半富马酸喹硫平的合成工艺研究

目的改进半富马酸喹硫平的合成工艺。方法 2-氨基二苯硫醚与三光气反应得到2-异氰酸基二苯硫醚,然后在多聚磷酸的作用下进行环合反应得到10H-二苯并[b,f][1,4]硫氮杂艹卓-11-酮,经三氯氧磷氯代、与无水哌嗪缩合、烷基化,最后与富马酸成盐得到半富马酸喹硫平。结果与结论改进了半富马酸喹硫平的合成路线,并且优化其合成工艺。目标化合物的结构经1H-NMR、13C-NMR、MS谱确证。新合成路线原料廉价易得、操作简便,为半富马酸喹硫平的工艺放大奠定了一定基础。     

我国医药原辅料中间体研究开发新动向

半富马酸喹硫平合成的研究半富马酸喹硫平(quetiapine hemifumarate，化学名为11-[4-[2-(2-羟基乙氧基)乙基]-1-哌嗪基]二苯并[b，f[1，4]硫氮杂卓半富马酸盐，是新一代非典型抗精神病药，英国Zeneca公司于1997年11月首次在英国上市，临床作为精神分裂症的一线治疗药物。     

欧盟批准富马酸喹硫平及其缓释片用于治疗双相情感障碍

2008年11月，阿斯利康公司（Astra Zeneca）宣布其一日1次用富马酸喹硫平缓释片（quetiapine fumarate，Seroquel XR，思瑞康XR）和富马酸喹硫平（quetiapine fumarate，Seroquel，思瑞康）获欧盟批准用于治疗双相情感障碍。此前，富马酸喹硫平及其缓释片已获准用于治疗抑郁发作的双相情感障碍，而富马酸喹硫平缓释片也已经获准用于治疗中度至重度躁狂发作的双相情感障碍。     

富马酸喹硫平致过敏性皮炎3例

［摘要］临床应用富马酸喹硫平过程中发生皮肤变态反应患者3例， 停服富马酸喹硫平，给予抗变态反后皮疹均消退。3例均在应用富马酸喹硫平1～2周后出现皮肤变态反应，应属Ⅳ变态反应（迟发性）。非典型抗精神病药已经越来越广泛地应用于临床，它比传统抗精神病药具有很多优势，作为治疗精神分裂症的一线用药，其不良反应值得临床重视和研究。     

要闻速递

欧盟批准富马酸喹硫平及其缓释片用于治疗双相情感障碍2008年11月,阿斯利康公司(AstraZeneca)宣布其一日1次用富马酸喹硫平缓释片(quetiapine fumarate,SeroquelXR,思瑞康XR)和富马酸喹硫平(quetiapine fumarate,Seroquel,思瑞康)获欧盟批准用于治疗双相情感障碍。此前,富马酸喹硫平及其缓释片已获准用于治疗抑     

富马酸喹硫平与利培酮治疗精神分裂症的对照研究

目的比较富马酸喹硫平与利培酮治疗精神分裂症的疗效与安全性。方法将80例精神分裂症患者随机分为两组,每组各40例,分别给予富马酸喹硫平和利培酮治疗,疗程8周,采用阳性与阴性症状量表（PANSS）,临床疗效总评量表（CGI-SI）、采用不良反应量表（TESS）评定疗效和不良反应。结果两组PANSS总分及CGI-SI评分均治疗前显著下降（P〈0.01）,富马酸喹硫平组显效率78%,利培酮组显效率75%两组疗效相仿（P〉0.05）.富马酸喹硫平组的嗜睡、体重增加的不良反应明显低于利培酮组（P〈0.01）,锥体外系反应、失眠、兴奋或激越与利培酮组相当,差异无统计学意义（P〉0.05）。结论富马酸喹硫平组与利培酮组治疗精神分裂症的疗效相当。富马酸喹硫平组的不良反应较利培酮组少而轻,阿利哌唑的安全性高,依从性好。     

半富马酸喹硫平的合成工艺及其质量研究

目的优化半富马酸喹硫平的合成工艺,并严格控制成品质量,为大规模生产奠定基础。方法选用廉价易得的二苯并[b,f][1,4]硫氮杂-11-[10H]酮(2)为起始原料,在催化量三乙胺的作用下,经氯代反应制备11-氯-二苯并[b,f][1,4]硫氮杂艹卓(3);以甲苯为溶剂,3与1-[2-(2-羟基乙氧基)乙基]哌嗪(4)经氨解反应制备喹硫平,再与富马酸成盐即得目标物。工艺优化过程中,对其有关物质谱进行分析、确定,并严格限量。结果与结论三步反应的总收率为79.9%,单个有关物质含量均小于0.1%,有关物质总量均小于0.2%,终产品的滴定含量均高于99.0%,有机溶剂的限量检测满足标准要求。     

喹硫平与利培酮治疗老年精神分裂症的对照研究

目的：探讨喹硫平治疗精神分裂症的疗效及副反应。方法：以喹硫平（思瑞康）与利培酮治疗精神分裂症各30例作对照研究,采用阳性症状与阴性症状量表（PANSS）、不良反应症状量表（TESS）评定疗效及副反应。结果：利培酮组有效率78％,显效率39％;喹硫平组有效率88％,显效率76％。均无明显锥外系反应,仅表现为兴奋激越等副反应。结论：两药对治疗精神分裂症均有确切疗效,且安全性相对高,喹硫平对症状的改善可能更好。     

富马酸喹硫平与氯丙嗪治疗精神分裂症的对照研究

目的:比较富马酸喹硫平与氯丙嗪对精神分裂症的疗效及不良反应。方法:80例精神分裂症患者随机分为治疗组和对照组各40例,治疗组予富马酸喹硫平300～450 mg·d^-1,对照组予氯丙嗪100～400 mg·d^-1治疗8周,用阳性与阴性症状量表（PANSS）评定临床疗效,不良反应量表（TESS）评定不良反应。结果:富马酸喹硫平和氯丙嗪治疗精神分裂症有效率分别为82.5%、77.5%,差异无统计学意义（P>0.05）,治疗组的不良反应发生率低于对照组,差异有统计学意义（P<0.05）。结论:富马酸喹硫平与氯丙嗪对治疗精神分裂症的疗效相当,富马酸喹硫平锥体外系不良反应明显少于氯丙嗪。     

丙戊酸镁缓释片联合富马酸喹硫平片在伴有焦虑症状双相情感障碍患者治疗中的应用

目的 探讨丙戊酸镁缓释片联合富马酸喹硫平片在伴有焦虑症状双相情感障碍患者治疗中的应用.方法 选取2020年3月～2021年4月收治的80例伴有焦虑症状双相情感障碍患者作为本次研究对象,随机将患者分为观察组(42例)和对照组(38例),观察组采用丙戊酸镁缓释片联合富马酸喹硫平片治疗,对照组采用富马酸喹硫平片治疗.观察两组...     

半富马酸喹硫平的合成研究

2-氨基二苯硫醚和三光气反应得到的2-异氰酸基二苯硫醚在多聚磷酸中闭环后,经氯代、与哌嗪缩合得到11-哌嗪-1-基二苯并[b,f][1,4]硫氮杂革,由2-(2-氯乙氧基)乙醇进行哌嗪N4-位烷基化反应后与富马酸成盐,制得抗精神病药半富马酸喹硫平,总收率63.4%(以2-氨基二苯硫醚计).     

Acidity constants in methanol/water mixtures of polycarboxylic acids used in drug salt preparations. Potentiometric determination of aqueous pKa values of quetiapine formulated as hemifumarate.

The acidic dissociation constants in a number of methanol/water mixtures of mono and polycarboxylic acids commonly used in the preparation of drug salts were determined. These solvent mixtures are usually used to determine the pKa of drugs of low aqueous solubility. However, when these drugs are prepared in salt form, the acid-base equilibria of both the basic drug and the counter-anion are involved in the potentiometric titration curves. In these instances, the inclusion of the pKa of acids as constant values in the curve fitting provides easy computation of the drug pKa without the need of any previous step to get the free base. As an application example, the aqueous pKa values of the quetiapine formulated as hemifumarate (Seroquel) were estimated by extrapolation from the experimental pKa in several methanol/water mixtures, which were then calculated according to the suitable constants of fumaric acid. The estimated aqueous pKa values of quetiapine are compared with those directly obtained in aqueous solution by potentiometry and by capillary electrophoresis.     

替诺福韦艾拉酚胺半D-(-)-酒石酸盐的制备及其稳定性研究

目的 制备替诺福韦艾拉酚胺半D-( )-酒石酸盐,并开展稳定性研究。方法 以替诺福韦（PMPA）为原料,经亚磷酸三苯酯缩合、二氯亚砜氯代、L-丙氨酸异丙酯缩合制得替诺福韦艾拉酚胺,再与D-( )-酒石酸成盐。结果 制得的替诺福韦艾拉酚胺半D-( )-酒石酸盐,经1H-NMR、13P-NMR、MS确证结构,并与半富马酸盐进行稳定性比较。结论 替诺福韦艾拉酚胺半D-( )-酒石酸盐比半富马酸盐具有更好的稳定性,值得进一步开发。     

Evaluation of the feasibility of switching from immediate release quetiapine to extended release quetiapine fumarate in stable outpatients with schizophrenia

This double-blind, double-dummy study (D1444C00146) evaluated the efficacy and safety of switching patients with clinically stable schizophrenia from quetiapine immediate release (IR) to the same dose of once-daily extended release quetiapine fumarate (quetiapine XR). Patients received quetiapine IR 400-800 mg/day twice daily for 4 weeks, and were then randomized (2 : 1) to a once-daily equivalent dose of quetiapine XR or maintained on IR for 6 weeks. The primary variable was the proportion of patients who discontinued treatment owing to lack of efficacy or whose Positive and Negative Syndrome Scale scores increased by at least 20% from randomization to any visit. In total, 497 patients were randomized to quetiapine XR (n=331) or IR (n=166). Noninferiority (6% margin; one-sided test, 2.5% significance level) was narrowly missed for the primary efficacy variable for the modified intention-to-treat population (9.1%, quetiapine XR; 7.2%, quetiapine IR; difference 1.86%; 95% confidence interval: -3.78, 6.57; P=0.0431), but was shown for the per-protocol population (5.3%, quetiapine XR; 6.2%, quetiapine IR; difference: -0.83%; 95% confidence interval: -6.75, 3.71; P=0.0017). Serious adverse event incidence was low for quetiapine XR and IR; there were no unexpected adverse events. In conclusion, efficacy was maintained without compromising safety/tolerability when switching patients with stable schizophrenia from twice-daily quetiapine IR to once-daily quetiapine XR (400-800 mg/day).     

Number needed to treat and time to response/remission for quetiapine monotherapy efficacy in acute bipolar depression: evidence from a large, randomized, placebo-controlled study

The objectives of this analysis are to elucidate the clinical significance of antidepressant effects with quetiapine by evaluating number needed to treat as well as time to response and remission with quetiapine monotherapy in patients with acute bipolar depression. A post-hoc analysis was conducted of 542 patients with bipolar I or II disorder, (moderate to severe depression), randomized to 8 weeks of double-blind treatment with quetiapine 600 mg/day (n=180), quetiapine 300 mg/day (n=181), or placebo (n=181). Number needed to treat, time to response (> or =50% reduction from baseline in Montgomery-Asberg Depression Rating Scale total score) and time to remission (Montgomery-Asberg Depression Rating Scale total score < or =12) were evaluated. Response rates at week 8 were 58.2 and 57.6% for quetiapine 600 and 300 mg/day, respectively, and 36.1% for placebo (P<0.001). Remission rates were 52.9% for both quetiapine groups and 28.4% for placebo (P<0.001). The number needed to treat was five for both response and remission for quetiapine (600 and 300 mg/day) compared with placebo. Median time to response and remission were significantly shorter with quetiapine 600 and 300 mg/day than placebo. No between-group difference was found in the incidence of treatment-emergent mania or hypomania (quetiapine 600 mg/day: 2.2%, quetiapine 300 mg/day: 3.9, and placebo: 3.9%). In conclusion, quetiapine compared with placebo significantly reduces time to response and remission compared with placebo, and has a favorable number needed to treat.     

Quetiapine or haloperidol as monotherapy for bipolar mania--a 12-week, double-blind, randomised, parallel-group, placebo-controlled trial.

METHODS: Patients (n=302) with bipolar I disorder (manic episode) were randomised to 12 weeks' double-blind treatment with quetiapine (flexibly dosed up to 800 mg/day), placebo, or haloperidol (up to 8 mg/day). The primary efficacy outcome variable was change from baseline to Day 21 in Young Mania Rating Scale (YMRS) score. RESULTS: YMRS score improved with quetiapine at Day 21 (-12.29 versus -8.32 for placebo; P<0.01). The difference in favor of quetiapine increased by Day 84 (-17.52 versus -9.48; P<0.001). Haloperidol also showed an advantage over placebo at Days 21 and 84 (P<0.001). There was no significant difference in efficacy measures between quetiapine and haloperidol groups at any assessment except Day 21. The only common adverse event with quetiapine was somnolence (12.7%). Extrapyramidal symptoms (EPS), including akathisia, occurred at 59.6% with haloperidol, 12.7% with quetiapine, 15.8% with placebo. Most quetiapine responders (84%) received a dose of 400-800 mg/day. CONCLUSIONS: Quetiapine was effective and well tolerated. The efficacy and tolerability profile of haloperidol (including its propensity for EPS) supported study validity.     

Extended release quetiapine fumarate (quetiapine XR) monotherapy as maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial

The objective of this study was to evaluate the efficacy and tolerability of extended release quetiapine fumarate (quetiapine XR) as maintenance monotherapy for patients with generalized anxiety disorder (GAD). Time-to-event (anxiety symptom recurrence; maximum 52 weeks) multicenter, randomized-withdrawal, parallel-group, double-blind, placebo-controlled study of quetiapine XR (50-300 mg/day) following open-label run-in (4-8 weeks) and open-label stabilization (≥ 12 weeks). Primary variable: time from randomization to anxiety event. Secondary variables included: Hamilton Anxiety Rating Scale (HAM-A) total, HAM-A psychic/somatic anxiety factors, Clinical Global Impression-Severity of Illness (CGI-S), and Quality of Life, Enjoyment and Satisfaction Questionnaire (Q-LES-Q) scores; adverse events (AE) reporting. Four hundred and thirty-two patients, stabilized on quetiapine XR, were randomized to continue quetiapine XR (N=216) or switch to placebo (N=216). Risk of anxiety symptom recurrence was significantly reduced by 81% for quetiapine XR versus placebo: hazard ratio=0.19 (95% confidence interval 0.12-0.31; P<0.001). Fewer patients receiving quetiapine XR (N=22, 10.2%) than placebo (N=84, 38.9%) experienced anxiety symptom recurrence. Significant differences were observed between quetiapine XR and placebo in: HAM-A total, psychic/somatic, CGI-S (all P<0.001) and Q-LES-Q (P<0.05) scores. AEs (>10%) during open-label treatment were dry mouth, sedation, somnolence, dizziness, fatigue, and constipation. During randomized treatment, the most common AEs for quetiapine XR were headache and nasopharyngitis. Quetiapine XR monotherapy reduced the risk of anxiety symptom recurrence in patients with GAD stabilized on quetiapine XR, with tolerability results consistent with the known profile of quetiapine.     

Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics

AIMS: To explore the potential for drug interactions on quetiapine pharmacokinetics using in vitro and in vivo assessments. METHODS: The CYP enzymes responsible for quetiapine metabolite formation were assessed using recombinant expressed CYPs and CYP-selective inhibitors. P-glycoprotein (Pgp) transport was tested in MDCK cells expressing the human MDR1 gene. The effects of CYP3A4 inhibition were evaluated clinically in 12 healthy volunteers that received 25 mg quetiapine before and after 4 days of treatment with ketoconazole 200 mg daily. To assess CYP3A4 induction in vivo, 18 patients with psychiatric disorders were titrated to steady-state quetiapine levels (300 mg twice daily), then titrated to 600 mg daily carbamazepine for 2 weeks. RESULTS: CYP3A4 was found to be responsible for formation of quetiapine sulfoxide and N- and O-desalkylquetiapine and not a Pgp substrate. In the clinical studies, ketoconazole increased mean quetiapine plasma C(max) by 3.35-fold, from 45 to 150 ng ml(-1) (mean C(max) ratio 90% CI 2.51, 4.47) and decreased its clearance (Cl/F) by 84%, from 138 to 22 l h(-1) (mean ratio 90% CI 0.13, 0.20). Carbamazepine decreased quetiapine plasma C(max) by 80%, from 1042 to 205 ng ml(-1) (mean C(max) ratio 90% CI 0.14, 0.28) and increased its clearance 7.5-fold, from 65 to 483 l h(-1) (mean ratio 90% CI 6.04, 9.28). CONCLUSIONS: Cytochrome P450 3A4 is a primary enzyme responsible for the metabolic clearance of quetiapine. Quetiapine pharmacokinetics were affected by concomitant administration of ketoconazole and carbamazepine, and therefore other drugs and ingested natural products that strongly modulate the activity or expression of CYP3A4 would be predicted to change exposure to quetiapine.     

喹硫平治疗精神分裂症伴抑郁症状的疗效

目的 :观察喹硫平治疗精神分裂症伴抑郁的疗效 ,并与利培酮作对照。方法 :对 5 2例精神分裂症伴抑郁病人分成喹硫平组与利培酮组 ,其中喹硫平组 2 7例 ,给予喹硫平 30 0～ 70 0mg·d- 1治疗。利培酮组 2 5例 ,给予利培酮 2～ 5mg·d- 1治疗。观察时间 6wk ,采用PANSS ,HAMD ,CGI等量表 ,分别于治疗前及治疗后wk 1,2 ,4 ,6末评定疗效 ,用TESS观察不良反应。结果 :经 6wk治疗后 ,喹硫平组与利培酮组疗效比较 ,经Ridit分析 ,差异无显著意义 (P >0 .0 5 )。但HAMD评分 ,喹硫平组治疗后减分率大于利培酮组 ,差异有非常显著意义 (P <0 .0 1)。结论 :喹硫平治疗精神分裂症伴抑郁与利培酮疗效相似 ,提示喹硫平除了具有抗精神病性症状作用外 ,还可能具有情感稳定的作用