Didilescu Cristian, Craiova U M F
Pneumologia. 2011 Oct-Dec;60(4):198-201.
After several decades without any notable progress, there are encouraging results in research and development of anti-TB drugs, the result of a large number of projects now in competition. Along with developing new drugs to treat tuberculosis (TMC207, SQ109, LL3858) are being reassessed others to optimize their effectiveness in order to shorten and simplify therapy (rifampin and rifapentine) and three other drugs, currently used for other indications, were forwarded towards TB (gatifloxacin and moxifloxacin, linezolid). Time to approval as a antiTB drug is 10-15 years, consisting of phases of preclinical and clinical research. Substitution of moxifloxacin for isoniazid during intensive phase treatment of pulmonary tuberculosis resulted in a small but statistically nonsignificant increase in 8th- week culture negativity. TMC207, a diarylquinoline with a unique way to address Mycobacterial ATP synthetase, shows high activity in vitro against Mycobacterial strains sensitive or resistant to all drugs in the first and second line, including fluoroquinolones, demonstrating exceptional qualities in vivo against several species of mycobacteria, in various animal models. TMC207 was added to a basic standard regimen in a study of MDR-TB patients. After two months and satisfactory tolerability, sputum conversion rate in culture was 48% (versus 9% in the placebo group). Two nitroimidazole (PA-824 and OPC-67683) are currently in clinical development. PA-824 demonstrated good safety and tolerability in adult patients with pulmonary TB in South Africa, when given once daily for 7 days. Associating isoniazid, would prevent the selection of mutants resistant to Isoniazid. Linezolid 600 mg is currently being tested in a Phase II for treatment of XDR-TB in the Republic of Korea. PNU-100480, analogous to the previous one, has the potential to significantly shorten the treatment in cases where there is sensitivity and in those with resistance to drugs. 300 mg dose is under investigation in a phase II pilot study in MDR-TB in South Africa. With this interest and commitment, it appears that there is a chance of having a new drug available soon.
在经历了几十年没有显著进展的情况后,抗结核药物的研发取得了令人鼓舞的成果,这是众多正在竞争的项目的成果。除了正在研发治疗结核病的新药(TMC207、SQ109、LL3858)外,其他药物也在重新评估以优化其疗效,从而缩短和简化治疗方案(利福平及利福喷汀),另外三种目前用于其他适应症的药物也被用于结核病治疗(加替沙星、莫西沙星、利奈唑胺)。一种抗结核药物从研发到获批需要10至15年,包括临床前和临床研究阶段。在肺结核强化期治疗中用莫西沙星替代异烟肼,使第8周培养阴转率有小幅但无统计学意义的增加。TMC207是一种二芳基喹啉,以独特方式作用于分枝杆菌ATP合酶,在体外对一线和二线所有药物敏感或耐药的分枝杆菌菌株均显示出高活性,包括氟喹诺酮类,在多种动物模型中对多种分枝杆菌在体内也表现出卓越特性。在一项耐多药结核病患者研究中,TMC207被添加到基本标准治疗方案中。两个月后,耐受性良好,培养痰菌转阴率为48%(安慰剂组为9%)。两种硝基咪唑类药物(PA - 824和OPC - 67683)目前正处于临床开发阶段。在南非,PA - 824对成年肺结核患者每日给药一次,连续7天,显示出良好的安全性和耐受性。与异烟肼联合使用,可防止对异烟肼耐药突变株的产生。利奈唑胺600毫克目前正在韩国进行治疗广泛耐药结核病的II期试验。与前者类似的PNU - 100480,在敏感及耐药病例中有可能显著缩短治疗时间。300毫克剂量正在南非进行的耐多药结核病II期试点研究中进行调查。有了这样的关注和投入,似乎很快就有可能推出一种新药。