利福昔明的研究

综述了利福昔明合成工艺、体外抗菌、生物利用度和临床新的进展.     

利福昔明的临床应用

利福昔明，英文名（INN）：rifaximin，化学名：4-deoxy-4＼’-methylpyriod[1＼’2＼’-1，2]imidazo[5，4-c][5，4-c]rifamycinSV。     

利福昔明和醌式利福昔明的HPLC分离分析

利福昔明(rifaximin)系利福霉素的衍生物，是第一个非氨基糖苷类肠道抗生素。本品作用强，抗菌谱广。对革兰氏阳性需氧菌中的金黄色绿脓葡萄球菌、表皮葡萄球菌及粪链球菌；对革兰氏阴性需氧菌中的沙门氏菌属、大肠杆菌、志贺氏菌属、小肠结膜炎耶尔森氏菌、球菌；革兰氏阴性厌氧菌中的拟杆     

反相高效液相色谱法测定利福昔明的含量

目的:采用反相高效液相色谱法测定利福昔明的含量。方法:色谱柱为C_(18)柱,流动相为甲醇—0.075mol·L~(-1)KH_2PO_4溶液-1.0mol·L~(-1)枸橼酸溶液(75:26:4),检测波长为254nm;流速为1.0mL·min~(-1)。结果:线性范围:10.0～100.0μg·mL~(-1),r=0.9999,回收率99.2％。供试品溶液在8h内稳定性良好,日内重复性RSD=0.24％,日间重复性RSD=0.50％。结论:本方法简单、快速,结果准确。     

利福昔明胶囊治疗急性细菌感染性腹泻的临床疗效观察

目的:评价利福昔明胶囊治疗急性细菌感染性腹泻的疗效和安全性。方法:采用随机双盲平行对照研究。利福昔明胶囊组,每次口服利福昔明胶囊0.4 g,首日t.i.d,以后b.i.d;对照环丙沙星胶囊组,每次口服环丙沙星0.2 g,首日t.i.d,以后b.i.d,疗程均为3-5 d。治疗前后查血、尿、大便常规、肝肾功能、心电图用于安全性评价。结果:利福昔明胶囊组治疗感染性腹泻16例,有效率93.8%,对照环丙沙星胶囊组治疗感染性腹泻19例,有效率89.5%,两组间疗效差异无显著性(P >0.05)。35例中有11例治疗前粪便细菌培养阳性,阳性率31.4%,治疗后细菌清除率为100%。利福昔明胶囊组未观察到不良反应和严重不良事件发生。结论:对治疗急性细菌感染性腹泻利福昔明胶囊具有与环丙沙星胶囊同等的疗效和安全性。     

利福昔明分散片的研制及质量控制

目的:制备利福昔明分散片及探讨制备利福昔明的处方与工艺。方法:采用正交法,以崩解时限为指标,对利福昔明分散片处方进行筛选。结果:分散片在60秒内完全崩解,颗粒能全部通过2号筛,符合《中国药典》关于分散片的要求。结论:利福昔明分散片处方与制备工艺是可行的。     

26-57 利福昔明胃肠道感染以外的临床应用

利福昔明是一种胃肠道内难吸收，具有广谱抗菌活性的半合成利福霉素衍生物，主要用于治疗各种肠道感染性腹泻。由于利福昔明对某些器质性、功能性胃肠道疾病的内脏病原菌也具有作用，从而大大拓宽了其临床应用。利福昔明广泛的抗菌谱覆盖了包括皮肤、阴道和牙周感染的病原菌，试验表明利福昔明还可用于皮肤、阴道和牙周感染的治疗。     

利福昔明可以治疗一些胃肠道不适

据发表在美国肠胃道医学会第70届年会的一项研究发现，除了旅行者腹泻之外，一些肠胃道不适也对利福昔明（rifaximin，Xifaxan）有反应。利福昔明目前被核准使用于治疗旅行者腹泻，这是一种被用来抵抗吸收，直到病原菌被排出体外的口服抗生素。     

利福昔明微生物限度检查验证方法的建立

目的 建立利福昔明微生物限度检查验证方法。方法 采用常规方法验证细菌、霉菌及酵母菌计数和控制菌检查，采用离心沉淀法加培养基稀释法合用检查验证细菌计数。结果 采用常规方法，霉菌及酵母菌计数的回收率均＞90%，细菌计数的回收率＜70%，采用离心沉淀法加培养基稀释法合用检查细菌数回收率＞70%。增加培养基的量用于控制菌的检查。结论 采用离心沉淀法加培养基稀释法合用检查细菌计数。用培养基稀释法检查控制菌。     

国产利福昔明治疗急性细菌感染性腹泻115例

目的评价国产利福昔明治疗急性细菌感染性腹泻的疗效与安全性。方法急性细菌感染性腹泻患者224例，随机分为治疗组和对照组，治疗组115例给予国产利福昔明片口服，第1天3次，每次0.4 g，第2天起每天两次，每次0.4 g;对照组109例给予左氧氟沙星片口服，第1天3次，每次0.2 g，第2天起每天2次，每次0.2 g。疗程均为3～5 d。结果治疗组与对照组临床有效率分别为93.9%和90.8%，细菌清除率分别为97.62%和100.00%，不良反应发生率分别为2.61%和1.83%，两组各对应指标均差异无显著性(均P＞0.05)。结论国产利福昔明片治疗急性细菌感染性腹泻安全、有效。     

Clinical trial: the combination of rifaximin with partially hydrolysed guar gum is more effective than rifaximin alone in eradicating small intestinal bacterial overgrowth

Aliment Pharmacol Ther 2010; 32: 1000–1006

Summary

Background Abnormal intestinal clearance is involved in the pathogenesis of small intestinal bacterial overgrowth (SIBO). It is known that partially hydrolysed guar gum affects intestinal motility. Eradication therapy of SIBO is based on antibiotic treatment: no data are available on the role of fibre supplementation in eradicating SIBO. Aim To assess whether the combination of partially hydrolysed guar gum and rifaximin is more effective than rifaximin alone in the treatment of SIBO. Methods A 50 g‐glucose breath test was given to 500 consecutive patients. Patients with a positive glucose breath test and predisposing conditions to SIBO entered into the study, and were randomized to receive rifaximin 1200 mg/day or rifaximin 1200 mg/day plus partially hydrolysed guar gum 5 g/day for 10 days. Patients completed a symptom questionnaire and glucose breath test both in basal condition and 1 month after withdrawal of therapy. Results Seventy‐seven patients had SIBO. Eradication rate of SIBO was 62.1% in the rifaximin group (both on per‐protocol and intention‐to‐treat analyses), and 87.1% (per‐protocol, P = 0.017) and 85.0% (intention‐to‐treat, P = 0.036) in the rifaximin‐plus‐partially hydrolysed guar gum group. Clinical improvement was observed in 86.9% and 91.1% of eradicated cases in rifaximin and rifaximin‐plus‐partially hydrolysed guar gum groups respectively (P = 0.677). Conclusion The combination of rifaximin with partially hydrolysed guar gum seems to be more useful in eradicating SIBO compared with rifaximin alone.     

Impurity profile of rifaximin produced in China

Impurity profiles of rifaximin produced in China were investigated systematically by LCMS methods. Eleven impurities from the raw materials of rifaximin produced in China were detected. We adopted the Diagnostic fragment-ion-based extension strategy (DFIBES) for deducing the structure of unknown impurities. Impurity 1 was the 30-hydroxylated product of rifaximin. Impurity 2 was the 25-deacetyled rifaximin. Impurity 6 was the isomeride of rifaximin. Impurity 9 was rifamycin-O.     

A randomized openly comparative study between rifaximin suspension versus rifaximin pills for the eradication of Helicobacter pylori

BACKGROUND: It has been recently shown that Rifaximin, although given as a suspension, plus omeprazole, may be a promising antibiotic against Helicobacter pylori (H pylori) and worthy of further study. AIM: We have therefore evaluated Rifaximin suspension versus Rifaximin pills, in a randomly openly allocated fashion study, in H pylori positive patients. METHODS: Twenty patients with upper gastrointestinal symptoms (M/F: 13/7, age range 28-68; mean 49.6 yrs) were found to have H. pylori associated gastritis. They were allocated in an open randomized study to two different treatment groups for two weeks: (A) Rifaximin suspension 1800 mg three times a day plus Omeprazole 20 mg twice a day (n = 10), (B): Rifaximin pills 1800 mg three times a day plus Omeprazole twice a day (n = 10). Symptoms such as pirosis, bloating, epigastric pain and nausea were recorded by diary card and were evaluated before and four weeks after stopping treatment. Patients were assessed by endoscopy, histology and urease testing at entry and four weeks after stopping treatments. All the twenty patients were available four weeks after stopping treatment. RESULTS: A statistically significant improvement of the symptoms were found overall after Rifaximin treatments for pirosis, bloating, epigastric pain (p < 0.001 respectively). A significant difference in the symptom's score at the end of the two treatments were recorded between the two groups for bloating alone (p < 0.070). A different and major fall in the neutrophils, between the two treatments was observed with Rifaximin pills compared to Rifaximin suspension. The same observation was obtained according to the intensity of H. pylori reaching an eradication rate of 40% and 60% for Rifaximin suspension versus Rifaximin pills plus omeprazole respectively. In conclusion, these data suggest that Rifaximin pills may be an effective antibiotic against H pylori and worthy of further study.     

利福昔明在消化道疾病中的应用进展

利福昔明具有较强抗菌活性和口服不吸收的特点,近年来应用于肝性脑病、肠道内细菌过度生长以及炎症性肠病等多种消化道疾病的治疗.本文综述利福昔明在消化道疾病中的临床应用进展.     

Biologic properties and clinical uses of rifaximin

INTRODUCTION: Rifaximin is increasingly being used to treat acute and chronic gastrointestinal infections and disorders. The drug exerts its beneficial effect through a variety of gut-selective mechanisms involving the host intestinal microbiota. AREAS COVERED: Abstracts of all publications listed in PubMed on the topic of rifaximin are reviewed to determine their potential value in the understanding of mechanisms of rifaximin activity. The author's extensive file on the drug is also used in the review. EXPERT OPINION: Rifaximin inhibits a broad spectrum of bacteria in the bile-rich small bowel and susceptible bacteria in the aqueous colon, and alters microbial virulence and epithelial cell function. The different mechanisms of action of rifaximin potentially explain the use of the drug in widely varied diseases and syndromes.     

利福昔明的药理作用和临床应用

利福昔明(rifaximi,n商品名希捷)系利福霉素SV的半合成衍生物,为广谱肠道抗生素。该药由意大利阿尔法公司研制开发,1987年作为抗感染性腹泻药物在意大利上市,之后在国外仍被广泛应用,2004年经SFDA批准已在我国临床应用。本文对利福昔明的药理作用、药代动力学及国内外临床应用情况作一介绍。利福昔明的结构式,见图1。化学名称:4-脱氧-4'-甲基吡啶[1',2'-1,2]咪唑并[5,4-环]利福霉素SV。分子式为C43H51N3O11,分子量为785.9。1药理作用1.1体外抗菌活性利福昔明的抗菌作用特点是抗菌谱广,抗菌活性强,对革兰阳性需氧菌中的金葡菌、表皮葡萄…     

Structural elucation of a novel impurity in rifaximin

Rifaximin is a semi-synthetic rifamycin derivate. It acts on RNA polymerase of the subunit of DNA beta-2 in bacteria to restrain synthesis of RNA leading to antibacterial activity. The purpose of this study was to analyse the structure of the prepared impurity a. We found that the impurity a is the isomeride of impurity G defined in the European Pharmacopoeia.     

利福昔明对腹泻病原菌的体外抗菌活性测定

目的　评价利福昔明 (rifaximin)、环丙沙星对腹泻病原菌的体外抗菌活性。方法　采用微量肉汤稀释法对 14 3株肠道分离病原菌进行利福昔明、环丙沙星 MIC测定。结果　利福昔明和环丙沙星对革兰氏阴性菌 (沙门菌属 31株 ,志贺菌属 2 0株 ,变形菌属 8株 ,致病性大肠埃希氏菌 5株 ,假单胞菌属 6株 ,克雷伯氏菌属 4 ,其他革兰氏阴性菌 4株 ) MIC范围 、MIC50 、MIC90 分别为 1～ >12 8、0 .0 15～ >12 8,4～ 6 4、0 .0 15～ 6 4 ,32～ 12 8、32～ 12 8mg/ L;利福昔明和环丙沙星对革兰氏阳性球菌 (金葡菌 31株 ,其他葡萄球菌 17株 ,肠球菌属 17株 ) MIC范围 、MIC50 、MIC90 分别为 0 .0 15～ 32、0 .0 15～ 6 4 ,0 .0 15～ 0 .0 3、0 .5～ 16 ,0 .0 6～ 1、16～ 6 4 mg/ L。结论　利福昔明对革兰氏阳性菌 MIC范围 、MIC50 、MIC90 均低于环丙沙星 ;革兰氏阴性菌 MIC范围 、MIC50 、MIC90虽然较环丙沙星高 ,但利福昔明在肠道中可达 80 0 0 μg/ g粪便 ,故利福昔明能有效杀灭肠道病原菌。     

利福昔明中有机溶剂残留量的测定

目的建立用气相色谱的顶空进样法测定利福昔明中二氯甲烷的残留量的方法.方法使用配置顶空进样器的气相色谱仪,采用DB-624毛细管色谱柱(94%二甲基聚硅氧烷和6%氰丙基苯聚硅氧烷),0.53 mm×30 m,液膜厚度为3 μm,以氮气为载气,FID检测器,顶空进样,通过外标法计算残留溶剂含量.结果利福昔明样品中未检出二氯甲烷;标准曲线的线性范围为3.280～8.528 mg·L-1(r=0.999 8);检出限为0.2 mg·L-1;平均回收率为100.5%(RSD＝2.3%,n＝5);结论该方法简便、灵敏度高,重复性好,结果准确.