丁螺环酮的合成

经6步反应合成了抗焦虑药丁螺环酮,各步收率稳定,操作简便,原料易得,总收率为22%(以环戊酮计)。     

Evidence of an enhanced central 5HT response in irritable bowel syndrome and in the rat maternal separation model

Abstract  Efforts to define either a biomarker for irritable bowel syndrome (IBS) or a valid animal model have proven disappointing. The aims of this study were to determine if buspirone stimulates prolactin release through the 5-hydroxytryptamine (5HT)1a receptor and whether this response is altered in patients with IBS and in the rat maternal separation model. Buspirone (30 mg) was used to stimulate prolactin release in 40 patients with IBS and in 40 healthy controls. In study 1, 10 IBS patients and 10 controls underwent pretreatment with pindolol (5HT1a antagonist) or placebo followed by buspirone. In study 2, 30 patients with IBS and 30 healthy controls had prolactin release stimulated by buspirone. Maternally separated and nonseparated rats were also treated with buspirone and prolactin monitored. Serotonin metabolites were measured together with the expression of the 5HT1a and serotonin transporter (SERT) gene. Pindolol produced a dose-dependent decrease in the buspirone prolactin response. Patients with IBS and maternally separated rats showed an exaggerated release of prolactin in response to buspirone. In the animal model, an increased turnover of 5HT was found in the brainstem together with a trend toward increased activity of the SERT gene. In conclusion altered central serotonin responses are found in both IBS and in an animal model.     

Modulation of Cytochrome P450 Activity by 18β‐Glycyrrhetic Acid and its Consequence on Buspirone Pharmacokinetics in Rats

The aim of this study was to elucidate the inhibition mechanism of 18β‐glycyrrhetic acid (GLY) on cytochrome P450 (CYP) activity and in vivo pharmacokinetic consequences of single GLY dose in rats. An in vitro CYP inhibition study in rat liver microsomes (RLM) was conducted using probe substrates for CYPs. Then, an in vivo pharmacokinetics of intravenous and oral buspirone (BUS), a probe substrate for CYP3A, was studied with the concurrent administration of oral GLY in rats. In the in vitro CYP inhibition study, CYP3A was involved in the metabolism of GLY. Moreover, GLY inhibited CYP3A activity with an IC₅₀ of 20.1 ± 10.7 μM via a mixed inhibition mechanism. In the in vivo rat pharmacokinetic study, single oral GLY dose enhanced the area under plasma concentration–time curve (AUC) of intravenous and oral BUS, but the extent of increase in AUC was only minimal (1.12–1.45 fold). These results indicate that GLY can inhibit the in vitro CYP3A‐mediated drug metabolism in RLM via a mixed inhibition mechanism. However, the impact of single oral GLY dose on the pharmacokinetics of BUS in rats was limited, showing that GLY could function as merely a weak inhibitor for CYP3A‐mediated drug metabolism in vivo. Copyright © 2015 John Wiley & Sons, Ltd.     

奥氮平联合丁螺环酮治疗精神分裂症疗效以及对认知功能的影响

目的：探讨奥氮平联合丁螺环酮治疗精神分裂症患者的疗效以及对认知功能的影响。方法将67例首发精神分裂症患者按随机数字表法分为研究组33例,对照组34例,均予以口服奥氮平治疗,研究组在此基础上联合丁螺环酮治疗,观察8周。于治疗前后采用阳性与阴性症状量表评定精神症状,威斯康星卡片分类测验和韦氏记忆量表测评认知功能,副反应量表评定不良反应。结果治疗后两组阳性与阴性症状评分均较治疗前显著下降（P＜0．01）,研究组总分及阴性症状、精神病理因子分显著低于对照组（ P＜0．05或0．01）。两组威斯康星卡片分类测验正确反应数、完成分类数较治疗前显著增加,研究组显著高于对照组（ P＜0．05或0．01）;错误反应数、随机错误数较治疗前显著减少,研究组显著少于对照组（ P＜0．05或0．01）。两组韦氏记忆量表评总分均较治疗前显著增加（P＜0．01）,但研究组显著高于对照组（P＜0．05）。两组不良反应较轻微,发生率比较差异无显著性（P＞0．05）。结论奥氮平联合丁螺环酮能有效改善精神分裂症患者的各种精神症状和认知功能,两药具有协同增效作用,安全性高。     

重复经颅磁刺激治疗广泛性焦虑障碍对照研究

目的：探讨重复经颅磁刺激治疗广泛性焦虑障碍患者的疗效和安全性。方法将60例广泛性焦虑障碍患者随机分为两组,研究组予以重复经颅磁刺激,同时口服复合维生素片治疗,对照组口服丁螺环酮治疗,同时予以经颅磁假刺激,观察4周。于治疗前后采用汉密顿焦虑量表、焦虑自评量表、匹兹堡睡眠质量指数量表评定临床疗效,随时记录治疗过程中出现的不良反应。结果治疗各时点两组各量表评分均较治疗前显著下降（P＜0.01）,同期两组间评分比较差异均无显著性（ P＞0.05）;治疗过程中两组均未出现严重不良反应。结论重复经颅磁刺激治疗广泛性焦虑障碍疗效显著,与丁螺环酮相当,治疗安全性高,依从性好。     

Effects of buspirone on an animal model of tardive dyskinesia

Queiroz, Claudio M.T. and Roberto Frussa-Filho: Effects of Buspirone on An Animal Model of Tardive Dyskinesia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1999, 23, pp. 1405–1418.

1. 1. The effects of buspirone were studied on an animal model of tardive Dyskinesia I.e., the quantification of orofacial dyskinesia in rats repeatedly treated with reserpine.

2. 2. Rats were co-treated with saline [SAL] or buspirone [BUS] (3. 0 mg/Kg I.p., twice daily) and vehicle [VEH] or reserpine [RES] (0. 1 mg/Kg S.c., once every other day) for 19 days. On the day 20, the animals were observed for quantification of the behavioral parameters of orofacial dyskinesia: tongue protrusion and vacuous chewing movements frequencies and duration of twitching of the facial musculature.

3. 3. Rats of the SAL+RES group exhibited a significant increase in the three behavioral parameters of orofacial dyskinesia relative to the rats of the SAL+VEH group. However, animals of the BUS+RES group showed only an increased frequency of vacuous chewing movements when compared to animals of the SAL+VEH group. In addition, the duration of the facial twitching was significantly decreased in the BUS+RES group in relation to rats of the SAL+RES group. There were no significant differences in the orofacial parameters between the BUS+VEH and the SAL+VEH groups.

4. 4. Because it was also verified that chronic buspirone treatment was able to increase apomorphine-induced yawning behavior, the possibility is raised that buspirone attenuates reserpine-induced orofacial dyskinesia through the development of dopamine autoreceptor supersensitivity.

     

丁螺环酮体外经皮渗透性的实验研究

目的:研究丁螺环酮的经皮渗透性,筛选出丁螺环酮贴剂的促渗剂及最佳促渗浓度.方法:采用全自动体外渗透释放仪,以雄性小鼠皮肤为渗透屏障,高效液相色谱法测定丁螺环酮的累积渗透浓度并计算其渗透动力学参数.结果:氮酮对丁螺环酮有明显的促渗透效果,但其渗透速率并不随着氮酮浓度的增大而增大,而是在氮酮含量为2%时有一最佳值,渗透速率常数为65.103g·cm-2·h-1/2,4和10h的累积渗透量分别为143.036和226.618μg.结论:氮酮能够促进丁螺环酮的透皮吸收,其最佳浓度为2%;丁螺环酮从贴剂基质向皮肤的渗透符合Higuchi方程.     

曲唑酮与丁螺环酮治疗广泛性焦虑症的比较

目的 :比较曲唑酮和丁螺环酮治疗广泛性焦虑症的疗效及安全性。方法 :6 0例广泛性焦虑症病人分成 2组 ,曲唑酮组男性 18例 ,女性 12例 ,给予曲唑酮每日 5 0～ 15 0mg,分 2次口服× 4wk ;丁螺环酮组男性 16例 ,女性 14例 ,给予丁螺环酮 5～30mg,分 2次口服× 4wk。结果 :曲唑酮组总有效率 83% ,丁螺环酮组总有效率 70 % ,2组疗效比较经Ridit分析 ,P >0 .0 5。药物不良反应发生率曲唑酮组与丁螺环酮组差异无显著意义 (P >0 .0 5 )。结论 :曲唑酮治疗广泛性焦虑症安全有效 ,其疗效与丁螺环酮相似     

丁螺环酮治疗焦虑性障碍伴发的抑郁症状的疗效

目的 :探讨丁螺环酮对焦虑性障碍伴发的抑郁症状的疗效。方法 :136 9例焦虑性障碍的患者口服丁螺环酮治疗 4周 ,剂量 5～ 6 0mg ,在治疗前后进行HAMD评定。结果 :治疗后HAMD减分率为 (5 6 .31± 33.76 ) % ,显效率为 6 1.4 % ,有效率为 85 .5 %。结论 :丁螺环酮对焦虑性障碍伴发的抑郁症状具有一定疗效。