富马酸沃诺拉赞的合成工艺改进

目的改进抑酸药富马酸沃诺拉赞的合成工艺。方法以5-(2-氟苯基)-1H-吡咯-3-甲醇为起始原料,经氧化、与吡啶-3-磺酰氯缩合、胺化还原、与富马酸成盐制得富马酸沃诺拉赞。结果与结论目标化合物的结构经1H-NMR和MS谱确证,总收率为53%[以5-(2-氟苯基)-1H-吡咯-3-甲醇计],纯度为99.5%。改进后的工艺无需色谱纯化,避免使用高毒试剂和昂贵催化剂,更适宜工业化生产。     

富马酸沃诺拉赞合成路线图解

<正>富马酸沃诺拉赞(vonoprazan fumarate,TAK-438,1),化学名称为5-(2-氟苯基)-N-甲基-1-(3-吡啶磺酰基)-1H-吡咯-3-甲胺富马酸盐,是由日本武田制药研发的新一类胃酸分泌抑制剂,于2014年12月在日本成功上市。富马酸沃诺拉赞是一种钾离子竞争性酸阻滞剂,通过抑制K+与H+-K+-ATP酶(质子泵)的结合,提前终止胃酸的分泌,且抑制胃酸分泌的作用强劲、持久[1-2],     

含沃诺拉赞方案根除幽门螺杆菌疗效及安全性的Meta分析

目的评价比较含沃诺拉赞方案和含质子泵抑制剂(PPI)方案根除幽门螺杆菌的疗效和安全性。方法检索PubMed、 Embase、 Cochrane Library、中国知网和万方数据库,收集有关沃诺拉赞和PPI根除幽门螺杆菌的文献,检索时限均为从建库到2018年10月。采用RevMan5.2软件进行Meta分析。结果最终纳入14篇文献,含沃诺拉赞组治疗幽门螺杆菌的合并根除率显著高于含PPI组(90.26%vs.73.58%, OR=2.74, 95%CI:2.39～3.13, I~2=81%, P <0.000 01),不良反应事件发生率无显著差异(7.31%vs. 5.17%, OR=1.03, 95%CI:0.85～1.26, P=0.76)。结论含沃诺拉赞方案根除幽门螺杆菌疗效高于含PPI方案,且不良反应发生率相似。     

钾离子竞争性酸阻滞剂——沃诺拉赞

沃诺拉赞为一新型口服钾离子竞争性胃酸分泌阻滞剂,由日本武田制药公司开发,在日本已获准用于治疗胃酸相关性疾病,包括腐蚀性食管炎、消化性溃疡、幽门螺杆菌的根除及预防阿司匹林或其他非甾体抗炎药所致的胃或十二指肠溃疡等。本文从理化特性、药效学、药动学、药物相互作用、临床疗效及不良反应等方面介绍沃诺拉赞。     

沃诺拉赞富马酸盐与传统质子泵抑制药临床疗效对比研究进展

摘 要沃诺拉赞富马酸盐是一种新型的钾离子竞争性抑酸药，主要用于胃酸相关性疾病的治疗和预防，2014年在日本批准上市。与传统质子泵抑制药相比，具有众多优势，自上市后引起了广泛的关注并成为研究热点。本文从沃诺拉赞富马酸盐的临床疗效及不良反应等方面进行总结，以期为医护人员及患者提供最新信息。     

HPLC法测定沃诺拉赞焦谷氨酸盐及富马酸盐的含量

摘 要 目的：建立沃诺拉赞焦谷氨酸盐及沃诺拉赞富马酸盐的HPLC测定方法。方法: 采用Intertsil ODS 3色谱柱(150 mm×4.6 mm,5 μm),有机相为甲醇,水相为0.15%磷酸（0.15%三乙胺调pH=3）,梯度洗脱,流速为1.0 ml·min-1,紫外检测波长为230 nm,柱温为30℃,进样量为10 μl。结果:沃诺拉赞焦谷氨酸盐在2.060~131.800 μg·ml-1范围内线性关系良好（r=0.999 7),平均加样回收率99.40%（RSD=0.63%,n=9）;原料药3批次含量分别为98.7%,99.0%,98.4%（n=3）。沃诺拉赞富马酸盐在1.844~118.000 μg·ml-1范围内线性良好（r=0.999 9）,平均加样回收率100.67%（RSD=0.52%,n=9）;原料药3批次含量分别为98.5%,98.2%,98.9%（n=3）。结论:建立含量测定方法准确,可靠,为沃诺拉赞焦谷氨酸盐的含量检测提供了依据。     

沃诺拉赞与质子泵抑制剂治疗反流性食管炎有效性比较

目的 本文旨在对沃诺拉赞与质子泵抑制剂（proton-pump inhibitor,PPI）治疗反流性食管炎（reflux esophagitis,RE）有效性和安全性作Meta分析,以期指导RE药物治疗选择。方法 计算机检索数据库：Pubmed、Cochrane、embase and medline、web of science及SinoMed、中国知网、万方和维普,收集沃诺拉赞与PPIs对比治疗RE的随机对照试验。从纳入文献提取资料、行质量评价,使用RevMan5.4.1软件对数据行Meta分析。结果 最终入选5篇文献,均为英文发表,合计1 666例患者。第2周沃诺拉赞组治疗有效率高于PPIs组[相对危险度（Relative risk,RR）=1.09,95%置信区间（confidence interval,CI）=(1.04,1.15),P=0.001 0]。第4周有效率、第8周治愈率无显著差别[RR=1.02,95%CI(0.99,1.06),P=0.19;RR=1.02,95%CI(1.00,1.05),P=0.10]。洛杉矶分级（Los Angeles,LA）C/D级患者中...     

沃诺拉赞治疗酸相关疾病研究进展

沃诺拉赞为新型钾离子竞争性酸阻断药,与传统质子泵抑制剂(PPIs)相比,在治疗酸相关疾病(ARDs)如胃食管反流病、消化性溃疡、幽门螺杆菌感染等方面具有非劣效或优效,该药为ARDs患者提供了一种新的治疗选择。     

新型质子泵抑制剂的研究进展

质子泵抑制剂是目前最有效的胃酸分泌抑制剂和抗溃疡药物,在治疗胃渍疡、十二指肠溃疡和反流性食管炎等疾病方面发挥着重要作用。新型质子泵抑制剂的不断涌现为相关疾病治疗带来了新的希望。本文综述近年来出现的几种新型质子泵抑制剂如泰妥拉唑、莱米诺拉唑和盐酸瑞伐拉赞的作用机制及其独特优点,为临床应用提供参考。     

富马酸氯马斯汀搽剂的制备与质量控制

目的制备富马酸氯马斯汀搽剂,并制定质量控制标准。方法以富马酸氯马斯汀为主药制成富马酸氯马斯汀搽剂,用高效液相色谱法进行质量控制。结果所制备的搽剂质量稳定、操作方法简便,质量控制准确、可靠。富马酸氯马斯汀的平均回收率为99.63%,RSD为0.83%(n=9)。结论该制剂制备工艺简单,含量测定方法操作简便、结果准确,适用于富马酸氯马斯汀搽剂的制备和质量控制。     

富马酸卢帕他定的合成

目的 合成富马酸卢帕他定并改进工艺。方法 以5-甲基烟酸为起始物料,经过酯化、还原、氯化、烷基化、成盐等步骤制得富马酸卢帕他定。结果 所得产物经核磁共振氢谱、质谱、红外等确证其结构,总收率为46.4%。结论 该工艺安全可靠,方法简便,适合工业化生产。     

替诺福韦酯相关性肾毒性的研究进展

替诺福韦酯是替诺福韦的前药,是一种与阿德福韦酯相似的单磷酸腺苷类似物,具有抑制人免疫缺陷病毒（HIV）逆转录酶的活性的作用。随着临床应用的日益广泛,替诺福韦酯相关性肾毒性的报道也越来越多。本文综述替诺福韦酯相关性肾毒性在国内外不同人群的临床表现、作用机制、潜在风险及处理措施等研究进展。     

Preparation of valnemulin hydrogen fumarate and its enhanced stability compared with valnemulin hydrochloride

Context: It is necessary to develop a new salt of valnemulin to replace the veterinary antibiotic, e.g. valnemulin hydrochloride, in order to overcome its instability during storage and preparation.

Objective: The objective of this study was to prepare a novel organic acid salt, valnemulin hydrogen fumarate, and to investigate its stability compared with valnemulin hydrochloride.

Materials and methods: The crystal of valnemulin hydrogen fumarate was prepared by modified crystallization method; the enhanced stabilities of valnemulin hydrogen fumarate were conducted under irradiation and humid conditions, and the experimental results were simulated at AM1 level of calculations.

Results: Valnemulin hydrogen fumarate was more stable than valnemulin hydrochloride. After irradiation for 180 days, the content of valnemulin hydrogen fumarate decreased slightly 2.7%, whereas the content of valnemulin hydrochloride had an obvious decrease of 32.8%. Meanwhile, valnemulin hydrogen fumarate showed better anti-RH (relative humidity) ability than valnemulin hydrochloride. Under conditions of 65% and 85% RH, the absorption values of valnemulin hydrogen fumarate towards water were 0.75% and 1.20% at 48?h, whereas those of valnemulin hydrochloride were 4.50% and 9.71%, respectively.

Conclusion: The enhanced stability of valnemulin hydrogen fumarate could be attributed to its good crystallinity in comparison with the amorphous valnemulin hydrochloride.     

富马酸西他沙星注射液体内抗菌作用研究

目的 研究富马酸西他沙星注射液对小鼠细菌感染的体内保护作用。方法 选取临床分离的大肠埃希菌、金黄色葡萄球菌、肺炎克雷伯菌和铜绿假单胞菌各1株,以0.5mL的最小致死量(MLD)腹腔注射细菌感染小鼠,建立小鼠腹腔感染模型;于造模1h后,分别静脉注射给予高中低剂量的富马酸西他沙星注射液、盐酸莫西沙星注射液和灌胃给予西他沙星。记录给药后1~7d小鼠存活数;用BLISS法计算ED50、ED95及P值。结果 富马酸西他沙星注射液对4株临床分离致病菌的ED50值在0.5~4.0mg/kg,ED95值在1.5~16.3mg/kg,明显优于对照药盐酸莫西沙星注射液和西他沙星(口服)(P<0.01)。结论 富马酸西他沙星注射液对临床分离的致病菌表现出较好的体内抗菌作用,其作用明显优于对照药盐酸莫西沙星注射液和西他沙星(口服)。尤其是对铜绿假单胞菌感染小鼠的体内保护作用,富马酸西他沙星注射液优于西他沙星(口服)。因此,富马酸西他沙星注射液有着良好的市场预期,具有很大的开发价值。     

富马酸卢帕他定胶囊的溶出度研究

目的:建立测定富马酸卢帕他定胶囊溶出度的方法。方法:以紫外分光光度法测定富马酸卢帕他定含量,测定波长为268nm;采用篮法,以0.1mol·L-1盐酸溶液作为溶出介质,转速为100r·min-1,对3批富马酸卢帕他定胶囊在5、10、15、20、30、45min内进行溶出度均一性和批间重现性试验。结果:富马酸卢帕他定检测浓度线性范围为3.99～19.95μg·mL-(1r=0.9999),平均回收率为99.8%(RSD=0.92%,n=9);3批样品在30min时累积溶出度均大于98%,RSD小于5%(n=6),即溶出度均一性和重现性良好。结论:建立的方法操作简便、结果准确、稳定性好,可作为富马酸卢帕他定胶囊溶出度的测定方法。     

Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen: A Guide to Its Use in HIV-1 Infection

The once-daily, single-tablet regimen of emtricitabine/rilpivirine/tenofovir disoproxil fumarate (Eviplera? [EU]; Complera? [US]) provides a convenient option for antiretroviral therapy in treatment-naive patients with HIV-1 infection. In well designed trials in this patient population, rilpivirine plus emtricitabine/tenofovir disoproxil fumarate was noninferior to efavirenz plus emtricitabine/tenofovir disoproxil fumarate in terms of reducing viral HIV-1 RNA level to <50 copies/mL and was generally better tolerated than efavirenz plus emtricitabine/tenofovir disoproxil fumarate.     

Decreased ciprofloxacin absorption with concomitant administration of ferrous fumarate

The effect of ferrous fumarate on the relative bioavailability of ciprofloxacin after a single 500 mg oral dose of ciprofloxacin was studied in eight healthy males. Blood samples were collected at regular intervals 0–24 h post-dose. Urine was collected during 24 h to determine the cumulative urine excretion of ciprofloxacin. Ciprofloxacin concentrations in serum and urine were determined by high pressure liquid chromatography. Mean area under the serum concentration—time curve decreased significantly (P<0.001) after ciprofloxacin was taken with 200 mg ferrous fumarate. The relative bioavailability was 30% when ciprofloxacin was given with ferrous fumarate. The maximum blood level decreased from 2.1±0.9 (control) to 0.6±0.2 mg/l (with ferrous fumarate). Further studies are needed to determine if chronic treatment with ferrous fumarate further decreases the relative bioavailability. For the moment administration of ciprofloxacin with ferrous fumarate should therefore be avoided.     

Acute iron poisoning

Intoxications with ferrous compounds are uncommon but ferrous sulphate is most frequently involved. Ferrous fumarate is less toxic than ferrous sulphate. Two cases of ferrous fumarate poisoning that resulted in digestive mucosal lesions are reported.