Clofazimine

5.1.7.1 History. Clofazimine belongs to a peculiar class of phenazines called rimino-phenazines. Studies on these compounds derived from the original observation that treating a solution of 2-aminodiphenylamine with ferric chloride produced a red crystalline pre cipitate that completely inhibited the growth of tubercle bacilli H37Rv strain in vitro and was not inactivated by human serum (212214). The in vivo activity was moderate and the toxicity low. Such a compound, named B-283 (31), was the leading structure for a se

Clofazimine Structure

ries of riminophenazines, which are alkyl or arylimino derivatives. Among the first compounds synthesized, B-663, later named clofazimine (32), was the most active (215,216).

5.1.7.2 Activity and Mechanism of Action. Clofazimine has an in vitro inhibitory activity against M. tuberculosis at concentrations of 0.1-0.5 jLLg/mL. Strains resistant to isoniazid, and/or streptomycin, PAS, and thioacetazone, are susceptible to the drug. Some MOTT are also susceptible to this compound. Minimal inhibitory concentrations for M. avium complex (MAC) are 0.125-1 /xg/mL (217). This activity has rendered the drug eligible for the treatment of infections caused by this organism.

Clofazimine is not only bacteriostatic, but also bactericidal (but the latter action is rather slow) and only on multiplying mycobacteria. The mechanism of action of riminophenazines has not been elucidated, mainly because of the low solubility of these compounds in aqueous media. The activity seems to be correlated with thep-quinoid system; in fact, when this is removed by reductive acylation, activity disappears. The mycobacteria under anaerobic conditions reduce the quinoid system. It has been shown that 20% of the respiratory hydrogen can be transferred from a respiratory enzyme to clofazimine (214). Its action has been also related to iron chelation, with resulting production of nascent oxygen radicals intracellu-larly (218).

In the treatment of murine tuberculosis. clofazimine was found to be very active, but much higher doses were necessary to achieve a therapeutic effect in guinea pigs and monkeys. Trials in chronic human pulmonary tuberculosis indicated that clofazimine had no significant effect on the disease at doses up to 10 mg/kg. In experimental infections with mycobacteria, clofazimine was found to be much more active than isoniazid against M. kansasii (219). Other studies have shown that clofazi-mine is also active in experimental infections with M. johnei (220), M. ulcerans (2211, M. lepraemurium (222,2231,and M. leprae (224231). In particular, M. leprae seems to be about 10 times more susceptible to clofazi-mine than M. tuberculosis (177). The marked activity against leprosy was confirmed in clinical trials (224-230). Generally speaking, the activity of clofazimine is similar to that cf dapsone. Dapsone-resistant mutants are susceptible to clofazimine. During treatment of lepromatous leprosy with clofazimine, the characteristic inflammatory reaction erythema nodosum leprosum (ENL) seldom develops; if clofazimine is combined with dapsone, the latter agent no longer causes ENL. This makes the concurrent use of corticosteroids unnecessary. It was suggested that clofazimine would have a corticosteroids like anti-inflammatory action (231). In a dye-hyaluronidase spreading test, clofazimine had a hyaluronidase inhibitory effect, after a single oral administration of 100-200 mg in humans (232). In agreement with these results, it was found that clofazimine (50-100 mg/kg per day) inhibited rat adjuvant arthritis and the inflammatory paw swelling following an adjuvant injection (233). It did not inhibit the primary antibody response to sheep erythro-cytes or the tuberculin skin response. Thus clofazimine seems to have anti-inflammatory but not immunosuppressive activity.

5.1.7.3 Pharmacokinetics. Clofazimine is an effective alternative drug in the therapy of leprosy. It is most active when administered twice weekly or daily, but can be administered at monthly intervals as well, permitting monitoring of the treatment. The daily dose should not exceed 100 mg. Clofazimine has a peculiar pharmacokinetic pattern, characterized by slow absorption, low blood concentration, and extremely slow excretion. All riminophena-zines are soluble in fats, and in micronized form, are well absorbed by the intestine. Rim-inophenazines, once absorbed by the intestine, are carried by lipoproteins in the blood and ingested by macrophages. After continued oral administration, the macrophages appear as red-orange phagosomes. Therefore, the compounds have a diffusion that is mainly in-tracellular. They are stored in the body for a long time, and this confers some prophylactic action on them (219).

To obtain compounds with better pharmacodynamic and pharmacoki-netic properties, which would be more useful than clofazimine in the treatment of mycobac-terial infections, a number of riminophena-zines were prepared and tested. All the derivatives with hydrophilic groups are either less active or inactive. Compound B-1912 (33)was selected for further investigation because it showed higher serum levels and lower tissues levels (except than in lipids) than clofazimine. In jd. leprae infections experimentally induced in mice, it was shown that clofazimine and B-1912 have the same activity (234). Newer riminophenazines, such as B746 and showed increased antimycobacterial activity and produced less skin pigmentation, which is the main drawback of this group of compounds, and both need further investigation (235).

5.1.7.5 Adverse Reactions. In laboratory animals, clofazimine has low acute and subacute toxicity (236). In clinical use, treatment with clofazimine is not accompanied by relevant toxicity. The main and sometimes unacceptable side effect is a red-purple coloration cf skin, particularly within skin lesions (231). Gastrointestinal intolerance may also occur.

5.1.8 Ethambutol

5.1.8.1 History. Extensive studies of the chemical and biological properties of compounds related to alkylenediamine were carried out after the discovery, during the screening of randomly selected compounds, of the antimycobacterial activity of N,N' -diisopropy-lethylenediamine (34) (237, 238). This com-

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