FDA警告：肺动脉高压治疗药物Revatio禁用于儿童

2012年8月,美国FDA发布了一则关于使用辉瑞公司西地那非（sildenafil,Revatio）治疗肺动脉高压（PAH）儿童患者的安全通告。经对长期临床研究数据的回顾性分析,FDA建议临床不要将Revatio用于1-17岁PAH患者。虽然本品从未获准用于PAH儿童患者的治疗,但FDA担心可能存在超适应证使用的问题。一项多中心随机双盲安慰剂对照临床研究中,234例年龄为1-17岁的PAH患者随机分别接受低剂量、中等剂量或大剂量西地那非或安慰剂,治疗为期16周。研究结果显示,与服用低剂量本品的患儿相比,服用大剂量Revatio的患儿死亡风险更高;然而低剂量本品对患者运动能力的改善无效。     

2005年11—12月欧洲批准和上市的新产品

获准新产品 Pfizer公司的Revatio（sildenafil，西地那非）在欧盟获准，用于肺动脉高压（PAH）治疗。EMEA将这个药物划为罕见病药物，它曾获准用于PAH，WHO分类为功能3类，以改善运动能力。EMEA的批准是依据一项涉及278例病人的双盲、安慰剂对照临床试验结果。它显示对6分钟行走距离的主要评价终点有统计学上明显的改善。     

利福昔明能有效改善肠易激综合征无便秘患者的症状

有研究提示肠道菌群可能参与了肠易激综合征（IBS）的病理过程：本研究评价了一种极少被肠道吸收的抗生素利福昔明（rifaximin）治疗IBS的疗效。在2项设计一致的Ⅲ期随机双盲安慰剂对照的试验中（RAILGET1和TAP-GET2）,IBS无便秘患者随机接受利福昔明或安慰剂550mg,tid,持续2w,再随访10w。     

使用选择性内皮素A受体拮抗剂sitaxsentan治疗肺动脉高压

目的:测定选择性内皮素A(ETA)受体拮抗剂sitaxsentan治疗肺动脉高压(PAH)的最佳剂量,为了便于观察,试验还包括了一个公开标签(OL)的波生坦(bosentan)治疗组。背景:内皮素是PAH的介导者。在一项初步的PAH研究中,选择性ETA受体拮抗剂sitaxsentan改善了6分钟步行(6MW)距离,世界卫生组织(WHO)功能分级(FC)以及血流动力学情况。方法:在此项双盲、安慰剂对照、为期18周的试验中,有247例PAH患者(原发性的,与结缔组织病或者先天性心脏病相关的)被随机纳入研究;245例患者接受了治疗:安慰剂组(n=62),sitaxsentan治疗组50mg(n=62)或者100mg…     

国产枸橼酸西地那非片治疗男性勃起功能障碍疗效和安全性的临床研究

目的　评价口服国产枸橼酸西地那非片治疗男性勃起功能障碍的临床有效性和安全性。方法　采用多中心、随机、双盲、安慰剂、平行对照的方法 ,对 2 40例患者进行为期 8周的临床观察 ,评价标准包括 :国际勃起功能指数 (IIEF)、记事本、总评题。结果　西地那非组IIEF评分明显高于安慰剂组 (P <0 0 1) ,记事本、总评题结果西地那非组亦明显优于安慰剂组 ,无不良反应中断研究者。结论　国产枸橼酸西地那非片是治疗男性勃起功能障碍的有效和安全的药物。     

紫锥菊液体提取物对成人感冒有效

在一项随机、双盲、安慰剂对照临床试验中，282例在前一年有过2次以上感冒的18～65岁健康男性和女性病人随机接受标准化的紫锥菊(Echinacea purpurea)液体提取物或安慰剂7天，并要求在与感冒有关的第一个症状出现时开始治疗。第一天服10个剂量，其余6天日服4个剂量。     

国产枸橼酸西地那非片治疗男性勃起功能障碍疗效和安全性的临床研究

目的评价口服国产枸橼酸西地那非片治疗男性勃起功能障碍的临床有效性和安全性。方法采用多中心、随机、双盲、安慰剂、平行对照的方法，对240例患进行为期8周的临床观察，评价标准包括：国际勃起功能指数(IIEF)、记事本、总评题。结果西地那非组皿亚评分明显高于安慰剂组(P＜0．01)，记事本、总评题结果西地那非组亦明显优于安慰剂组，无不良反应中断研究。结论国产枸橼酸西地那非片是治疗男性勃起功能障碍的有效和安全的药物。     

托吡酯治疗慢性下腰痛：一项随机、双盲、安慰剂对照研究

慢性下腰痛(C L B P)是一种常见的疾病。Muehlbacher M等人进行了一项研究[Clin J Pain,2006,22(6):526-531.],目的是评价托吡酯(topiramate)对CLBP的疗效,以及患者在治疗期间情绪、体重、主观疼痛所致的功能障碍和与健康相关的生活质量的改变。研究者们进行了一项为期10周、随机、双盲、安慰剂对照研究,共纳入96例CLBP患者(36例女性),评估托吡酯对其的疗效。将研究对象随机分为托吡酯治疗组(n=48)和安慰剂对照组(n=48)。初级观察终点为McGill疼痛问卷、STAI问卷、Oswestry腰痛问卷、SF-36健康调查量表以及体重的改变。与安慰剂…     

抗便秘药Linaclotide

美国FDA于2012年8月30日批准了抗便秘新药linaclotide（商品名：Linzess）用于治疗成人慢性特发性便秘（CIC）和便秘型肠易激综合征（IBS-C,主要症状为腹痛和大便成硬块状）。该药的获准是基于4项关键性的双盲、随机、安慰剂对照临床试验阳性结果。其中两项在IBS-C患者中进行,     

西地那非治疗骨盆骨折尿道损伤后并发勃起功能障碍

目的 :观察西地那非治疗骨盆骨折尿道损伤后阴茎勃起功能障碍 (ED)的疗效和安全性。方法 :采用随机、交叉、双盲和安慰剂对照方法 ,将 5 2例骨盆骨折尿道损伤后ED病人 ,分为A ,B 2组 ,A组 2 8例 ,性交前 1h口服西地那非 5 0～ 10 0mg ,2～3日口服 1次 ,连续 4wk ;B组 2 4例 ,同时给予安慰剂治疗 4wk。间隔 1wk后 ,2组用药顺序进行自身前后交叉治疗。采用勃起功能国际问卷 (IIEF 5 )进行评价。结果 :A ,B 2组服用西地那非总有效率分别为 79%与 71% (P >0 .0 5 )。A ,B 2组在交叉服药后 ,其治疗ED总有效率西地那非治疗组为75 % ,而安慰剂组为 2 1% (P <0 .0 5 )。不良反应较轻微而且短暂。结论 :西地那非治疗骨盆骨折尿道损伤后阴茎勃起功能障碍疗效确切 ,且无明显不良反应     

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.