奥氮平的合成工艺改进

目的：合成奥氮平工艺改进。方法：以硫、丙醛、丙二腈为起始原料，缩合得到2-氨基-5-甲基噻吩-3-腈，在相转移催化剂下与邻氟硝基苯反应制得2-（2-硝基苯氨基）-5-甲基噻吩-3-腈，再经过还原、环合和缩合得到纯度99％以上的奥氮平。结粜：目标化合物经核磁共振等确证其化学结构，总收率达到33．8％。结论：改进后的工艺路线反应条件温和，产率较高，操作简单，更适合工业化生产。     

奥氮平的药理学和临床应用

奥氮平(Olanzapine)是一种新型非典型抗精神病药物，系噻吩苯二氮卓类五羟色胺／多巴胺(5-HT／DA)拮抗剂，能改善脑内多种神经通路功能，尤其是选择性作用于中脑边缘多巴胺通路。该药自1996年在国外上市以来，因能全面改善精神分裂症症状，包括阳性、阴性症状，情感和认知障碍，     

氯氮平、奥氮平与糖尿病的关系

长期使用抗精神病药能导致糖尿病发病增多,这是目前精神科临床上已公认的情况。氯氮平及同属于二苯并二氮革类的奥氮平在治疗精神疾病时,患者可发生糖代谢失调（包括糖尿病发生和加重）,且其发生率比其它新的抗精神病药或传统的抗精神病药为多,从而提示这类药物可能较易破坏体内糖代谢平衡,并且与糖尿病危险因子如肥胖、糖耐受异常或糖尿病家族史患者有更密切关系。为此,特对这一方面的资料作一综述。     

奥氮平对脑电图的影响

目的 :观察奥氮平 (olanzapine)对脑电图的影响。方法 :开放性收集门诊和住院诊断为分裂样精神障碍及精神分裂症的首诊病人 98例 ,男性 65例、女性 3 3例 ,年龄为 (3 7±s1 5 )a,病程为 (3 .6±2 .4)mo,奥氮平 (2 .5～ 1 5mg·d-1)治疗前和治疗后 8wk末分别进行脑电描记术 (electroen cephalography,EEG)描记检查 ;疗效评定用简明精神病量表 (BPRS)。结果 :经 8wk治疗奥氮平对分裂样精神障碍 (2 1例 )、精神分裂症 (77例 )疗效肯定 ,脑电图轻度异常 1 5例 ,轻～中度异常 1 1例 ,异常发生率为 2 7% ,多以慢波增多θ活动散在各导为主 ,未发现有痫样活动。临床也未见病人有抽搐发作。结论 :奥氮平治疗后脑电图异常变化有一定的发生率 ,但异常的程度低 ,不影响其临床应用 ,但长期治疗的安全性需进一步研究     

奥氮平替换其他抗精神病药治疗老年精神分裂症的疗效分析

目的分析奥氮平替换其他抗精神病药治疗老年精神分裂症的临床疗效。方法研究对象搜集自2016年3月至2018年3月内在我院治疗的经口服其他抗精神病药物12周时间但仍无法获得良好治疗效果或不良反应严重而无法耐受的老年精神分裂症患者120例,使用奥氮平采取重叠交叉逐步增减剂量的方法来替换患者原来应用的抗精神病药物。结果 120例患者中,临床痊愈56例、显著进步36例、进步14例、无效14例,显效率76.67%,总有效率88.33%。与换药前相比,患者换药2周时的阳性症状评分、精神病性评分和PANSS总分均有显著降低,比较差异均具有统计学意义P<0.05;而换药4周时的阴性症状评分也有显著降低,比较差异具有统计学意义P<0.05。且以上各项评分,随着换药时间的延长,下降也越来越显著。120例患者治疗中出现体质量增加8例、嗜睡5例、口干4例、流涎4例、便秘2例,锥体外系反应1例,但其程度均较轻。结论采用奥氮平替换其他抗精神病药的治疗方法对老年精神分裂症患者实施治疗,临床疗效理想,并能够显著改善患者的PANSS评分,且不良反应较轻。     

奥氮平致非典型的抗精神病药恶性综合征

1例73岁女性精神分裂症患者,口服氯丙嗪（早150 mg、晚100 mg）及苯海索（4 mg,2次/d）治疗30年,加用奥氮平10 mg,1次/d口服2个月后出现CK升高,达15 570 U/L,同时伴发热、肌张力增高、心动过速,P 105次/min。停用奥氮平,继续应用氯丙嗪及苯海索,并给予对症支持治疗,CK水平逐渐下降至接近正常值。停药第19天患者自行应用奥氮平10 mg,1次/d,4 d后CK再次升高达700 U/L,停药后恢复正常。     

奥氮平与氯氮平增加高脂血症危险

据美国的研究人员报告，与典型抗精神病药比较，奥氮平（Ⅰ）和氯氮平（Ⅱ）（程度稍轻）在精神分裂症患者中似与高脂血症危险增加有关。     

SCAP显示奥氮平的远期利益及经济优势

Eli Lilly公司主办的为期三年的“真实世界”精神分裂症医疗与评估项目(SCAP)研究中在美国评估2400例精神分裂症目前治疗的纵行观察性研究，比较新开始使用Zyprexa(olanzapine，奥氮平，390例)(Ⅰ)，利培酮(risperidone，287例)     

奥氮平的药物相互作用

奥氮平作为非典型抗精神病药,能显著改善精神分裂症患者的阴性、阳性症状及情感症状,由于疗效高,锥体外系不良反应少见,病人易于接受,目前已广泛用于临床,常用于精神病的急性期和维持治疗,亦可缓解精神分裂症及相关疾病常见的继发性情感症状。随着临床使用的增加,与其他药物相互作用的几率也增加,作者根据有关文献综述如下：     

Olanzapine Abuse

ABSTRACT

Olanzapine is a thienobenzodiazepine that blocks especially the serontonin (5-hydroxytryptamine [5-HT]) 5-HT2A and the dopamine D2 receptors as well as muscarinic (M1), histamine (H1), 5-HT2C, 5-HT3 to 5-HT6, adrenergic (α_l), and D4 receptors. This case report presents an olanzapine abuse. A 48-year-old, primary school graduate, married woman applied to psychiatry clinic with tachycardia, insomnia, and anxiety complaints. In psychiatric evaluations, it was determined that these complaints have been continuing for 15 years at intervals and that she has been using citalopram 40 mg/day and olanzapine 50 mg/day for the last 3 years. As diabetes mellitus was diagnosed in follow-ups, interruption of olanzapine treatment was planned. The patient stated that she started taking the medicine again upon discomfort, increase in anxiety, dysphoria, insomnia, and nervousness, which started just after olanzapine was interrupted. She said that she was feeling dense stress when she did not take the medicine, and she thought that this situation would recover only by taking that medicine and hence she could not discontinue the medicine. In addition to medications with obvious abuse potential such as benzodiazepines and methylphenidate, and other stimulants, abuse of a number of commonly prescribed psychiatric medications has been reported. There are only 2 cases of olanzapine abuse in literature.     

Olanzapine: review of safety 2008

Background: Olanzapine is a second-generation antipsychotic approved for the treatment of schizophrenia, bipolar mania and associated agitation. Objective: To assess the safety profile of olanzapine, including its propensity to be associated with weight gain, diabetes mellitus and dyslipidemias. Methods: Review of English-language reports located through PubMed and information available on regulatory agency websites. Results/conclusion: The use of olanzapine can pose a therapeutic dilemma in that on one hand, a number of large scale studies have found effectiveness advantages for olanzapine in comparison to other first-line second-generation medications. On the other hand, olanzapine is associated with substantial weight gain and the development of dyslipidemia. Regarding other important safety concerns, olanzapine has a favorable profile in terms of extra-pyramidal side effects and is also relatively prolactin-sparing. The effectiveness benefits may outweigh the risks, particularly in patients with low baseline risk for metabolic syndrome but monitoring for untoward metabolic effects is crucial. Switch-or-stay and other intervention decisions need to be made early before substantial weight gain has occurred.     

Olanzapine treatment of an adolescent girl with anorexia nervosa

This case report presents a severe case of anorexia nervosa in a 15-year-old female adolescent. The patient suffered from extreme weight loss and agitation that required hospitalization in the Intensive Care Unit. The initial treatment consisted of fluoxetine management. Marked improvements, both in weight and psychological adjustment, were observed with the later addition of olanzapine. The findings reported here support previous findings that suggest the beneficial use of olanzapine in the treatment of anorexia nervosa.     

阿立哌唑的合成

7-羟基-3,4-二氢-2（1H）-喹诺酮和4-溴-1-丁醇经醚化制得7-（4-羟基丁氧基）-3,4-二氢-2（1H）-喹诺酮，再经磺酰化、1-（2，3-二氯苯基）哌嗪取代制得抗精神病药阿立哌唑，总收率77．5％。     

伊潘立酮的合成

(2,4-二氟苯基)-哌啶-4-基甲酮盐酸盐经肟化得到(2,4-二氟苯基)-哌啶-4-基甲酮肟盐酸盐,然后与4-(3-氯丙氧基)-3-甲氧基苯乙酮发生N-烷基化反应,再在氢氧化钾作用下闭环制得抗精神病药伊潘立酮,总收率约57%.     

氨磺必利的合成

4-乙酰胺基-2-甲氧基苯甲酸甲酯经浓硫酸磺化、水解、氯化、还原后与溴乙烷反应,再水解得到3-乙基磺酰基-4-氨基-6-甲氧基苯甲酸,最后与1-乙基-2-氨甲基吡咯烷在三乙胺和氯甲酸乙酯作用下缩合制得抗精神分裂症药氨磺必利,总收率约61％.     

Olanzapine treatment of eight adolescent patients with psychosis

Although olanzapine is known as a widely used atypical antipsychotic there have been very few studies about its use in children and adolescents. Eight adolescent patients who were diagnosed as having schizophrenia or schizoaffective disorder, and treated with olanzapine are reported in this case series. The patients were followed-up for 17.5 weeks in the range 4-26 weeks. According to the CGI improvement assessment at the end of the follow-up period, three of eight cases were rated as very much or much improved, three as minimally improved and two as not improved. Olanzapine was well tolerated by the adolescents in this case series except for weight gain. Our results suggest that olanzapine may be an effective antipsychotic for some psychotic adolescents and during olanzapine trials weight gain. Should be monitored.     

反相高效液相色谱法测定人血清中奥氮平浓度

目的建立测定血清中奥氮平浓度的反相高效液相色谱（RP-HPLC）法。方法血清碱化后用乙醚提取，采用RP-HPLC法检测，色谱柱为Hypersil ODS柱（150mm×4．6mm，2．5μm），流动相为磷酸盐缓冲液（pH=6．86，内含0．5％三乙胺）-甲醇（40：60，V／V），流速为1．0mL／min，检测波长为270nm，柱温25℃。结果血清中奥氮平质量浓度线性范围为10．16～203．00μg／L（r=0．9998），最低检测质量浓度为1．22μg／L，相对回收率为99．4％～100．6％，日内RSD为2．00％～2．29％（n=5），日内RSD为2．05％～4．28％（n=5）。结论该方法简便、准确，重现性好，灵敏度高，适用于奥氮平血药浓度的监测。     

奥氮平临床不良反应文献分析

目的探讨奥氮平引起不良反应的规律及特点,为临床安全合理用药提供依据。方法检索中国知网、万方数据和维普网从建库至2019年9月30日有关奥氮平引发不良反应的文献报道进行回顾性分析。结果共筛选出82篇有效文献,104例病例,男女比例为1∶1.08,年龄集中在18~44岁(51例,49.04%)。奥氮平引起不良反应多发生在用药时间2~7 d(33例,31.73%);累及的系统-器官以中枢及外周神经系统(56例,29.79%)为主,表现为迟发型肌张力障碍、不安腿综合征等症状,其次为代谢和营养障碍(33例,17.55%)。结论临床应高度重视奥氮平的不良反应,加强用药监护,确保用药安全。