氯法齐明治疗耐多药结核病的基础和临床研究的初步探讨
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摘要
研究背景
氯法齐明(Clofazimine,Cfz),是1944年在开发抗结核新药时被发现的,但在当时的豚鼠及猴子结核病模型中未显示活性,此后一直被忽视对其抗结核作用的进一步研究和应用。所幸的是在抗麻风杆菌的研究中发现了它具有很好的抗分枝杆菌作用,至今已用于治疗麻风病及鸟型分枝杆菌病多年,是一种较为有效的抗麻风病药物。对于氯法齐明抗结核活性的研究仅有个别报道,在世界范围内尤其是我国的耐多药以及严重耐多药结核病治疗十分困难的情况下,进行氯法齐明抗结核作用的基础与临床研究,评价其抗结核活性显然是十分必要的,将为临床应用提供依据,为肺结核特别是耐药肺结核患者提供可能的治疗药物打下基础。
研究目的
通过评价氯法齐明对结核分枝杆菌标准株及耐药结核分枝杆菌临床株的体外活性、小鼠结核病模型的体内治疗作用观察;以及氯法齐明的组织分布和异烟肼、吡嗪酰胺对其组织分布的影响的研究,并采用自身对照的方法评价氯法齐明联合其他抗结核药治疗耐多药肺结核的有效性和安全性,为氯法齐明治疗耐药结核病的临床应用提供帮助。
研究方法
1.应用微孔板指示剂法测定氯法齐明对结核分枝杆菌标准株及对30株临床分离耐多药结核分枝杆菌的最低抑菌浓度;通过建立小鼠静脉感染H37Rv 1×105CFU/只的结核病模型,按照氯法齐明20mg/kg(Cfz-1)每周给药5次;10 mg/kg(Cfz-2)每周给药5次及20 mg/kg (Cfz-3)每周给药2次的方案给予治疗;30天时进行活菌计数评价氯法齐明在小鼠体内的抗结核活性;并将耐药结核分枝杆菌临床分离株感染小鼠,应用氯法齐明和联合化疗方案治疗60天,评价氯法齐明对耐药结核病模型小鼠的效果。
2.采用昆明种小鼠和BALB/C小鼠,单次给药研究氯法齐明的组织分布并在小鼠体内研究异烟肼、吡嗪酰胺对氯法齐明组织分布的影响:灌胃给药,于给药后1h、5h、24h,眶下取血或摘眼球取血。解剖取小鼠肝、肾、脾、肺、脂肪等,测量组织浓度。
3.氯法齐明治疗耐多药结核病的初步研究。选择耐多药结核病患者,自愿签署知情同意书;年龄18-65岁;采用为期24个月自身对照的临床试验。根据药敏试验结果,选择含氯法齐明(Cfm)、丙硫异烟胺(Pto)、对氨基水杨酸钠(PAS)、左旋氧氟沙星(Lfx)、克拉霉素(Clr)、丁胺卡那霉素(Am)以及敏感药组成的5-7种药的强化期为6个月,巩固期为24个月的化疗方案,观察治疗耐多药结核病的有效性和安全性。
结果:
1.氯法齐明对结核分枝杆菌H37Rv的MIC为0.12ug/ml,对耐多药结核分枝杆菌MIC范围是0.12-1.96μg/ml。
2.在标准株感染小鼠的结核病模型中显示:氯法齐明虽然抗结核的活性不如异烟肼,但可以将小鼠肺脏中的结核分枝杆菌降低1.8～2.9Log10 CFU,脾脏中降低1.5～2.5 Log10 CFU,表明具有较好的体内抗结核作用。
3.在耐药株感染小鼠的结核病模型中显示:治疗2月后氯法齐明可以将肺中的活菌数降低2.32 Log10 CFU,而5药联合化疗后可以降低3.9 Log10 CFU。
4.氯法齐明在小鼠体内的组织分布顺序依次为脂肪、脾、肾、肝、肺等组织,异烟肼和吡嗪酰胺均可提高氯法齐明在肺组织的浓度,氯法齐明在给药2月停药后的2月仍不能彻底消除。
5.氯法齐明在治疗的9例耐多药结核病患者中,疗程从3个月到10个月不等,有3例患者在3个月时痰菌阴转,同时病灶有吸收,在治疗的9例病人中,临床症状均有不同程度的改善。血药浓度的测定显示个体差异比较大,且与疗效关系不密切。主要的副作用为面部、头发和四肢暴露皮肤的色素沉着。
研究结论
1.氯法齐明具有较好的体外及体内抗结核分支杆菌活性,对敏感菌及耐药菌均有效。
2.氯法齐明在脂肪、脾、肾、肝、肺等组织分布浓度比较高,异烟肼和吡嗪酰胺均可提高氯法齐明在肺组织的浓度。氯法齐明在组织中消除所需时间较长,这也是皮肤红染的主要原因。
3.氯法齐明对耐药结核病可能有效,但由于例数较少,仍需要进行大样本的临床对照研究。
Background:
Clofazimine, which was found in 1944 during the developing of new anti-tuberculosis drugs, no more research and application on tuberculosis because it has no activity against Mycobacterium tuberculosis in the guinea pigs and monkeys models. Fortunately, it was effect on the research of anti-leprosy bacilli, used in treating leprosy and bird-Mycobacterium disease for many years. There was few report on the research of anti-tuberculosis activity with Clofazimine. Because it is very difficult to treat the MDR-TB and XDR-TB in the world especially in China, we carried out the basic and clinical studies on the tuberculosis of Clofazimine, the object is to estimate the activity of anti-tuberculosis and supply the base to clinical application, which will be an anti-tuberculosis drug especially to the drug-resistant TB.
Object:
We observed the in vitro activity against Mycobacterium tuberculosis standard strain and Mycobacterium tuberculosis clinical resistant strains, and the effect in vivo in mice TB models treated with Clofazimine. The tissue distribution of Clofazimine and the effect of Isoniazid、Pyrazinamide to the tissue distribution of it. We adopted the method of self-control to estimate the efficacy and safety of Clofazimine combined with other anti-tuberculosis drugs in treating the MDR-TB, and help the clinical application of Clofazimine to treat the drug resistant TB.
Method:
1. Apply the microplate Alamar Blue method to determine the MIC of Clofazimine to standard strains of mycobacterium tuberculosis and 30 clinical isolates of MDR mycobacterium tuberculosis. Design tuberculosis mice model infected with H37RV 1×105CFU through vein, administer Clofazimine 20mg/kg(CLF-1) 5 times a week; 10 mg/kg(CLF-2) 5 times a\week and 20 mg/kg (CLF-3) 2 times a week; after 30 days we achieved the viable count to evaluate the anti-TB activity of Clofazimine in mice, and estimate the effect on the tuberculosis model mice which infected the clinical isolates of drug resistant mycobacterium tuberculosis were treated with Clofazimine and combined chemotherapy for 60 days.
2. Study the tissue distribution of Clofazimine and the effect by isoniazid、pyrazinamide which administration one time in BALB/C mice, after administration 1h,5h,24h, blood from infraorbital or eyeball extraction. Determined the concentration of liver, kidney, spleen, lungs, fat, etc using by HPLC.
3. Preliminary study on MDR-TB treated with Clofazimine. We choose the multi-drug resistant TB patients, signed informed consent voluntarily, aged from 18 to 65 years, and adopt the 24-month own control clinical trials. Based on the sensitivity test results, We select 5-7 kinds of drugs to strengthen period for 6 months and consolidation period for 24 months including Clofazimine (Cfm), Protionamide (Pto), Sodium Aminosalicylate (PAS), Levofloxacin (Lfx), Clarithromycin (Clr ), Amikacin (Am) and sensitive drugs , to observe the efficacy and safety of the treatment to MDR-TB .
Results:
1.The MIC of Clofazimine to Mycobacterium tuberculosis H37Rv was 0.12 ug / ml, The range of MIC to multi-drug resistant Mycobacterium TB was 0.12-1.96μg / ml.
2.In the TB mice model infected with standard strains showed: Clofazimine has less anti-TB activity than Isoniazid, but it can reduce 1.8 ~ 2.9 Log 10 CFU of Mycobacterium tuberculosis in lungs, 1.5 ~ 2.5 Log 10 CFU in spleen, which has good anti-tuberculosis activity in vivo.
3. In the mice model infected with resistant strain showed: after 2 months treatment, Clofazimine can reduce 2.32 Log 10 CFU of the viable count in lung, and 3.9 Log 10 CFU with 5 kinds of drugs combined chemotherapy.
4.The order of tissue distribution in mice about Clofazimine is fat, spleen, kidney, liver, lung, and other organizations, Isoniazid and Pyrazinamide can improve the concentration of Clofazimine in lung tissue, after 2 months treatment with Clofazimine it is still not complete elimination in the followed 2 months.
5.In the 9th multi-drug resistant TB patients treated with Clofazimine, the course of treatment is from 3 months to 10 months, 3 of them has sputum negative after 3 months, while focus of infection were absorbed. All of them have different degrees of improvement in the clinical symptoms. Determination of plasma display larger differences individually, which has no close relationship with the effect. The main side effect is pigmentation in the face, hair and exposed skin of limbs.
Conclusion:
1.Clofazimine has good anti- Mycobacterium TB activity in vitro and in vivo, against the sensitive and drug-resistance TB.
2.The distribution of Clofazimine is higher in fat, spleen, kidney, liver, lungs and other organization, Isoniazid and Pyrazinamide can improve the concentration of Clofazimine in lung tissue. The main reason of skin pigmentation is Clofazimine eliminated from the organization after a longer period of time since withdrawal.
3.Clofazimine may be effective to the drug-resistant TB, but there is few case, we will need a large samples of clinical control study.
氯法齐明(Clofazimine,Cfz),是1944年在开发抗结核新药时被发现的,但在当时的豚鼠及猴子结核病模型中未显示活性,此后一直被忽视对其抗结核作用的进一步研究和应用。所幸的是在抗麻风杆菌的研究中发现了它具有很好的抗分枝杆菌作用,至今已用于治疗麻风病及鸟型分枝杆菌病多年,是一种较为有效的抗麻风病药物。对于氯法齐明抗结核活性的研究仅有个别报道,在世界范围内尤其是我国的耐多药以及严重耐多药结核病治疗十分困难的情况下,进行氯法齐明抗结核作用的基础与临床研究,评价其抗结核活性显然是十分必要的,将为临床应用提供依据,为肺结核特别是耐药肺结核患者提供可能的治疗药物打下基础。
研究目的
通过评价氯法齐明对结核分枝杆菌标准株及耐药结核分枝杆菌临床株的体外活性、小鼠结核病模型的体内治疗作用观察;以及氯法齐明的组织分布和异烟肼、吡嗪酰胺对其组织分布的影响的研究,并采用自身对照的方法评价氯法齐明联合其他抗结核药治疗耐多药肺结核的有效性和安全性,为氯法齐明治疗耐药结核病的临床应用提供帮助。
研究方法
1.应用微孔板指示剂法测定氯法齐明对结核分枝杆菌标准株及对30株临床分离耐多药结核分枝杆菌的最低抑菌浓度;通过建立小鼠静脉感染H37Rv 1×105CFU/只的结核病模型,按照氯法齐明20mg/kg(Cfz-1)每周给药5次;10 mg/kg(Cfz-2)每周给药5次及20 mg/kg (Cfz-3)每周给药2次的方案给予治疗;30天时进行活菌计数评价氯法齐明在小鼠体内的抗结核活性;并将耐药结核分枝杆菌临床分离株感染小鼠,应用氯法齐明和联合化疗方案治疗60天,评价氯法齐明对耐药结核病模型小鼠的效果。
2.采用昆明种小鼠和BALB/C小鼠,单次给药研究氯法齐明的组织分布并在小鼠体内研究异烟肼、吡嗪酰胺对氯法齐明组织分布的影响:灌胃给药,于给药后1h、5h、24h,眶下取血或摘眼球取血。解剖取小鼠肝、肾、脾、肺、脂肪等,测量组织浓度。
3.氯法齐明治疗耐多药结核病的初步研究。选择耐多药结核病患者,自愿签署知情同意书;年龄18-65岁;采用为期24个月自身对照的临床试验。根据药敏试验结果,选择含氯法齐明(Cfm)、丙硫异烟胺(Pto)、对氨基水杨酸钠(PAS)、左旋氧氟沙星(Lfx)、克拉霉素(Clr)、丁胺卡那霉素(Am)以及敏感药组成的5-7种药的强化期为6个月,巩固期为24个月的化疗方案,观察治疗耐多药结核病的有效性和安全性。
结果:
1.氯法齐明对结核分枝杆菌H37Rv的MIC为0.12ug/ml,对耐多药结核分枝杆菌MIC范围是0.12-1.96μg/ml。
2.在标准株感染小鼠的结核病模型中显示:氯法齐明虽然抗结核的活性不如异烟肼,但可以将小鼠肺脏中的结核分枝杆菌降低1.8～2.9Log10 CFU,脾脏中降低1.5～2.5 Log10 CFU,表明具有较好的体内抗结核作用。
3.在耐药株感染小鼠的结核病模型中显示:治疗2月后氯法齐明可以将肺中的活菌数降低2.32 Log10 CFU,而5药联合化疗后可以降低3.9 Log10 CFU。
4.氯法齐明在小鼠体内的组织分布顺序依次为脂肪、脾、肾、肝、肺等组织,异烟肼和吡嗪酰胺均可提高氯法齐明在肺组织的浓度,氯法齐明在给药2月停药后的2月仍不能彻底消除。
5.氯法齐明在治疗的9例耐多药结核病患者中,疗程从3个月到10个月不等,有3例患者在3个月时痰菌阴转,同时病灶有吸收,在治疗的9例病人中,临床症状均有不同程度的改善。血药浓度的测定显示个体差异比较大,且与疗效关系不密切。主要的副作用为面部、头发和四肢暴露皮肤的色素沉着。
研究结论
1.氯法齐明具有较好的体外及体内抗结核分支杆菌活性,对敏感菌及耐药菌均有效。
2.氯法齐明在脂肪、脾、肾、肝、肺等组织分布浓度比较高,异烟肼和吡嗪酰胺均可提高氯法齐明在肺组织的浓度。氯法齐明在组织中消除所需时间较长,这也是皮肤红染的主要原因。
3.氯法齐明对耐药结核病可能有效,但由于例数较少,仍需要进行大样本的临床对照研究。
Background:
Clofazimine, which was found in 1944 during the developing of new anti-tuberculosis drugs, no more research and application on tuberculosis because it has no activity against Mycobacterium tuberculosis in the guinea pigs and monkeys models. Fortunately, it was effect on the research of anti-leprosy bacilli, used in treating leprosy and bird-Mycobacterium disease for many years. There was few report on the research of anti-tuberculosis activity with Clofazimine. Because it is very difficult to treat the MDR-TB and XDR-TB in the world especially in China, we carried out the basic and clinical studies on the tuberculosis of Clofazimine, the object is to estimate the activity of anti-tuberculosis and supply the base to clinical application, which will be an anti-tuberculosis drug especially to the drug-resistant TB.
Object:
We observed the in vitro activity against Mycobacterium tuberculosis standard strain and Mycobacterium tuberculosis clinical resistant strains, and the effect in vivo in mice TB models treated with Clofazimine. The tissue distribution of Clofazimine and the effect of Isoniazid、Pyrazinamide to the tissue distribution of it. We adopted the method of self-control to estimate the efficacy and safety of Clofazimine combined with other anti-tuberculosis drugs in treating the MDR-TB, and help the clinical application of Clofazimine to treat the drug resistant TB.
Method:
1. Apply the microplate Alamar Blue method to determine the MIC of Clofazimine to standard strains of mycobacterium tuberculosis and 30 clinical isolates of MDR mycobacterium tuberculosis. Design tuberculosis mice model infected with H37RV 1×105CFU through vein, administer Clofazimine 20mg/kg(CLF-1) 5 times a week; 10 mg/kg(CLF-2) 5 times a\week and 20 mg/kg (CLF-3) 2 times a week; after 30 days we achieved the viable count to evaluate the anti-TB activity of Clofazimine in mice, and estimate the effect on the tuberculosis model mice which infected the clinical isolates of drug resistant mycobacterium tuberculosis were treated with Clofazimine and combined chemotherapy for 60 days.
2. Study the tissue distribution of Clofazimine and the effect by isoniazid、pyrazinamide which administration one time in BALB/C mice, after administration 1h,5h,24h, blood from infraorbital or eyeball extraction. Determined the concentration of liver, kidney, spleen, lungs, fat, etc using by HPLC.
3. Preliminary study on MDR-TB treated with Clofazimine. We choose the multi-drug resistant TB patients, signed informed consent voluntarily, aged from 18 to 65 years, and adopt the 24-month own control clinical trials. Based on the sensitivity test results, We select 5-7 kinds of drugs to strengthen period for 6 months and consolidation period for 24 months including Clofazimine (Cfm), Protionamide (Pto), Sodium Aminosalicylate (PAS), Levofloxacin (Lfx), Clarithromycin (Clr ), Amikacin (Am) and sensitive drugs , to observe the efficacy and safety of the treatment to MDR-TB .
Results:
1.The MIC of Clofazimine to Mycobacterium tuberculosis H37Rv was 0.12 ug / ml, The range of MIC to multi-drug resistant Mycobacterium TB was 0.12-1.96μg / ml.
2.In the TB mice model infected with standard strains showed: Clofazimine has less anti-TB activity than Isoniazid, but it can reduce 1.8 ~ 2.9 Log 10 CFU of Mycobacterium tuberculosis in lungs, 1.5 ~ 2.5 Log 10 CFU in spleen, which has good anti-tuberculosis activity in vivo.
3. In the mice model infected with resistant strain showed: after 2 months treatment, Clofazimine can reduce 2.32 Log 10 CFU of the viable count in lung, and 3.9 Log 10 CFU with 5 kinds of drugs combined chemotherapy.
4.The order of tissue distribution in mice about Clofazimine is fat, spleen, kidney, liver, lung, and other organizations, Isoniazid and Pyrazinamide can improve the concentration of Clofazimine in lung tissue, after 2 months treatment with Clofazimine it is still not complete elimination in the followed 2 months.
5.In the 9th multi-drug resistant TB patients treated with Clofazimine, the course of treatment is from 3 months to 10 months, 3 of them has sputum negative after 3 months, while focus of infection were absorbed. All of them have different degrees of improvement in the clinical symptoms. Determination of plasma display larger differences individually, which has no close relationship with the effect. The main side effect is pigmentation in the face, hair and exposed skin of limbs.
Conclusion:
1.Clofazimine has good anti- Mycobacterium TB activity in vitro and in vivo, against the sensitive and drug-resistance TB.
2.The distribution of Clofazimine is higher in fat, spleen, kidney, liver, lungs and other organization, Isoniazid and Pyrazinamide can improve the concentration of Clofazimine in lung tissue. The main reason of skin pigmentation is Clofazimine eliminated from the organization after a longer period of time since withdrawal.
3.Clofazimine may be effective to the drug-resistant TB, but there is few case, we will need a large samples of clinical control study.
引文
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9. Desikan K V,Balakrishnan S. Tissue levels of clofazimine in a case of leprosy . Lepr Rev,1976,47:107-114.
10. Jadhav M V,Sathe A G, Deore S S, Patil P G, Joshi N G. Tissue concentration , systemic distribution and toxicity of clofazimine– an autopsy study . Indian J Pathol Microbiol,2004,47:281-283.
11. Krishnamurthy Venkatesan , Nirmala Deo,Umesh Dutt Gupta. Tissue Distribution and Deposition of Clofazimine in Mice Following Oral Administration with without Isoniazid. Arzneimittel-Forschung(Drug Research) ,2007,57(7):472- 474.
12.Yawalkar S J ,Vischer W. Lamprene (clofazimine) in leprosy. Leprosy Reviews, 1979, 50:135-144.
13.Barry V C, Buggle K, Byme J, et al. Absorption, distribution and retention of the imino compounds in the experimental animals. lrish Jourmal of Medical Sciences,1960, 416:345-352.
14.Schmidt L H, Hoffman R, Jolly P N. Induced pulmonary tuberculosis in the rhesus monkey: its usefulness in evaluating chemotherapeutic agents. Proceedings of 14th Conference V A F. Tuberculosis,1955,226-231.
1.全国结核病流行病学抽样调查技术指导组.第四次全国结核病流行病学抽样调查报告.中华结核和呼吸杂志2002;25:3-7.
2. Barry V C ,Belton J V ,Conalty M L . A new series of phenazines with high antituberculosis activity.Nature 1957;179: 1013-1015.
3. Barry V C ,Conalty M L .The antituberculosis activity of B663. Lepr Rev 1965;36:1-7.
4. Barry V C .Synthetic phenazine derivatives and mycobac- terial diseases:a twenty year investigation.Scientific Proceedings of Royal Dublin(Series A) 1969;3:153-170.
5. Barry V C ,Belton J G ,Conalty M L .Twomey D . Antitube- rculosis activity of oxidation products of substituted o-phenylene diamines.Nature 1948;162:622-623.
6. Barry V C ,Buggle K ,Byme J ,et al . Absorption , distribution and retention of the imino compounds in the experimental animals. lrish Jourmal of Medical Sciences 1960;416:345-352.
7. Barry V C ,Conalty M L . Antituberculosis activity in the phenazine series. American Review of Tuberculosis 1958; 78: 62一73.
8.含氯苯吩嗪方案成功治疗四例耐多药肺结核.全国复治肺结核诊断与鉴别诊断进展研讨会.中华医学会结核病学分会;2007年4月贵阳会议.
9.世界卫生组织.耐药结核病规划管理指南. 2006.
10. Mukiherjee J,et al. Programmes and principles in treatment of multidrug-resistant tuberculosis . Lancet ,2004;363:474-481.
11. Du Toit L ,et al .Tuberculosis chemotherapy : current drug delivery approaches .Respir Res,2006;7:181.
12.Field SK, Cowie RL. Treatment of Mycobacterium avium-intracellularecomplex lung disease with amacrolide, ethambutol, and clofazimine. Chest. 2003 Oct;124(4):1482-6.
13.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.
1.World Health Organization. Removing Obstacles to Healthy Development, 1999.
2.World Health Organization (WHO) Tuberculosis global report. Geneva WHO 2006:343.
3.Reid, Scano F, Getahum H, et al. Towards universal access to HIV prevention, treatment, care and support: the role of TB/HIV collaboration. Lancet Infect Dis ,2006, 6:483-495.
4.Zignol M, Hosseini M S, Wright A, et al .Global incident of multidrug-tuberculosis. J Infect Dis 2006, 194:479-485.
5.全国结核病流行病学抽样调查技术指导组.第四次全国结核病流行病学抽样调查报告.中华结核和呼吸杂志,2002, 25:3-7.
6.含氯苯吩嗪方案成功治疗四例耐多药肺结核.全国复治肺结核诊断与鉴别诊断进展研讨会.中华医学会结核病学分会,2007年4月贵阳会议.
7.世界卫生组织.耐药结核病规划管理指南. 2006.
8.British pharmacopoeia Commission. The British pharmacopoeia Her Majesty′s Stationary Office. London, 1988.
9.Barry V C, Belton J V, Conalty M L. A new series of phenazines with high antituberculosis activity. Nature ,1957, 179:1013-1015.
10.Barry V C, Conalty M L. The antituberculosis activity of B663. Lepr Rev ,1965, 36:1-7.
11.Barry V C. Synthetic phenazine derivatives and mycobac-terial diseases: a twenty year investigation. Scientific Proceedings of Royal Dublin (Series A) ,1969, 3:153-170.
12.Barry V C, Belton J G, Conalty M L. Twomey D. Antituber-culosis activity of oxidation products of substituted ophenylene diamines. Nature ,1948, 162:622-623.
13.Barry V C, Buggle K, Byme J, et al. Absorption, distribution and retention of the imino compounds in the experimental animals. lrish Jourmal of Medical Sciences,1960, 416:345-352.
14.Barry V C, Conalty M L. Antituberculosis activity in the phenazine series. American Review of Tuberculosis ,1958, 78:62-73.
15.Steenken W J, Montalbine V, Smith M M. Antituberculosis activity of rimino compound of the phenazine series. Am Rev Resp Dis ,1959:764-767.
16.Barry V C, et al. The development of chemotherapeutic agent for tuberculosis. Butterworths, London: 46-64.
17.Vischer W A. The experimental properties of G30320 (B663) a new antileprotic agent. Leprosy Reviews,1969, 40:107-110.
18.Schmidt L H, Hoffman R, Jolly P N. Induced pulmonary tuberculosis in the rhesus monkey: its usefulness in evaluating chemotherapeutic agents. Proceedings of 14th Conference V A F. Tuberculosis,1955:226-231.
19.Browne S G, Hogerzeh L M. B663 in the treatment of leprosy: a preliminary report of a pilot trial. Leprosy Reviews ,1962, 33:6-10.
20.Ji B, Lounis N, Truftot Pernot C, et al. Effectiveness of various antimicrobial agents against Mycobacterium avium complex in the beige mice model. Antimicrobial Agents and Chemotherapy ,1994;38:2521-2529.
21.Schultz E J. Forty-four months experience in the treatment of leprosy with clofazimine (Lamprene (R)). Leprosy Reviews ,1971, 42:178-187.
22.World Health Organization. Chemotherapy of leprosy for control programs; report of WHO study groups. WHO Technical Report Series ,1982, 675:7-33.
23.Yawalkar S J ,Vischer W. Lamprene (clofazimine) in leprosy. Leprosy Reviews,1979, 50:135-144.
24.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.
25.Schaad Lanyi Z, Dieterle W, Dubois J P, et al. Pharmacokinetics of clofazimine in healthy volunteers, Int J Lepr Other Mycobact Dis,1987, 55(1):9-15.
26.Nix D E, Adam R D ,Auclair B, Krueger T S, et al. Pharmacokinetics and relative availability of clofazimine in relation to food, orange juice and antacid. Tuberculosis ,2004, 84:365-373.
27.Conalty M L. Methods of preclinical evaluation of antituberculosis drugs. Chemotherapy of tuberculosis. Butterworths, London: 150-174.
28.O'Connor R, O'Sullivan J F, O'kennedy R. The pharmacology, metabolism, and chemistry of CFZ. Drug Metabolism Reviews ,1995, 27:591-614.
29.Desikan K V, Balakrishnan S. Tissue levels of clofamine in a case of leprosy. Leprosy Reviews,1976, 47:107-113.
30.Mansfield R E. Tissue concentrations of CFZ in man. Am J Trop Med Hyg ,1974, 23(6):1116-1119.
31.Levy L. Pharmacologic studies of clofazimine. American Journal of Tropical Medicine and Hygiene,1974, 23:1097-1109.
32.Weiss S J, Peppin G L. Collagenolytic metalloenzymes of the human neutrophil. Biochem Pharmacol ,1986, 35:3189-3197.
33.Van Zyl J M, Basson K, Kriegler A, et al.Mechanisms by which clofazimine and dapsone inhibit the myeloperoxidase system. Biochem Pharmacol ,1991, 42:599-608.
34.Morrison N E, Marley G M. The mode of action of clofazimine DNA binding studies. International Journal of Leprosy, 1976, 44:133-134.
35.Anderson R, Smit MJ. Clofazimine and B669 inhibit the proliferative responses and NA+,K+ adenosine triphosphatase activity of human lymphocytes by a lysophospholipase dependent mechanism. Biochemical Pharmacology 1993, 46:2029-2038.
36.Krajewska M M, Anderson R.An in vitrocomparison of the effects of the pro-oxidative riminophenazines clofazimine and B669 on neutrophil phospholipase A2 activity and superoxide generation. Journal of Infectious Diseases ,1993, 167:899-904.
37.Van Rensburg C J, Joone G K, O'Sullivan J F, Anderson R. Antimicrobial activities of clofazimine and B669 are mediated by lysophospholipids. Antimicrobial Agents and Chemotherapy ,1992, 36:2729-2735.
38.Van Rensburg C E, van Staden A M, Anderson R. The riminophenazine agents clofazimine and B669 inhibit the proliferation of cancer cell lines in vitro by phospholipase A2-mediated oxidative and nonoxidative mechanisms. Cancer Research, 1993, 53:318-323.
39.Wadee A A, Kuschke R H, Dooms T G, Anderson R. The pro-oxidative riminophenazine B669 neutralizes the inhibitory effects of Mycobacterium tuberculosis on phagocyte antimicrobial activity. International Journal of Immunopharmacology, 1995, 17:849-56.
40.Zeis B M, Anderson R. Clofazimine-mediated stimulation of prostaglandin synthesis and free radical production as novel mechanisms of druginduced immunosuppression. International Journal of Immunopharmacology, 1986, 8:731-739.
41.Anderson R, Beyers A D, Savage J E, et al. Apparent involvement of phospholipase A2, but not protein kinase C, in the prooxidative interactions of clofazimine with human phagocytes. Biochem, Pharmacol ,1988, 37:4635-4641.
42.Anderson R, Lukey P, Van Ransburg C, et al. Clofazimine mediated regulation of human polymorphonuclear leukocyte migration by pro-oxidative inactivation of both leukoattractants and cellular migratory responsiveness. Int J lmmunnopharmacol ,1986, 8:605-620.
43.Gangadharam P R J, Pabst M J, Hedegaard K. Clofazimine (B663) triggers the release of superoxide anion (02) from hamster peritoneal macrophages. Bulletin of International Union against Tuberculosis, 1982, 57: 32 (abstract).
44.Wadee A A, Cohen J D. Rabson A R. Gamma interferon reverses inhibition of leukocyte bactericidal activity by a 25-kilodalton fraction from Mycobacterium tuberculosis. Infection Immunity ,1987, 55:2777-2782.
45.Wadee A A, Anderson R, Rabson A R. Clofazimine reverses the inhibitory effects of Mycobacterium tuberculosis derived factors on phagocyte intracellular killing mechanisms. Journal of Antimicrobial Chemotherapy ,1988, 21:65-74.
46.Mackey J P, Barnes J. Clofazimine in the treatment of discoid lupus erythematosus. British Journal of Dermatology, 1974, 91:93-96.
47.Bor S. Clofazimine (Lamprene (R)) in the treatment of vitiligo. South African Medical Journal ,1973, 47:1451-1454.
48.Shepard C C. Minimal effective dosages in mice of clofazimine (B663) and of ethionamide against Mycobacterium eprae (34162). Proceedings of Society for Experimental Biology and Medicine ,1969, 132:120-124.
49.Browne S G, Harman D J, Waudby H, McDougall A C. Clo- fazimine (Lamprene (R)) in the treatment of lepromatous leprosy in the United Kingdom, A 12 year review of cases, 1966-1978. International Journal of Leprosy, 1981, 49:167-176.
50.Hastings R C, Trautman J R. B663 in lepromatous leprosy, Effect in erythema nodosum leprosum. leprosy Reviews ,1968, 39:3-7.
51.Franzblau S G, O'Sullivan J F. Structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro. Antimicrobial Agents and Chemotherapy, 1988, 32:1583-1585.
52.Freerksen E, Seydel J K. Critical comments on the treatment of leprosy and other mycobacterial infections with clofazimine. Arzneimittelforsching ,1992, 42:1243-1245.
53.Franzblau S G, White KE, O'Sullivan J F. Structure activity relationships of tetraethyl piperidine-substituted phenazines against Mycobacrium leprae in vitro. Antimicrobial Agents and Chemotherapy ,1989, 33:2004-2005.
54.Venkata M, Reddy, John F, et al. Antimycobacterial activities of riminophenazines. Journal of Antimicrobial Chemotherapy, 1999, 43:615-623.
55.Jaganneath C, Reddy M V, Kallasam S, et al. Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis: in vitro, intracellular ,and vivo studies . Am J Respire Care Med, 1995, 151:1083-1086.
56.Gangadharam P R J, Candler E R. Activity of some antileprosy compounds against Mycobacterium intracellulare in vitro. American Review of Respiratory Diseases, 1977, 115:705-707.
57.LindholmLevy P J, Heifets L. Clofazimine and other riminocompounds: minimal inhibitory and minimal bactericidal concentrations at different PHS for Mycobacterium avium complex. Tubercle, 1988, 69:179-186.
58.Gangadharam P R J, Ashtekar D, O'Sullivan J F. In vitro, in vivo, and intracellularchemotherapeutic activity of B746, a clofazimine analogue against Mycobacterium avium complex. Tubercle and Lung Diseases ,1992, 73:192-199.
59.Fattorini L, Li B, Piersimoni C, et al. In vitro and ex vivo activities of antimicrobial agents used in combination with clarithromycin, with or without amikacin, against Mycobacgerium avium. Antimicrobial Agents and Chemotherapy, 1995, 39:680-685.
60.Rastogi N, Bauriaud R M, Bourgoin A, Carbonelle B, et al. French multi center study involving eight test sites for radiometric determination of activities of 10 antimicrobial agents against Mycobacterium avium complex. Antimicrobial Agents and Chemotherapy ,1995, 39:638-644.
61.Rastogi N, Labrousse V, Bryskier A. Intracellular activities of roxithromycin used alone and in association with other drugs against Mycobacterium avium complex in human macrophages. Antimicrobial Agents and Chemotherapy, 1995, 39:976-978.
62.Yajko D M, Sanders C A, Madej J J, et al. In vitro activities of rifabutin, azithromycin, ciprofloxacin, clarithromycin, clofazimine, ethambutol, and amikacin in combinations of two, three, and four drugs against Mycobacterium avium. Antimicrobial Agents and Chemotherapy ,1996, 40:743-749.
63.Davidson P T, Fernandez E, Goble M, Gangadharam P A J. Evaluation of the role of clofazimine (B663) for the treatment of Mycobacterium intracellular disease. American Review of Respiratory Diseases, 1979, 119:398.
64.Young L S. Mycobacterium avium complex infection. Journal of Infectious Diseases ,1988, 157:863-867.
65 Abrams D I, Mitchell T F, Child C C, et al. Clofazimine as prophylaxis for disseminated Mycobacterium avium complex infection in AIDS. Journal of Infectious Diseases, 1993, 167:1459-1463.
66.Armstrong D, Gold J W M, Dyjanski I, et al. Treatment of infections in patients with the acquired immunodeficiency syndrome. Annals of Internal Medicine, 1985, 103:738-743.
67.Hawkins C C, Gold J W M, Whimbey E, et al. Mycobacterium avium complex infections in patients with the acquired immunodeficiency syndrome. Annals of Internal Medicine ,1986:184-188.
68.Horsburgh C A, Mason U G, Farhi D C, Iseman M D. Disseminated infection with Mycobacterium avium-intracellular. A report of 13 cases and a review of the literature Medicine ,1985, 64:36-48.
69.Woods G L, Washington J A. Mycobacteria other than Mycobacterium tuberculosis: review of the microbiologic and clinical aspects. Reviews of Infectious Diseases ,1987, 9:275-294.
70.Masur H, Tuazon G, Gill V, et al. Effect of combined clofazimine and ansamycin therapy on Mycobacterium avium-intracellular bacteraemia in patients with AIDS. Journal of Infectious Diseases ,1987, 155:127-129.
71.Krishnamurthy Venkatesan, Nirmala Deo, Umesh Dutt Gupta. Tissue Distribution and Deposition of Clofazimine in Mice Following Oral Administration with without Isoniazid. Arzneimittel-Forschung (Drug Research) ,2007, 57(7):472-474.
72.Mamidi N V S R, Rajasekhar A, Prabhakar M C, et al. Tissue distribution and deposition of clofazimine in rat following sub chronic treatment with or without rifam-picin. Arzneimittel-Forschung (Drug Research) ,1995, 45:1028-1031.
73.Garrelts J C. Clofazimine: a review of its use in leprosy and Mycobacterium avium complex infection. Ann Pharm-ocother ,1991, 25:525-531.
2. Venkata M. Reddy, Geeta Nadadhur, Donna Daneluzzi,et al.Antituberculosis Activity of Clofazimine and Its New Analogs B4154 and B4157. Antimicrobiai.Agents and Chemotherapy, Mar.1996; 40:633-6.
3. Damle PB, McClathy JK, Gangadharam PRJ, et al.Antimycobacterial Activity of some potential chemotherapeutic compounds. Tuberclc. 1978; 59:135.
4. Geera N, Reedy MV, Jagannath C , et al.Activity of riminophenazine compounds against susceptible and resistant M. tuberculosis , Tuber Lung Dis . 1994; 75:25-26
1. Barry V C , et al .The development of chemotherapeutic agent for tuberculosis.1964 , 46-64. In V.C.Barry (ed), Chemotherapy of tuberculosis .Butterworths, London.
2. Barry V C ,Belton J V ,Conalty M L . A new series of phenazines with high antituberculosis activity.Nature 1957;179: 1013-1015.
3. Barry V C ,Conalty M L .The antituberculosis activity of B663. Lepr Rev 1965;36:1-7.
4. Venkata M. Reddy,Geeta Nadadhur , Donna Daneluzzi,et al.Antituberculosis Activity of Clofazimine and Its New Analogs B4154 and B4157. Antimicrobiai.Agents and Chemotherapy, Mar.1996; 40:633-6.
5 . Krishnamurthy Venkatesan , Nirmala Deo,Umesh Dutt Gupta. Tissue Distribution and Deposition of Clofazimine in Mice Following Oral Administration with without Isoniazid. Arzneimittel-Forschung(Drug Research) 2007;57(7):472- 474.
1. Brown S G, Hogerzeil L M.“B663”in the treatment of leprosy . Preliminary report of a pilot trial .Lepr Rev,1962,33:6-10.
2. Holdiness M R. Clinical pharmacokinetics of clofazimine– A review. Clin pharmacokinet,1989,16:74-85.
3. Venkatesan K. Clinical pharmacokinetic consideration in the treatment of leprosy patients. Clin pharmacokinet,1989,16:365-386..
4. O'Connor R , O'Sullivan J F , O'kennedy R .The phar- macology ,metabolism ,and chemistery of Cfz .Drug Metabolism Reviews ,1995,27:591-614.
5. Reddy V M, O'Sullivan J F, Gangadharam P R J. Antimycobactrial activities of riminophenazines. J Antimicrob Chemother.,1999,43:615-623.
6. Nix D E ,Adam R D ,Auclair B ,Krueger T S ,et al. Pharma- cokinetics and relative availability of clofazimine in relation to food ,orange juice and antacid. Tuberculosis, 2004, 84:365-373.
7. Vischer W A. The experimental properimental of G30 320 (B 663)-a new antileprotic agent. Lepr Rev,1969,40:107-110.
8. Mansfield R E .Tissue concentrations of Cfz in man .Am J Trop Med Hyg ,1974,23(6):1116-1119.
9. Desikan K V,Balakrishnan S. Tissue levels of clofazimine in a case of leprosy . Lepr Rev,1976,47:107-114.
10. Jadhav M V,Sathe A G, Deore S S, Patil P G, Joshi N G. Tissue concentration , systemic distribution and toxicity of clofazimine– an autopsy study . Indian J Pathol Microbiol,2004,47:281-283.
11. Krishnamurthy Venkatesan , Nirmala Deo,Umesh Dutt Gupta. Tissue Distribution and Deposition of Clofazimine in Mice Following Oral Administration with without Isoniazid. Arzneimittel-Forschung(Drug Research) ,2007,57(7):472- 474.
12.Yawalkar S J ,Vischer W. Lamprene (clofazimine) in leprosy. Leprosy Reviews, 1979, 50:135-144.
13.Barry V C, Buggle K, Byme J, et al. Absorption, distribution and retention of the imino compounds in the experimental animals. lrish Jourmal of Medical Sciences,1960, 416:345-352.
14.Schmidt L H, Hoffman R, Jolly P N. Induced pulmonary tuberculosis in the rhesus monkey: its usefulness in evaluating chemotherapeutic agents. Proceedings of 14th Conference V A F. Tuberculosis,1955,226-231.
1.全国结核病流行病学抽样调查技术指导组.第四次全国结核病流行病学抽样调查报告.中华结核和呼吸杂志2002;25:3-7.
2. Barry V C ,Belton J V ,Conalty M L . A new series of phenazines with high antituberculosis activity.Nature 1957;179: 1013-1015.
3. Barry V C ,Conalty M L .The antituberculosis activity of B663. Lepr Rev 1965;36:1-7.
4. Barry V C .Synthetic phenazine derivatives and mycobac- terial diseases:a twenty year investigation.Scientific Proceedings of Royal Dublin(Series A) 1969;3:153-170.
5. Barry V C ,Belton J G ,Conalty M L .Twomey D . Antitube- rculosis activity of oxidation products of substituted o-phenylene diamines.Nature 1948;162:622-623.
6. Barry V C ,Buggle K ,Byme J ,et al . Absorption , distribution and retention of the imino compounds in the experimental animals. lrish Jourmal of Medical Sciences 1960;416:345-352.
7. Barry V C ,Conalty M L . Antituberculosis activity in the phenazine series. American Review of Tuberculosis 1958; 78: 62一73.
8.含氯苯吩嗪方案成功治疗四例耐多药肺结核.全国复治肺结核诊断与鉴别诊断进展研讨会.中华医学会结核病学分会;2007年4月贵阳会议.
9.世界卫生组织.耐药结核病规划管理指南. 2006.
10. Mukiherjee J,et al. Programmes and principles in treatment of multidrug-resistant tuberculosis . Lancet ,2004;363:474-481.
11. Du Toit L ,et al .Tuberculosis chemotherapy : current drug delivery approaches .Respir Res,2006;7:181.
12.Field SK, Cowie RL. Treatment of Mycobacterium avium-intracellularecomplex lung disease with amacrolide, ethambutol, and clofazimine. Chest. 2003 Oct;124(4):1482-6.
13.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.
1.World Health Organization. Removing Obstacles to Healthy Development, 1999.
2.World Health Organization (WHO) Tuberculosis global report. Geneva WHO 2006:343.
3.Reid, Scano F, Getahum H, et al. Towards universal access to HIV prevention, treatment, care and support: the role of TB/HIV collaboration. Lancet Infect Dis ,2006, 6:483-495.
4.Zignol M, Hosseini M S, Wright A, et al .Global incident of multidrug-tuberculosis. J Infect Dis 2006, 194:479-485.
5.全国结核病流行病学抽样调查技术指导组.第四次全国结核病流行病学抽样调查报告.中华结核和呼吸杂志,2002, 25:3-7.
6.含氯苯吩嗪方案成功治疗四例耐多药肺结核.全国复治肺结核诊断与鉴别诊断进展研讨会.中华医学会结核病学分会,2007年4月贵阳会议.
7.世界卫生组织.耐药结核病规划管理指南. 2006.
8.British pharmacopoeia Commission. The British pharmacopoeia Her Majesty′s Stationary Office. London, 1988.
9.Barry V C, Belton J V, Conalty M L. A new series of phenazines with high antituberculosis activity. Nature ,1957, 179:1013-1015.
10.Barry V C, Conalty M L. The antituberculosis activity of B663. Lepr Rev ,1965, 36:1-7.
11.Barry V C. Synthetic phenazine derivatives and mycobac-terial diseases: a twenty year investigation. Scientific Proceedings of Royal Dublin (Series A) ,1969, 3:153-170.
12.Barry V C, Belton J G, Conalty M L. Twomey D. Antituber-culosis activity of oxidation products of substituted ophenylene diamines. Nature ,1948, 162:622-623.
13.Barry V C, Buggle K, Byme J, et al. Absorption, distribution and retention of the imino compounds in the experimental animals. lrish Jourmal of Medical Sciences,1960, 416:345-352.
14.Barry V C, Conalty M L. Antituberculosis activity in the phenazine series. American Review of Tuberculosis ,1958, 78:62-73.
15.Steenken W J, Montalbine V, Smith M M. Antituberculosis activity of rimino compound of the phenazine series. Am Rev Resp Dis ,1959:764-767.
16.Barry V C, et al. The development of chemotherapeutic agent for tuberculosis. Butterworths, London: 46-64.
17.Vischer W A. The experimental properties of G30320 (B663) a new antileprotic agent. Leprosy Reviews,1969, 40:107-110.
18.Schmidt L H, Hoffman R, Jolly P N. Induced pulmonary tuberculosis in the rhesus monkey: its usefulness in evaluating chemotherapeutic agents. Proceedings of 14th Conference V A F. Tuberculosis,1955:226-231.
19.Browne S G, Hogerzeh L M. B663 in the treatment of leprosy: a preliminary report of a pilot trial. Leprosy Reviews ,1962, 33:6-10.
20.Ji B, Lounis N, Truftot Pernot C, et al. Effectiveness of various antimicrobial agents against Mycobacterium avium complex in the beige mice model. Antimicrobial Agents and Chemotherapy ,1994;38:2521-2529.
21.Schultz E J. Forty-four months experience in the treatment of leprosy with clofazimine (Lamprene (R)). Leprosy Reviews ,1971, 42:178-187.
22.World Health Organization. Chemotherapy of leprosy for control programs; report of WHO study groups. WHO Technical Report Series ,1982, 675:7-33.
23.Yawalkar S J ,Vischer W. Lamprene (clofazimine) in leprosy. Leprosy Reviews,1979, 50:135-144.
24.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.
25.Schaad Lanyi Z, Dieterle W, Dubois J P, et al. Pharmacokinetics of clofazimine in healthy volunteers, Int J Lepr Other Mycobact Dis,1987, 55(1):9-15.
26.Nix D E, Adam R D ,Auclair B, Krueger T S, et al. Pharmacokinetics and relative availability of clofazimine in relation to food, orange juice and antacid. Tuberculosis ,2004, 84:365-373.
27.Conalty M L. Methods of preclinical evaluation of antituberculosis drugs. Chemotherapy of tuberculosis. Butterworths, London: 150-174.
28.O'Connor R, O'Sullivan J F, O'kennedy R. The pharmacology, metabolism, and chemistry of CFZ. Drug Metabolism Reviews ,1995, 27:591-614.
29.Desikan K V, Balakrishnan S. Tissue levels of clofamine in a case of leprosy. Leprosy Reviews,1976, 47:107-113.
30.Mansfield R E. Tissue concentrations of CFZ in man. Am J Trop Med Hyg ,1974, 23(6):1116-1119.
31.Levy L. Pharmacologic studies of clofazimine. American Journal of Tropical Medicine and Hygiene,1974, 23:1097-1109.
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