The killing of<i>Mycobacterium leprae</i>in mice by various dietary concentrations of clofazimine and ethionamide

Rh, Gelber

doi:10.5935/0305-7518.19870043

Cited by 6 publications

(6 citation statements)

References 3 publications

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“…In vivo, isoniazid is reported to be active in mice against some strains of M. leprae (41) and inactive against others (40). In contrast, ethionamide was effective in our system at concentrations of 2 ,ug/ml, while its MIC against M. leprae in mice is reported to range from concentrations in serum of 0.2 ,ug/ml (15) to about 25 ,ug/ml (42). In the cell-free system, ethionamide was shown to decrease the intracellular ATP content of M. leprae (8), although it was reported to enhance the synthesis of PGL-I in the same system (21).…”

Section: Resultscontrasting

confidence: 38%

In vitro effects of antimicrobial agents on Mycobacterium leprae in mouse peritoneal macrophages

Ramasesh

Krahenbuhl

Hastings

1989

Antimicrob Agents Chemother

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Mycobacterium leprae synthesizes large quantities of a specific phthiocerol-containing phenolic glycolipid in vivo. We had shown earlier that viable M. leprae readily incorporates radiolabeled palmitic acid into phenolic glycolipid I when residing in cultured macrophages in vitro and that this process is inhibited by the antileprosy drug rifampin. In the present paper we report the application of this observation to the rapid evaluation of over 25 antimicrobial agents for potential antileprosy activity in vitro. All the known antileprosy drugs rifampin, dapsone, clofazimine, and ethionamide inhibited phenolic glycolipid I synthesis. Rifabutin, a spiropiperidyl derivative of rifamycin, also reported to be active in the mouse model, was very effective. Interestingly, the macrolides erythromycin, clarithromycin, and roxithromycin were also found to be active in this system, while D-cycloserine and other cell wall synthesis inhibitors showed no effect. Many of the compounds found to be active in this system have been reported to be effective in vivo in mice. This correlation lends support to the feasibility of using phenolic glycolipid I synthesis for the rapid evaluation of new drugs against leprosy.The increased emergence of drug-resistant strains of Mycobacterium leprae in recent years has emphasized the need to identify new compounds effective in the treatment of leprosy. Since M. leprae does not multiply in vitro, conventional microbiological assays cannot be used for primary evaluations of new drugs for antileprosy activity. Prior to 1960, antileprosy drugs were selected primarily on the basis of empirical results of clinical trials with leprosy patients. The mouse footpad technique developed in 1960 by Shepard (38) proved to be an invaluable tool in the primary selection of new drugs by facilitating comparison of the bactericidal potency of different compounds and by making it possible to differentiate bactericidal activity from bacteriostatic effects. The activity of a drug in the mouse model is strongly correlated with its ultimate efficacy in humans. However, primary evaluation of new drugs by this approach has severe practical limitations since the assay is time-consuming (requires 4 to 8 months) and laborious, requires at least 4 to 5 g of a test compound for a test screening, and is heavily dependent on the compound's having favorable pharmacokinetics in the mouse. The development of a rapid and reliable in vitro drug-screening system would allow primary screening and selection of more compounds with potential antileprosy activity, the activity of which could then be tested in mice prior to clinical trials.A number of in vitro metabolic assay systems have been reported in recent years, and these have been extensively reviewed (22,47,48). These assays are based on the observation that M. leprae, although incapable of proliferation in vitro, retains many of its metabolic functions for a limited period of time outside the host either in tissue culture or in cell-free systems. The metabolism of the organism...

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Section: Resultscontrasting

confidence: 38%

In vitro effects of antimicrobial agents on Mycobacterium leprae in mouse peritoneal macrophages

Ramasesh

Krahenbuhl

Hastings

1989

Antimicrob Agents Chemother

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“…In a previous studies in M. leprae-infected mice, 5,13 ethionamide and prothionamide showed similar activity, with minimal effective doses in mouse diets of 0.01% and minimal inhibitory serum concentrations of 0.05 g/mL. 5 Although a minimal dietary concentration of ethionamide of 0.02% was observed in mice, 7 higher concentrations (0.05-0.3%) were consistently more bacteriocidal. In the treatment of tuberculosis, prothionamide has advantages over ethionamide because it is slightly superior 30 in its activity against M. tuberculosis and is generally better tolerated.…”

Section: Discussionmentioning

confidence: 70%

“…Unfortunately, with this therapy, double-digit relapse rates have been obtained in those with multibacillary leprosy and particularly in those with high bacterial burdens in three disparate locales. [2][3][4] Of the three antimicrobials included in the WHO regimens, only rifampin has been found to be bactericidal both for Mycobacterium leprae in the mouse model [5][6][7][8] and in clinical trials, [8][9][10][11] it being advocated by the WHO only once a month, primarily because of its expense. Clofazimine, although bactericidal in mice, 7 is only bacteriostatic in humans, 9 while dapsone is bacteriostatic in mice 6,12 and in humans.…”

Section: Introductionmentioning

confidence: 99%

“…9 Ethionamide and prothionamide were bactericidal in several studies in mice. 5,7,12,13 In addition, 102 lepromatous leprosy patients were treated with ethionamide, 1 gram a day initially, and later due to gastrointestinal toxicity, 500 a day in adults and 250 mg a day in children, with most patients becoming bacteriologically skin smear negative after four years. 14 In that study, unfortunately, the actual loss of M. leprae viability by the standard mouse inoculation was not conducted.…”

Section: Introductionmentioning

confidence: 99%

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A Clinical Trial of Ethionamide and Prothionamide for Treatment of Lepromatous Leprosy

Fajardo¹,

Guinto²,

Cellona³

et al. 2006

The American Journal of Tropical Medicine and Hygiene

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In 1982-1984 we conducted a six-month clinical trial in 50 previously untreated lepromatous leprosy patients randomly assigned to directly observed monotherapy with one of two thioamides, ethionamide or prothionamide, each given six times a week at doses of either 250 mg or 500 mg. The findings of this study have only recently been analyzed, and the potential for the use of these thioamides in leprosy patients placed in perspective. However, because of the small number of patients included in this study, the results must be interpreted with some caution. Clinical improvement was noted in 74% of the patients treated with ethionamide and in 83% of those treated with prothionamide. Therapy was well tolerated and drug-related hepatotoxicity did not require discontinuation of therapy. The 500-mg dose of both ethionamide and prothionamide resulted in loss in Mycobacterium leprae viability more rapidly than did the 250-mg dose, and prothionamide at both dose levels was superior to the equivalent dose of ethionamide. Overall killing of M. leprae in this study was found to be similar to that obtained previously with dapsone and clofazimine, but less than was obtained with rifampin, minocycline, clarithromycin, pefloxacin, and ofloxacin.

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“…Although bactericidal activity for M. leprae in mice (6, 7, 10-13) generally translates well to leprosy patients (3-5, 9), this is not always the case, as, for example, with clofazimine (8,20).…”

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confidence: 98%

The Diarylquinoline R207910 Is Bactericidal against Mycobacterium leprae in Mice at Low Dose and Administered Intermittently

Gelber¹,

Andries²,

Paredes³

et al. 2009

Antimicrob Agents Chemother

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The diarylquinoline R207910 is profoundly bactericidal in a murine model of tuberculosis. Previously, R207910 was also found to be bactericidal for Mycobacterium leprae-infected mice during lag phase. Herein we evaluate the bactericidal efficacy of R207910 (1 to 120 mg/kg of body weight) when administered five times weekly, once weekly, and once monthly during logarithmic multiplication of M. leprae organisms. All treatments were found to be bactericidal, suggesting that both low and intermittent dosing with R207910 holds promise for leprosy patients.The diarylquinoline R207910 (also known as TMC207) represents a new class of antimicrobials uniquely active against mycobacteria, killing mycobacteria in vitro by blocking energy production (1). In vitro, R207910 has been found to inhibit a wide range of Mycobacterium tuberculosis clinical isolates and other mycobacterial species (1). In murine tuberculosis, daily administration of R207910 alone exceeds the bactericidal activity of the standard WHO regimen (isoniazid, rifampin [rifampicin], and pyrazinamide) (1). Also a combination with rifapentine and pyrazinamide given once weekly proved to be more active than the daily regimen recommended by the WHO (22). R207910 has several virtues that heighten its promise for the therapy of tuberculosis, such as a low MIC and a low minimal bactericidal concentration (1), demonstrable activity against nonreplicating M. tuberculosis organisms (15), and a prolonged plasma half-life in human volunteers (1).Previously, Ji et al. (14) demonstrated that single doses of 25 mg/kg of body weight or 100 mg/kg given 1 day after infection of mice with Mycobacterium leprae (i.e., during lag phase) were equally bactericidal and that the bactericidal activity was equipotent to those of rifampin, rifapentine, and moxifloxacin while being superior to those of minocycline, PA-824, and linezolid. In order to further evaluate the activity of R207910 and assess different doses and frequencies of administration, we initiated a dose fractionation study wherein the activity of R207910 against M. leprae in infected mice was evaluated by a different technique, the standard kinetic method of Shepard (19). In this protocol, CBA/J mice were infected in both hind footpads with 5,000 M. leprae organisms and orally treated by gavage during logarithmic multiplication from day 60 to day 150 after infection with several dosage schedules of R207910, formulated in 20% hydroxypropyl-ß-cyclodextrin.Study mice were (i) untreated (controls); (ii) treated five times weekly with 1 mg/kg, 3 mg/kg, 6 mg/kg, 12.5 mg/kg, and 25 mg/kg for 3 months; (iii) treated once weekly with 25 mg/kg, 30 mg/kg, 50 mg/kg, and 100 mg/kg for 3 months; and (iv) treated once monthly with 25 mg/kg, 50 mg/kg, 100 mg/kg, and 120 mg/kg (three doses). Keeping in mind that for murine tuberculosis the total weekly dosage has been shown to be the driver of activity, irrespective of the frequency of administration (22), we specifically designed several dosage schedules to deliver the same monthly dos...

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The killing ofMycobacterium lepraein mice by various dietary concentrations of clofazimine and ethionamide

Cited by 6 publications

References 3 publications

In vitro effects of antimicrobial agents on Mycobacterium leprae in mouse peritoneal macrophages

In vitro effects of antimicrobial agents on Mycobacterium leprae in mouse peritoneal macrophages

A Clinical Trial of Ethionamide and Prothionamide for Treatment of Lepromatous Leprosy

The Diarylquinoline R207910 Is Bactericidal against Mycobacterium leprae in Mice at Low Dose and Administered Intermittently

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