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

A CLINICAL TRIAL OF ETHIONAMIDE AND PROTHIONAMIDE FOR TREATMENT OF LEPROMATOUS LEPROSY

TRANQUILINO T. FAJARDO, RICARDO S. GUINTO, ROLAND V. CELLONA, RODOLFO M. ABALOS, EDUARDO C. DELA CRUZ, AND ROBERT H. GELBER* Leonard Wood Memorial Center for Leprosy Research, Cebu City, The Philippines

Abstract. 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.

INTRODUCTION which other companion agent should be used with rifampin so as to preclude emergent rifampin resistance. For this purpose, Concerns over primary and secondary dapsone-resistant either clofazimine or a thioamide, the only other agents leprosy in 1982 prompted the World Health Organization known to be active against M. leprae at the time, were being (WHO)1 to recommend multidrug regimens for the treatment considered. In 1982, clofazimine was selected primarily by the of all forms of leprosy. These regimens include combinations WHO1 over a thioamide for this purpose because of the es- of rifampin, dapsone, and clofazimine and have been widely tablished hepatotoxicity of daily thioamides when combined implemented worldwide. Unfortunately, with this therapy, with daily rifampin17 and the limited experience with killing double-digit relapse rates have been obtained in those with of M. leprae in humans by thionamides. However, the WHO1 multibacillary leprosy and particularly in those with high bac- allowed for the supplementation of clofazimine by ethiona- terial burdens in three disparate locales.2–4 Of the three an- mide/prothionamide and substitution of clofazimine by thio- timicrobials included in the WHO regimens, only rifampin amides in light-skinned individuals where the pigmentation has been found to be bactericidal both for Mycobacterium changes induced by clofazimine were considered to be cos- leprae in the mouse model5–8 and in clinical trials,8–11 it being metically unacceptable. Because of the aforementioned lack advocated by the WHO only once a month, primarily because of experience with thioamides in treating leprosy and particu- of its expense. Clofazimine, although bactericidal in mice,7 is larly their ability to kill the bacterium, in 1982 the WHO only bacteriostatic in humans,9 while dapsone is bacteriostatic solicited and sponsored the present study to compare the in mice 6,12 and in humans.9 Ethionamide and prothionamide safety and efficacy of ethionamide against prothionamide in were bactericidal in several studies in mice.5,7,12,13 In addi- multibacillary patients, with each being administered for six tion, 102 lepromatous leprosy patients were treated with months at six weekly doses of 250 mg and 500 mg. In this ethionamide, 1 gram a day initially, and later due to gastro- study, clinical response, loss of M. leprae viability, side effects/ intestinal toxicity, 500 a day in adults and 250 mg a day in toxicities, and lepra reactions were carefully monitored. children, with most patients becoming bacteriologically skin These findings are only now being reported due to a serious smear negative after four years.14 In that study, unfortu- delay in a thorough analysis of the results. In the intervening nately, the actual loss of M. leprae viability by the standard years, greater antimicrobial activity and lesser toxicity of mouse inoculation was not conducted. Although both other antimicrobial agents and regimens largely dampened ethionamide and prothionamide have been used as single the enthusiasm to pursue thioamides for treatment of leprosy. agents in a small number of leprosy patients9 monitored by Furthermore, even prior to the completion of this present mouse inoculation to assess the rate of loss of M. leprae vi- work the WHO recommended that clofazimine rather than a ability, it has never been done in an organized study. thioamide be a component of multidrug therapy (MDT), at Nonetheless, prothionamide was used in combination with least in part because of the established hepatoxicity17 when rifampin, isoniazid, and dapsone in leprosy patients in Malta15 daily rifampin and ethionamide were administered together. and resulted in reliable cures, while being well tolerated. This However, because of the large number of patients and mice experience in Malta provided the first suggestion that finite required for monitoring this trial and since to date few agents and not life- long therapy could result in a cure for all forms are yet established to be effective for leprosy, this trial re- of leprosy. More than two decades ago with concerns for an mains germane. This report was prompted by the findings increase in dapsone resistance,16 the WHO concluded that that both thioamides resulted in moderate killing of M. leprae, dapsone was no longer reliable and was trying to determine the higher dosage of each agent was superior to the lower one, prothionamide resulted in a more rapid killing of bacilli at comparable dosage levels than ethionamide, and both thio- * Address correspondence to Robert H. Gelber, 220 Scenic Avenue, amides were well tolerated and resulted in a generally salu- San Anselmo, CA 94960. E-mail: [email protected] tory clinical response. 457 458 FAJARDO AND OTHERS

MATERIALS AND METHODS levels of tumor necrosis factor-␣,19 and reversal reactions that are associated with an increasing cellular immune response20 This study was conducted between 1982 and 1984, and all and elevation in lesional21,22 and circulating cytokine levels.19 study patients were clinically and histopathologically polar The ENL was considered mild when there were less than 10 lepromatous or borderline lepromatous without a history of tender papulonodules, moderate if there were 10–20 papu- leprosy therapy. The study was reviewed and approved by the lonodules with or without slight edema, joint pains, and se- Institutional Review Board of the Leonard Wood Memorial vere if these were associated with either severe joint pains, Center, which is registered with the National Institutes of edema, high fever and other constitutional signs and symp- Health. All trial patients provided informed written consent, toms. Iritis, laryngitis, orchitis, and other involvement may were hospitalized for the six-month duration of treatment, also occur in severe ENL. Reversal reactions were considered and received directly observed therapy. A total of 50 previ- mild if the manifestations were only confined to the original ously untreated lepromatous patients were admitted into the lesions, moderate if new lesions also appeared with or without study and randomly assigned by a table of random numbers to nerve involvement, and severe when constitutional signs and receive single doses six days a week for 24 weeks: group 1, symptoms were present with or without ulcers, blebs, or ethionamide 250 mg; group 2, ethionamide 500 mg; group 3, edema. In most instances, nerves were also involved. Slit skin prothionamide 250 mg; group 4, prothionamide 500 mg.. The smears for bacteriologic analysis and biopsy specimens for patients, clinical staff, and clinical assessment were entirely histologic analysis were obtained before the start of treatment blinded as to which regimen was used. and at the end of 24 weeks. There were six sites for bacterial In group I, 12 patients were admitted and completed 24 smears per patient, both earlobes, and four others, preferably weeks of treatment. In group II, 13 patients were admitted, 11 lesional skin sites. Pretherapy and 24-week clinical pho- completed 24 weeks of treatment, 1 patient left the study, and totransparencies were taken to assist clinical assessments. 1 patient was excluded because of surreptitious intake of dap- The site large enough for sequential biopsies was selected sone. In Group III, 13 patients were admitted, 12 completed on preliminary examination of the patient. From this site pa- 24 weeks of treatment and 1 patient left the study. In group tients underwent serial skin biopsies prior to therapy and at 4, IV, 12 patients were admitted, 11 completed 24 weeks of 8, 16, and 24 weeks after the initiation of therapy. Bacilli from treatment, and 1 patient left the study. None of those who left these biopsies were injected into groups of mice in both hind the study dropped out for reasons of drug intolerance, lepra footpads (5,000 M. leprae/footpad). One year after inocula- reaction, or worsening of the disease. tion, two mice (four feet) were analyzed, and M. leprae Table 1 shows some of the salient features of the 46 patients therein were enumerated. If Ն 105 bacilli were found viable who completed 24 weeks of therapy. During the course of the M. leprae were considered to have been present in the corre- study, patients were seen six times a week, and clinical, der- sponding biopsy. The number of patients found to harbor matologic, and neurologic examinations were done. Blood viable bacilli by the four treatment regimens and at various chemistry and liver enzyme examinations were done every time intervals was compared statistically by the use of Fis- four weeks. At the conclusion of therapy, improvement was cher’s exact test. formally assessed. Definite improvement was considered to After the completion of this trial, all thionamide-treated have occurred when marked subsidence of papulonodular le- patients were then treated with dapsone (100 mg/day) and sions or fading and flattening of erythematous plaques were rifampin (600 mg/day) for one week and then transferred to noted. Less dramatic improvement, such as softening and par- the General Health Services where they received standard tial flattening of papulonodular lesions was graded as moder- three-drug WHO MDT for two years. ate improvement. Throughout this study, patients were regularly and care- RESULTS fully monitored for the appearance of any side effects/drug toxicities and reactional states. It is noteworthy that during The power of many of the observations was limited by the the treatment of lepromatous leprosy two kinds of inflamma- small number of patients enrolled in this study. Table 2 shows tory reactional states commonly complicated the death of ba- the clinical changes observed, by therapy group, for the 46 cilli: erythema nodosum leprosum (ENL) that was believed to patients who completed 24 weeks of treatment. Clinical im- be an immune complex disorder18 associated with elevated provement was noted in 36 (78.2%) patients and no observ-

TABLE 1 Salient features by therapy group for patients completing 24-weeks of therapy*

Histopathologic diagnosis Duration of disease Therapy No. of Mean (SD) prior to therapy, year group patients Sex (no.) age, years, range (mean) BL LLs LLp BI (six sites) range (mean) I2M614–42 (25.8) – 12 – 4.5 (0.3) 3–19 (8.6) F612–59 (23.6) II 11 M 6 17–48 (33.0) – 10 1 4.6 (0.2) 2–15 (7.3) F515–31 (23.6) III 12 M 10 14–43 (23.7) – 12 – 4.4 (0.5) 2–29 (6.5) F217–20 (18.5) IV 11 M 8 18–38 (24.8) 1 10 – 4.6 (0.2) 2–20 (7.8) F317–23 (20.0) Total 46 M 30 14–48 (26.8) 1 44 1 4.5 (0.3) 2–29 (7.6) F1612–59 (21.4) .bacteriologic index ס polar lepromatous leprosy; BI ס subpolar lepromatous leprosy; LLp ס borderline leprosy; LLs סBL* CLINICAL TRIAL OF ETHINOAMIDE AND PROTHIONAMIDE 459

TABLE 2 TABLE 4 Clinical response of patients completing 24 weeks of therapy, by Frequency and severity of lepra reactions for patients completing 24 therapy group weeks of therapy

Therapy No. of No Slight Definite No. of patients with reaction group patients change improvement improvement Worse Therapy No. of No. of patients Moderate I122 10 ––group patients without reaction Mild to severe Total (%) II 11 4 4 3 – I 12 5 5 2 7 (58.3%) III 12 3 9 ––II 11 5 4 2 6 (54.5%) IV 11 1 8 2 – III 12 7 3 2 5 (41.7%) Total 46 10 31 5 – IV 11 6 4 1 5 (45.5%) 21.7% 67.30% 10.90% 0% Total 46 23 16 7 23 (50.0%) able clinical change in 10 (21.7%) patients. None of the pa- 3 patients, respectively, without any regimen showing signifi- tients showed deterioration of their illness or became clini- cant differences in the onset of these events. Erythema no- cally worse. Definite clinical improvement was noted in only dosum leprosum neuritis was observed in two patients, one in five patients, all receiving the 500-mg dose, three receiving the fourth month of therapy and one in the sixth month of ethionamide and two receiving prothionamide. No statisti- therapy. Reversal reactions developed in two other patients af- cally significant differences in clinical response between the ter the first month of therapy, one in the fifth month of therapy four treatment regimens were noted. However, the group re- and one in the sixth month of therapy. All reaction lesions in the ceiving 500 mg of prothionamide appeared to have the best trial patients were easily controlled with prednisone. clinical response. To monitor hepatic toxicity, monthly serum aspartate ami- Table 3 shows the average bacteriologic index (BI) (a loga- notransferase (AST) levels were determined. An AST level rithmic function of the number of acid-fast bacilli with a range grater than 35 units was considered elevated. Eighteen of 0 to 6) after 24 weeks of treatment. There was an overall (39.1%) of 46 patients had elevated AST levels. Elevated 0.4 reduction in the average BI from a preliminary or pre- AST levels were noted in four patients in group I, four pa- therapy average of 4.5 to an average BI of 4.1 in all 46 patients tients in group II, four patients in group III, and six patients after 24 weeks of therapy, with no therapy regimen being in group IV. In 14 patients, the highest levels of AST ranged more effective. from 35 to 88 units in any examination of the series of Table 4 shows the occurrence and severity of lepra reac- monthly examinations. However, in four patients, AST levels tions during the course of therapy by treatment group in the were greater than 100 units in at least one instance: one in 46 patients who completed therapy. Lepra reactions occurred group 1, one in group 2, and 2 in group 3. Only one of these at rates similar to that found with other effective antimicro- four patients had signs and symptoms of hepatitis including bial regimens23 in 23 (50.0%) of the patients. They were mild anorexia, nausea, and vomiting. During the eighth week of in 16 (34.8%) patients and moderate to severe in 7 (15.2%) treatment with 250 mg of prothionamide, this patient became patients. Lepra reactions were observed in groups I and II in jaundiced and had a total/direct bilirubin level of 6.9/4.2 mg/ 13 (56.6%) patients. They were moderate to severe in 4 dL and a maximum AST level of 690 units. After discontinu- (17.3%) patients and mild in 9 (39.1%) patients. In groups III ation of prothionamide therapy, signs and symptoms of hepa- and IV, lepra reactions occurred in 10 (43.4%) patients. They titis resolved and AST and bilirubin levels returned to normal were moderate to severe in 3 (13.0%) patients and mild in 7 in two weeks. At that time, prothionamide therapy was rein- (30.4%) patients. The occurrence of lepra reactions among stituted without recurrence of signs and symptoms of hepatitis patients in groups I and II was slightly higher (56.5%) than in or elevations in AST levels throughout the six-month course groups III and IV (43.5%), but this difference was not statis- of prothionamide therapy. This patient and one of the other tically significant. First attacks of lepra reactions occurred four who had AST levels greater than 100 units had IgM during the first month in two patients as reversal reactions of antibody to hepatitis B core antigen, and four were positive moderate severity: one patient in group II whose reactive for hepatitis B antigen. lesions subsequently subsided in a few weeks, and the other in Clinical drug intolerance in the form of salivation and nau- group IV who subsequently developed ENL during the 11th sea associated with drug intake was reported by one patient in week of treatment in addition to a reversal reaction and flare- group IV. This was relieved by premedication with meto- up and generalization of an underlying atopic dermatitis. In clopramide. No abnormal liver function was noted at any the five subsequent months, ENL developed in 4, 3, 5, 6, and time in this patient. Another patient, also in group IV, had headaches associated with drug intake within the first weeks TABLE 3 of treatment. She subsequently developed subacute atopic Bacteriologic evaluation of patients completing 24 weeks of therapy, eczema and a reversal reaction. Her AST levels were normal, by therapy group except for an AST level of 48 units during the 16th week.

Mean (SD) bacteriologic The viability of M. leprae from serial skin biopsies obtained index (six sites) in these studies is summarized in Table 5. Prior to the initia- Therapy No. of group patients Preliminary 24 Weeks % Reduction tion of therapy, M. leprae grew in mice tested with specimens I 12 4.5 (0.3) 4.0 (0.6) 11.1 from the 46 trial patients completing therapy (Table 5). At II 11 4.6 (0.2) 4.0 (0.5) 13.0 four weeks of therapy, no significant loss of M. leprae viability III 12 4.4 (0.5) 3.9 (1.1) 11.3 was noted in the thioamide-treated patients (viable M. leprae IV 11 4.6 (0.2) 4.1 (0.6) 10.8 were found in 47 of 50 patients) or in any of the four treat- Total 46 4.5 (0.3) 4.1 (0.7) 11.5 ment regimens. By eight weeks of therapy, significant loss of 460 FAJARDO AND OTHERS

-Five hundred milligrams of ethionamide was su .(0.04 ס TABLE 5 (P –during the 16 :(0.02 ס Summary of viability of Mycobacterium leprae obtained in perior to 250 mg of ethionamide (P serial biopsies 24-week period, viable M. leprae being found in 5 of 22 and 14 of 24 biopsies, respectively, but this difference was not sig- Growth of M. leprae/total no. of patients nificantly different when eight-week data were included as 4 weeks 8 weeks 16 weeks 24 weeks well. The number of biopsies with viable M. leprae from pa- Group 1 tients treated with 500 mg of ethionamide either over 8–24 Ethionamide, 250 mg/day 11/12 10/12 9/12 5/12 weeks (17 of 35) or 16–24 weeks (5 of 22) was not significantly Group 2 Ethionamide, 500 mg/day 13/13 12/13 3/11 2/11 different from that observed with 250 mg of prothionamide: Group 3 11 of 36 and 2 of 23, respectively. Prothionamide, 250 mg/day 12/13 9/13 2/11 0/12 Group 4 Prothionamide, 500 mg/day 11/12 3/11 0/11 0/11 DISCUSSION Although the number of patients per group in this study M. leprae viability was observed only in those patients treated was small, being limited by the large number of mice required with 500 mg of prothionamide daily (P < 0.01), wherein only to monitor this trial (more than 4,000), published studies on 3 of 11 treated patients harbored viable M. leprae. At eight the activity of other agents used to treat leprosy patients also weeks the fraction of patients treated with 500 mg of pro- include only 8–10 patients per group.23–29 Nonetheless, be- thionamide per day harboring viable M. leprae was signifi- cause of the small number of patients enrolled in the current cantly less than either those treated with 250 mg of ethion- study, the results should be interpreted with caution. How- or 500 mg of ethionamide ever, certain findings do emerge. In this 24-week clinical trial (0.01 ס amide per day (10 of 12; P Although the fraction of patients treated of ethionamide and prothionamide monotherapy, each in a .(0.002 ס of 13; P 12 with 250 mg of prothionamide 250 (9 of 13) was greater than single six times a week dose of 250 mg or 500 mg for previ- that found for 500 mg of prothionamide, this result was not ously untreated lepromatous leprosy patients, clinical im- By 16 weeks of therapy, provement was noted in 17 (74%) of 23 patients treated with .(0.1 ס statistically significant (P highly significant killing (P < 0.01) of M. leprae was observed ethionamide, which was not significantly different from that for all treatment regimens except 250 mg of ethionamide. At provided by prothionamide (19 [83%] of 23 patients). The that time no viable M. leprae were found in patients treated decrease in the average BI was also not significantly different with 500 mg of prothionamide. At 16 weeks of therapy the between those treated with ethionamide (12.1%) and those fraction of patients (9 of 12) treated with 250 mg of ethion- treated with prothionamide (11.1%). These rates were similar amide who harbored viable bacilli was higher than in those to those found previously with other agents active against M. -leprae. Occurrence of lepra reactions was also not signifi 250 ,(0.04 ס treated with 500 mg of ethionamide (3 of 11; P [and 500 mg of cantly different in those treated with ethionamide (13 [57% ,(0.01 ס mg of prothionamide (2 of 11; P prothionamide (0 of 11; P < 0.001). By 24 weeks significant of 23 patients) than in those treated with prothionamide (10 killing of M. leprae was evident for all four treatment groups [44%] of 23 patients). Although hepatotoxicity17 can be a and for the first time in those treated with 250 mg of ethion- significant problem when daily ethionamide is used with daily amide, although 5 of 12 patients receiving this regimen still rifampin for treatment of pulmonary tuberculosis, drug intol- harbored some viable M. leprae. At 24 weeks, none of the erance and symptomatic hepatotoxicity due to thioamide patients treated with 250 mg of prothionamide or 500 mg of therapy were not observed in this study. This may be due to prothinamide harbored viable M. leprae. At 24 weeks the the monotherapy used herein and the relatively short dura- fraction of patients harboring viable M. leprae was signifi- tion of treatment used in this study. cantly less (P < 0.05) for the two prothionamide treatment In a previous studies in M. leprae-infected mice,5,13 groups compared with those treated with 250 mg of ethion- ethionamide and prothionamide showed similar activity, with amide 250 mg, but not 500 mg of ethionamide. minimal effective doses in mouse diets of 0.01% and minimal When the total percentage of biopsies harboring viable M. inhibitory serum concentrations of 0.05 ␮g/mL.5 Although a leprae was compared for 8–24 weeks and 16–24 weeks, the minimal dietary concentration of ethionamide of 0.02% was two prothionamide treatment regimens resulted in a signifi- observed in mice,7 higher concentrations (0.05–0.3%) were cantly reduced fraction (P < 0.0001%) of biopsies with viable consistently more bacteriocidal. In the treatment of tubercu- bacilli compared with the two ethionamide treatment regi- losis, prothionamide has advantages over ethionamide be- mens. Although biopsies obtained from the prothionamide- cause it is slightly superior30 in its activity against M. tuber- treated patients between 8 and 24 weeks had viable bacilli culosis and is generally better tolerated.31 present in 14 of 69 instances, those treated with ethionamide In the current study, both ethionamide and prothionamide had viable M. leprae in 41 of 71 instances. Similarly at 16–24 resulted in significant killing of M. leprae. Both 250 mg and weeks, prothionamide resulted in the detection of viable ba- 500 mg of prothionamide were superior to equivalent doses of cilli in 2 of 45 biopsies, while ethionamide-treated patients ethionamide. For both ethionamide and prothionamide, a harbored viable bacilli in 19 of 46 biopsies obtained over the 500-mg dose resulted in greater killing of M. leprae then did same period. Between 8 and 24 weeks, significantly fewer 250 mg, and killing of M. leprae with 250 mg of prothionamide viable M. leprae (P < 0.0001) were obtained in biopsies from was indistinguishable from killing with 500 mg of ethion- those treated with 500 mg of prothionamide (3 of 33) than amide. However, the rate of loss of M. leprae viability ob- those treated with 500 mg of ethionamide (17 of 35). Over this tained with these thioamides was similar to that obtained with same period 500 mg prothionamide also resulted in less viable dapsone9 and clofazimine9 and considerably less than that M. leprae (3 of 33) than 250 mg of prothionamide (11 of 36) obtained with the bactericidal agents rifampin7,10,11 (days to CLINICAL TRIAL OF ETHINOAMIDE AND PROTHIONAMIDE 461 weeks), minocycline,23–25 clarithromycin,26,27 and fluoroqui- 7. Gelber RH, 1987. The killing of Mycobacterium leprae in mice by nolones28,29 (weeks to a few months). various dietary concentrations of clofazimine and ethionamide. In conclusion, ethionamide and prothionamide appeared to Lep Rev 58: 407–411. 8. Rees RJW, Pearson JMH, Waters MFR, 1974. Experimental and be well tolerated and without significant gastrointestinal or clinical studies on rifampin in treatment of leprosy. BMJ 1: hepatic toxicity. The perceived drawbacks of thioamide in 89–92. treatment of leprosy have been gastrointestinal intolerance, 9. Shepard CC, 1981. A brief review of experiences with short-term which we did not observe to an appreciable extent, and hepa- clinical trials monitored by mouse-footpad inoculation. Lepr Rev 52: 299–308. toxicity when combined daily with rifampin. However, in our 10. Shepard CC, Levy L, Fasal P, 1972. Rapid bactericidal effect of study, hepatoxicity caused by ethionamide and prothiona- rifampicin on M. leprae. Am J Trop Med Hyg 21: 446–449. mide was minimal. Since the WHO is recommending rifampin 11. Shepard CC, Levy L, Fasal P, 1974. Further experience with the for treatment of leprosy only once a month, this toxicity in rapid bactericidal effect of rifampin on Mycobacterium leprae. that setting may not be a significant problem. Both ethion- Am J Trop Med Hyg. 23: 1120–1130. 12. Shepard CC, 1969. Further experience with the kinetic method amide and prothionamide in this present study showed de- for the study of drugs against Mycobacterium leprae in mice. monstrable, although not superior, killing of M. leprae. Con- Activities of DDS, DFD, ethionamide, capreomycin and PAM versely, ethambutol, a bacteriostatic agent, is used for treat- 1392. Int J Lepr 37: 389–397. ment of infection with M. tuberculosis principally to guard 13. Pattyn SR, 1978. Further data on the effect of ethionamide and against emergent isoniazid and rifampin resistance. Similarly prothionamide in experimental leprosy. Lep Rev 49: 199–202. 14. Rollier R, Rollier M, 1972. 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