氯苯吩嗪抗结核作用的研究进展

doi:10.3969/j.issn.1000-6621.2015.01.017

摘要/Abstract

摘要： 氯苯吩嗪是一种吩嗪类衍生物，具有抗微生物活性，最初被用来治疗麻风病。近年来发现其具有很强的体内外抗结核活性，尤其是其对多耐药结核分枝杆菌菌株具有杀菌活性，相关研究也证实了该药对治疗多耐药和广泛耐药结核病具有很好的前景，其抗结核作用新靶点和作用机制的研究是近年的热点。本研究旨在介绍氯苯吩嗪抗结核作用的药理学特性及其临床应用情况，并重点阐述其抗结核作用机制的研究进展。

关键词: 分枝杆菌, 结核, 抗结核药, 氯苯吩嗪

Abstract: Clofazimine, a phenazine derivative possessing antimicrobial activity, was originally used to cure leprosy. Recently it has been found that clofazimine has potency against Mycobacterium tuberculosis, especially for multidrug-resistant strains. Related studies showed clofazimine has good potency in the treatment of multidrug and extensively multidrug-resistant tuberculosis. Thereby, study on the new targets and mechanisms of clofazimine have become the research hotspot in recent years. This review aims to introduce the latest advancement of clofazimine in terms of pharmacological properties and clinical applications, focusing on the mechanisms of anti-tuberculous action.

Key words: Mycobacterium tuberculosis, Antitubercular agents, Clofazimine

左小淑，陆宇. 氯苯吩嗪抗结核作用的研究进展[J]. 中国防痨杂志, 2015, 37(1): 90-94. doi: 10.3969/j.issn.1000-6621.2015.01.017

ZUO Xiao-shu, LU Yu. Advance in anti-tuberculous activity of clofazimine[J]. Chinese Journal of Antituberculosis, 2015, 37(1): 90-94. doi: 10.3969/j.issn.1000-6621.2015.01.017

参考文献

［1］World Health Organization(WHO). Global tuberculosis report 2013. Geneva: World Health Organization，2013.
［2］Lu Y, Zheng M, Wang B, et al. Clofazimine analogs with efficacy against experimental tuberculosis and reduced potential for accumulation. Antimicrob Agents Chemother, 2011, 55(11): 5185-5193.
［3］Mariani F,Goletti D, Ciaramella A,et al. Macrophage response to Mycobacterium tuberculosis during HIV infection: relationships between macrophage activation and apoptosis. Curr Mol Med, 2001, 1(2): 209-216.
［4］Barry VC, Belton JG, Conalty ML, et al. A new series of phenazines (rimino-compounds) with high antituberculosis activity. Nature, 1957, 179(4568): 1013-1015.
［5］Reddy VM, Nadadhur G, Daneluzzi D, et al. Antituberculosis activity of clofazimine and its new analogs B4154 and B4157. Antimicrob Agents Chemother, 1996, 40(3): 633-636.
［6］Jagannath C, Reddy MV, Kailasam S, et al. Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis: In vitro, intracellular, and in vivo studies. Am J Respir Crit Care Med, 1995, 151(4): 1083-1086.
［7］Reddy VM, O’Sullivan JF, Gangadharam PR. Antimycobacterial activities of riminophenazines. J Antimicrob Chemother, 1999, 43(5): 615-623.
［8］Xu J, Lu Y, Fu L, et al. In vitro and in vivo activity of clofazimine against Mycobacterium tuberculosis persisters. Int J Tuberc Lung Dis, 2012，16(8): 1119-1125.
［9］Grant SS, Kaufmann BB, Chand NS, et al. Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals. Proc Natl Acad Sci U S A, 2012, 109(30): 12147-12152.
［10］Irwin SM, Gruppo V, Brooks E, et al. Limited activity of clofazimine as a single drug in a mouse model of tuberculosis exhibiting caseous necrotic granulomas. Antimicrob Agents Chemother, 2014, 58(7): 4026-4034.
［11］O’Neill AJ, Miller K, Oliva B, et al. Comparison of assays for detection of agents causing membrane damage in Staphylococcus aureus. J Antimicrob Chemother, 2004, 54(6): 1127-1129.
［12］Tasneen R, Li SY, Peloquin CA, et al. Sterilizing activity of novel TMC207- and PA-824-containing regimens in a murine model of tuberculosis. Antimicrob Agents Chemother, 2011, 55(12): 5485-5492.
［13］Grosset JH, Tyagi S, Almeida DV, et al. Assessment of clofazimine activity in a second-line regimen for tuberculosis in mice. Am J Respir Crit Care Med, 2013, 188(5): 608-612.
［14］Williams K, Minkowski A, Amoabeng O, et al. Sterilizing activities of novel combinations lacking first- and second-line drugs in a murine model of tuberculosis. Antimicrob Agents Chemother, 2012, 56(6): 3114-3120.
［15］Morrison NE, Marley GM. The mode of action of clofazimine DNA binding studies. Int J Lepr Other Mycobact Dis, 1976, 44(1/2): 133-134.
［16］Van Rensburg CE, Jooné GK, O’Sullivan JF, et al. Antimicrobial activities of clofazimine and B669 are mediated by lysophospholipids. Antimicrob Agents Chemother,1992, 36(12): 2729-2735.
［17］Yano T, Kassovska-Bratinova S, Teh JS, et al. Reduction of clofazimine by mycobacterial type 2 NADH: quinone oxidoreductase: a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem, 2011, 286(12): 10276-10287.
［18］De Bruyn EE, Steel HC, van Rensburg EJ, et al. The riminophenazines, clofazimine and B669, inhibit potassium transport in gram-positive bacteria by a lysophospholipid-dependent mechanism. J Antimicrob Chemother, 1996, 38(3): 349-362.
［19］Steel HC, Matlola NM, Anderson R. Inhibition of potassium transport and growth of mycobacteria exposed to clofazimine and B669 is associated with a calcium-independent increase in microbial phospholipase A2 activity. J Antimicrob Chemother, 1999, 44(2): 209-216.
［20］Matlola NM, Steel HC, Anderson R. Antimycobacterial action of B4128, a novel tetramethylpiperidyl-substituted phenazine. J Antimicrob Chemother, 2001, 47(2): 199-202.
［21］Kagan VE. Tocopherol stabilizes membrane against phospholipase A, free fatty acids, and lysophospholipids. Ann N Y Acad Sci, 1989, 570: 121-135.
［22］Anderson R, Zeis BM, Anderson IF. Clofazimine-mediated enhancement of reactive oxidant production by human phagocytes as a possible therapeutic mechanism. Dermatologica, 1988, 176(5): 234-242.
［23］Cho SH, Warit S, Wan B, et al. Low-oxygen-recovery assay for high-throughput screening of compounds against nonreplicating Mycobacterium tuberculosis. Antimicrob Agents Chemother, 2007, 51(4): 1380-1385.
［24］陆宇，王彬，赵伟杰，等.氯法齐明与其他抗结核药物联用对结核分枝杆菌的作用.中华结核和呼吸杂志,2010,33（9）：675-678.
［25］Adams LB, Sinha I, Franzblau SG, et al. Effective treatment of acute and chronic murine tuberculosis with liposome-encapsulated clofazimine. Antimicrob Agents Chemother, 1999, 43(7): 1638-1643.
［26］张天民,杨树旺.氯苯吩嗪的药理学和临床应用.结核病临床与控制, 2002, 1(1): 39-42.
［27］Schaad-Lanyi Z, Dieterle W, Dubois JP, et al. Pharmacokinetics of clofazimine in healthy volunteers. Int J Lepr Other Mycobact Dis, 1987, 55(1): 9-15.
［28］Yawalkar SJ, Vischer W. Lamprene (clofazimine) in leprosy. Basic information. Lepr Rev, 1979, 50(2): 135-144.
［29］Desikan KV, Balakrishnan S. Tissue levels of clofamine in a case of leprosy. Lepr Rev, 1976, 47(2):107-113.
［30］Manseld RE. Tissue concentrations of clofazimine（B663）in man. Am J Trop Med Hyg, 1974, 23(6): 1116-1119.
［31］Garrelts JC. Clofazimine: a review of its use in leprosy and Mycohacterium avium complex infection. DICP, 1991, 25(5): 525-531.
［32］Holdiness MR. Adverse cutaneous reactions to antituberculosis drugs（Review）. Int J Dermatol, 1985, 24(5): 280-285.
［33］O’Connor R, O’Sullivan JF, O’Kennedy R. The pharmacology, metabolism, and chemistry of clofazimine. Drug Metab Rev，1995, 27(4): 591-614.
［34］Gangadharam PR, Ashtekar D, O’Sullivan JF, et al. In vitro, in vivo, and intracellular chemotherapeutic activity of B746, a clofazimine analogue against Mycobacterium avium complex. Tuber Lung Dis, 1992, 73(4): 192-199.
［35］Venkatesan K, Deo N, Gupta UD. Tissue distribution and deposition of clofazimine in mice following oral administration with or without isoniazid. Arzneimittelforschung, 2007, 57(7): 472-474.
［36］Horita Y, Doi N, et al. Comparative study of the effects of antituberculosis drugs and antiretroviral drugs on cytochrome P450 3A4 and P-glycoprotein. Antimicrob Agents Chmother, 2014, 58(6): 3168-3176.
［37］Levy L. Pharmacologic studies of clofazimine. Am J Trop Med Hyg, 1974, 23(6): 1097-1109.
［38］Van Deun A, Maug AK, Salim MA, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med, 2010, 182(5): 684-692.
［39］Mukherjee JS, Rich ML, Socci AR, et al. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet, 2004, 363(9407): 474-481.
［40］Hawkins CC, Gold JW, Whimbey E, et al. Mycobacterium avium complex infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med, 1986, 105(2):184-188.
［41］Xu HB, Jiang RH, Xiao HP. Clofazimine in the treatment of multidrug-resistant tuberculosis. Clin Microbiol Infect, 2011, 18(11): 1104-1110.
［42］Dey T, Brigden G, Cox H, et al. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J Antimicrob Chemother, 2013, 68(2): 284-293.
［43］Gopal M, Padayatchi N, Metcalfe JZ,et al. Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. Int J Tuberc Lung Dis, 2013, 17(8): 1001-1007.
［44］TB Alliance. Clofazimine. Tuberculosis (Edinb), 2008, 88(2): 96-99.
［45］Van Rensburg CE, Anderson R, O’Sullivan JF. Riminophenazine compounds: pharmacology and anti-neoplastic potential. Crit Rev Oncol Hematol, 1997, 25(1): 55-67.

[1]	张静, 陈曦, 王彬, 付雷, 陆宇, 陈效友. 改良单叠氮丙啶-荧光定量PCR法的建立及其检测抗结核药物活性的价值[J]. 中国防痨杂志, 2020, 42(5): 472-480.
[2]	高天慧,舒薇,高静韬,陆宇,李琦. 254例耐药肺结核患者克拉霉素耐药情况及影响因素分析[J]. 中国防痨杂志, 2020, 42(3): 259-265.
[3]	陈浩,武楠楠,胡文辉,杨忠金. 抗结核药物作用新靶点及其研究进展[J]. 中国防痨杂志, 2020, 42(3): 286-292.
[4]	王静,张蒙,贺建清. 抗结核药物引起的艰难梭状芽胞杆菌相关性腹泻一例并文献复习[J]. 中国防痨杂志, 2020, 42(3): 293-296.
[5]	邱磊,张少言,郭晓燕,付际游,田黎明,张惠勇,鹿振辉. 化疗方案加芩部丹片治疗复治涂阳肺结核患者的临床价值[J]. 中国防痨杂志, 2020, 42(2): 108-114.
[6]	王雪迪,江锋,代倩兰,王京,王冬梅. 中西医联合与单纯西医治疗结核病所致药物性肝损伤的对比分析(2000—2019年文献复习)[J]. 中国防痨杂志, 2020, 42(2): 126-132.
[7]	李蒙, 路丽苹, 江琦, 洪建军, 高谦, 杨崇广, 郭晓芹. 上海市松江区肺结核患者治疗药品的种类及费用分析[J]. 中国防痨杂志, 2020, 42(12): 1329-1332.
[8]	唐亮, 鲍玉成, 张文龙. 抗结核药品对肠道菌群的改变及其对机体的影响[J]. 中国防痨杂志, 2020, 42(12): 1333-1338.
[9]	陈曦,刘忠泉,王彬,朱慧,付雷,李媛媛,陆宇. 14种抗结核药物在巨噬细胞内的抗结核活性评价[J]. 中国防痨杂志, 2019, 41(9): 993-998.
[10]	《中国防痨杂志》编委会. 耐药结核病化疗过程中药品不良反应处理的专家共识[J]. 中国防痨杂志, 2019, 41(6): 591-603.
[11]	邓国防,张培泽,杨敏,付亮. 二线注射剂治疗耐多药结核病的现状与思考[J]. 中国防痨杂志, 2019, 41(6): 604-608.
[12]	赵皎洁,陆宇. 抗结核药物药代动力学/药效学的研究及进展[J]. 中国防痨杂志, 2019, 41(6): 700-704.
[13]	郭存炳,李辉,郑淑兰. 参芪十一味颗粒治疗抗结核药物所致白细胞减少症的疗效[J]. 中国防痨杂志, 2018, 40(3): 274-279.
[14]	吴虹，李钧，安琴，等. 水飞蓟宾胶囊预防抗结核药物所致肝损伤的疗效分析[J]. 中国防痨杂志, 2017, 39(7): 757-760.
[15]	赵嫄，雷倩，党丽云，等. 抗结核药物血药浓度监测工作的思考和展望[J]. 中国防痨杂志, 2017, 39(11): 1228-1232.