Methimazole in the Treatment of Leprosy

Sg, Browne; Lm, Hogerzeil

doi:10.5935/0305-7518.19620021

“…Clofazimine [3-(p-chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-(isopropylimino)phenazine; B663] has been used effectively in treating leprosy for over 25 years (2). The World Health Organization recommends its use along with rifampin and dapsone in multidrug therapy of lepromatous leprosy (8).…”

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confidence: 99%

Structure-activity relationships of selected phenazines against Mycobacterium leprae in vitro

Franzblau

¹

,

O’Sullivan

²

1988

Antimicrob Agents Chemother

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Structure-activity relationships of phenazines against Mycobacterium leprae were investigated by using an in vitro radiorespirometric assay. In general, activity in ascending order was observed in compounds containing no chlorine atoms, a monochlorinated phenazine nucleus, and chlorines in the para positions of both the anilino and phenyl rings. The most active compounds contained a 2,2,6,6-tetramethylpiperidine substitution at the imino nitrogen. Most of these chlorinated phenazines were considerably more active in vitro than clofazimine (B663).Clofazimine [3-(p-chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-(isopropylimino)phenazine; B663] has been used effectively in treating leprosy for over 25 years (2). The World Health Organization recommends its use along with rifampin and dapsone in multidrug therapy of lepromatous leprosy (8). Major advantages of B663 include low host toxicity (16); suppression of erythema nodosum leprosum (10, 11), a reactive state in leprosy; and few reports of bacterial resistance. The single most common drawback of B663 is a dose-related reddish-black skin pigmentation, making its continued use objectionable to a number of patients. The most serious and dose-limiting toxicity is gastrointestinal (16).Recently, a series of phenazines were synthesized. They share a number of properties, including activity against clofazimine-resistant Mycobacterium smegmatis 607 and lack of uptake by body fat (and thus nonpigmentation) (13). We studied the relative activities of these compounds against Mycobacterium leprae in vitro to determine structure-activity relationships with a view to ultimately finding a less toxic substitute for clofazimine in treating leprosy.Unlike that for in vitro-cultivable microorganisms, drug susceptibility testing of M. leprae has, until recently, been possible only in vivo. The established mouse footpad model is expensive and time-consuming, taking 6 to 12 months to complete, requiring gram quantities of new compounds for maximum-tolerated-dose determinations, and relying upon favorable pharmacokinetics in a nonhuman system (8). Therefore, a number of in vitro systems have been devised which involve exposure of intracellular or extracellular M. leprae to test compounds followed by measurement of some bacillary metabolic activity (6-9, 12, 15). Although these systems appear to be useful, most are somewhat cumbersome for large-scale screening or clinical use. We therefore recently used a simpler, semiautomated, radiorespirometric assay for rapidly assessing the metabolic status of M. leprae (4). This assay is based on the oxidation of palmitic acid to carbon dioxide and is similar to that used for rapid drug * Corresponding author. susceptibility testing of cultivable mycobacteria in the BACTEC method (14). We describe here its use in investigating structure-activity relationships of a number of phenazine derivatives against M. leprae.Susceptibility testing was performed by a slight modification of the method of Franzblau (4). Briefly, footpads of M. leprae-infecte...

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“…However, in three of five patients who had received B 663 for 6 months and ditophal for the first three months in addition (and standard dapsone alone after six months) (BROWNE and HOGERZEIL, 1962 (a)), normal bacilli appeared in the smears; and in two of them the Bacterial Index rose-both phenomena occurring at the same time as in the group who had received B 663 alone for twelve months. The magni tude of the rise in B.l.…”

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confidence: 99%

“…

One incidental and unexpected finding during our treatment of five cases of severe lepromatous leprosy fo r twelve months with B 663 (J. R. GEIGY S.A.) alone (BROWNE and HOGERZEIL, 1962 (a) and (b», » appears to shed some light on the controversial question of drug resistance in leprosy.Following our preliminary report in this pilot trial (BROWNE and {JOGERZEIL, 1962 (a» » , clinical progress (marked in some and moderate in others) continued to be satisfactory in all 5 patients for the whole period of twelve months during which B 663 was given alone, and for the three months subsequently, when standard dapsone treatment was given. (BROWNE and HOGERZEIL, 1962 (b» » .

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APPARENT RESISTANCE OFM. LEPRAETO "B 663"

Browne¹,

Hogerzeil²

1962

Leprosy Review

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One incidental and unexpected finding during our treatment of five cases of severe lepromatous leprosy fo r twelve months with B 663 (J. R. GEIGY S.A.) alone (BROWNE and HOGERZEIL, 1962 (a) and (b», » appears to shed some light on the controversial question of drug resistance in leprosy.Following our preliminary report in this pilot trial (BROWNE and {JOGERZEIL, 1962 (a» » , clinical progress (marked in some and moderate in others) continued to be satisfactory in all 5 patients for the whole period of twelve months during which B 663 was given alone, and for the three months subsequently, when standard dapsone treatment was given. (BROWNE and HOGERZEIL, 1962 (b» » . Bacteriological improvement continued to be satisfactory, as shown by progressive red uction in the Bacterial I ndex calculated from smears taken every fo rtnight from eight comparable sites (four from skin; two from ear lobes; two from nasal mucosa). The degener ation of the individual M. leprae was also satisfactorily progressive, normal fo rms having almost completely disappeared from all eight sites in all five patients: only five sites showed a few (about 10%) of normal bacilli in the 24th and 25th series of smears (i.e., a total of 80 sites) made towards the close of the trial period on 5th and 19th January, 1962.The features of bacteriological relapse during treatment with B 663

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“…While the substituted iminophenazine c'lofazimine (I) has been used in the treatment of leprosy patients for twenty years (Browne & Hogerzeil, 1962) and is in many ways the best antileprosy drug currently available (Jacobson, 1981 We have, therefore, recently begun to examine the structural and electronic properties of these phenazine derivatives with the aim of establishing the essential structural and/or electronic features for antileprosy activity in this important class of molecules. We hope that this will allow the rational design of active drugs which contain these crucial parameters.…”

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confidence: 99%