Kinetics and Mechanisms of Acetylcholinesterase and Butyrylcholinesterase Inhibition by Cardiovascular Drugs and Benzodiazepines

The goal of this work is to determine enzyme kinetics and mechanisms of acetylcholinesterase and butyrylcholinesterase inhibition by five cardiovascular drugs, lovastatin, simvastatin, amlodipine besylate, nifedipine, and hydralazine hydrochloride, and two benzodiazepines, diazepam and chlordiazepoxide hydrochloride. All drugs in this study are reversible mixed‐type inhibitors of acetylcholinesterase and butyrylcholinesterase. The pK_i values for acetylcholinesterase and butyrylcholinesterase inhibition by the cardiovascular drugs are linearly correlated with the molecular weights of the drugs with the slopes of 0.005 and 0.0021, respectively. Therefore, van der Waals' interactions between acetylcholinesterase and the cardiovascular drugs are stronger than those between butyrylcholinesterase and the drugs. This is probably due to a smaller active site gorge and a more significant peripheral anionic substrate binding site of acetylcholinesterase than those of butyrylcholinesterase. The fact that the pK_i values for both butyrylcholinesterase and acetylcholinesterase inhibition by the cardiovascular drugs are linearly correlated with each other suggests that both enzyme inhibition reactions proceed via a common mechanism. Furthermore, amlodipine besylate may be useful in Alzheimer's disease treatment similar to donepezil.     

Adsorption study of acetylcholine and cholinergic and anticholinergic drugs onto an electrode surface

As a type of interaction of acetylcholine and cholinergic and anticholinergic drugs with a charged surface, their adsorption onto a gold electrode has been examined by measuring the specular reflectivity and differential capacity of the electrode-solution interface.Based on the adsorption potential profiles, the drugs have been divided into three groups: (I) carbamylcholine and methacholine; (II) tetraethylammonium ion and hexamethonium; (III) nicotine, atropine, scopolamine and pilocarpine. Group I includes cholinergic drugs. Group II and III include antichilinergic drugs whose adsorptivity is stronger than that of acetylcholine. The results of the adsorption of acetylcholine and drugs onto a charged electrode surface should provide information about the competitive inhibitory effects on the attachement of acetylcholine to receptor sites.     

壳聚糖基质与蛋白质药物的释放

为了达到治疗的目的,很多蛋白质药物正在被广泛地研究,但是目前蛋白质药物仍然存在着很多问题,如容易变性,被蛋白酶降解而失去疗效等等。如果使用合适的药物载体,就可以保护蛋白质药物不被酶降解并能控制药物的释放,达到缓释或者控释的目的,这将有助于延长药物在体内的生物活性。壳聚糖作为天然的生物大分子,被广泛地应用在生物材料、制药工业和医疗卫生领域中。本文主要介绍了壳聚糖基质具有适合作为药物缓释载体的特性,并分析了影响药物包封率和微球释放药物速率的因素。     

药物分子设计和核酸的分子识别分析

分子识别分析理论应用于药物分子设计是新药开发的要求，也是分析化学一个极具潜力的发展方向，分子识别分析不仅为药物分子设计提供了生物大分子的组成，结构基基本信息，还为了解药物分子与生物大分子相互作用位点及作用方式提供了模型，本文评述了与药物分子设计中有关的核酸物质的分子识别分析，它们是设计好的抗癌药物的基础。     

Photophysical properties and photobiological behavior of amodiaquine, primaquine and chloroquine

This article describes the results of a coupled photophysical and photobiological study aimed at understanding the phototoxicity mechanism of the antimalarial drugs amodiaquine (AQ), primaquine (PQ) and chloroquine (CQ). Photophysical experiments were carried out in aqueous solutions by steady-state and time-resolved spectrometric techniques to obtain information on the different decay pathways of the excited states of the drugs and on the transient species formed upon laser irradiation. The results showed that all three drugs possess very low fluorescence quantum yields (10(-2)-10(-4)). Laser flash photolysis experiments proved the occurrence of photoionization processes leading to the formation of a radical cation in all three systems. In the case of AQ the lowest triplet state was also detected. Together with the photophysical properties the photobiological properties of the antimalarial drugs were investigated under UV irradiation, on various biological targets through a series of in vitro assays. Phototoxicity on mouse 3T3 fibroblast and human keratinocyte cell lines NCTC-2544 was detected for PQ and CQ but not for AQ. In particular, PQ- and CQ-induced apoptosis was revealed by the externalization of phosphatidylserine. Furthermore, upon UV irradiation, the drugs caused significant variations of the mitochondrial potential (Deltapsi(mt)) measured by flow cytometry. The photodamages produced by the drugs were also evaluated on proteins, lipids and DNA. The combined approaches were useful in understanding the mechanism of phototoxicity induced by these antimalarial drugs.     

毒品与化学*

毒品与化学的种种纠葛在2018年中国毒品形势报告中得到了淋漓尽致的体现,因此为做好禁毒工作,必须厘清化学与毒品的关系。从为什么毒品是化学品(毒品的本质),毒品检验和识别,毒品成瘾的本质,由传统毒品到新型毒品的转变等4个方面系统阐述毒品与化学的关系。     

Recent studies of the electrospray ionisation behaviour of selected drugs and their application in capillary electrophoresis-mass spectrometry and liquid chromatography-mass spectrometry

This review is concerned with recent studies of electrospray ionisation-mass spectrometry (ESI-MS) of selected small molecular mass drugs and their application in qualitative and quantitative analytical methods using the techniques liquid chromatography mass spectrometry (LC-ESI-MS) and capillary electrophoresis mass spectrometry (CE-ESI-MS). The publications reviewed are taken from the Web of Knowledge database for the year 2006. The drugs have molecular mass less than 1000 Da and are chosen according to selected drug classifications in which they give ESI signals primarily as [M+H]+ ions. The drug classifications are antibiotics/antibacterials, steroids, anti-tumour drugs, erectile dysfunction agents, anti-epileptic drugs, antiasthmatic drugs, psychoactive drugs and miscellaneous drugs. Details are given on the fragmentations, where available, that these ionic species exhibit in-source and in ion trap, triple quadrupole and time-of-flight mass spectrometers. Analytical methods for the detection and determination of these small molecular mass drug molecules are also discussed, where appropriate, under the particular drug classifications. Analytical information on, for example, sample concentration techniques, separation conditions, recoveries from biological media and limits of detection/quantitation (LODs and LOQs) are provided.     

A new way to detect the interaction of DNA and anticancer drugs based on the decreased resonance light scattering signal and its potential application

A novel assay has been developed to detect the interaction of DNA and anticancer drugs based on the decreased resonance light scattering (RLS) technique. The proposed method can be used to study those drugs which do not produce a RLS-signal after binding to DNA. RLS was used to monitor the interaction of five anticancer drugs with DNA. The reaction between anticancer drugs and DNA took place in BR buffer solution. From the RLS assay, the sequence of five anticancer drugs activities was as follows: CTX < MTX < Pt < MMC < 5-Fu. Mammary cancer cell DNA (mcDNA) was involved to validate the RLS assay. The results showed that the sensitivities of the five anticancer drugs targeting both mcDNA and ctDNA increased in the same order. However the sensitivity of each drug to mcDNA was higher than that to ctDNA It is a significant innovation of the RLS method to detect the interaction of DNA and anticancer drugs and to obtain drug sensitivity, which provides new strategies to screen DNA targeted anticancer drugs.     

Cyclodextrins and the Biopharmaceutics Classification System of Drugs

Although the biopharmaceutics classification system (BCS) was originally developed for solid oral dosage forms this system can be extended to other types of drug delivery forms. According to the BCS aqueous solubility and permeability are the most important parameters affecting drug bioavailability. Cyclodextrins can enhance the aqueous solubility of lipophilic drugs without changing their intrinsic ability to permeate biological membranes. Thus, through cyclodextrin complexation it is possible to move Class II drugs, and sometimes even Class IV drugs, into Class I. However, cyclodextrins can decrease bioavailability of Class I drugs and will in most cases not improve bioavailability of Class III drugs. Through formation of drug/cyclodextrin/polymer ternary complexes it is possible to enhance the complexation efficacy of cyclodextrins and at the same time improve drug bioavailability from cyclodextrin containing drug formulations.     

Interaction of carbamazepine and phenobarbital in rabbits

The interaction of carbamazepine and phenobarbital in rabbits was investigated. The drugs were administered to the rabbit orally as a single dose. By simultaneous administration the sequence of drugs was varied, with an interval between doses of 15 min. The doses of carbamazepine and phenobarbital were 100 and 25 mg, respectively. It was established that phenobarbital appears to be an inductor for carbamazepine independently sequence of administration of the drugs. Carbamazepine reveals inductive properties for phenobarbital in the case where phenobarbital enteres in the organism first. It was ascertained also that, by simultaneous administration, these drugs reduce absorption of each other in plasma.     

Potential drugs and nondrugs: prediction and identification of important structural features

Using decision trees, a model to discriminate between potential drugs and nondrugs has been developed. Compounds from the Available Chemical Directory and the World Drug Index databases were used as training set; the molecular structures were represented using extended atom types. The error rate on an independent validation data set is 17.4%. The number of false negatives can be reduced by penalizing the misclassification of drugs so that 92 out of 100 potential drugs are correctly recognized. At the same time, 34 out of 100 nondrugs are classified as potential drugs. The predictions of the model can be used to guide the purchase or selection of compounds for biological screening or the design of combinatorial libraries. The visualization of the generated models in the form of colored trees allowed us to identify a few, surprisingly simple features that explain the most significant differences between drugs and nondrugs in the training set: Just by testing the presence of hydroxyl, tertiary or secondary amino, carboxyl, phenol, or enol groups, already three quarters of all drugs could be correctly recognized. The nondrugs, on the other hand, are characterized by their aromatic nature with a low content of functional groups besides halogens. The general applicability of the model is shown by the predictions made for several Organon databases.     

Ruthenium anticancer compounds: myths and realities of the emerging metal-based drugs

Ruthenium anticancer drugs have attracted an increasing interest in the last 20 years and two of them have entered clinical trials. Compared to platinum drugs, the complexes based on ruthenium are often identified as less toxic and capable of overcoming the resistance induced by platinum drugs in cancer cells. These activities were attributed to the transportation to tumour cells by transferrin and to the selective activation to more reactive species by the reducing environment of solid tumours as compared to healthy tissues. Ruthenium anticancer drugs have been almost always designed to mimic platinum drugs, particularly for targeting DNA. Indeed, none of the above properties has never been clearly demonstrated even for the ruthenium drugs that entered clinical trials. The suggestion for the future is to change the perspective when designing new chemical entities, abandoning the philosophy that guided the actual panel of ruthenium drugs and to look further into the fine mechanism by which the most relevant ruthenium complexes available kill the target tumour cells, then focusing on targets selective of tumour cells and responsible for cell growth and malignancy.     

溴的药物动力学及药效动力学

本世纪以来,含溴药物及其临床应用的研究得到了空前的发展,在2001-2010年十年间,有关含溴药物的药物动力学和药效动力学中文文献数亦占相关文献总数的80％左右,目前研究的药物主要集中于呼吸系统用药和神经肌肉阻断药.综述了溴化物的生物半衰期、8种药物的药物动力学和5种药物的药效动力学研究概况.     

金属抗癌药物设计的新策略和新趋势*

金属药物有许多其它药物无法比拟的独特性质,以顺铂为代表的铂类抗癌药物在癌症临床化疗中发挥了巨大作用。但是铂类药物的毒副作用严重限制了它们的实际疗效和适用范围,因此需要继续研究具有不同作用机理的新型金属抗癌药物,以改良或补充现有铂类药物的性能。本文重点介绍了近年来设计金属抗癌药物的一些新策略,包括改变铂类药物与DNA的作用模式、改进铂类药物对肿瘤的靶向性、研发非铂类金属抗癌药物和寻找DNA以外的作用靶标等。这些内容体现了该领域的最新发展趋势,为从事金属抗癌药物开发研究的科技人员提供了有益的参考信息。     

饲料中常见的兽药及其检测技术

根据治疗、预防疾病和促进动物生长的需要,兽药在饲料中得到广泛应用。阐述了饲料中常见兽药种类及其化学特性,兽药在饲料中的应用情况及其对人体的危害性。对饲料中兽药的检测技术及其进展进行了简要介绍。     

荧光光谱在研究氯霉素与沙拉沙星间拮抗作用中的应用

氯霉素(CHL)和沙拉沙星(SLFX)均能够猝灭牛血清白蛋白(BSA)的荧光. 当两种药物共存时使BSA荧光进一步猝灭, 据此利用荧光光谱法研究了氟喹诺酮类药物SLFX与CHL间相互作用. 结果表明: 两种药物间存在拮抗作用, 使药物与蛋白的结合稳定性增加, 致使能够转运到作用部位产生药理效应的游离型药物含量减少, 造成药效降低; 药物对蛋白荧光的猝灭属于静态猝灭; 药物与蛋白结合位点数约为1. 根据Forster非辐射能量转移理论, 确定了药物与蛋白之间的结合距离r, 药物间拮抗作用的存在使r值降低, 结合距离减小. 同步荧光光谱研究表明, 药物间的拮抗作用对蛋白质构象产生影响, 使蛋白质分子伸展, 疏水性降低.     

Photophysical and photobiological behavior of antimalarial drugs in aqueous solutions

This article describes the results of a combined photophysical and photobiological study aimed at understanding the phototoxicity mechanism of the antimalarial drugs quinine (Q), quinacrine (QC) and mefloquine (MQ). Photophysical experiments were carried out in aqueous solutions by stationary and time-resolved fluorimetry and by laser flash photolysis to obtain information on the various decay pathways of the excited states of the drugs and on transient species formed on irradiation. The results obtained showed that fluorescence and intersystem crossing account for all the adsorbed quanta for Q and MQ (quantum yield of about 0.1 and 0.9, respectively) and only for 24% in the case of QC, which has a negligible fluorescence quantum yield (0.001). Laser flash photolysis experiments evidenced, for QC and MQ, the occurrence of photoionization processes leading to the formation of the radical cations of the drugs. The effects of tryptophan and histidine on the excited states and transient species of the three drugs were also investigated. In parallel, the photoactivity of the antimalarial drugs was investigated under UV irradiation on various biological targets through a series of in vitro assays in the presence and in the absence of oxygen. Phototoxicity on 3T3 cultured fibroblasts and lipid photoperoxidation were observed for all the drugs. The photodamage produced by the drugs was also evaluated on proteins by measuring the photosensitized cross-linking of spectrin. The combined approaches were proven to be useful for understanding the mechanism of phototoxicity induced by the antimalarial drugs.     

靶向抑制拓扑异构酶和端粒酶的钌配合物研究进展

金属配合物抗肿瘤研究,尤其是铂类药物,已取得了相对令人瞩目的成功,但同时也面临着包括耐药性和毒副作用等诸多问题。近年来钌配合物作为新的抗癌药物引起了人们的注意。在非铂系药物中,金属钌配合物是最有前途的抗癌药物之一,国际上普遍认为钌和钌的配合物属于低毒性,容易吸收并在体内很快排泄。本文将着重介绍钌配合物与DNA结合后进一步引发的细胞内核酶活性抑制研究,从新的角度来诠释钌配合物的抗肿瘤研究最新进展。     

靶向抑制拓扑异构酶和端粒酶的钌配合物研究进展

金属配合物抗肿瘤研究,尤其是铂类药物,已取得了相对令人瞩目的成功,但同时也面临着包括耐药性和毒副作用等诸多问题。近年来钌配合物作为新的抗癌药物引起了人们的注意。在非铂系药物中,金钌配合物;拓扑异构酶;G-四链体;端粒酶属钌配合物是最有前途的抗癌药物之一,国际上普遍认为钌和钌的配合物属于低毒性,容易吸收并在体内很快排泄。本文将着重介绍钌配合物与DNA结合后进一步引发的细胞内核酶活性抑制研究,从新的角度来诠释钌配合物的抗肿瘤研究最新进展。     

Preformulation compatibility studies of etamsylate and fluconazole drugs with lactose by DSC

Chemical compatibility of two drugs, namely, etamsylate and fluconazole was studied with lactose as excipient, employing differential scanning calorimetry (DSC) and X-ray diffraction (XRD) techniques. The DSC patterns recorded for the mixtures of both the drugs with the common excipient (lactose) indicated that fluconazole as well as etamsylate were incompatible with lactose at high temperatures. X-ray diffraction patterns recorded for pure drugs and lactose and the mixtures of individual drugs with lactose prepared at room temperature by intimate grinding of the components revealed incompatibility of both the drugs with lactose also at room temperature. This revised version was published online in July 2006 with corrections to the Cover Date.