催化气候条件下抗结核药物固定剂量复合剂的物理与化学稳定性

目的：检测印度市场销售的抗结核药物固定剂量复合剂(FDC)中的利福平、异烟肼、吡嗪酰胺及乙胺丁醇的物理及化学稳定性。方法：包装或散装药品储存于有光照或避光的ICH/WHO催化条件下(40℃/75％相对湿度)3个月。结果：RMP、INH、PZA的初始含量界于标注剂量的90-110％之间。然而，药品的某些化学特性甚至在观察刚开始时就不稳定。有一种片剂还存在物理性质的不稳定。在催化条件下，散装产品性状改变严重，包装制剂也有物理及化学性状的变化，光照条件下物理改变更为明显。PZA或许还有EMB可促进INH与RMP间的相互作用，这是一项有意义的发现。结论：本研究提示非坚固包装的抗结核药物FDC性状不稳定，应对抗结核药物FDC的药剂发展、包装以及稳定性检测试验予以关注。     

A pilot stability study on four-drug fixed-dose combination anti-tuberculosis products.

A pilot stability study was carried out on four fixed-dose combination anti-tuberculosis products at 40 degrees C and 75% RH. The strip-packed products were stable, while the blister-packed products showed both physical and chemical changes. The products in unpacked conditions showed severe (approximately 60%) decomposition of rifampicin and extensive physical changes. The main decomposition product in the solid state was isonicotinyl hydrazone of 3-formylrifamycin and isoniazid. It is suggested that attention should be paid to the detection and quantitation of this product in the marketed formulations. The packing material used in the manufacture of FDC products should also be of the highest quality.     

Pharmaceutical formulation of a fixed-dose anti-tuberculosis combination.

SETTING: Department of Pharmacy and Pharmacology, University of the Witwatersrand. Despite the availability of highly effective treatment regimens for tuberculosis (TB), the cure rate still remains relatively low. This may be attributed to the high incidence of patient non-compliance, which subsequently leads to the emergence of multidrug-resistant TB (MDR-TB). To avoid the problem of further creation and propagation of MDR-TB, it may be proposed that patients should be given fixed-dose combinations of anti-tuberculosis drugs whenever self-administration is permitted. OBJECTIVE: To optimise an anti-tuberculosis extemporaneous powder formulation for suspension in order to develop a fixed combination of rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as a powder to be reconstituted with water by the patient prior to administration. METHODS: Different suspending agents were evaluated for their influence on powder flow properties, and sediment volume on the powder blends. Sodium starch glycolate was selected as the suspending agent because of its favourable powder flow properties and sediment volume produced. The dissolution characteristics of the extemporaneous powder for suspension were also compared to the dissolution profiles of commercially available anti-tuberculosis tablet dosage forms. RESULTS: The powder for suspension for rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride all compared favourably to the dissolution rate from the commercially available tablet dosage forms.     

抗结核固定复合剂药物不良反应观察

目的观察国产抗结核FDC在治疗初治涂阳肺结核疗程中的不良反应。为临床治疗和不良反应的处理提供一定参考资料。方法从全省的地理环境和经济状况抽取7个点,每个点共纳入120例初治涂阳肺结核病例,分3组:观察组、对照组1和对照组2,每组40例。对3组病人进行药物不良反应发生率及疗程中不良反应变化趋势观察。结果不良反应总发生率:神经系统20.7%。胃肠道系统19.4%。皮肤系统11.8%。肝功能异常37.3%。白细胞降低方面18.5%。结论以上各系统不良反应发生率与国内多家报道基本一致。从发病趋势来看,只有白细胞降低的发生率随着疗程有升高的趋势,其他不良反应发生率都呈下降趋势。     

Quality control of anti-tuberculosis fixed-dose combination formulations in the global market: an in vitro study.

OBJECTIVE: To determine the quality, and especially the dissolution properties of rifampicin, of fixed-dose combination (FDC) formulations of anti-tuberculosis agents manufactured by major market holders in the anti-tuberculosis sector and supplied for use in national tuberculosis control programmes. METHODS: Dissolution studies were performed for four formulations supplied by four different manufacturers in four dissolution media (0.1N and 0.01N HCl, phosphate buffer [PB] and 20% vegetable oil in PB), at four different agitation rates using USP apparatus II. The formulations were subjected to 4-week accelerated stability studies (40 degrees C / 75% RH) and evaluated for physical, chemical and dissolution stability. RESULTS: The formulations tested complied with pharmacopeial quality control (QC) tests. The extent of rifampicin release was independent of dissolution medium; however, a slight decrease in the dissolution rate was observed in two products. More than 75% of drug was released in 45 min at all agitation intensities except 30 rpm, and 20% oil in the medium reflected fed state. Formulations were stable in the packaging conditions recommended by the manufacturer for at least 4 weeks. CONCLUSIONS: The formulations tested passed the QC tests and were found to be stable. A decrease in the rate, although not the extent, of dissolution necessitated multiple point dissolution in gastric and intestinal pH conditions to ensure consistency in in vivo bioavailability.     

抗结核固定复合制剂与板式组合药治疗肺结核可行性的对照研究

目的　评价国产抗结核FDC制剂化疗及管理的可行性。方法 自2003年6月1日至2003年12月31日在深圳市6个区就诊的肺结核病人,按往年的病人分布、各个区的经济文化程度等将深圳市6个区分别划分为观察区(FDC制剂组,包括罗湖区、南山区和宝安区)和对照区(组合药组,包括福田区、盐田区和龙岗区)。对2组病人治疗期间的耐受性、管理效果、治疗效果、不良反应进行比较。结果 (1)更多的FDC制剂组病人认为服药方式可以接受,药片大小合适,药片数适中(P＜0.05);(2)2组完成治疗率接近(P＞0.05),但FDC制剂组治愈率高于对照组(P＜0.05);(3)不良反应无显著性差异(P＞0.05);2组病人因肝损害停药率接近,分别为8.9%与5.4%,2组之间均无显著性差异(P＞0.05);(4)更多的FDC制剂组督导管理医生认为发放药物的难度大、药品的量化管理困难、目前药物管治病人不方便、同时说不清能增加病人的依从性(P＜0.05);(5)对照组药物的成本效果分析优于FDC制剂。结论 国产FDC制剂可以改善病人的接受性,提高治愈率;但是由于制作工艺、技术和市场等多方面原因,医务人员的接受性和成本效果方面比组合药差,有待进一步改进。     

提高抗结核药品固定剂量复合剂在省市级结核病定点医院推广使用的实施性研究

目的：评价在国家结核病防治规划实施中,省市级结核病定点医院推广使用抗结核药品固定剂量复合剂(FDC)使用的可行性。方法：按照典型抽样的方法,在全国选择5个省,每省一个省级和一个地市级结核病定点医院作为研究现场,采取观察性研究方法,对新诊断的利福平敏感或无耐药检测结果的肺结核患者,根据 FDC的纳入标准和排除标准进行治疗观察,分析使用抗结核 FDC 患者的纳入和退组情况。结果：2021年4月1日至7月31日,10个机构登记新诊断的利福平敏感或无耐药检测结果的肺结核患者3558例,抗结核 FDC 使用率为71.9%(2559/3558),其中最高为94.5%(346/366),最低为45.6%(215/472);12.1%(431/3558)的患者因禁忌证未使用抗结核 FDC,有禁忌证的患者占登记患者数的比例最高为43.9%(207/472),最低为2.3%(5/215)。使用抗结核 FDC的患者中22.3%(571/2562)在疗程中途停止使用抗结核 FDC,各机构中最高为44.8%(155/346),最低为3.6%(13/365);退组患者中54.5%(311/571)由于发生不良反应...     

全球市场上抗结核药物固定剂量复合剂的质量控制:体外研究结果报告

目的：评价在国家结核病控制规划中大范围供应使用抗结核药物固定剂量复合剂(FDC)的质量，尤其是FDC中利福平的溶解特性。方法：对4家药厂供应的4种制剂采用不同的溶媒(0．1NHCL及0．01NHCL、磷酸缓冲液(PB)及含20％植物油的PB)、不同振荡强度(USPⅡ型仪)进行溶解度研究。并对FDC进行了4周的催化稳定性研究(40℃／75％相对湿度[RH])，评价其物理、化学和溶解稳定性。结果：根据药典中的质控试验(CQC)对待评价制剂进行检测。利福平的溶解程度不受溶媒影响；有两种产品的利福平溶解速度有轻微降低。75％以上的药物成分在除30rpm外的各种振荡强度下，代表饱食状态的含20％植物油溶媒中45分钟内溶解。在制药厂建议的包装条件下，各制剂至少在4周内性能稳定。结论：所检测的制剂均通过了质量控制试验并证明其性能稳定。虽然有的制剂溶解速度有所降低，但其溶解程度未发生改变，但这就需要胃及肠道不同PH条件下的多点溶解，以保证制剂体内生物利用度的稳定性。     

The fixed-dose combination drug for secondary cardiovascular prevention project: improving equitable access and adherence to secondary cardiovascular prevention with a fixed-dose combination drug. Study design and objectives

In spite of advances in prevention and treatment, the burden of cardiovascular diseases is increasing. A fixed-dose combination (FDC) pill, or "polypill," composed of evidence-based drugs has been proposed as a means of improving cardiovascular prevention by reducing cost and increasing patient adherence to treatment. The aim of the FOCUS project, funded by the 7th Framework Programme of the European Commission, is to characterize the factors that underlie inadequate secondary prevention and to test a new FDC. To achieve these goals, a 9-member consortium has been constituted, including institutions from Argentina, France, Italy, Spain, and Switzerland. FOCUS Phase-1 will examine factors potentially related to lack of adequate secondary prevention in 4,000 post-myocardial infarction (MI) patients and analyze the relationship between these factors and patient treatment adherence. Primary end points will be (1) the percentage of patients receiving aspirin, angiotensin-converting enzyme inhibitors, and statins and (2) adherence to treatment measured by the Morisky-Green test. FOCUS Phase-2 is a randomized trial that will compare adherence to treatment in 1,340 post-myocardial infarction patients either receiving an FDC comprising aspirin (100 mg), ramipril (2.5, 5, or 10 mg), and simvastatin (40 mg) or receiving the same 3 drugs separately.     

国产抗结核固定剂量复合剂的药效学和药代动力学研究

目的 研究国产固定剂量复合剂的药效学和药代动力学，评价其抗结核作用及产品质量。方法 采用二倍稀释法测定最低抑菌浓度（MIC），以半数动物存活时间为指标比较药物对实验性结核病的疗效。高效液相色谱法测定健康志愿者口服同剂量国产及进口三药复方片剂（卫非特）的血药浓度，求出各组分的主要药代动力学参数及相对生物利用度，并用双单侧t检验分析药物等效性。结果 复方制剂各成分对结核分枝杆菌的MIC均低于单独应用时各自的MIC；对小鼠试验性结核病均显著优于三者相应剂量单独应用的效果，与国外相应产品卫非特比较未见显著性；国产与进口片剂的主要药代动力学参数t1/2、Cmax、AUC、tmax未见显著性差异，相对生物利用度生物等效性检验合格。结论 三药复方的抗结核作用具有协同作用；国产与进口片剂为等效制剂。     

The management of anti-tuberculosis drug-induced hepatotoxicity.

SETTING: A tuberculosis ward in a chest disease teaching hospital. OBJECTIVE: To compare the efficacy of two different retreatment protocols on hepatotoxicity recurrence in tuberculosis treatment. DESIGN: In a prospective, randomised study, 45 patients with new tuberculosis developed hepatotoxicity after anti-tuberculosis treatment. Patients in Group I (n = 20) were retreated with a drug regimen consisting of isoniazid, rifampicin, ethambutol and streptomycin administered by gradually increasing the number and dosage of the drugs. Patients in Group II (n = 25) were retreated with the same regimen (isoniazid, rifampicin, pyrazinamide and ethambutol) in the same dosages throughout. RESULTS: Hepatotoxicity recurred in respectively zero and six (24%) patients in Groups I and II (P = 0.021). Of the six patients with recurrence of hepatitis, one could not be followed up. The other five received the same retreatment protocol as Group I. By the end of retreatment, all patients were cured. CONCLUSION: The recurrence rate of hepatotoxicity in the retreatment of tuberculosis is higher in the reintroduction of a full-dose regimen including pyrazinamide, which causes more hepatotoxicity than gradual reintroduction of a regimen without pyrazinamide.     

固定剂量复合剂治疗肺结核患者依从性调查与分析

Objective To survey and analyse the treatment compliance of fixed-dose combination （FDC）,so as to provide evidences for expending use FDC nationwide. Methods Nine hundred and sixty-six primary smear positive pulmonary tuberculosis cases registered in 17 counties TB institutions from 4 provinces were randomly divid- ed into experiment and control groups. Compared compliance difference with uniform questionnaires, and analysed compliance changes with time throughout the treatment. Results Nine hundred and sixty-one cases were surveyed at the beginning, 899（93.5% ）preferred receiving treatment. There was significant difference on the percentage who prefer had drugs per day between experiment（86.8% ）and control group（42.1% ）（ P 〈 0.01 ）.At the end of intensive phase, 261（28.3 % ）cases perceived difficulty with the treatment ;213 （23.1% ）cases thought that were the doctors who lead to the insist of treatment.At the end of treatment,only 138 cases（15.5% ）thought that were the doctom who lead to the insist of treatment. Conclusion The compliance of FDC was better than control group. It might increase the compliance when decreasing the number of tablets and should expend used on TB control. The ef- fect of TB doctors decreased through the treatment. More intention should be paid in intense phase.     

固定剂量复合剂治疗肺结核患者依从性调查与分析

目的调查和分析固定剂量复合剂(FDC)治疗肺结核的患者依从性,为FDC在我国推广应用提供参考。方法选择4省17县结防机构登记的966例初治涂阳肺结核患者,随机分为研究组和对照组,使用统一调查问卷,调查患者不同治疗时期依从性。结果在治疗前调查961例患者回答问题,899例(93.5%)自愿接受治疗;研究组选择每日服药比例86.8%,高于对照组的42.1%,组间有显著性差异(P<0.01)。强化期末,261例(28.3%)感到坚持治疗有困难,213例(23.1%)认为医生督导是坚持治疗的原因。疗程末,138例(15.5%)认为坚持治疗的关键是医生。结论采用固定剂量复合剂患者依从性优于对照组,药片数量减少是提高依从性原因之一,应加以推广;随疗程进展,医生督导作用下降,应加强对患者强化期的管理和督导。     

Effects of sampling height and climatic conditions in aerobiological studies.

This study examined the effect of sampling height on the measurement of airborne particles (pollen grains) common in the sampling area in the outskirts of the city of Córdoba, Spain. The effect of certain meteorological parameters on variations in concentration at different heights were also examined. The study was carried out throughout 1991 and 1992 using two Hirst samplers placed at two different heights (1.5 and 15 m) at the Faculty of Science at the University of Córdoba. The statistical results indicated that there were significant differences in the concentrations obtained at different heights, the values at 1.5 m being generally higher with the exception of pollen belonging to the Urticaceae family. The pollen counts of this type were greater at the higher elevation, probably due to the small size of the pollen, especially in the Urtica membranacea species, and to the convective phenomena in this climatic zone in spring, the season in which this species blooms. When these height comparison studies were conducted, the importance of the effect of placing the sampler in relation to a nearby building was also observed. Higher pollen concentrations were detected when the lower sampler was located on the leeward side. The meteorological parameters studied had some influence on the vertical dispersion of the pollen, although the percentage of variation according to height was very small, probably due to the short duration of the study. However, a certain relation between the differences in concentration per height and the degree of atmospheric stability was observed.     

在DOTS管理下应用国产4药固定剂量复合剂治疗初治菌阳肺结核的可行性研究

目的评价在DOTS管理下应用4药(HRZE)固定剂量复合剂(FDC),和2药(HR)的抗结核疗效及不良反应。方法将225例初治涂阳肺结核患者,随机分为治疗组(2个月4药FDC/4个月2药FDC)和对照组(2HRZE/4HR),观察近期痰菌阴转率、X线病变改变情况及不良反应。结果治疗组和对照组2个月痰菌阴转率分别为94.6%、93.8%;满疗程痰菌阴转率分别为99.1%、96.5%;胸部X线明显改善,治疗组和对照组病灶吸收率分别为98.2%和97.4%;2组空洞闭合率分别为72.2%和56.4%;治疗组和对照组各有4例和3例肝功异常。结论国产4药固定剂量复合剂是一种安全、高效、易被患者接受的抗结核药物制剂。且有很好的依从性,适于在国内广泛推广应用。