常用抗精神病药物对肝功能影响的临床研究报道实录

在精神分裂症的治疗中,抗精神病药物治疗依然起主要作用。由于绝大多数抗精神病药物主要经肝脏进行分解代谢,且精神分裂症患者使用抗精神病药物治疗的周期长、剂量大以及联合用药多见,因此易对肝脏产生不同程度的毒性作用。本文通过查阅大量文献以及结合多年临床经验发现,几乎所有抗精神病药物均有导致肝功能损害的文献报道[1-32],其中典型抗精神病药物氯丙嗪及非典型抗精神病药物氯氮平     

双重作用的多巴胺D2/5-HT2A受体拮抗剂比较药效团分析

双重作用的多巴胺D₂/5-HT_2A受体拮抗剂是开发非典型抗精神病药物的有效途径,但最新研究显示, 非典型抗精神病药物将显著增加患者因心律失常及其他心脏疾病而猝死的风险,本文对D₂/5-HT_2A受体拮抗剂的药效团模型以及可能引起心血管风险的α_1A肾上腺素受体拮抗剂和hERG K⁺通道阻断剂的药效团模型进行比较分析,从药效团模型的角度分析多靶点药物的设计。     

新型非典型抗精神病药临床应用评价

目前非典型抗精神病药应用越来越广泛,有逐渐取代典型抗精神病药的趋势,不但用于精神分裂症的治疗,而且作为心境稳定剂治疗情感障碍。本文对非典型抗精神病药的概念、治疗阴性症状和较少锥体外系不良反应的机制、在精神分裂症和情感障碍治疗中的临床应用评价等文献进行综述,重点讨论奥氮平、利司哌酮、喹硫平、阿立哌唑、齐哌西酮、氨磺必利和哌罗匹隆。     

4种非典型抗精神病药物对精神分裂症患者代谢综合征的影响

目的比较研究4种非典型抗精神病药物对精神分裂症患者代谢综合征的影响。方法将160例精神分裂症患者分为4组,分别给予4种不同的非典型抗精神病药物(利培酮,喹硫平,阿立哌唑,齐拉西酮)单药进行治疗,在治疗4、8、12周末测身高、体重、血糖、血脂、血压。结果 4组间基线资料差异无显著统计学意义(P>0.05)。根据观察统计的结果可以看出,利培酮、喹硫平、阿立哌唑、齐拉西酮这4种药物都可以引起患者发生代谢综合征,12周后其患病率分别为20%、12.5%、10%、5%,这4种药物中利培酮所致的代谢综合征最高,齐拉西酮所致的代谢综合征最低,两者间具有统计学差异(P<0.05)。结论非典型抗精神病药物对于机体代谢存在一定的影响,其中以利培酮最为明显,阿立哌唑与齐拉西酮的影响较小,因此临床上对于药物的选择时要尤为注意。     

抗精神病类药物对患者血糖影响的观察与治疗分析

目的观察抗精神病类药物对患者血糖的影响。方法将2011年2月至2012年4月我院收治的160例精神病患者作为研究对象,将患者随机分为4组。4组患者分别使用喹硫平、奥氮平、利培酮和氯氮平进行治疗。监测患者3周、5周以及7周的血糖变化情况,对比分析这些抗精神病类药物对患者的血糖影响情况。结果喹硫平、奥氮平、利培酮和氯氮平这4种药物均可以使患者血糖升高,而且影响程度也都有所不同,其中奥氮平和氯氮平对血糖变化影响最为明显,利培酮对血糖变化影响较为明显,喹硫平对血糖变化影响最小。结论不同的抗精神病药物均可以使血糖升高,但是升高程度不尽相同,奥氮平和氯氮平对血糖的影响最大。     

非典型抗精神病药物血液系统不良事件信号挖掘和数据分析

目的 基于美国食品药品监督管理局（FDA）不良事件报告系统（FAERS）挖掘6种非典型抗精神病药物氯氮平、奥氮平、阿立哌唑、喹硫平、利培酮、齐拉西酮血液系统不良事件（ADE）信号,为临床安全使用非典型抗精神病药物提供参考。方法 下载2017年第1季度—2021年第3季度共19个季度的FAERS数据,采用比值失衡法中的报告比值比（ROR）法和综合标准法（MHRA）检测数据库中非典型抗精神病药物的ADE信号,统计并分析血液系统ADE信号的相关信息。结果 从FAERS数据库得到以氯氮平、奥氮平、阿立哌唑、利培酮、喹硫平、齐拉西酮6种非典型抗精神病药物为首要怀疑药物的ADE共389431例次,涉及报告病例116706例。血液系统ADE报告共计47144例次,涉及报告病例9658例。氯氮平产生血液系统信号22个,涉及报告病例6808例;奥氮平产生血液系统信号19个,涉及报告病例736例;喹硫平产生血液系统信号18个,涉及报告病例560例;阿立哌唑产生血液系统信号8个,涉及报告病例60例;利培酮产生血液系统信号3个,涉及报告病例16例;齐拉西酮产生血液系统信号1个,涉及报告病例5例。结论 基于真实世界的非典型抗精神病药物血液系统ADE信号挖掘有助于开展安全性评价,为临床安全应用提供参考。     

氯哌胺对15-甲基前列腺素F2α致泻和兴奋子宫作用的影响

氯哌胺(Loperamide)是一种新型止泻药,能拮抗15-M-PGF_2α引起的小鼠小肠内碳粉推进加速和腹泻,作用比吗啡和阿托品强,对离体大鼠回肠的抑制作用也比吗啡、阿托品强。氯哌胺能降低肠平滑肌张力,抑制离体大鼠回肠对15-M-PGF_2α的反应性,但却增强子宫平滑肌对15-M-PGF_2α的反应性。氯哌胺对离体大鼠子宫自发收缩活动低浓度兴奋、高浓度抑制。氯哌胺对15-M-PGF_2α促进大鼠空肠水和钠离子分泌也有拮抗作用,此作用不能被纳洛酮翻转。氯哌胺在小鼠的急性半数致死量为77.9 mg/kg。     

药物透过血脑屏障的3D-QSPR:H2受体拮抗剂的CoMFA和EVA分析

目的：药物透过血脑屏障是药代动力学的重要过程,H₂受体拮抗剂是作用于神经外周的抗溃疡药物,为避免该类药物透过血脑屏障损伤中枢神经,产生毒副作用,指导该类药物的设计与合成。方法和结果：选择了不依赖于实验参数的比较分子力场分析(CoMFA)方法和最近发展的本征值(EVA)方法,建立了有关的三维药代动力学性质(3D-QSPR)模型。CoMFA模型的统计参数为：交叉验证系数r²_cv=0.625,相关系数r2=0.893,F_3,17=47.270,标准偏差SE=0.254;EVA模型的统计参数为：交叉验证系数r²_cv=0.697,相关系数r²=0.922,F_3,17=67.766,标准偏差SE=0.203。结论：两种方法都能建立三维定量构效模型,EVA模型有更高的预测能力。     

依那普利对2型糖尿病大鼠血浆Ang II水平及血管、肾脏AT1受体表达的影响

目的研究依那普利对2型糖尿病大鼠血浆Ang II和AT₁受体表达的影响。方法用放射免疫法测定血浆Ang II水平，免疫组化法观察血管和肾脏AT₁受体表达。结果糖尿病大鼠血浆Ang II明显高于对照组，应用依那普利后大鼠血浆Ang II明显降低。免疫组化染色发现糖尿病大鼠血管内皮细胞、平滑肌细胞和肾脏AT₁受体表达明显增加，依那普利治疗组大鼠血管内皮细胞、平滑肌细胞和肾脏AT₁受体表达与正常组接近。结论糖尿病大鼠血浆Ang II升高，血管和肾脏AT₁受体表达增加，依那普利可降低糖尿病大鼠血浆Ang II水平，下调血管和肾脏AT₁受体表达。     

In vivo occupancy of dopamine D2 receptors by antipsychotic drugs and novel compounds in the mouse striatum and olfactory tubercles

Interaction with dopamine D₂-like receptors plays a major role in the therapeutic effects of antipsychotic drugs. We examined in vivo dopamine D₂ receptor occupancy of various established and potential antipsychotics in mouse striatum and olfactory tubercles 1 h after administration of the compound, using [³H]nemonapride as a ligand. All the compounds reduced in vivo binding of [³H]nemonapride in the striatum. When administered systemically, conventional antipsychotics, D₂ antagonists, nemonapride (ID₅₀: 0.034 mg/kg), eticlopride (0.047), haloperidol (0.11) and raclopride (0.11) potently inhibited [³H]nemonapride binding. The ‘atypical’ antipsychotics, risperidone (0.18), ziprasidone (0.38), aripiprazole (1.6), olanzapine (0.99), and clozapine (11.1) were less potent for occupying D₂-like receptors. New compounds, displaying marked agonism at 5-HT_1A receptors in addition to D₂ receptor affinity, exhibited varying D₂ receptor occupancy: bifeprunox (0.25), SLV313 (0.78), SSR181507 (1.6) and sarizotan (6.7). ID₅₀ values for inhibition of [³H]nemonapride binding in the striatum correlated with those in the olfactory tubercles (r=0.95, P<0.0001). These values also correlated with previously-reported in vitro affinity of the compounds at rat D₂ receptors (r=0.85, P=0.0001) and with inhibition of apomorphine-induced climbing in mice (r=0.79 P=0.0005). In contrast, there was no significant correlation between ID₅₀ values herein and previously-reported ED₅₀ values for catalepsy in mice. These data indicate that: (1) there is no difference in D₂ receptor occupancy in limbic versus striatal regions between most classical and atypical or potential antipsychotics; and (2) high occupancy of D₂ receptors can be dissociated from catalepsy, if the drugs also activate 5-HT_1A receptors. Taken together, these data support the strategy of simultaneously targeting D₂ receptor blockade and 5-HT_1A receptor activation for new antipsychotics.     

Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors

In the introductory section an overview is given of the strategies which have been proposed in the search for side-effect free antipsychotics. Special attention is paid to the role of predominant 5HT₂ receptor blockade over D₂ blockade. Whereas D₂ receptor blockade seems to be essential for the treatment of positive symptoms of schizophrenia, it also underlies the induction of extrapyramidal side effects (EPS). Predominant 5HT₂ receptor blockade may reduce the EPS liability and can ameliorate negative symptoms of schizophrenia. We further report a nearly complete list of neuroleptics that are on the European market and eight new antipsychotics that recently entered clinical trial, 5HT₂ and D₂ receptor binding affinity (K_i values) and the rank order in affinity for various neurotransmitter receptor subtypes are also discussed. For the eight new antipsychotics and for six reference compounds the complete receptor binding profile (including 33 radioligand receptor binding and neurotransmitter uptake models) is reported. Furthermore, for a series of 120 compounds the relative affinity for D₂ receptors and D₃ receptors (a recently cloned new dopamine receptor subtype) is compared. Finally, original findings are reported for the new antipsychotic risperidone and for haloperidol and clozapine on the in vivo occupation of neurotransmitter receptors in various brain areas after systemic treatment of rats or guinea pigs. The receptor occupation by the drugs was measured ex vivo by quantitative receptor autoradiography. The receptor occupancy was related to the motor activity effects of the test compounds (measurements were done in the same animals) and to the ability of the drugs to antagonize various 5HT₂ and D₂ receptor mediated effects. With risperidone a high degree of central 5HT₂ receptor occupation was achieved before other neurotransmitter receptors became occupied. This probably co-underlies the beneficial clinical properties of the drug. Antagonism of the various D₂ receptor-mediated effects was achieved at widely varying degrees of D₂ receptor occupancy, from just about 10% to more than 70%. For therapeutic application it may be of prime importance to carefully titrate drug dosages. Antipsychotic effects may be achieved at a relatively low degree of D₂ receptor occupancy at which motor disturbances are still minimal. With drugs such as risperidone that produce shallow log dose-effect curves, differentiation between the various D₂ receptor mediated effects may be made more easily, allowing EPS-free maintenance therapy of schizophrenic patients.     

The receptor mechanisms underlying the disruptive effects of haloperidol and clozapine on rat maternal behavior: A double dissociation between dopamine D2 and 5-HT2A/2C receptors

Many antipsychotic drugs disrupt active components of maternal behavior such as pup approach, pup retrieval and nest building at clinically relevant doses in postpartum female rats. However, the neurochemical mechanisms underlying such a disruptive effect remain to be determined. This study examined the neurochemical mechanisms that mediate the disruptive effects of haloperidol (a typical antipsychotic) and clozapine (an atypical antipsychotic) on rat maternal behavior. Postpartum rats were administered with haloperidol (0.2 mg/kg, sc) or clozapine (10.0 mg/kg, sc) together with either vehicle (saline or water), quinpirole (a selective dopamine D₂/D₃ agonist, 0.5 or 1.0 mg/kg, sc), or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT_2A/2C agonist, 1.0 or 2.5 mg/kg, sc), and their maternal behaviors were tested at different time points before and after drug administration. Haloperidol and clozapine treatment disrupted pup approach, pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, dose-dependently reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, dose-dependently reversed the clozapine-induced disruptions. Quinpirole pretreatment even exacerbated the clozapine-induced disruption of pup retrieval and nest building. These findings suggest a double dissociation mechanism underlying the disruption of haloperidol and clozapine on rat maternal behavior. Specifically, haloperidol disrupts maternal behavior primarily by blocking dopamine D₂ receptors, whereas clozapine exerts its disruptive effect primarily by blocking the 5-HT_2A/2C receptors. Our findings also suggest that 5-HT receptors are involved in the mediation of rat maternal behavior.     

Catalepsy produced by striatal microinjections of the D1 dopamine receptor antagonist SCH 23390 in neonatal rats

Systemic injection of the D₁ dopamine receptor antagonist SCH 23390 produces catalepsy that is of lesser magnitude in neonatal than in adult rats. The present experiments were conducted in order to determine if SCH 23390 would produce catalepsy in neonatal rats following intrastriatal injection and if the ontogenetic pattern of catalepsy induced by intrastriatal SCH 23390 would be similar to the pattern observed with systemic injections. Rat pups (11 or 28 days of age) were microinjected unilaterally with SCH 23390 (0.2, 1, 5 or 10 μg) and tested for catalepsy using the forepow-on-horizontal-bar test. The results demonstrated that robust catalepsy occurred at both ages following intrastriatal injection and that catalepsy induced by 5 μg SCH 23390 was of lesser magnitude in 11-day-olds than in 28-day-olds. A separate study assessed the distribution of [³H]SCH 23390 (5 μg) following intrastriatal injection in 28-day-olds. Results of the distribution study indicated that [³H]SCH 23390 was localized primarily within the striatum. Taken together, these results suggest that the striatal mechanisms for catalepsy produced by D₁ receptor blockade are present, but not fully mature, in preweanling rat pups.     

The effects of CCK-4 on dopamine D1 agonist-induced grooming are blocked by a CCKA receptor antagonist: Evidence for a novel CCK receptor subtype?

The neuropeptide cholecystokinin (CCK) has been shown to interact with dopamine in various ways, including attenuation of dopamine D₁ receptor-mediated vacuous chewing and grooming. While we have demonstrated a clear role for the CCK_A receptor in the attenuation of dopamine D₁ agonist-induced vacuous chewing, studies of grooming yielded anomolous results. We examined the effects of selective CCK receptor antagonists on the attenuation of SKF 38393-induced grooming by the CCK_B agonist CCK-4. Administration of SKF 38393 (5 mg/kg s.c.) to male Sprague-Dawley rats resulted in a significant increase in grooming which was reduced to control levels by CCK-4 (20 mg/kg i.p.). Pretreatment with either the CCK_A receptor antagonist devazepide or the CCK_B receptor antagonist L-365,260 significantly attenuated this effect over a range of doses (20, 100, 500 μg/kg i.p.). The suppression of dopamine D₁ agonist-induced grooming by CCK-4 does not appear to reflect a non-specific effect of anxiogenesis, as it was unaffected by the anxiolytic diazepam. The CCK receptor antagonists alone were without behavioural effect. Taken together with previous studies in models of anxiety and analgesia, our findings lend further support to the hypothesis that CCK-4 may act at a novel receptor subtype.     

Occupancy of dopamine D2 receptors by the atypical antipsychotic drugs risperidone and olanzapine: theoretical implications

Rationale To examine the D₂ occupancy of two commonly used antipsychotic medications and relate this to the D₂ occupancy by endogenous dopamine in schizophrenia.Objectives The aim of this study is to compare the occupancy of striatal D₂ receptors by the atypical antipsychotic medications risperidone and olanzapine at fixed dosages and to estimate the effect on D₂ occupancy by dopamine as a result of these treatments.Methods Seven patients with schizophrenia taking risperidone 6 mg/day and nine patients with schizophrenia taking olanzapine 10 mg/day underwent an [¹²³I]IBZM SPECT scan after 3 weeks of treatment. The specific to non-specific equilibrium partition coefficient (V₃) after bolus plus constant infusion of the tracer was calculated as [(striatal activity)/(cerebellar activity)]–1. D₂ receptor occupancy was calculated by comparing V₃ measured in treated patients to an age-corrected V₃ value derived from a group of untreated patients with schizophrenia, previously published, according to the following formula: OCC=1–(V₃ treated/V₃ drug free).Results V₃ was significantly lower in risperidone treated patients compared with olanzapine treated patients (0.23±0.06 versus 0.34±0.08, P=0.01), which translated to a significantly larger occupancy in schizophrenic patients treated with risperidone compared to olanzapine (69±8% versus 55±11%, P=0.01). Data from our previous study were used to calculate the occupancy of striatal D₂ receptors by antipsychotic medications required to reduce the occupancy of these receptors by endogenous dopamine to control values. In medication-free patients with schizophrenia, the occupancy of striatal D₂ receptors by endogenous dopamine is estimated at 15.8%. In healthy controls, the occupancy of striatal D₂ receptors by dopamine is estimated at 8.8%. In order to reduce the dopamine occupancy of striatal D₂ receptors in patients with schizophrenia to control values, 48% receptor occupancy by antipsychotic medications is required.Conclusions These data indicate that the dosage of these medications, found to be effective in the treatment of schizophrenia, reduces DA stimulation of D₂ receptors to levels slightly lower than those found in unmedicated healthy subjects.     

关于维生素D2有关物质检查方法的探讨

目的:探讨维生素D₂有关物质的各种检测方法。方法:采用高效液相色谱法,分别考察《中国药典》项下的正相色谱方法和《欧洲药典》项下的反相色谱方法,对维生素D₂有关物质检测结果的影响。结果:采用反相色谱系统,能够更多检出维生素D₂中的有关物质。结论:反相色谱方法更适用于维生素D₂的有关物质检测。     

Roles of BDNF, dopamine D3 receptors, and their interactions in the expression of morphine-induced context-specific locomotor sensitization

Drug seeking, craving, and relapse can be triggered by environmental stimuli that acquire motivational salience through repeated associations with the drug's effects. Previous studies indicated that the dopamine D₃ receptor (Drd3) might be involved in the expression of drug-conditioned responses in rats, and brain-derived neurotrophic factor (BDNF) could modulate Drd3 expression in the nucleus accumbens (NAc). However, the involvement of neural regions with Drd3 activation and the underlying interaction between BDNF and Drd3 in the expression of behavioral responses controlled by a drug-associated environment have remained poorly understood. The present study used a conditioning procedure to assess the roles of BDNF, Drd3, and their interactions in the NAc in the expression of morphine-induced context-specific locomotor sensitization. We showed that the expression of locomotor sensitization in the morphine-paired environment was accompanied by significantly increased expression of Drd3 mRNA and BDNF mRNA and protein levels. Both sensitized locomotion in morphine-paired rats and enhanced Drd3 mRNA were suppressed by intra-NAc infusion of anti-tyrosine kinase receptor B (TrkB) IgG. Furthermore, intra-NAc infusion of the Drd3-selective antagonist SB-277011A significantly decreased the expression of context-specific locomotor sensitization and upregulated BDNF mRNA. Altogether, these results suggest that BDNF/TrkB signaling and activation of Drd3 in the NAc are required for the expression of morphine-induced context-specific locomotor sensitization.     

Effects of age on dopamine D2 receptor availability in striatal subdivisions: A high-resolution positron emission tomography study

The purpose of the present study was to examine the relationship between age and dopamine D₂ receptor availability in striatal subdivisions of young and middle-aged healthy subjects using high-resolution positron emission tomography (PET) with [¹¹C]raclopride to better characterize the nature of age-related decrements in striatal D₂ receptor availability. Twenty-four healthy volunteers completed 3-Tesla magnetic resonance imaging and high-resolution [¹¹C]raclopride PET scans. The analyses using linear and exponential models revealed that age had a significant negative correlation with D₂ receptor availability in the post-commissural putamen (postPU) and that D₂ receptor binding in the postPU decreased significantly more with age than in the ventral striatum, suggesting subregional differences in age-related changes in D₂ receptor binding. The postPU, which belongs to the sensorimotor striatum, may be particularly vulnerable to the effects of age in young and middle-aged subjects.