ethionamide and Leprosy

Today, the emergence of the phenomenon of drug or multidrug-resistance for community-associated diseases represents a major concern in the world. In these contexts, the chronic infectious disease, leprosy, grounded by a slow-growing bacterium called Mycobacterium leprae or Mycobacterium lepromatosis is a leadingcause of severe disfiguring skin sores and nerve damage in the arms, legs, and skin areas around the body. Even, over 200,000 new leprosy cases are being accounted every year along with the relapsed leprosy cases. Nonetheless, this has been considered a curable disease with a higher dose of multidrug therapy (MDT) for a long period of time. The prolonged action of a high dose of combination drugs administration may cause an adverse reaction that can significantly affect patient compliance, particularly the outbreak of multidrug-resistance in the infected person. To overcome these shortfalls or prevent the resistance-associated problems, researchers are diligently involved in the structural modifications of the clinically used anti-leprosy drugs or the allied compounds for the structure-antimycobacterial activity relationship study. This review article described the detailed synthesis and biological assays of different anti-leprosy compounds reported by several research groups.

Topics: Humans; Leprostatic Agents; Leprosy; Structure-Activity Relationship

Topics: Animals; Clofazimine; Dapsone; Drug Resistance, Microbial; Ethionamide; Humans; Leprosy; Mice; Microbial Sensitivity Tests; Rifampin

Topics: Clofazimine; Dapsone; Ethionamide; Humans; Leprosy; Rifampin; Sulfonamides; Thioacetazone; Thiourea

Topics: Aniline Compounds; Dapsone; Drug Resistance, Microbial; Ethionamide; Humans; Leprosy; Mycobacterium leprae; Phenazines; Rifampin; Sulfonamides; Sulfones; Thioacetazone; Thiosemicarbazones; Thiourea

We compared 2 single-dose regimens for the treatment of paucibacillary leprosy in a randomized clinical trial in Zaïre. The regimens were: C2 (rifampicin 40 mg/kg and 1200 mg clofazimine once) and C4 (rifampicin 40 mg/kg, clofazimine 100 mg, DDS 100 mg and ethionamide 500 mg once). An analysis of the results of patients enrolled between May 1987 and December 1988, with a maximum follow-up of 4 years, is presented. A total of 622 patients were enrolled and 14 paucibacillary and 1 multibacillary relapses occurred. The overall paucibacillary relapse rate was 2.4 per 100 person years. This relapse rate was higher for older patients as well as for patients with 3 or more lesions. The probability of cure at 3 years is 0.816 for C2 and 0.823 for C4, the difference not being statistically significant. The probability of cure at 3 years with either regimen is higher for patients with 1 or 2 lesions (0.872) than for patients with 3 or more lesions (0.787), and it is higher for patients with a bacterial index of 0 (0.831) than for patients with a bacterial index of 1 (0.699). These results are compared to other studies. We also discuss the potential of single-dose treatment regimens for paucibacillary leprosy.

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Clofazimine; Dapsone; Drug Administration Schedule; Drug Therapy, Combination; Ethionamide; Female; Humans; Infant; Leprosy; Male; Middle Aged; Prognosis; Recurrence; Rifampin

In a prospective study 559 multibacillary patients in Zaire were treated for 13 weeks with twice weekly rifampicin (600 mg) and daily ethionamide (500 mg) and dapsone (100 mg), 13-RED, or clofazimine (100 mg), 13-REC. The patients were followed for a total of 1418 person years, mean 3.2 years. The incidence of hepatitis was 3.3%. The incidence of relapses was 0.28 per 100 person years. Relapses were due to drug-sensitive organisms. In patients who received the same drug regimens but with a reduced dosage of ethionamide to 5 mg/k bodyweight, the incidence of hepatitis was significantly lower but the relapse rate was 7.8 per 100 person years of follow-up in the RED group, no relapses were diagnosed in the REC group. It is concluded that by the use of potent antileprosy drugs in suitable combinations and dosages, it will be possible to shorten the duration of antibacterial treatment in multibacillary leprosy to 3 months.

Topics: Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Humans; Leprostatic Agents; Leprosy; Prospective Studies

In 1981, 1982 and 1983, 216 multibacillary patients in Anjouan (Comores) and Burundi were treated for 8 weeks with daily rifampicin (600 mg) ethionamide (500 mg) and dapsone (100 mg) or clofazimine (100 mg) followed for 44 weeks by once weekly rifampicin (600 mg) and daily ethionamide (500 mg) and dapsone (100 mg) or clofazimine (100 mg). There were 109 previously untreated patients and 107 patients who had dapsone monotherapy, 16 of whom were infected with proven dapsone resistant Mycobacterium leprae. Clinical and bacteriological results were excellent but hepatotoxicity of this regimen remains a problem. No relapses were observed during a 2 to 6 years (mean: 4.29 years) follow-up period after the end of treatment (upper 95% confidence limit of 0.40 per 100 persons years). It is concluded that multibacillary leprosy can be successfully treated with a regimen of one year duration, but less toxic regimens, more easily applicable in the field, are necessary.

Topics: Clinical Trials as Topic; Clofazimine; Cohort Studies; Dapsone; Drug Administration Schedule; Ethionamide; Female; Humans; Leprostatic Agents; Leprosy; Male; Rifampin

From 1981 to 1983 all multibacillary patients presenting at the collaborating centres in Zaire and Rwanda were treated with one of the following regimens: 6 months supervised daily RMP 600 mg, ETH 500 mg and DDS 100 mg or CLO 100 mg followed by 6 months unsupervised daily DDS 100 mg or CLO 100 mg with ETH 500 mg added or not. These regimens gave rise to hepatotoxicity, reversal and erythema nodosum leprosum reactions as described previously. Bactericidal activity was excellent. Among the 289 patients in the trial, with a mean follow-up period of 3.88 years, no relapses were observed, with an upper 95% confidence limit of 0.35 per 100 person years. Because of the hepatotoxicity, alternative short-course therapies need to be tested.

Topics: Clinical Trials as Topic; Clofazimine; Cohort Studies; Dapsone; Drug Administration Schedule; Ethionamide; Female; Humans; Leprostatic Agents; Leprosy; Male; Rifampin

Topics: Clinical Trials as Topic; Clofazimine; Dapsone; Drug Administration Schedule; Drug Therapy, Combination; Ethionamide; Humans; Leprosy; Random Allocation; Rifampin

During treatment of multibacillary leprosy with the combination rifampin (RMP) 600 mg, ethionamide (ETH) 500 mg, and either dapsone (DDS) or clofazimine (CLO) 100 mg, hepatotoxicity was observed in 4.5% of 596 patients. Hepatitis appeared after 5-186 days, with a mean of 93 days and a median of 76 days. Mortality was 26%. ETH and DDS or CLO were administered daily in all regimens in which hepatitis occurred. RMP was given either daily or daily during the first two weeks or eight weeks, followed by a once-weekly dose. It is concluded that the combination RMP + ETH is the toxic component. In some patient groups there was a high correlation of toxicity with age. A regimen in which RMP was administered only twice a week during three months was not accompanied by hepatotoxicity. Future studies should show if reduction of the daily dose of ETH or reduction of the duration of the administration of RMP + ETH might reduce the incidence of hepatotoxicity while conserving the efficacy.

Topics: Adolescent; Adult; Chemical and Drug Induced Liver Injury; Child; Clinical Trials as Topic; Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Female; Humans; Leprosy; Male; Middle Aged; Prospective Studies; Rifampin

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target-drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

Topics: Antitubercular Agents; Bacterial Proteins; Crystallography, X-Ray; Drug Design; Drug Resistance, Multiple, Bacterial; Ethionamide; Humans; In Vitro Techniques; Leprostatic Agents; Leprosy; Models, Molecular; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Mycobacterium leprae; Mycobacterium tuberculosis; NAD; Oxidoreductases; Prothionamide; Tuberculosis; Tuberculosis, Multidrug-Resistant

In 1982, following the recommendations of a WHO study group, multidrug therapy (MDT) was introduced into French Polynesia to treat all patients suffering from active leprosy, and--only on request--those still on dapsone monotherapy. After 5 years, a clear-cut decrease of prevalence and mean annual detection rates for leprosy (except for detection rates among children aged less than 15 years, many of such cases being detected early by increased household contact training) has been observed. There was also a decrease in the proportion of newly detected cases with disabilities. During the 21-year period preceding the introduction of MDT into the control programme, mean annual detection rates for leprosy had remained stable, and this led to the consideration that such a decrease was due neither to the natural decline of the disease nor to the economic improvement of the country. Our results, together with the fact that, to date, the relapse rate was nil in the Polynesian patients put on MDT, strongly suggest that the implementation of MDT has resulted in a decrease of detection rates for leprosy which may be a consequence of a decrease in the transmission of the disease.

Topics: Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Humans; Leprosy; Polynesia; Rifampin

An ambulatory treatment regimen for multibacillary leprosy, of 34 weeks duration composed of 8 weeks daily supervised rifampicin, ethionamide (ETH), dapsone (DDS) and clofazimine (CLO) followed by 26 weeks of unsupervised ETH, DDS and CLO, introduced in 1983 has been evaluated; 268 patients were followed for a mean of 4.4 years and a total of 1188 patient years. The relapse rate was 0.33 per 100 patient years of follow up. The reduction of the duration of the combined administration of RMP + ETH reduced the hepatotoxicity to 1.4%. It is possible that both phases of the regimen studied could still be reduced, however, in the near future ETH will be replaced by alternative bactericidal drugs, avoiding the hepatotoxicity.

Topics: Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Humans; Leprostatic Agents; Leprosy

Since the application of short duration multidrug therapy (MDT) in leprosy, it has been reported that reversal reactions (RR) may occur after withdrawal of treatment. Surprisingly, such "late reversal reactions" have quite never been described after monosulphonotherapy. Such RR, especially in endemic areas, may represent diagnostic and therapeutic difficult problems. We report 5 cases of late RR. In 4 cases (1 BT patient and 3 BL-LLs patients), the RR occurred 1 month 1/2 to 3 years after cessation of MDT. In the last case (form LLs), the RR happened 6 months after that a 14 years monosulphonotherapy has been stopped. These observations strengthen the need of a complete clinical, bacteriological and immunological evaluation at the time of the diagnostic, more useful than a single bacteriological study, to differentiate late RR from relapses. Moreover, the last case confirms that late RR may occur after monosulphonotherapy.

Topics: Clofazimine; Dapsone; Drug Combinations; Ethionamide; Female; Humans; Leprosy; Male; Recurrence; Rifampin

Topics: Animals; Clofazimine; Dapsone; Drug Resistance, Microbial; Drug Therapy, Combination; Ethionamide; Humans; Leprosy; Mycobacterium leprae; Prothionamide; Rifampin

Topics: Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Humans; Leprosy; Rifampin

Topics: Administration, Oral; Animals; Clofazimine; Dose-Response Relationship, Drug; Ethionamide; Female; Leprosy; Mice; Mice, Inbred BALB C; Mycobacterium leprae

The acceptance of the WHO regimen in a group of 220 patients was approximately 84.5%. Only 11% abandoned the treatment, and the substitution of ethionamide or prothionamide for clofazimine due to excessive hyperpigmentation was necessary in only eight cases. The WHO regimens adopted provided a more frequent (monthly) relationship between the patients and their health service. It was necessary to: a) reorganize the technical-administrative infrastructure, with the intention of providing an improved service to the patients for treatment and control; and b) pay more attention to the problem of deformities and health education activities. As for the side effects of the drugs, 54 patients showed alterations in their liver function tests, which were usually mild and which resolved despite continuation of the treatment. Of the reactional episodes observed during MDT, it would not appear that the therapeutic regimens contributed to their occurrence or aggravation.

Topics: Adolescent; Adult; Brazil; Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Female; Humans; Leprostatic Agents; Leprosy; Male; Patient Acceptance of Health Care; Patient Compliance; Prednisolone; Prothionamide; Rifampin; Urban Population

Topics: Adolescent; Adult; Aged; Dapsone; Drug Therapy, Combination; Ethionamide; Female; Humans; Isoniazid; Isonicotinic Acids; Leprosy; Male; Middle Aged; Patient Compliance; Prothionamide; Self Administration; Thioacetazone

Melanesian leprosy patients from New Caledonia were studied for the following parameters during the course of polychemotherapy: peripheral blood T-cell subsets, as identified in an immunofluorescence assay with monoclonal antibodies OKT3 ("pan-T"), OKT4 ("helper/inducer"), and OKT8 ("cytotoxic-suppressor"), and anti-Mycobacterium leprae antibodies in the serum, as measured by the fluorescent leprosy antibody absorption test. A group of Melanesian healthy subjects with no known exposure to M. leprae served as controls. Healthy contacts of leprosy patients were also studied for the presence of anti-M. leprae antibodies. Untreated, nonreactional lepromatous patients displayed moderate but significant T-cell abnormalities, consisting of a decrease in the percentage of OKT3+ and OKT4+ cells with a decrease in the OKT4:OKT8 ratio. These abnormalities disappeared within nine months of treatment. A transient decrease in the percentage of OKT8+ cells with an increase in the OKT4:OKT8 ratio was seen in patients suffering erythema nodosum leprosum (ENL). Tuberculoid patients, whether treated or not, did not show any T-cell marker disturbances. Positive serological tests for anti-M. leprae antibodies were found in 100% of lepromatous patients, 92% of tuberculoid patients, and 56% of healthy contacts. No significant decline in the antibody titer was observed with treatment during the survey period.

Topics: Adolescent; Adult; Antibodies, Bacterial; Child; Clofazimine; Dapsone; Drug Therapy, Combination; Erythema Nodosum; Ethionamide; Fluorescent Antibody Technique; Humans; Leprosy; Middle Aged; Mycobacterium leprae; New Caledonia; Rifampin; T-Lymphocytes; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

Sera from 92 patients were tested by the ELISA method for the presence of IgM antibodies to phenolic glycolipid-1 (PGL-1) of Mycobacterium leprae, and of both IgM and IgG antibodies to the whole M. leprae bacillus. All untreated lepromatous patients exhibited high antibody levels in all three assays. A sharp decline of IgM antibodies to PGL-1 and whole M. leprae was observed during the first two years of therapy, while IgG antibodies to whole M. leprae showed a progressive decrease only over a number of years. Low titers of IgM antibodies to PGL-1 and IgG antibodies to whole M. leprae could be detected in about 50% and 75% of patients, respectively, after more than ten years of treatment, with only 15% showing persisting IgM antibodies to the whole bacillus. Antibody levels as measured by the three assays used were correlated with the bacterial index in patients treated for less than four years. In patients treated longer than four years, only IgM antibodies, whether directed to PGL-1 or to whole M. leprae, remained correlated to the bacillary load. Tuberculoid patients exhibited a different antibody pattern, showing a lower frequency (and lower levels) of antibodies of PGL-1 and of IgG antibodies to whole M. leprae than lepromatous patients, and no detectable IgM antibodies to the whole bacillus. IgG antibodies to whole M. leprae were more frequently noted than antibodies to PGL-1, the latter declining more rapidly during therapy.

Topics: Antibodies, Bacterial; Antigens, Bacterial; Clofazimine; Dapsone; Drug Therapy, Combination; Ethionamide; Glycolipids; Humans; Immunoglobulin G; Immunoglobulin M; Leprostatic Agents; Leprosy; Longitudinal Studies; Mycobacterium leprae; Rifampin; Time Factors

A systematic study was performed on the reactions occurring during several short-course therapy regimens for the treatment of paucibacillary and multibacillary patients. Most type 1 upgrading reactions in paucibacillary (PB) leprosy were mild to moderate and of short duration, while the time of onset was extremely variable. Their incidence was higher in the regimen rifampin (RMP) 900 mg once weekly for ten weeks than when a single dose of RMP 40 mg/kg body weight was given or 1500 mg in one dose followed by one year of dapsone (DDS) 100 mg daily. In multibacillary (MB) leprosy, three regimens were compared: MB-WHO regimen; regimen C, consisting of daily RMP 600 mg, ethionamide (ETH) 500 mg, and DDS or clofazimine (CLO) 100 mg for six months, followed by six months of daily DDS or CLO; and regimen D, identical to regimen C but comprising daily DDS or CLO plus ETH 500 mg during the second semester. Type 1 upgrading reactions occurred more frequently in MB patients and were more severe than in PB patients. They occurred more frequently and were more severe in regimens C and D than in the MB-WHO regimen. CLO 100 mg daily prevented type 1 reactions in MB patients and rendered them less severe. ENL was also more frequent in regimens C and D and was not prevented by CLO in the dosage used. Although there is some correlation between type 1 reactions and the total amount of RMP administered, other aspects of RMP administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Child; Clofazimine; Dapsone; Drug Therapy, Combination; Edema; Erythema Nodosum; Ethionamide; Female; Humans; Leprostatic Agents; Leprosy; Male; Neuritis; Prospective Studies; Rifampin

Topics: Clofazimine; Dapsone; Drug Hypersensitivity; Ethionamide; Humans; Leprostatic Agents; Leprosy; Rifampin; Thioacetazone

Topics: Adult; Animals; Clofazimine; Dapsone; Drug Resistance, Microbial; Erythema Nodosum; Ethionamide; Humans; Leprosy; Mycobacterium leprae; Patient Compliance; Prothionamide; Rifampin

Topics: Clofazimine; Dapsone; Drug Packaging; Ethionamide; Humans; Leprostatic Agents; Leprosy; Prothionamide; Rifampin; Tablets

In this study we assess the degree of prolonged bacteriostasis of Mycobacterium leprae after temporary exposure to ehtionamide or thiacetazone, and relate this to their efficacy when administered intermittently to mice with experimental leprosy infections. The results show that temporary exposure of M. leprae to either of these drugs results in a prolonged bacteriostatic effect, but that efficacy is rapidly lost as the interval between doses is increased. Using the mouse foot pad system, growth of M. leprae is not inhibited by thiacetazone when the frequency of administration is less than three times weekly. When ethionamide is administered once weekly, growth of M. leprae is inhibited but bactericidal activity is lost. When ethionamide is administered in combination with continuous dapsone therapy, either continuously or three times weekly, the bactericidal activity of the drug combination is greater than when either drug is administered alone. However, when ethionamide is administered once weekly in combination with continuous dapsone treatment, the bactericidal effect is identical to that when dapsone is given alone: that is, ethionamide makes no contribution to the combination.

Topics: Animals; Dapsone; Drug Administration Schedule; Ethionamide; Female; Leprosy; Mice; Mycobacterium leprae; Thioacetazone

Topics: Acedapsone; Animals; Dapsone; Drug Therapy, Combination; Ethionamide; Humans; Leprostatic Agents; Leprosy; Mice; Prothionamide; Rifampin; Thioacetazone

Topics: Drug Administration Schedule; Ethionamide; Follow-Up Studies; Humans; Leprosy; Rifampin

Topics: Clofazimine; Drug Resistance, Microbial; Ethionamide; Humans; Leprostatic Agents; Leprosy; Prothionamide; Rifampin

Topics: Animals; Drug Therapy, Combination; Ethionamide; Isonicotinic Acids; Leprosy; Mice; Prothionamide

Topics: Animals; Ethionamide; Isonicotinic Acids; Leprosy; Mice; Prothionamide

Topics: Animals; Animals, Laboratory; Antitubercular Agents; Clofazimine; Dapsone; Ethionamide; Humans; In Vitro Techniques; Isoniazid; Leprosy; Mice; Mycobacterium lepraemurium; Rifampin; Sulfonamides; Trimethoprim

Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Ethionamide; Female; Humans; Infant; Infant, Newborn; Isoniazid; Leprosy; Male; Mediterranean Islands; Middle Aged; Public Health; Rifampin; Sulfonamides

Topics: Adolescent; Adult; Age Factors; Aged; Avitaminosis; Child; Ethionamide; Female; Gastrointestinal Diseases; Humans; Leprosy; Liver Cirrhosis, Biliary; Male; Middle Aged; Mycobacterium leprae; Niacinamide; Psychoses, Substance-Induced

Topics: Aniline Compounds; Animals; Dapsone; Disease Models, Animal; Drug Combinations; Ethionamide; Humans; Isoniazid; Leprosy; Mice; Models, Biological; Mycobacterium Infections; Phenazines; Pyrazines; Rabbits; Rifampin; Sulfonamides; Trimethoprim