多药耐药基因多态性对利培酮及9-羟基利培酮稳态血药浓度的影响

多药耐药基因(MDR1)是跨膜转运体P-糖蛋白(P-gp)的编码基因。胃肠道和血脑屏障等组织中的P-gp可以将包括药物在内的外源性底物排出细胞,影响P-gp底物药物的吸收和分布。MDR1基因多态性会影响P-gp表达和活性,进而影响底物药物的血药浓度和临床疗效,非典型性抗精神药物利培酮及代谢物9-羟基利培酮都是P-gp底物,MDR1基因多态性与这类药物的血药浓度和临床疗效可能相关。     

儿童精神分裂症住院患者不同年代用药比较

目的探讨儿童精神分裂症住院患儿不同年代使用精神药物的变化趋势.方法回顾性分析相隔15年,1年内住院的儿童精神分裂症患儿病例资料共306例,比较两组使用精神药物情况、疗效和不良反应.结果15年前组用药前三位为氯丙嗪、奋乃静、舒必利,以典型抗精神病药为主;15年后组用药前三位为利培酮、氯氮平、奎硫平,以非典型抗精神病药为主.结论儿童精神分裂症住院患儿临床用药由典型抗精神病药转向非典型抗精神病药,利培酮、氯氮平等非典型抗精神病药可作为儿童精神分裂症的首选药物.     

抗精神病药所致药疹284例临床分析

本文对 6486例住院患者在使用抗精神病药治疗过程中所出现的皮疹作一回顾性调查 ,现将结果报道如下 :一、资料对象为 1 988年～ 2 0 0 0年我院住院使用抗精神药物治疗的患者共 6486例 ,通过查阅病历 ,发现药疹 2 84例 ,均符合下列入组标准 :1 .使用抗精神病药物之前无皮疹 ;2 .     

抗P-糖蛋白多肽模拟物的设计、合成与活性评价抗P-糖蛋白多肽模拟物的设计、合成与活性评价

目的设计、合成抗P-糖蛋白抗体（PHMA02）的多肽模拟物，测定其与P-gp结合活性。方法模建出PHMA02的互补决定簇（complementarity-determining region, CDR）三维结构，构建出抗P-gp的多肽模拟物。流式细胞仪测定其活性。结果该模拟物竞争P-gp抗体与P-gp结合，并部分阻断P-gp药物外排泵的功能。结果显示抗P-gp肽模拟物对P-gp具有相同结合活性。结论根据抗体CDR区的构象特征可以构建具有生物活性的肽模拟物。基于抗体结构的药物设计将推动药物研究的发展。     

精神科合理用药的若干问题

精神药物应用于精神科临床30多年来已有很大进展,但如何合理用药仍有许多问题尚未阐明,本文综合国内外文献,对其中某些问题作一介绍。一、抗精神病药的剂量问题不同国家、不同地区、不同医生之间,掌握抗精神病药剂     

366例住院患者精神药物的临床应用分析

目的了解住院患者精神药物的临床使用情况,为合理用药及科学管理提供参考。方法抽查1日住院患者处方,统计所有精神药物的用量及用药频率。分病种按限定日剂量(DDD)进行分析,病种以临床诊断为依据。结果住院患者精神分裂症占70%,情感障碍占18%,器质性精神障碍占5%,其它占7%。非典型抗精神病药使用占69%,传统抗精神病药使用占31%。新型抗抑郁药占94%,传统抗抑郁药占6%。结论传统抗精神病药用量大,副作用多,使用逐渐减少。非典型抗精神病药疗效肯定,副作用轻,患者依从性强,在使用中逐步占主导地位。新型抗抑郁药疗效肯定,不良反应少,有显著优势。精神药物药物利用指数(DUI)均未大于1,使用合理。     

精神药物研究进展

自氯丙嗪于1952年问世以来,精神病的治疗即进入了一个崭新的阶段。30余年来陆续发展了100余种药物,使精神病的治疗从“休克治疗时代”进入到“化学治疗时代”。不仅抗精神分裂症药陆续出现,在抗抑郁和抗焦虑症方面也发展了许多疗效卓著的药物。精神疾病的治疗状况已在近30年中大为改观。精神药物的分类目前尚未统一,本文仅涉及用于治疗各种精神失常的药物,按临床用途分为(1)抗精神病药,(2)抗焦虑药,(3)抗抑郁药三类,简介如下:     

抗精神病药致药物性肝炎的调查分析

目的分析抗精神病药致药物性肝炎的发病规律与临床特点,加深对药物性肝炎的认识。方法根据服药史、临床表现、血象、肝功能检验、腹部B型超声检查等,对抗精神病药物治疗过程中出现肝损害的112例患者进行回顾性分析。结果影响抗精神病药致药物性肝炎的相关因素有患者年龄、用药时间、抗精神药物种类。典型和非典型抗精神病药致药物性肝炎发生率分别75.0%和25.0%,其中以氯丙嗪（25.9%）和利培酮（8.9%）应用最多。大多数药物性肝炎出现于服药后1～3个月。结论认识影响抗精神病药致药物性肝炎有多种因素,在药物性肝损害的高发时期加强监测肝功能,做到早发现、早诊断、早治疗。     

抗精神病药物的评价与临床选择

抗精神病药物（antipsychotic drugs）是指用于治疗精神分裂症或精神病性症状的一类药物。20世纪50年代初出现的第一个精神药物氯丙嗪标志着现代精神药物治疗的里程碑。近10多年来,精神药物治疗学是临床医学领域发展最为迅速的学科之一,品种繁多、结构各异的新型抗精神病药物正不断研发、上市。     

盐城市第四人民医院住院老年精神分裂症患者抗精神病药物用药情况调查

目的分析盐城市第四人民医院住院老年精神分裂症患者抗精神药物使用情况,以期指导临床合理用药。方法回顾性分析2013年1月-2014年12月医院1061例老年抗精神药物使用情况,比较2年抗精神药物使用变化。结果 2年内联合用药比例分别是44.51%、43.23%,联合用药比例有所降低;从用药频率来看,目前主要抗精神药物是奥氮平(23.28%)、利培酮(20.45%)、喹硫平(17.15%)、阿立哌唑(7.72%),用药剂量分别为(13.4±2.2)mg/d、(2.6±0.6)mg/d、(345.5±43.4)mg/d、(11.5±2.1)mg/d。结论就目前来看,老年类抗精神药物单一用药还是占主导,且以非典型抗精神病药物为主,用药剂量均较小。     

2016-2018年南京市儿童医院小儿Ⅰ类切口手术围手术期抗菌药物使用合理性分析

目的分析2016-2018年南京市儿童医院小儿Ⅰ类切口手术围手术期抗生素的使用情况,为规范临床合理使用提供参考。方法回顾性分析2016-2018年南京市儿童医院小儿Ⅰ类切口手术病例,对比分析Ⅰ类手术抗生素的适应症、品种选择、首剂时机、应用时间和应用合理率。结果 2016-2018年抗生素的使用率分别为28.07%、28.19%、28.49%,抗生素使用率总体平稳。抗生素选用种类均为7种,主要为头孢唑林和头孢呋辛,构成比分别为35.69%、31.43%。2016-2018年Ⅰ类切口手术患者使用抗生素在术前30 min^2 h分别为525例(94.94%)、675例(95.88%)、636例(95.64%)。用药时间主要为<48 h,≤24 h的例数为827例,构成比为43.03%,24~48 h的的例数为1 051例,构成比为54.68%。2016-2018年抗生素应用合理率依次为98.19%、98.01%、98.35%。结论 2016-2018年南京市儿童医院小儿Ⅰ类切口手术围手术期抗生素使用种类无显著差异,在抗生素选择、应用时间、首剂时机等方面执行较好。     

抗消化性溃疡药物的相互作用评价

目的：评价消化性溃疡药物的相互作用。方法：通过查阅近期国内、外相关文献对消化性溃疡药物的相互作用进行评价、分析。结果：治疗消化性溃疡的药物可从通过改变胃肠道pH值，影响药物代谢酶、P-蛋白、吸附等方面与其他药物发生相互作用。结论：消化性溃疡药物相互作用临床较常见，在使用时应当注意。     

Interactions between P-glycoprotein substrates and other cationic drugs at the hepatic excretory level

1. In the present study it was tested whether known P-glycoprotein (P-gp) substrates/MDR reversal agents interact with small (type 1) and bulky (type 2) cationic drugs at the level of biliary excretion in the rat isolated perfused liver model (IPRL). The studies were performed with model compounds tri-n-butylmethylammonium (TBuMA) (a relatively small type 1 organic cation), rocuronium (Roc) (a bulky type 2 organic cation) and the classical P-gp substrate doxorubicin (Dox).
2. Inhibitors were given in a 4 fold molar excess to the substrate studied. To minimize an interaction of the substrates at the hepatic uptake level, the competing compounds were added when over 55% to 85% of the administered dose of the model compounds had been removed from the perfusate and taken up by the liver.
3. We found a mutual interaction between TBuMA and procainamidethobromide (PAEB), both type 1 cationic compounds during biliary excretion. Interestingly, type 2 compounds, such as rocuronium, clearly inhibited type 1 cationic drugs as well as Dox secretion into bile, whereas type 1 compounds did not significantly inhibit type 2 drug excretion into bile. The type 1 cations PAEB and TBuMA only moderately inhibited Dox biliary excretion. Dox did not inhibit the biliary excretion of the type 2 agent rocuronium whereas rocuronium reduced Dox biliary excretion by 50% compared to controls.
4. MDR substrates/reversal agents like verapamil, quinine, quinidine and vinblastine strongly reduced both type 1 and type 2 organic cation excretion into bile. Dox secretion into bile was also profoundly reduced by these drugs, vinblastine being the most potent inhibitor in general.
5. The lack of mutual inhibition observed in some combinations of substrates may indicate that major differences in affinity of the substrates for a single excretory system exist. Alternatively, multiple organic cation transport systems with separate substrate specificities may be involved in the biliary excretion of amphiphilic drugs. Furthermore, the present study revealed a clear positive correlation between the lipophilicity of the potential inhibitors studied and their respective inhibitory activity on the biliary excretion of the model drugs investigated.
6. Our data are compatible with a potential involvement of P-glycoprotein in the hepatobiliary excretion of doxorubicin as well as of some type 1 and type 2 organic cations. Furthermore we postulate that the hydrophobic properties of the amphiphilic cationic drugs studied play a crucial role in the accommodation of these agents by P-glycoprotein and/or other potential cationic drug carrier proteins in the canalicular membrane.

     

Inhibition of P-Glycoprotein: Rapid Assessment of Its Implication in Blood-Brain Barrier Integrity and Drug Transport to the Brain by an In Vitro Model of the Blood-Brain Barrier

Purpose. The objective of this work was to assess, in vitro, the passage of P-glycoprotein dependent drugs across brain capillary endothelial cells, when these drugs are associated with a reversing agent. Methods. An in vitro model of the blood-brain barrier consisting of a coculture of brain capillary endothelial cells and astrocytes was used. Results. We demonstrate that P-glycoprotein expression is upregulated by the presence of astrocytes. Uptake in the cells and transport across endothelial cell monolayers of vincristine, cyclosporin A and doxorubicin were studied. Using S9788 or verapamil as reversing agents, we found an increase in vincristine transport across the endothelial cell monolayers. On the other hand, the association of S9788 or verapamil with cyclosporin A failed to increase the transport of this drug. An increase in the transport of doxorubicin from luminal to abluminal compartment was also observed, due to endothelial cell monolayer breakdown. Conclusions. Using this model, it is possible to predict the passage of a P-glycoprotein dependent drug to the brain or its sequestration in brain capillary endothelial cells when this drug is associated with a reversing agent, or its toxicity on the blood-brain barrier integrity.     

The multidrug transporter P-glycoprotein in pharmacoresistance to antiepileptic drugs

This review provides an overview of the knowledge on P-glycoprotein (P-gp) and its role as a membrane transporter in drug resistance in epilepsy and drug interactions. Overexpression of P-gp, encoded by the ABCB1 gene, is involved in resistance to antiepileptic drugs (AEDs), limits gastrointestinal absorption and brain access of AEDs. Although several association studies on ABCB1 gene with drug disposition and disease susceptibility are completed to date, the data remain unclear and incongruous. Although the literature describes other multidrug resistance transporters, P-gp is the main extensively studied drug efflux transporter in epilepsy.     

The role of changes in the functional activity and the amount of p-glycoprotein in drug pharmacokinetics

Data on the structure of P-glycoprotein, the mechanisms of interaction with drugs, the general properties of substrates, the role in the distribution of drugs, and the modulation of their interactions are summarized. Being an ATP-dependent transport agent in the reverse yield, P-glycoprotein participates in the intestinal secretion, limitation of the permeability of histohematic barriers, and the renal and bile excretion of exogenous substrates, thus protecting the organism against xenobiotics. The interactions of drugs on the level of P-glycoprotein either leads to a decrease in these effects, when this transporter is activated by one of the drugs, or causes undesired reactions if P-glycoprotein is inhibited. Poly- or mononucleotide polymorphism of MDRI gene encoding P-glycoprotein can lead to a change in the pharmacokinetics of related substrates. Pharmacotherapy must take into account both the substrate specificity of drugs with respect to P-glycoprotein and the individual features of patients, in particular, race and sex (allele homozygotes versus heterozygotes).     

利伐沙班与抗癫痫药物相互作用的研究进展

心房颤动（房颤）导致的卒中是其严重并发症,非瓣膜性房颤导致脑梗死患者并发癫痫的风险比其他原因卒中患者更高,可能需要利伐沙班联合抗癫痫药物治疗。新型口服抗凝药物利伐沙班是口服直接Xa因子抑制剂,同时是CYP3A4和P-糖蛋白（P-gp）的底物,某些抗癫痫药物对CYP3A4和/或P-gp有诱导作用,与利伐沙班合用,可使利伐沙班血药浓度下降,血栓风险增加。对利伐沙班与丙戊酸钠、卡马西平、苯巴比妥、奥卡西平、左乙拉西坦以及其他抗癫痫药物合用的相互作用进行综述,并根据相关研究和病例报道给出推荐意见,为临床合理用药提供参考。     

Mechanism of inhibition of P-glycoprotein-mediated drug transport by protein kinase C blockers

P-glycoprotein is a membrane ATPase that transports drugs out of cells and confers resistance to a variety of chemically unrelated drugs (multidrug resistance). P-glycoprotein is phosphorylated by protein kinase C (PKC), and PKC blockers reduce P-glycoprotein phosphorylation and increase drug accumulation. These observations suggest that phosphorylation of P-glycoprotein stimulates drug transport. However, there is evidence that PKC inhibitors directly interact with P-glycoprotein, and therefore the mechanism of their effects on P-glycoprotein-mediated drug transport and the possible role of phosphorylation in the regulation of P-glycoprotein function remain unclear. In the present work, we studied the effects of different kinds of PKC inhibitors on drug transport in cells expressing wild-type human P-glycoprotein and a PKC phosphorylation-defective mutant. We demonstrated that PKC blockers inhibit drug transport hy mechanisms independent of P-glycoprotein phosphorylation. Inhibition by the blockers occurs by (i) direct competition with transported drugs for binding to P-glycoprotein, and (ii) indirect inhibition through a pathway that involves PKC inhibition, but is independent of P-glycoprotein phosphorylation. The effects of the blockers on P-glycoprotein phosphorylation do not seem to play an important role, but the PKC-signaling pathway regulates P-glycoprotein-mediated drug transport.     

白血病细胞多药耐药逆转方法的研究进展

白血病细胞耐药的产生是药物治疗中的一大阻碍,耐药细胞过表达的跨膜转运蛋白（主要为P-糖蛋白）导致胞内药物浓度降低是产生耐药的主要原因。此外,凋亡基因的异常表达、药物作用靶点的改变也产生多药耐药（MDR）。针对这些特点寻找合适的药品与化疗药合用以增加肿瘤细胞对化疗药的敏感性,或者利用高分子材料改变释药系统,以及开发新型药物是逆转白血病细胞耐药的主要手段。通过对逆转白血病MDR的方法进行探讨,旨在为白血病治疗提供新思路。