药物相互作用的临床意义(英文)

阿片类物质已经被证实在临床上能与多种药物发生相互作用,多数是药代动力学上的相互作用,也有部分药物是在药效学方面发生的相互作用。药代动力学上的相互作用包括对肝药酶P450的抑制或诱导。药效学上的相互作用包括对中枢神经系统附加的抑制作用。抑制肝药酶活性的药物能引起血浆中药物浓度的增高,易导致过量或中毒。诱导肝药酶活性的药物能加速药物的代谢,降低血浆中药物浓度和药物有效性;对阿片物质来说,可能导致戒断症状。药效学的相互作用发生在同时使用抑制呼吸的药物(如苯二氮卓艹类药物)和丁丙诺啡或美沙酮的情况下,两者共同滥用可导致死亡。本文还讨论了HIV和阿片治疗之间相互作用的例子,这种相互作用可导致依从性降低以及较差的临床结局。苯二氮卓艹类药物与可加强心血管效应的药物之间的相互作用也需要被考虑到。     

半个世纪的争议——苯二氮()类药物临床应用50年

上个世纪50年代,苯二氮(艹卓)类药物进入临床使用,由于此类药物高效、安全、耐受性良好,目前苯二氮(艹卓)类药物已成为抗焦虑和失眠领域应用最广泛的药物。根据统计,全球有超过5000万人服用苯二氮(艹卓)类药物。苯二氮(艹卓)类药物目前仍是失眠和抗焦虑的一线治疗药物。 然而,由于许多原因,苯二氮(艹卓)类药物只是用于短期的抗焦虑及失眠的治疗,这是因为人们担心长期使用     

专家论坛:焦虑症及其治疗药物

传统的药物(如苯二氮(艹卓)类、三环类药物)有很多不良反应10多年来焦虑症药物治疗有了实质性变化,研究证实.SSRI治疗抑郁症和焦虑症是有效和安全的.现在SSSI已成为治疗惊恐障碍的一线药物.同样在广泛性焦虑症的长期治疗中,文拉法辛.帕罗西汀和某些三环类药物优于苯二氮(艹卓)类.作者认为文拉法辛、帕罗西汀、曲唑酮、黛力新以及某些三环类药物可考虑作为广泛性焦虑症的一线药物.苯二氮(艹卓)类药起效快,能立即减轻焦虑症状可短期应用或与SSRI短期联用.     

门诊苯二氮（艹卓）类药物应用分析

目的 了解我院门诊苯二氮（艹卓）类药物（BZD）的使用情况,评价其合理性.方法 对我院2009年1月1日至12月31日使用苯二氮（艹卓）类药物的门诊处方共17 185张进行统计与分析.结果 苯二氮（艹卓）类药物广泛应用于精神科和心理科门诊,主要联合用药处方有苯二氮（艹卓）类与抗抑郁药7011张（40.80%）,苯二氮（艹卓）类与抗精神病药物6149张（35.78%）,不合理用药处方占所统计总处方数的1.32%.结论 苯二氮（艹卓）类药物在我院门诊的使用是基本合理的,但亦存在少数不合理用药现象,是造成苯二氮（艹卓）类药物滥用的主要原因.     

瑞马唑仑的临床研究进展

苯二氮卓类药物是麻醉领域最常用的药物之一。瑞马唑仑是一种新开发的超短效苯二氮卓类药，它具有起效快、恢复快、安全性高等特点，并且低血压、呼吸抑制等副作用少。本综述旨在概述瑞马唑仑的药代动力学、临床药理学作用机制和临床应用的研究进展。     

治疗精神疾病的药物

治疗精神疾病可用许多种药物,但常难于作出选择。本文根据临床对照试验的结果及医师的经验和意见作一介绍。 治疗焦虑的药物 焦虑是精神综合征(如抑郁或精神病)的一种症状,该综合征的特异性疗法通常比使用非特异性抗焦虑药(如苯二氮(艹卓)类)有效。需要药物治疗且与较特异的综合征无关的焦虑通常用一个苯二氮(艹卓)类药物治疗。虽然地西泮(安定,Valium)、氯氮(艹卓)(Librium)、阿普唑仑(Xandax)、氯氮(艹卓)酸     

精神病专科医院300例住院患者中应用苯二氮（艹卓）类药物情况分析

目的：探讨精神病专科医院住院患者应用苯二氮(艹卓)类药物的使用情况。方法：随机选取我院300例住院患者作为研究对象,通过住院精神病患者调查表分析住院精神病患者使用苯二氮(艹卓)类药物的整体情况。结果：我院精神病住院患者使用苯二氮(艹卓)类药物人数为110例、占比36.7%。药物共有4种,其中使用氯硝西洋的69例、占比62.7%;使用艾司唑仑的3例,占比2.7%;精神分裂症患者中使用苯二氮(艹卓)类药物83例,占比75.6%。结论：精神病专科医院住院患者应用苯二氮(艹卓)类药物能够起到一定作用,但不宜过度使用。     

高效液相色谱法测定正常志愿者血液中安定及其代谢物的浓度

<正> 安定是苯二氮(艹卓)类的主要药物,临床应用甚为广泛,有关其产生药物依赖性的报道日益增多,因此有必要对其药代动力学进行研究。本文报道了应用高效液相色谱法测定正常人一次口服安定的药代动力学。正常     

浅述苯二氮■类药物的依赖性

<正> 苯二氮■类药物是目前临床常用的镇静催眠药,因其药理作用理想,安全范围较大,治疗效果显著,因而临床用途较广,发展较快,是目前属于首位常用的一类镇静催眠药。 由于苯二氮(艹卓)类药物的广泛应用及滥用,随之而带来的依赖性问题也较为严重;至今已有10多种该类药广泛地用于临床,如苯甲二氮(艹卓)、氢氮(艹卓)、硝基安定、氢羟安定、舒乐安定、氢硝安定、氟苯安定、去甲羟安定和氟硝安定等,均具有较强的镇静催眠抗焦虑作用,已成为临床一类首选药物;如果不全面地考虑这类药物的利和弊,不严格掌握其适应症,用药不合理或误用,易产生一些不良反应,最严重和最常见的就是药物所致的依赖性。     

精神科门诊长期使用苯二氮[艹卓]类药物的病人的状况

目的：了解长期应用苯二氮[艹卓]类药物的精神科门诊病人的状况，便于在精神科更好管理和使用苯二氮[艹卓]类药物。方法：我们对安徽省精神卫生中心2004．10．1～2005．3．31门诊就诊的连续使用苯二氮[艹卓]类药物≥1．5年的门诊病人，随机整群抽取66名进行前瞻性调查，并分析所得。结果：长期应用苯二氮[艹卓]类药物精神科门诊病人中神经症、癔症病人占45．5％，分裂症、躁郁症占42．4％；40～59岁占47．0％，老年人（≥60岁）占28．8％；女性病人占66．7％；病程中应用过1～2种苯二氮[艹卓]类药物占81．8％，剂量≤2片／d占95．5％；苯二氮[艹卓]类药物停药失败的首要原因66．7％是停用药后失眠。精神科门诊长期应用苯二氮[艹卓]类药物病人主要是神经症、癔症、分裂症、躁郁症病人，女性、40～59岁占多数，老年人亦占相当部分，精神科门诊病人要停用苯二氮[艹卓]类药物首先需解决的问题是停药之后如何应对失眠。     

评价HPPH对细胞色素P450酶体外代谢活性的影响

目的:评价HPPH在体外对大鼠及人肝微粒CYP450酶的6种亚型酶活性的影响,预测使用HPPH可能出现的药物相互作用。方法:将注射用HPPH与CYP450酶的6种亚型的特异性探针底物非那西汀(CYP1A2)、甲苯磺丁脲(CYP2C9)、S-美芬妥因(CYP2C19)、右美沙芬(CYP2D6)、氯唑沙宗(CYP2E1)、咪达唑仑(CYP3A4)和睾酮(CYP3A4)与大鼠及人肝微粒进行孵育反应,采用HPLC-MS/MS法测定对应的7种代谢产物(对乙酰氨基酚、羟基甲苯磺丁脲、4-羟基美芬妥因、O-去甲基右美沙芬、6-羟基氯唑沙宗、1′-羟基咪达唑仑、6β-羟基睾酮)的浓度。结果:在本实验条件下,HPPH浓度为1.00~50.00μmol·L-1时,未发现其对大鼠的CYP1A2、CYP2C9、CYP2D6、CYP2E1、CYP3A4产生抑制作用。在本实验条件下,HPPH浓度为0.50~10.00μmol·L-1时,未发现其对人CYP1A2产生抑制作用;但对人CYP2C9、CYP2C19、CYP2D6、CYP2E1均存在抑制作用;对人CYP3A4,对底物咪达唑仑存在抑制作用,对底物睾酮未发现抑制作用。结论:HPPH对CYP450酶的抑制作用存在种属差异,在人体内HPPH与CYP450酶作用有待体内实验进一步证明。     

CYP450与药物相互作用

目的 探讨细胞色素P450（CYP450）与药物相互作用的关系.方法 检索国内外数据库中与药物相互作用的相关文献,并查阅相关书籍,总结CYP450酶与药物相互作用的关系.结果 CYP450与药物相互作用关系最密切的是酶系统,凡参与代谢的酶都与药物相互作用有关,其中最主要的是CYP1 A2,2C9,2C19,2D6,3A4.结论 充分了解药物的药理及药代动力学特点,当与可能发生相互作用的药物合用时,应密切监测患者的情况,必要时进行药物剂量调整或换用其他药物.     

Comparative effects of thiazolidinediones on in vitro P450 enzyme induction and inhibition.

Rosiglitazone and pioglitazone are thiazolidinediones used for treatment of noninsulin-dependent diabetes mellitus. These compounds, along with troglitazone, were evaluated for the ability to induce cytochrome P450 enzymes (P450) in primary human hepatocyte cultures and to inhibit P450 in human microsomes. In induction studies, all three thiazolidinediones caused a dose-dependent increase in CYP3A4 activity and immunoreactive protein. While troglitazone was the most potent, rosiglitazone and pioglitazone generally exceeded troglitazone in absolute CYP3A4 activity achieved at concentrations > or =10 microM. A comparable concentration-dependent increase in CYP2B6 immunoreactive protein was observed with all three thiazolidinediones. Microarray analysis revealed rifampin > troglitazone > pioglitazone > rosiglitazone in terms of CYP3A4 mRNA induction potential with 10 microM compound. Inhibition studies conducted for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP2A6, and CYP2E1 showed troglitazone to be the most nonselective and potent inhibitor followed by rosiglitazone and pioglitazone. In vitro, the thiazolidinediones were strong inhibitors of CYP2C8, with K(i) values between 1.7 and 5.6 microM, and of CYP3A4, with K(i) values between 1.6 and 11.8 microM. Troglitazone, in addition, inhibited CYP2C9 (K(i) 0.6 microM). Although the inhibitory effects of the thiazolidinediones have not been demonstrated clinically, our results suggest there is potential for interactions with CYP2C8 substrates. This is the first report of in vitro induction of P450 enzymes by rosiglitazone and pioglitazone. While only the induction of CYP3A4 by troglitazone has been demonstrated in vivo, these results suggest that other thiazolidinediones may have the potential to cause clinically significant drug interactions at sufficiently high doses.     

Evaluation of p450 inhibition and induction by artemisinin antimalarials in human liver microsomes and primary human hepatocytes

Artemisinin drugs have become the first-line antimalarials in areas of multidrug resistance. However, monotherapy with artemisinin drugs results in comparatively high recrudescence rates. Autoinduction of cytochrome P450 (P450)-mediated metabolism, resulting in reduced exposure, has been supposed to be the underlying mechanism. To better understand the autoinduction and metabolic drug-drug interactions (DDIs), we evaluated the P450s (particularly CYP2B6 and CYP3A4) inhibited or induced by two artemisinin drugs, Qing-hao-su (QHS) and dihydroartemisinin (DHA) using human liver microsome, recombinant P450 enzymes, and primary human hepatocytes. The results suggested that QHS was a weak reversible inhibitor of CYP2B6 (K(i) 4.6 μM), but not CYP3A4 (IC(50) ～ 50 μM) and did not show measurable time-dependent inhibition of either CYP2B6 or CYP3A4. DHA inhibited neither CYP2B6 nor CYP3A4 (IC(50) > 125 μM). In addition, it was found that QHS induced the activity of CYP3A4 (E(max) 3.5-fold and EC(50) 5.9 μM) and CYP2B6 (E(max) 1.9-fold and EC(50) 0.6 μM). Of the other P450s, UDP glucuronosyltransferases, and transporters studied, QHS and DHA had no significant effect except for minor induction of mRNA expression of CYP1A2 (E(max) 7.9-fold and EC(50) 5.2 μM) and CYP2A6 (E(max) 11.7-fold and EC(50) 4.0 μM) by QHS. Quantitative prediction of P450-mediated DDIs indicate autoinduction of QHS clearance with the AUC(i)/AUC ratio decreasing to 59%, as a result of a 1.9-fold increase in CYP3A4 and a 1.6-fold increase in CYP2B6 activity. These data suggest that QHS drugs are potential inducers of P450 enzymes, and the possible drug interactions (or lack thereof) with artemisinin drugs may be clinically relevant.     

CYP-mediated clozapine interactions: how predictable are they?

Despite the introduction of newer drugs, the atypical antipsychotic clozapine remains the most effective drug in psychotic patients who are resistant to treatment with conventional agents. Optimal therapeutic responses to clozapine have been reported with serum concentrations between 350 microg/L and 1000 microg/L. Clozapine is frequently combined with other drugs to enhance efficacy and reduce adverse reactions but pharmacokinetic interactions can have a significant impact on drug response. The majority of the interactions with clozapine are reported to be mediated by cytochrome P450 (CYP) enzymes. CYP1A2 has a major role in the oxidative metabolism of clozapine, with a minor contribution from CYP3A4, and possibly CYP2D6, CYP2C9 and CYP2C19. Interactions mediated by potent CYP1A2 inhibitors (such as fluvoxamine) or inducers (like cigarette smoke) appear to be consistent, predictable and usually clinically significant. There are many case reports of interactions between clozapine and weak CYP1A2 inhibitors or inducers which are also potent inhibitors or inducers of CYP3A4 or CYP2D6. Researchers often explain these observations on the basis of the CYP1A2 involvement. In addition, there are case reports of clinically significant interactions between clozapine and drugs that are not substrates, inhibitors or inducers of CYP1A2. These interactions are difficult to predict and may not be consistent, as reflected by the conflicting literature reports. Further research to elucidate individual differences in clozapine metabolism, with the potential to detect the dominant roles of CYPs other than CYP1A2, may assist us in predicting these interactions.     

Inhibitory effects of limonin on six human cytochrome P450 enzymes and P-glycoprotein in vitro

Among the various possible causes for drug interactions, pharmacokinetic factors such as inhibition of drug-metabolizing enzymes and transporters, especially cytochrome P450 (CYP) isoenzymes and P-glycoprotein (P-gp), are regarded as the most frequent and clinically important. Limonin is a widely used dietary supplement and one of the most prevalent citrus limonoids, which are known to have inhibitory effects on CYPs and P-gp. In this study, the in vitro inhibitory effects of limonin on the major human CYP isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) activities in human liver microsomes were examined using liquid chromatography–tandem mass spectrometry. The inhibitory effects of limonin on P-gp activity in a human metastatic malignant melanoma cell line WM-266-4 were examined using a calcein-AM fluorometry screening assay. It demonstrates that limonin has negligible inhibitory effects on human CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and P-gp. However, potent inhibition of CYP3A4 by limonin is observed with IC₅₀ values of 6.20 μM (CYP3A4/testosterone) and 19.10 μM (CYP3A4/midazolam). This finding has important implications with regard to food–drug interactions between limonin and several narrow therapeutic index drugs that are metabolized by CYP3A4.     

Drug interaction potential of toremifene and N-desmethyltoremifene with multiple cytochrome P450 isoforms

Toremifene is an effective agent for the treatment of breast cancer in postmenopausal women and is being evaluated for its ability to prevent bone fractures in men with prostate cancer taking androgen deprivation therapy. Due to the potential for drug-drug interactions, the ability of toremifene and its primary circulating metabolite N-desmethyltoremifene (NDMT) to inhibit nine human cytochrome P450 (CYP) enzymes was determined using human liver microsomes. Induction of CYP1A2 and 3A4 by toremifene was also investigated in human hepatocytes. Toremifene did not significantly inhibit CYP1A2 or 2D6. However, toremifene is a competitive inhibitor of CYP3A4, non-competitive inhibitor of CYP2A6, 2C8, 2C9, 2C19 and 2E1 and mixed-type inhibitor of CYP2B6. CYP inhibition by NDMT was similar in magnitude to toremifene. Toremifene did not induce CYP1A2 but increased CYP3A4 monooxygenase activity and gene expression in drug-exposed human primary hepatocytes. Although clinical doses of toremifene produce steady state exposures to toremifene and NDMT that may be sufficient to cause pharmacokinetic drug-drug interactions with other drugs metabolised by CYP2B6, CYP2C8, CYP3A4, CYP2C9 and CYP2C19, these data indicate that toremifene is unlikely to play a role in clinical drug-drug interactions with substrate drugs of CYP1A2 and CYP2D6.     

Molecular modeling of human cytochrome P450-substrate interactions

The results of homology modeling of 10 human cytochrome P450 (CYP) enzymes involved in the Phase 1 metabolism of drugs and other foreign compounds are reported. The models have been constructed from the CYP102 hemoprotein domain template for which the substrate-bound crystallographic coordinates are available. Selective substrates of individual human P450s: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, and CYP4A11 are all shown to fit within the corresponding enzymes' active sites in such a manner that is consistent with reported experimental data for both known pathways of substrate metabolism and from the results of site-directed mutagenesis, either in those particular human P450 enzymes concerned or for ones within the same subfamily. The self-consistency of these homology models indicates that they may have potential utility for the pre-screening of novel drug structures.     

An in vitro evaluation of cytochrome P450 inhibition and P-glycoprotein interaction with goldenseal, Ginkgo biloba, grape seed, milk thistle, and ginseng extracts and their constituents

Drug-herb interactions can result from the modulation of the activities of cytochrome P450 (P450) and/or drug transporters. The effect of extracts and individual constituents of goldenseal, Ginkgo biloba (and its hydrolyzate), grape seed, milk thistle, and ginseng on the activities of cytochrome P450 enzymes CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 in human liver microsomes were determined using enzyme-selective probe substrates, and their effect on human P-glycoprotein (Pgp) was determined using a baculovirus expression system by measuring the verapamil-stimulated, vanadate-sensitive ATPase activity. Extracts were analyzed by HPLC to standardize their concentration(s) of constituents associated with the pharmacological activity, and to allow comparison of their effects on P450 and Pgp with literature values. Many of the extracts/constituents exerted > or = 50 % inhibition of P450 activity. These include those from goldenseal (normalized to alkaloid content) inhibiting CYP2C8, CYP2D6, and CYP3A4 at 20 microM, ginkgo inhibiting CYP2C8 at 10 microM, grape seed inhibiting CYP2C9 and CYP3A4 at 10 microM, milk thistle inhibiting CYP2C8 at 10 microM, and ginsenosides F1 and Rh1 (but not ginseng extract) inhibiting CYP3A4 at 10 microM. Goldenseal extracts/constituents (20 microM, particularly hydrastine) and ginsenoside Rh1 stimulated ATPase at about half of the activity of the model substrate, verapamil (20 microM). The data suggest that the clearance of a variety of drugs may be diminished by concomitant use of these herbs via inhibition of P450 enzymes, but less so by Pgp-mediated effects.