Antimycobacterial activities of riminophenazines.

Riminophenazines were specifically developed as drugs active against Mycobacterium tuberculosis but extensive research over several decades has shown that these compounds are also active against many other mycobacterial infections, particularly those caused by Mycobacterium leprae and the Mycobacterium avium complex (MAC). Clofazimine, the lead compound in this series, is included in the regimens that are approved by the WHO for the treatment of leprosy and has contributed significantly to the control of that disease, particularly that caused by dapsone-resistant bacteria. Despite early problems, clofazimine has shown clinical efficacy in tuberculosis, in particular that caused by multiple drug resistant strains. Clofazimine does not induce resistance and also inhibits emergence of resistance to isoniazid in M. tuberculosis. The efficacy of clofazimine against MAC is more varied and the availability of better drugs has limited its use. Newer riminophenazines, such as B746 and B4157, not only showed increased anti-mycobacterial activity but also produced less skin pigmentation, which is the main drawback of this group of compounds. The most important virtues of riminophenazines, such as intracellular accumulation in mononuclear phagocytic cells, anti-inflammatory activity, a low incidence of drug resistance and slow metabolic elimination, make them attractive candidates for the treatment of mycobacterial infections. It is essential, however, to investigate the newer analogues clinically, while continuing the pursuit of alternate candidates that demonstrate higher anti-mycobacterial activity and lower rates of skin pigmentation.

Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis. In vitro, intracellular, and in vivo studies.

Clofazimine (CFM), a riminophenazine drug, is primarily used in therapy for leprosy and Mycobacterium avium infections. With an objective of identifying drugs active against Mycobacterium tuberculosis, including those with multi-drug resistance, we investigated CFM and nine of its chemical analogues. Among these, B746 and B4101 had better activity than CFM against six drug-susceptible and nine single/multiple drug-resistant M. tuberculosis strains. B746 also showed slightly better activity than CFM against intracellular M. tuberculosis in J774A.1 macrophages and was comparable to CFM in its in vivo activity against experimental tuberculosis in C57BL/6 mice. Interestingly, it caused less pigmentation in internal organs.

Bioavailability and chemotherapeutic activity of clofazimine against Mycobacterium avium complex infections in beige mice following a single implant of a biodegradable polymer.

We have studied the bioavailability of clofazimine following administration of a single dose of the drug in the biodegradable polymer polylactic-co-glycolic acid (PLGA). We compared the levels of clofazimine achieved in the liver with single implants with those obtained with daily oral treatment. Even though the levels achieved with implants were much lower than those obtained after daily oral treatment, they were higher than the MIC of clofazimine for Mycobacterium leprae, Mycobacterium tuberculosis and Mycobacterium avium complex (MAC). Experimental studies in beige mice after infection with MAC strain 101 showed similar reductions in cfu counts, after both single dose polymer and daily oral treatment. Macroscopically, hyperpigmentation giving an orange-yellow colour to all visceral organs, was seen in animals after daily oral treatment but not in those animals that received polymer implants.

Utility of beige mouse in leprosy research.

Dissemination of M. leprae to visceral organs is seen by four months onwards only in beige (C57BL/6/bgj) but not BALB/c mice following intravenous or intraperitoneal infections. Inoculation of the beige mouse derived M. leprae showed all the characteristics of M. leprae, including growth pattern in the foot-pads of BALB/c mice. M. leprae inoculated into foot-pads of beige mice multiplied faster than those in the foot-pads of BALB/c mice. The possibility of using beige mouse in chemotherapeutic studies in leprosy is discussed.

Activity of some antileprosy compounds against Mycobacterium intracellulare in vitro.

A series of 12 compounds, consisting of 3 known antileprosy drugs (dapsone, B663, and Ciba 1906) and 9 structural derivatives of dapsone, were tested for their antimycobacterial activity against 50 strains of Mycobacterium intracellulare. Detailed investigations of B663, the only compound showing considerable in vitro activity, were carried out. All of the strains of M. intracellulare were inhibited by a B663 concentration of 1.6 mug per ml, and 88% were inhibited by a drug concentration of 0.8 microng per ml. The rate of emergence of in vitro resistance was similar to that of M. tuberculosis against streptomycin and isoniazid. Preliminary experiments indicated that the action of the drug on M. intracellulare may be bacteriocidal in nature.