新型口服抗凝药利伐沙班

介绍新型口服抗凝药利伐沙班的药理作用和临床研究。通过文献分析,总结利伐沙班的作用机制、药效学、药动学、临床研究和安全性。利伐沙班通过直接抑制Xa因子发挥抗凝作用,该药在以下领域的研究已经完成或正在进行：预防和治疗静脉血栓,房颤和急性冠状动脉综合征的预防和治疗,肝素诱导的血小板减少症。现有的研究显示患者应用该药具有良好的耐受性,不良反应较少,而且与食物和一些常用药物合用时不发生相互作用。利伐沙班有望成为临床上安全、有效的口服抗凝药物。     

利伐沙班与抗癫痫药物相互作用的研究进展

心房颤动（房颤）导致的卒中是其严重并发症,非瓣膜性房颤导致脑梗死患者并发癫痫的风险比其他原因卒中患者更高,可能需要利伐沙班联合抗癫痫药物治疗。新型口服抗凝药物利伐沙班是口服直接Xa因子抑制剂,同时是CYP3A4和P-糖蛋白（P-gp）的底物,某些抗癫痫药物对CYP3A4和/或P-gp有诱导作用,与利伐沙班合用,可使利伐沙班血药浓度下降,血栓风险增加。对利伐沙班与丙戊酸钠、卡马西平、苯巴比妥、奥卡西平、左乙拉西坦以及其他抗癫痫药物合用的相互作用进行综述,并根据相关研究和病例报道给出推荐意见,为临床合理用药提供参考。     

艾多沙班用于非瓣膜性心房颤动抗凝治疗的研究进展

口服抗凝药物是非瓣膜性房颤患者降低血栓栓塞和卒中风险的有效治疗方法。既往临床长期应用的口服抗凝药为维生素K拮抗剂及肝素,近年来新型口服抗凝剂逐渐得到广泛应用,包括直接凝血酶抑制剂达比加群和Xa因子抑制剂如利伐沙班、阿哌沙班及艾多沙班,均可用于非瓣膜性心房颤动患者的卒中预防。艾多沙班作为新型口服抗凝剂,为房颤患者提供了更多的用药选择。本研究对艾多沙班在房颤患者抗凝预防和临床治疗中的作用进行综述。     

新型口服抗凝药利伐沙班在欧美申报用于预防中风

基于一项名为ROCKETAF的临床试验阳性结果,拜耳公司及其合作伙伴强生公司近日在欧美申报拜耳公司上市的新型口服抗凝药利伐沙班（rivaroxaban,Xarelto）用于包括房颤病人在内的心血管疾病患者预防中风。利伐沙班为凝血因子FXa直接抑制剂,     

新型口服抗凝药在急性冠脉综合征的研究进展

早期研究提示,抗血小板治疗联合华法林能减少急性冠脉综合征(ACS)患者的心血管病事件。新型口服抗凝药物用药更为方便,为ACS患者的二级预防提供了新的机遇。新型抗凝药物在ACS患者的Ⅱ期临床研究提示,出血发生率随剂量增加。随后,口服因子Ⅹa抑制剂利伐沙班和阿哌沙班的Ⅲ期临床研究,APPRAISE-2研究提前终止,而ATLAS ACS-TIMI 51研究证实利伐沙班2.5 mg,每天2次在双联抗血小板治疗的基础上进一步降低了心血管病事件。但是冠心病二级预防中抗血小板和抗凝联合治疗还需要更多的研究证据。     

综合性医院住院药房新型口服抗凝药应用调查

新型口服抗凝药物具有起效迅速,效果稳定,个体差异小,与食物相互作用少,无需定期测定国际标准化比值的优点,近年来在临床抗凝治疗中应用日益频繁。本文调查分析我院住院药房新型口服抗凝药物阿哌沙班、利伐沙班、达比加群酯使用情况,归纳总结科室使用分布和不同抗凝指征应用情况,旨在为新型口服抗凝药物合理应用提供参考,改善住院患者药物治疗水平。     

新型抗凝药与华法林用于非瓣膜性房颤患者卒中防治的成本效果分析

目的:评估中国非瓣膜性房颤患者使用新型抗凝药预防卒中的成本效果,为中国房颤患者抗凝治疗药物的合理选用提供理论依据。方法:基于全球性临床试验ARISTOTLE、RE-LY及ROCKET-AF的研究数据及我国目前医疗成本,建立一年期决策树及长期外推Markov模型的方法,通过分别计算3种新型口服抗凝药物阿哌沙班(5 mg bid)、达比加群(150 mg bid、110 mg bid)、利伐沙班(20 mg qd)和华法林的调整质量生命年(QLAYs)及治疗成本,对新型抗凝药物用于中国房颤患者卒中预防的成本效果进行了分析和研究。结果:NOACs治疗的总成本为163586~582710元,使用NOACs患者可获得的质量调整生命年为6.812~7.010。以华法林为参考的增效成本效果分析显示,成本效果比(ICER)为177271~739480元/QLAY,ICER_利伐沙班> ICER_阿哌沙班> ICER_{达比加群150 mg}> ICER_{达比加群110 mg}。3种抗凝药物与华法林比较的ICER均大于我国人均国民生产总值(GDP)的3倍,但小于部分城市人均GDP的3倍。一维敏感度分析显示该成本效果分析结果稳定可靠。结论:目前在我国,与华法林相比,使用新型抗凝药物预防非瓣膜性房颤患者卒中不具备成本效果优势。目前仅在我国经济发达的某些城市,可推荐阿哌沙班或达比加群用于房颤卒中的治疗。     

新型口服抗凝药治疗非瓣膜病房颤的成本-效用分析

摘要：目的:评价3种新型口服抗凝药物达比加群酯、阿哌沙班、利伐沙班治疗非瓣膜病房颤（NVAF）的成本-效用值,为合理用药及医保目录的评审、药品集中采购、价格谈判等提供决策依据。方法:构建Markov模型模拟NVAF发展过程,依据3种新型口服抗凝药物的国际多中心随机对照试验获得安全性和有效性数据,从文献中获取效用值,运行Treeage Pro 2011软件计算新型口服抗凝药物的成本-效用比,同时进行敏感性分析。结果:新型口服抗凝药治疗NVAF中达比加群酯110 mg成本-效用比18 155.17,达比加群酯150 mg成本-效用比23 034.72,阿哌沙班成本-效用比25 979.16,利伐沙班成本-效用比18 517.53。结论:达比加群酯110 mg在治疗NVAF过程中更具有经济优势,同时利伐沙班在治疗此类疾病相对于达比加群酯110 mg所增加的成本可以接受。     

心房颤动抗栓药物治疗进展

心房颤动(房颤)是导致卒中和外周栓塞的重要独立预测因素,华法林抗凝治疗可降低卒中率,但目前华法林临床应用不足。正在研究或已经上市的新型抗栓药物包括达比加群酯、利伐沙班和阿派沙班等可能革命性的改变这一现状。     

临床药师参与利伐沙班抗凝治疗会诊的案例分析

探讨临床药师在抗凝治疗会诊中协助制定抗凝方案并为患者降低出血风险的作用。选取4例会诊使用利伐沙班的病例，重点分析房颤合并短肠综合征患者、肝硬化合并静脉血栓患者选择利伐沙班抗凝的原因，以及当利伐沙班与其他治疗药物存在相互作用并发生出血时，临床药师主动发现、调整方案并监护的过程，4例患者后期随访中未再发生血栓及出血事件，转归良好。临床药师通过个体化的药学服务为患者在抗凝治疗中平衡血栓与出血的风险，保证患者治疗的安全及有效性。     

Safety assessment of poloxamers 101, 105, 108, 122, 123, 124, 181, 182, 183, 184, 185, 188, 212, 215, 217, 231, 234, 235, 237, 238, 282, 284, 288, 331, 333, 334, 335, 338, 401, 402, 403, and 407, poloxamer 105 benzoate, and poloxamer 182 dibenzoate as used in cosmetics

Poloxamers are polyoxyethlyene, polyoxypropylene block polymers. The impurities of commercial grade Poloxamer 188, as an example, include low-molecular-weight substances (aldehydes and both formic and acetic acids), as well as 1,4-dioxane and residual ethylene oxide and propylene oxide. Most Poloxamers function in cosmetics as surfactants, emulsifying agents, cleansing agents, and/or solubilizing agents, and are used in 141 cosmetic products at concentrations from 0.005% to 20%. Poloxamers injected intravenously in animals are rapidly excreted in the urine, with some accumulation in lung, liver, brain, and kidney tissue. In humans, the plasma concentration of Poloxamer 188 (given intravenously) reached a maximum at 1 h, then reached a steady state. Poloxamers generally were ineffective in wound healing, but were effective in reducing postsurgical adhesions in several test systems. Poloxamers can cause hypercholesterolemia and hypertriglyceridemia in animals, but overall, they are relatively nontoxic to animals, with LD(50) values reported from 5 to 34.6 g/kg. Short-term intravenous doses up to 4 g/kg of Poloxamer 108 produced no change in body weights, but did result in diffuse hepatocellular vacuolization, renal tubular dilation in kidneys, and dose-dependent vacuolization of epithelial cells in the proximal convoluted tubules. A short-term inhalation toxicity study of Poloxamer 101 at 97 mg/m(3) identified slight alveolitis after 2 weeks of exposure, which subsided in the 2-week postexposure observation period. A short-term dermal toxicity study of Poloxamer 184 in rabbits at doses up to 1000 mg/kg produced slight erythema and slight intradermal inflammatory response on histological examination, but no dose-dependent body weight, hematology, blood chemistry, or organ weight changes. A 6-month feeding study in rats and dogs of Poloxamer 188 at exposures up to 5% in the diet produced no adverse effects. Likewise, Poloxamer 331 (tested up to 0.5 g/kg day(-1)), Poloxamer 235 (tested up to 1.0 g/kg day(-1)), and Poloxamer 338 (at 0.2 or 1.0 g/kg day(-1)) produced no adverse effects in dogs. Poloxamer 338 (at 5.0 g/kg day(-1)) produced slight transient diarrhea in dogs. Poloxamer 188 at levels up to 7.5% in diet given to rats in a 2-year feeding study produced diarrhea at 5% and 7.5% levels, a small decrease in growth at the 7.5% level, but no change in survival. Doses up to 0.5 mg/kg day(-1) for 2 years using rats produced yellow discoloration of the serum, high serum alkaline phosphatase activity, and elevated serum glutamicpyruvic transaminase and glutamic-oxalacetic transaminase activities. Poloxamers are minimal ocular irritants, but are not dermal irritants or sensitizers in animals. Data on reproductive and developmental toxicity of Poloxamers were not found. An Ames test did not identify any mutagenic activity of Poloxamer 407, with or without metabolic activation. Several studies have suggested anticarcinogenic effects of Poloxamers. Poloxamers appear to increase the sensitivity to anticancer drugs of multidrug-resistant cancer cells. In clinical testing, Poloxamer 188 increased the hydration of feces when used in combination with a bulk laxative treatment. Compared to controls, one study of angioplasty patients receiving Poloxamer 188 found a reduced myocardial infarct size and a reduced incidence of reinfarction, with no evidence of toxicity, but two other studies found no effect. Poloxamer 188 given to patients suffering from sickle cell disease had decreased pain and decreased hospitilization, compared to controls. Clinical tests of dermal irritation and sensitization were uniformly negative. The Cosmetic Ingredient Review (CIR) Expert Panel stressed that the cosmetic industry should continue to use the necessary purification procedures to keep the levels below established limits for ethylene oxide, propylene oxide, and 1,4-dioxane. The Panel did note the absence of reproductive and developmental toxicity data, but, based on molecular weight and solubility, there should be little skin penetration and any penetration of the skin should be slow. Also, the available data demonstrate that Poloxamers that are introduced into the body via routes other than dermal exposure have a rapid clearance from the body, suggesting that there would be no risk of reproductive and/or developmental toxicity. Overall, the available data do not suggest any concern about carcinogenesis. Although there are gaps in knowledge about product use, the overall information available on the types of products in which these ingredients are used, and at what concentration, indicates a pattern of use. Based on these safety test data and the information that the manufacturing process can be controlled to limit unwanted impurities, the Panel concluded that these Poloxamers are safe as used.     

HPLC法测定抗妇炎胶囊中木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱

目的 采用高效液相色谱（HPLC）法同时测定抗妇炎胶囊中木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱10种活性成分。方法 采用InerSustain AQ-C₁₈色谱柱（250 mm×4.6 mm,5 μm）,流动相A：乙腈–无水乙醇（80∶20）,流动相B：0.1%磷酸溶液,梯度洗脱,检测波长220 nm,体积流量1.0 mL/min,柱温30℃,进样量10 μL。结果 木兰花碱、黄柏碱、药根碱、巴马汀、小檗碱、槐果碱、苦参碱、氧化槐果碱、槐定碱和氧化苦参碱分别在2.69～134.50、1.95～97.50、0.63～31.50、0.86～43.00、11.95～597.50、0.59～29.50、6.08～304.00、4.85～242.50、1.66～83.00、19.79～989.50 μg/mL线性关系良好（r≥0.999 3）;平均回收率分别为99.11%、98.23%、96.95%、97.78%、100.02%、97.21%、99.66%、99.52%、98.81%、100.08%,RSD值分别为1.04%、1.23%、1.37%、1.65%、0.70%、1.28%、0.65%、0.81%、1.11%、0.63%。结论 建立的HPLC法可用于抗妇炎胶囊中10种活性成分的测定,作为抗妇炎胶囊质量控制方法。     

Arformoterol: (R,R)-eformoterol, (R,R)-formoterol, arformoterol tartrate, eformoterol-sepracor, formoterol-sepracor, R,R-eformoterol, R,R-formoterol

Sepracor in the US is developing arformoterol [R,R-formoterol], a single isomer form of the beta(2)-adrenoceptor agonist formoterol [eformoterol]. This isomer contains two chiral centres and is being developed as an inhaled preparation for the treatment of respiratory disorders. Sepracor believes that arformoterol has the potential to be a once-daily therapy with a rapid onset of action and a duration of effect exceeding 12 hours. In 1995, Sepracor acquired New England Pharmaceuticals, a manufacturer of metered-dose and dry powder inhalers, for the purpose of preparing formulations of levosalbutamol and arformoterol. Phase II dose-ranging clinical studies of arformoterol as a longer-acting, complementary bronchodilator were completed successfully in the fourth quarter of 2000. Phase III trials of arformoterol began in September 2001. The indications for the drug appeared to be asthma and chronic obstructive pulmonary disease (COPD). However, an update of the pharmaceutical product information on the Sepracor website in September 2003 listed COPD maintenance therapy as the only indication for arformoterol. In October 2002, Sepracor stated that two pivotal phase III studies were ongoing in 1600 patients. Sepracor estimates that its NDA submission for arformoterol, which is projected for the first half of 2004, will include approximately 3000 adult subjects. Sepracor stated in July 2003 that it had completed more than 100 preclinical studies and initiated or completed 15 clinical studies for arformoterol inhalation solution for the treatment of bronchospasm in patients with COPD. In addition, Sepracor stated that the two pivotal phase III studies in 1600 patients were still progressing. In 1995, European patents were granted to Sepracor for the use of arformoterol in the treatment of asthma, and the US patent application was pending.     

欧洲刺柏（Juniper）

活性成分与药理作用欧洲刺柏药用部位是其浆果，具有促水排泄、防腐、抗胃肠胀气和抗风湿作用，还可改善胃功能。用作促水排泄药可增加尿量（水丢失），但不增加钠排泄。成分萜品烯-4-醇可增加肾小球滤过率，但刺激肾。欧洲刺柏浆果对单纯疱疹病毒体外显示抗病毒活性，并具抗真菌活性。动物实验显示，欧洲刺柏浆果提取物具有堕胎、抗生育、抗炎、抗胚胎植入、降血压、升血压和降血糖作用。欧洲刺柏浆果油具有兴奋子宫的活性，以及利尿、胃肠道抗菌和刺激作用，该油对平滑肌有阻止解痉作用。     

Oral Presentations (LDD, LPES, LNM, LPAT, LNT, LPPT, LPM)

Probiotic microorganisms have been shown to provide specific health benefits when consumed as food supplements or as food components. The main problem of such products is the poor survival of the probiotic bacteria in the low pH of gastric fluid. However the use of synthetic excipients for enteric coating to prevent the exposure of microorganisms to gastric fluid is limited in food supplementary industry. Therefore the aim of this study was to develop an enteric coating formulation containing shellac as a natural polymer. Shellac possesses good resistance to gastric juice; the major disadvantage of this polymer is its low solubility in the intestinal fluid [1, 2]. Thus films containing different ratios of shellac and water-soluble polymers (sodium alginate, hydroxypropyl methylcellulose (HPMC) and polyvinylpyrrolidon (PVP)) or plasticizers (glycerol and glyceryl triacetate (GTA)) were prepared in order to analyse the films’ melting temperatures (T_m), the changes in enthalpy (ΔH), their capability of taking up water, and their solubility in different media. The release characteristics of the films were studied by loading pellets with Enterococcus faecium M74 and coating them with formulations containing different amounts of shellac and polymer or plasticized shellac. Using dissolution tests, performed according to USP XXXI paddle method, the resistance of the coatings to simulated gastric fluid (SGF, pH 1.2) and the release of cells in simulated intestinal fluid (SIF, pH 6.8) was investigated.The trials showed that an increasing amount of plasticizer results in a decrease of T_m and ΔH of the films whereat glycerol had a superior plasticization effect to GTA. The compatibility of films made of water-soluble polymers and shellac was also concentration dependent. HPMC and PVP showed superior compatibility with shellac compared to sodium alginate, since films containing shellac and more than 10% [w/w] sodium alginate tended to separate into two phases. In the end five formulations containing shellac and either 5% [w/w] glycerol, 10% [w/w] PVP, 20% [w/w] PVP, 10% [w/w] HPMC, or 5% [w/w] sodium alginate emerged as feasible for enteric coating purposes.