A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism

Objective: Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder. Method: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. Results: The dose of olanzapine given after a 2-week pre-treatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for C_max and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased. Conclusion: Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population. Received: 22 July 1997 / Accepted in revised form: 1 June 1998     

Two selective 5-HT1A receptor antagonists, WAY-100 635 and NDL-249, stimulate locomotion in rats acclimatised to their environment and alter their behaviour: a behavioural analysis

The aim was to study firstly, the motor effects of a new 5-HT_1A antagonist, NDL-249 [(R)-3-(N-cyclopentyl-N-propylamino)-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrochloride] and of the reference 5-HT_1A antagonist WAY-100 635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl))ethyl)-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride], in comparison to the 5-HT_1A agonist (±)-8-OH-DPAT [(8-hydroxy-2-(di-N-propylamino) tetralin, hereafter 8-OH-DPAT], in rats acclimatised to the automated activity cages; secondly, to study whether the behavioural effects of NDL-249 and 8-OH-DPAT are sensitive to the 5-HT depleting effects of p-chlorophenylalanine (PCPA); thirdly, to characterise the nature of the antagonist-induced activation seen in the automatic activity cages with the aid of a behavioural observation analysis; fourthly, to examine the interaction between the 5-HT_1Areceptors mediating the behavioural effects and dopamine (DA) receptors. NDL-249 was found to bind in vitro to rat hippocampal 5-HT_1A receptors with high affinity and selectivity. In second messenger studies, it was devoid of agonist-like effects. In the locomotor activity studies, each antagonist significantly increased the incidence of horizontal activity, peripheral activity and rearing. 8-OH-DPAT, while significantly increasing peripheral and horizontal activities, decreased the incidence of rearing. PCPA blocked the motor effects of NDL-249 but did not affect those of 8-OH-DPAT. Observational analyses indicated that NDL-249 induced significant increases at one or more doses in sniffing, rearing and locomotion together with a significant reduction in stillness. WAY-100 635 significantly increased the incidence of rearing, intense grooming and vacuous chewing. The significant increases in sniffing, grooming and intense grooming and the significant decrease in stillness induced by the DA D₁ agonist, SK&F 38393 [(±)-1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol hydrochloride], were not altered by concomitant pre-treatment with NDL-249. Pre-treatment of rats with either the DA D₁ antagonist SCH-23390 (2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol) or the DA D₂ antagonist, raclopride, blocked the reduced stillness and increased sniffing and rearing induced by NDL-249. In conclusion, 5-HT_1A antagonists including the new selective antagonist, NDL-249, induce mild behavioural activation in rats, which is mediated probably indirectly via DA systems. Received: 3 April 1997/Final version: 23 February 1998     

Differential effects of IL-1ra on sickness behavior and weight loss induced by IL-1 in rats

Peripheral and central injections of recombinant human interleukin-1β (IL-1β) have been shown to decrease social exploration and to induce body weight loss in rats. To characterize the receptor mechanisms of these effects, we used as a tool a specific antagonist of the receptors of IL-1, IL-1ra. Intraperitoneal (i.p.) administration of IL-1ra (8 mg/kg) blocked the effect of i.p. injection of IL-1β (4 μg/rat) on social behaviour but not on body weight. Central administration of IL-1ra (60 μg/rat, i.c.v.) abrogated the effects of centrally administered IL-1β (30 ngn/rat, i.c.v.) on both social behaviour and body weight. Central injection of IL-1ra (4 μg/rat, i.c.v.) also attenuated the effects of i.p. administered IL-1β (4 μg/rat) on social behaviour but not on body weight. These results suggest that the effects of IL-1β on social behavior are mediated centrally and that its effect on the loss of body weight involves different receptor mechanisms.     

地高辛和卡托普利相互作用的监测

本文选择20例充血性心力衰竭患者。联合应用地高辛和卡托普利治疗,观察两药的相互作用。先口服地高辛0.25mg,1次/d,达稳态血浓度后,加服卡托普利12.5mg～25mg,3次/d。监测加服卡托普利前后的血清地高辛浓度。两者问无显著性差异,提示卡托普利对血清地高辛浓度影响不大,无明显相互作用。     

The Basomedial and Basolateral Amygdaloid Nuclei Contribute to the Induction of Long-term Potentiation in the Dentate Gyrus In Vivo

Recent behavioural studies have provided evidence that the amygdala modulates hippocampal-dependent memory. To test the possibility that the amygdala modulates hippocampal synaptic plasticity, we investigated the effects of surgical lesions of the amygdaloid nuclei on the induction of long-term potentiation (LTP) in the dentate gyrus of anaesthetized rats. Previously we reported that LTP in the dentate gyrus was attenuated by lesion of the basolateral amygdala, but was not affected by lesion of the central amygdala. In the present study, dentate gyrus LTP was significantly attenuated by basomedial amygdala lesion but not by medial amygdala lesion. These results suggest that, among the amygdaloid nuclei, the basomedial and basolateral nuclei are involved in the modulation of hippocampal plasticity. The roles of the basomedial and basolateral amygdala were further supported by experiments examining the effects of electrical stimulation of these nuclei. High-frequency stimulation of the basomedial amygdala alone did not induce dentate gyrus LTP, but when applied at the same time as tetanic stimulation of the perforant path increased the magnitude of the dentate gyrus LTP. Similarly, high-frequency stimulation of the basolateral amygdala enhanced LTP induced by tetanic stimulation of the perforant path. Furthermore, facilitation of dentate gyrus LTP by basomedial or basolateral amygdala stimulation was observed even in rats lesioned in either amygdala, suggesting that neurons in the basomedial and basolateral amygdala can modulate dentate gyrus LTP independently. Activity-dependent facilitation of hippocampal plasticity by the basomedial and basolateral amygdala may underlie memory processing associated with emotion.     

企业职工社会心理调查的方法学研究

作者自行设计一种问卷对某企业职工进行社会心理调查。问卷由 A、B两表构成。A 表列出42个问题,包含可能影响该企业职工社会心理的三大类11项因素,要求从该企业中随机抽取的被调查者针对问题回答“是”或“否”。其后附开放式问题一个,被调查者可自由作答,以补封闭式提问的不足。B 表按心理投射机制设计,以解除被调查者的疑虑。测试结果表明,此问卷的信度和效度令人满意。     

Variation in serum binding of tertatolol mediated by disease-induced modification of alpha-acid glycoprotein concentration

Summary The serum concentrations of ₁-acid glycoprotein (AAG), albumin (HSA) and non-esterified fatty acids, and the serum binding of tertatolol were measured in four groups of individuals: healthy control subjects (n=24), and patients with inflammation (n=28), and hepatic (n=20) and renal (n=27) insufficiency.Serum binding of tertatolol was increased in patients with inflammation (94.6%), decreased in patients with hepatic insufficiency (88.8%) and it was unchanged in patients with renal insufficiency (92.8%) as compared to controls (92.7%).Multivariate analysis indicated that the changes were mainly related to concomitant changes in AAG concentration, which could account for 57% of intersubject variability in the bound/free ratio, and to a lesser extent in HSA, which accounted for only 4% of the variability in the binding.The data show that the free fraction of the basic drug tertatolol in serum is affected by pathological conditions that cause changes in AAG concentration.     

306名大学生错失恐惧与社交媒体倦怠的关系:睡眠质量和负性情绪的链式中介作用

目的 探讨大学生睡眠质量、负性情绪在错失恐惧与社交媒体倦怠间的中介作用。 方法 采用错失恐惧量表、社交媒体倦怠量表、匹兹堡睡眠质量指数量表、抑郁-焦虑-压力量表简体中文版对306名大学生进行调查。 结果 错失恐惧、社交媒体倦怠、睡眠质量和负性情绪之间呈两两正相关;错失恐惧能正向预测社交媒体倦怠;睡眠质量和负性情绪在错失恐惧和社交媒体倦怠之间起单独中介作用,且睡眠质量和负性情绪在错失恐惧与社交媒体倦怠之间起链式中介作用,负性情绪各维度效应皆成立。 结论 睡眠质量和负性情绪能够为错失恐惧对社交媒体倦怠的影响提供一个解释机制,大学生的错失恐惧既可以直接影响其社交媒体倦怠水平,也可以通过睡眠质量、负性情绪的独立中介效应以及睡眠质量-负性情绪的链式中介效应间接影响。     

Specific modulation of social memory in rats by cholinomimetic and nootropic drugs,by benzodiazepine inverse agonists,but not by psychostimulants

The recognition of an unfamiliar juvenile rat by an adult rat has been shown to imply short-term memory processes. In this study the effect of various psychotropic drugs on this investigatory behaviour was examined. The procedure was as follows: an unfamiliar juvenile rat was placed in the home cage of an adult rat for 5 min. The time spent by the adult rat in investigating the juvenile was recorded. The adult rat was then immediately treated with vehicle or test compounds, and was again exposed for 5 min to the same juvenile 2 h later. At this time point vehicle-treated rats no longer recognized the juvenile rat, i.e. the time of investigation was similar to that observed during the first presentation. Arecoline (1 and 3 mg/kg IP), physostigmine (0.05 and 0.1 mg/kg SC), RS86 (0.5 mg/IP) and nicotine (0.125 and 0.5 mg/kg IP) reduced in a dose-dependent fashion the time spent in investigating the juvenile during the second exposure. This result cannot be attributed to nonspecific effects, since it was not observed when a different juvenile was used for the second exposure. The effect of arecoline was reversed by scopolamine, but not by methylscopolamine. Aniracetam reduced investigatory behaviour at the dose of 50 mg/kg IP. FG 7142 (5 mg/kg IP) and -CCM (0.4 mg/kg IP) were also active and their effect was reversed by Ro 15-1788. dl-Amphetamine (0.5 and 1 mg/kg IP), nomifensine (1.25–10 mg/kg IP) and strychnine (0.25 and 0.5 mg/kg IP) were ineffective or reduced this behaviour unspecifically. Social recognition may therefore represent a useful and simple test to detect compounds which enhance short-term, olfactory, memory and to assess in the same animals the specificity of this activity.