生物活性

• 描述Isonicotinic acid hydrazide (INH) is a synthetic antibiotic used for the treatment of tuberculosis. Isoniazid has outstanding bactericidal action against M. tuberculosis with a minimal inhibitory concentration of 0.1 – 0.7 µM. The treatment of 100 µM INH in an human granuloma model significantly reduced bacterial growth 6 days after the infection. However, INH-induced mycobactericidal activity was not altered when granuloma-like structures were depleted from CD3⁺ T cells. When P. berghei-infected mice were treated with 25 or 50 mg/kg INH intraperitoneally and fed to An. stephensi mosquitoes, the exflagellation level in mosquito gut was significantly reduced, as well as the number of oocyst per gut, indicating decreased parasite development by INH treatment. Dose-response curve showed that INH dose (10 – 150 mg/kg) was positively correlated with its transmission-blocking effect in P. berghei/mouse model, and the half-maximal effective dose of INH was 109 mg/kg.
• 作用机制Isonicotinic acid hydrazide (INH) passively enters mycobacterial cell through the cell wall and is activated by a mycobacterial enzyme called KatG. Activated IHN led to the accumulation of reactive oxygen species. The produced isonicotinoyl radical binds to a NAD molecule, resulting in the inhibition of FASII enoyl-ACP reductase InhA, which is essential in the mycolic acid biosynthesis pathway. The inhibition impedes cell wall synthesis, and eventually leads to cell death.

• 动物研究
  剂量	Rat: 0.05 g/kg[3] (s.c.)
  给药途径	s.c.

• 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
  NCT02114684	Recurrent Tuberculosis	Phase 1 Phase 2	Completed	-	South Africa ... more >> CAPRISA eThekwini Clinical Research Site (eCRS) Durban, KwaZulu Natal, South Africa, 4001 Collapse <<
  NCT00018083	Tuberculosis ... more >>HIV Infections Collapse <<	Not Applicable	Unknown	-	United States, North Carolina ... more >> Duke University Medical Center Recruiting Durham, North Carolina, United States, 27710 Contact: Carol D Hamilton, M.D.    919-684-3279 Collapse <<
  NCT02381470	Tuberculosis	Phase 2	Not yet recruiting	March 2018	Philippines ... more >> Lung Center Philippines Not yet recruiting Manila, Philippines Contact: Vincent Balanag          Principal Investigator: Vincent Balanag          Philippines Tuberculosis Society (Quezon Institute) Not yet recruiting Manila, Philippines Contact: Jubert Benedicto          Principal Investigator: Jubert Benedicto          Singapore Changi General Hospital Not yet recruiting Singapore, Singapore Contact: Augustine Tee          Principal Investigator: Augustine Tee          National University Hospital, Singapore Not yet recruiting Singapore, Singapore Contact: Meera Gurumurthy    +65 6772 7861    meera@nuhs.edu.sg    Principal Investigator: Nicholas Paton Collapse <<

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• 参考文献

• [1] Slayden RA, Lee RE, Barry CE 3rd. Isoniazid affects multiple components of the type II fatty acid synthase system of Mycobacterium tuberculosis. Mol Microbiol. 2000 Nov;38(3):514-25.

  [2] Mdluli K, Slayden RA, et al. Inhibition of a Mycobacterium tuberculosis beta-ketoacyl ACP synthase by isoniazid. Science. 1998 Jun 5;280(5369):1607-10.