Serotonin (5-HT) release in the dorsal raphé and ventral hippocampus: Raphé control of somatodendritic and terminal 5-HT release

Summary Somatodendritic and terminal release of serotonin (5-HT) was investigated by simultaneously measuring extracellular concentrations of 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the dorsal raphé and ventral hippocampus in freely moving rats. Perfusion of tetrodotoxin (TTX, 1M and 10M) into the dorsal raphé simultaneously decreased dorsal raphé and hippocampal 5-HT release. However, following TTX perfusion into the hippocampus (10M), hippocampal 5-HT release was profoundly reduced but dorsal raphé 5-HT remained unchanged.Systemic injections with the 5-HT_1a agonist, buspirone (1.0–5.0mg/kg, i.p.) decreased 5-HT and 5-HIAA and increased HVA concentrations in the dorsal raphé and in the hippocampus. The decreases in raphé and hippocampal 5-HT induced by systemic buspirone were antagonized in rats pretreated with 1.OmM (–) pindolol, locally perfused into the dorsal raphé. Local dorsal raphé perfusion of (–) pindolol alone (0.01–1.0mM) increased dorsal raphé 5-HT and concomitantly induced a small increase in hippocampal 5-HT. Buspirone perfusion into the dorsal raphé did not change (10 nM, 100nM), or produced a small increase (1.0mM) in raphé 5-HT, without changing hippocampal 5-HT.These data provide evidence that 5-HT release in the dorsal raphé is dependent on the opening of fast activated sodium channels and that dorsal raphé 5-HT_1a receptors control somatodendritic and hippocampal 5-HT release.     

Iontophoretic transdermal delivery of buspirone hydrochloride in hairless mouse skin

The transdermal delivery of buspirone hydrochloride across hairless mouse skin and the combined effect of iontophoresis and terpene enhancers were evaluated in vitro using Franz diffusion cells. Iontophoretic delivery was optimized by evaluating the effect of drug concentration, current density, and pH of the vehicle solution. Increasing the current density from 0.05 to 0.1 mA/cm² resulted in doubling of the iontophoretic flux of buspirone hydrochloride, while increasing drug concentration from 1% to 2% had no effect on flux. Using phosphate buffer to adjust the pH of the drug solution decreased the buspirone hydrochloride iontophoretic flux relative to water solutions. Incorporating buspirone hydrochloride into ethanol:water (50:50 vol/vol) based gel formulations using carboxymethylcellulose and hydroxypropylmethylcellulose had no effect on iontophoretic delivery. Incorporation of three terpene enhancers (menthol, cineole, and terpineol) into the gel and when combined with iontophoresis it was possible to deliver 10 mg/cm²/day of buspirone hydrochloride.     

九味虑平颗粒治疗广泛性焦虑症的临床疗效观察

目的:观察九味虑平颗粒治疗广泛性焦虑症(心脾两虚证)的临床疗效和安全性.方法:采用随机双盲双模拟阳性对照试验设计,将72例广泛性焦虑症(心脾两虚证)患者按3:1的比例随机分入九味虑平组(54例)和丁螺环酮组(18例)治疗4周,比较两组的临床疗效和不良反应发生率.结果:两组疗效相似,九味虑平组总有效率为94.34%,显效率为64.15%;丁螺环酮组总有效率100%,显效率77.78%.两组不良反应相似,不良反应发生率均为11.11%.九味虑平的主要不良反应有口干、便秘,个别病例出现心电图T波改变,但患者无自觉症状.结论:九味虑平颗粒用于治疗广泛性焦虑症(心脾两虚证)安全有效.     

Dopamine D3 receptors as a therapeutic target for methamphetamine dependence

Background: Methamphetamine (MA) use disorders are major public health problems nationally and worldwide and treatment remains an unmet need. Objectives: (1) To review preclinical and clinical studies identifying the dopamine D3 receptor as a therapeutic target for substance use disorders (SUDs), including MA dependence, (2) to consider buspirone (Buspar®) as a potential medication based on its dopamine D3 receptor antagonist properties, and (3) to evaluate the safety and initial efficacy of buspirone in a pilot study of MA-dependent individuals. Methods: Literature on the dopamine D3 receptor as a therapeutic target and on the potential of buspirone as a novel therapy for MA dependence was reviewed. The cardiovascular and subjective effects of intravenous MA challenge were assessed in five non-treatment seeking individuals. Participants met DSM-IV criteria for MA dependence and were treated subacutely (9 days) with buspirone (60?mg daily). Results: The literature identified the dopamine D3 receptor as a therapeutic target for MA dependence, a safe and approved medication, and a valuable opportunity to re-purpose buspirone for treating MA dependence and perhaps other SUDs. Pilot data (n?=?5) indicated that buspirone is safe in MA-using individuals and comparison against historical placebo data from this laboratory suggested that at least some aspects of the subjective properties of MA may be diminished during buspirone treatment. Conclusion: Future studies should include a small-scale, placebo-controlled Phase IIa trial of buspirone in MA dependence.     

Hospital Management of Acute Iron Ingestion

Abstract

This overview summarizes the major and minor side effects and drug interactions of fluoxetine. The adverse reactions include the “serotonin syndrome”, cardiovascular complications, extrapyramidal side effects such as akathisia, dyskinesias, and parkinsonian-like syndromes and an apparently increased risk of suicidality. Fluoxetine-induced mania and hypomania, seizures and sexual disorders are evaluated along with minor symptoms of allergic reactions, stuttering, hematological changes, psoriasis, and inappropriate secretion of the antidiuretic hormone. The major fluoxetine-drug interactions involve the amino acids L-dopa and L-tryptophan, anorexiants, anticonvulsants, antidepressants, anxiolytics, calcium channel blockers, cyproheptadine, lithium salts, and drugs of abuse. The underlying mechanism and the paradoxical effects of fluoxetine are addressed.     

丁螺环酮与帕罗西汀联合治疗抑郁症的临床研究

目的探讨丁螺环酮与帕罗西汀联合治疗抑郁症的疗效。方法符合ICD-10或CCMD-3抑郁症诊断标准的门诊和住院病人79例，随机分成两组，分别用丁螺环酮联合帕罗西汀和单用帕罗西汀治疗6周，采用汉密尔顿抑郁量表（HAMD）、汉密尔顿焦虑量表（HAMA）评定疗效，用副反应量表（TESS）评定副反应。结果6周末联合组HAMD和HAMA评分低于单用组。在第2周末、第6周末联合组的HAMD和HAMA的平均减分率高于单用组。两组间的副反应情况相仿。结论丁螺环酮联合帕罗西汀治疗抑郁症的疗效优于单用帕罗西汀。     

Characteristics of metabolic stability and the cell permeability of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione with antidepressant‐ and anxiolytic‐like activities

A series of 2‐pyrimidinyl‐piperazinyl‐alkyl derivatives of 1H‐imidazo[2,1‐f]purine‐2,4(3H,8H)‐dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5‐HT_1A, 5‐HT₇, and phosphodiesterases PDE4 and PDE10. The most potent compound 2‐pyrimidinyl‐1‐piperazinyl‐butyl‐imidazo[2,1‐f]purine‐2,4‐dione ( 4b ) behaved as strong and selective antagonist of 5‐HT_1A. Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands’ affinity and potency in the 5‐HT_1A receptor. Compound 4b in silico models demonstrated drug‐likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient P_app for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant‐ and anxiolytic‐like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first‐pass effect.     

枳壳对丁螺环酮在健康大鼠体内药物动力学的影响

目的：研究枳壳对丁螺环酮在健康大鼠体内药物动力学的影响。方法将SD大鼠随机分为丁螺环酮组,丁螺环酮加枳壳低剂量组（15 g/kg）,丁螺环酮加枳壳高剂量组（30 g/kg）,测定给药后5、10、20、30、45、60、90、120、240、360、480、600 min丁螺环酮的血药浓度,计算并比较其药动学参数。结果与丁螺环酮组比较,丁螺环酮加枳壳低剂量组和高剂量组中丁螺环酮AUC(0-t)分别增加2.49和4.18倍,Cmax分别增加1.63和2.57倍,Tmax从0.28 h分别延长至0.52和1.06 h,t1/2从0.96 h分别延长至2.18和4.87 h,差异具有统计学意义（P＜0.05）。结论枳壳可增加同服药物丁螺环酮的AUC(0-t)和Cmax,提高丁螺环酮生物利用度,并有剂量依赖性趋势,枳壳与丁螺环酮发生显著的药动学相互作用。     

丁螺环酮联合米氮平与正念认知疗法对高血压合并抑郁症患者血压、HAMD17评分的影响

目的观察丁螺环酮联合米氮平与正念认知疗法治疗对高血压合并抑郁症患者血压、17项汉密尔顿抑郁量表(HAMD17)评分的影响。方法选取高血压合并抑郁症患者112例,随机分为对照组和观察组各56例。对照组给予药物治疗(丁螺环酮+米氮平),观察组在对照组基础上给予正念认知疗法,比较两组血压变化情况、HAMD17评分、不良反应发生率以及生活质量。结果观察组干预后血压改善优于对照组,HAMD17评分和不良反应发生率低于对照组(P＜0.05);观察组干预后生活质量高于对照组(P＜0.05)。结论丁螺环酮联合米氮平与正念认知疗法可有效改善高血压合并抑郁症患者血压变化情况,减轻抑郁症状,降低不良反应发生率,改善生活质量。