生物活性

• 描述PA-824, a new chemical entity and a member of a class of compounds known as nitroimidazo-oxazines, has significant antituberculosis activity and a unique mechanism of action. When co-administration of darunavir could decrease the amount of PA-824 in vivo and extend the elimination half-life^[3]. Lead compound PA-824 showed potent bactericidal activity against multidrugresistant M. tuberculosis and promising oral activity in animal infection models^[4]. PA-824 minimum inhibitory concentrations of 90% of bacterial growth (MIC90s) against MTB and Mycobacterium kansasii were 0.12 mg/L and 8 mg/L, respectively, but >32 mg/L for Mycobacterium spp. M. avium, M. intracellulare, M. abscessus and M. fortuitum^[5]. The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 microg/ml, similar to that of metronidazole, in a dose-dependent manner^[6].
• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02589782	Tuberculosis, Multidrug-Resist... more >>ant Extensively Drug-Resistant Tuberculosis Tuberculosis, Pulmonary Collapse <<	Phase 2 Phase 3	Recruiting	March 2021	Belarus ... more >> Republican Scientific and Practical Centre for Pulmonology and Tuberculosis hospital Recruiting Minsk, Belarus Contact: Animesh Sinha, MD       minsk-ct-mtl@oca.msf.org    Principal Investigator: Alena Skrahina, MD          South Africa Doris Goodwin Hospital Recruiting Pietermaritzburg, KwaZulu Natal, South Africa Contact: Suzanne Staples       s.staples@thinksa.org.za    Principal Investigator: Ronelle Moodliar, MBBS, MMed          Don McKenzie Hospital Not yet recruiting Durban, KwaZulu-Natal, South Africa Contact: Suzanne Staples       s.staples@thinksa.org.za    Principal Investigator: Ronelle Moodliar, MBBS,MMed          Uzbekistan Republican TB Hospital No. 2 Recruiting Nukus, Karakalpakstan, Uzbekistan Contact: Timur Gilmanov       NukusCT-crc@oca.msf.org    Principal Investigator: Tigay N Zinaida, MD          Sh Alimov Republican Specialised Scientific-Practical Medical Centre for Phthysiology and Pulmonology Hospital Not yet recruiting Tashkent, Uzbekistan Contact: Viktoria Prymaka          Principal Investigator: Irina Liverko, MD Collapse <<
  NCT03338621	Tuberculosis, Pulmonary ... more >> Tuberculosis, Multidrug-Resistant Tuberculosis, MDR Tuberculosis Drug-Resistant Tuberculosis Collapse <<	Phase 2	Recruiting	January 31, 2022	Georgia ... more >> National Center for Tuberculosis and Lung Diseases Recruiting Tbilisi, Georgia, 0101 Contact: Marike Eristavi, MD    +99 559 954 0393    ma.eristavi@gmail.com    Contact: Nestan Tukvadze Collapse <<
  NCT01215851	Pulmonary Tuberculosis	Phase 2	Completed	-	South Africa ... more >> Centre for Tuberculosis Research Innovation, UCT Lung Institute Cape Town, South Africa, 7700 Task Applied Science, Karl Bremer Hospital Cape Town, South Africa Collapse <<

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• 参考文献

• [1] Dawson R, Diacon AH, et al. Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis. Lancet. 2015 May 2;385(9979):1738-47.

  [2] Vera-Cabrera L, Campos-Rivera MP, et al. In vitro activities of the new antitubercuar agents PA-824 and BTZ043 against Nocardia brasiliensis. Antimicrob Agents Chemother. 2012 Jul;56(7):3984-5.

  [3] Wang L, Zhao J, Zhang R, et al. Drug-Drug Interactions Between PA-824 and Darunavir Based on Pharmacokinetics in Rats by LC-MS-MS. J Chromatogr Sci. 2018;56(4):327–335

  [4] Stover CK, Warrener P, VanDevanter DR, et al. A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature. 2000;405(6789):962–966

  [5] Zhang F, Li S, Wen S, et al. Comparison of in vitro Susceptibility of Mycobacteria Against PA-824 to Identify Key Residues of Ddn, the Deazoflavin-Dependent Nitroreductase from Mycobacterium tuberculosis. Infect Drug Resist. 2020;13:815–822. Published 2020 Mar 11

  [6] Lenaerts AJ, Gruppo V, Marietta KS, et al. Preclinical testing of the nitroimidazopyran PA-824 for activity against Mycobacterium tuberculosis in a series of in vitro and in vivo models. Antimicrob Agents Chemother. 2005;49(6):2294–2301

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