Drugs for Combined Therapy Experimental Studies on the Antileprosy Activity of Ethionamide and Prothionamide, and a General Review

Colston, M. Joseph; Ellard, G. A.; Gammon, Patricia T.

doi:10.5935/0305-7518.19780014

Cited by 15 publications

(9 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There appears to be a general correlation between degree of bactericidal activity in vivo (1) and degree of activity in radiorespirometric systems (2,4). It was radiorespirometric systems which initially demonstrated the antileprosy activity of macrolides and further identified clarithromycin as the most active drug in this class (4); the latter has been confirmed in the mouse footpad system by my colleague and me (4) and others (17).…”

mentioning

confidence: 68%

In vitro activities of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae

Franzblau

1991

Antimicrob Agents Chemother

View full text Add to dashboard Cite

The in vitro activities of a variety of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae were evaluated with the BACTEC 460 system. At 20 ,g/ml, gentamicin, kanamycin, tobramycin, streptomycin, and amikacin were inactive. Lincomycin was active at 20 ,ug/ml, and clindamycin was active at 0.31 ,ug/mi. Rifamycin SV, rifabutin, and rifampin were active at 3.1, 3.1 to 12.5, and 200 ng/ml, respectively. The M. leprae inoculum was prepared from infected nude mouse footpads and partially purified by differential centrifugation as previously described (6).All drugs, except for rifabutin (Farmitalia Carlo ERB, Milan, Italy), were obtained from Sigma Chemical Co. (St. Louis, Mo.). Aminoglycosides and lincosamides were dissolved in water, and rifamycins were dissolved in ethanol. All were adjusted for potency, filter sterilized, and diluted in Middlebrook 7H9 broth to 40 times the final desired concentrations.Susceptibility testing was performed with the BACTEC 460 as previously described (3). In brief, i07 M Ieprae organisms were inoculated into BACIEC 12B medium, and drugs were added in 0.1-ml aliquots to quadruplicate vials. All drugs were tested at fourfold dilutions; aminoglycosides and lincosamides were tested at 0.31 to 20 ,ug/ml, and rifamycins were tested at 3.1 to 200 ng/ml. Ampicillin and amphotericin B were added to control occasional contaminants. Vials were flushed with 2.5% 02-10% CO2 (balance, N2) and incubated at 33°C. The growth index (14C02 evolution) was measured at 1-week intervals with the BACTEC 460. Drugs at various concentrations were considered to be active if they effected a significant (Student's t test) reduction in the growth index during the reading interval of days 7 to 14, relative to that of drug-free controls. When these experiments were repeated a second time, essentially identical results were obtained (data not shown).None of the aminoglycosides effected a significant reduction in the growth index at concentrations of 20 ,ug/ml or less after 2 weeks of incubation (Fig. 1). Subsequent readings taken at 3, 4, and 5 weeks postincubation gave similar results (data not shown). In contrast, lincomycin was active at 20 ,ug/ml, and clindamycin was active at 0.31 ,g/ml. At 20 ,ug/ml, clindamycin effected a reduction of 61% in 14CO2evolution.The rifamycins were tested at ¼lo of the concentrations of the aminoglycosides and lincosamides. As previously noted, rifampin was active at 200 ng/ml (Fig. 2). Both rifabutin and rifamycin SV showed significant activity at 3.1 to 200 ng/ml, although the latter effected a greater reduction in the growth index at the lower concentrations.Gelber et al. (10) demonstrated the bactericidal activities of streptomycin, kanamycin, and amikacin at high (100 to 150 mg/kg) daily doses against M. leprae in the footpads of mice. Gentamicin and tobramycin at 20 mg/kg were much less active. Reducing the dose or frequency of administration resulted in a reduction of the activity of streptomycin and a loss of the bactericidal activity of kanamycin (9...

show abstract

mentioning

confidence: 68%

In vitro activities of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae

Franzblau

1991

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…The most promising drugs for use in combination with dapsone or for the treatment of patients with dapsone resistant leprosy are rifampicin, c1ofazimine, ethionamide, prothionamide and thiacetazone. 28 The regularity with which such companion drugs are taken is likely to be a major factor in determining their potential value in preventing the emergence of dapsone resistance. An experimental investigation in the mouse fo ot-pad model has indicated that poor compliance would probably severely impair the efficacy of thiacetazone, since it is an inherently weak bacteriostatic drug,59 and would compromise the bactericidal activities of ethionamide and prothionamide.…”

Section: Monitoring the Ingestion Of Other Antileprosy Drugsmentioning

confidence: 99%

Drug Compliance in the Treatment of Leprosy

Ga¹

1981

Leprosy Review

Self Cite

View full text Add to dashboard Cite

“…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%

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

View full text Add to dashboard Cite

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.

show abstract

Drugs for Combined Therapy Experimental Studies on the Antileprosy Activity of Ethionamide and Prothionamide, and a General Review

Cited by 15 publications

References 22 publications

In vitro activities of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae

In vitro activities of aminoglycosides, lincosamides, and rifamycins against Mycobacterium leprae

Drug Compliance in the Treatment of Leprosy

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

Contact Info

Product

Resources

About