research and development, and patient treatment. Repurposing existing drugs that may have unanticipated effects as potential candidates is one way to meet this important goal. Systematic investigation of efficient anticancer drugs could provide valuable insights into trends in the discovery of anticancer drugs, which may contribute to the systematic discovery of new anticancer drugs.

Results

In this study, we collected and analyzed 150 anticancer drugs approved by the US Food and Drug Administration (FDA). Based on drug mechanism of action, these agents are divided into two groups: 61 cytotoxic-based drugs and 89 target-based drugs. We found that in the recent years, the proportion of targeted agents tended to be increasing, and the targeted drugs tended to be delivered as signal drugs. For 89 target-based drugs, we collected 102 effect-mediating drug targets in the human genome and found that most targets located on the plasma membrane and most of them belonged to the enzyme, especially tyrosine kinase. From above 150 drugs, we built a drug-cancer network, which contained 183 nodes (150 drugs and 33 cancer types) and 248 drug-cancer associations. The network indicated that the cytotoxic drugs tended to be used to treat more cancer types than targeted drugs. From 89 targeted drugs, we built a cancer-drug-target network, which contained 214 nodes (23 cancer types, 89 drugs, and 102 targets) and 313 edges (118 drug-cancer associations and 195 drug-target associations). Starting from the network, we discovered 133 novel drug-cancer associations among 52 drugs and 16 cancer types by applying the common target-based approach. Most novel drug-cancer associations (116, 87%) are supported by at least one clinical trial study.

Conclusions

In this study, we provided a comprehensive data source, including anticancer drugs and their targets and performed a detailed analysis in term of historical tendency and networks. Its application to identify novel drug-cancer associations demonstrated that the data collected in this study is promising to serve as a fundamental for anticancer drug repurposing and development.

     

Drug-target network

The global set of relationships between protein targets of all drugs and all disease-gene products in the human protein-protein interaction or 'interactome' network remains uncharacterized. We built a bipartite graph composed of US Food and Drug Administration-approved drugs and proteins linked by drug-target binary associations. The resulting network connects most drugs into a highly interlinked giant component, with strong local clustering of drugs of similar types according to Anatomical Therapeutic Chemical classification. Topological analyses of this network quantitatively showed an overabundance of 'follow-on' drugs, that is, drugs that target already targeted proteins. By including drugs currently under investigation, we identified a trend toward more functionally diverse targets improving polypharmacology. To analyze the relationships between drug targets and disease-gene products, we measured the shortest distance between both sets of proteins in current models of the human interactome network. Significant differences in distance were found between etiological and palliative drugs. A recent trend toward more rational drug design was observed.     

多肽药物的发展现状

随着生物技术与多肽合成技术的日臻成熟,越来越多的多肽药物被开发并应用于临床。因适应证广、安全性高且疗效显著,多肽药物目前已广泛应用于肿瘤、肝炎、糖尿病、艾滋病等疾病的预防、诊断和治疗,具有广阔的开发前景。简介多肽药物的来源与特点及制备方法,重点综述国内外多肽药物的研发概况、国外近年获准上市的主要多肽药物和我国自主研发并进入临床研究的主要多肽药物,旨在为该类新药的研发提供参考。     

结核杆菌的药物外排泵

外排泵基因过度表达促使细胞内的药物转移到细胞外,胞内药物浓度下降,致使药物临床疗效降低或无效。外排泵上有多个与识别底物结构无关的阴离子凹穴(底物结合位点),通过静电引力非特异性结合各种含阳离子的药物,在能量协助下将药物排到细胞外,进而导致细菌抗药性的产生。研究表明,结核杆菌基因组中存在外排泵基因,但仅分离到几个有功效的外排泵。本文就相关研究进展进行综述。     

某三级甲等医院营养类药物使用情况调查

目的:通过对某三级甲等医院2012年全年处方进行分析,调查营养类药物使用情况。方法:通过回顾性方法、Microsoft Excel 2007、SPSS 16.0对数据进行分析。结果:肠内营养乳剂(TP)使用量最大;葡萄糖注射液(20 ml)使用量排名第一;脑外科应用营养类药物比较多;肠外营养类药物的发放量大于肠内营养类药物,差异具有统计学意义(P0.05);营养类药物应用年龄区间大,男女比例约为1:1。结论:本研究调查此三级甲等医院营养类药物的使用情况,为医生、患者和医院管理者在选择营养类药物提供了参考,为我国基本药物目录修改提供了依据。     

生物技术药物药代动力学研究的方法学和实验设计

生物技术药物由于自身具有的特点 ,使得其在体内的药代动力学机制比传统药物更为复杂。近年来 ,对于这类药物在体内的代谢机制的研究日趋增加 ,研究方法也日趋成熟。概述了生物技术药物的药代动力学研究方法以及实验设计的特点。     

Reasons for failure of antihypertensive treatment.

One hundred patients whose hypertension was originally well controlled were carefully screened when a routine clinic visit showed that their blood pressure was above 170/100 mm Hg. Simple misconceptions accounted for 75 failures: 38 did not know they had to continue their drugs, 14 thought they should not take antihypertensive drugs if they had not had a meal, 13 did not know which drugs controlled their blood pressure, and 10 believed it was better not to take their drugs on clinic days. Eleven patients were using racemic alpha-methyldopa, which was ineffective; 11 others said they could not afford the drugs; only three intentionally stopped their drugs because of unpleasant side effects. Patients need to be thoroughly informed about their treatment and the number of drugs kept to a minimum.