RESUMO
Cynomolgus monkeys are a useful model for human tuberculosis, but susceptibility to M. leprae is unknown. A cynomolgus model of leprosy could increase understanding of pathogenesis-importantly, neuritis and nerve-damaging reactions. We administered viable Mycobacterium leprae to 24 cynomolgus monkeys by three routes, with a median follow-up period of 6 years (range = 1-19 years) involving biopsies, nasal smears, antiphenolic glycolipid-1 (PGL-1) antibody serology, and lepromin skin testing. Most developed evanescent papules at intradermal M. leprae inoculation sites that, on biopsy, showed a robust cellular immune response akin to a lepromin skin test reaction; many produced PGL-1 antibodies. At necropsy, four monkeys, without cutaneous or gross neurological signs of leprosy but with elevated PGL-1 antibodies, including three with nasal smears (+) for acid fast bacilli (AFB), showed histological features, including AFB, suggestive of leprosy at several sites. Overall, however, cynomolgus monkeys seem minimally susceptible to leprosy after experimental M. leprae administration.
Assuntos
Hanseníase/imunologia , Macaca fascicularis , Doenças dos Macacos/microbiologia , Mycobacterium leprae/imunologia , Animais , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/imunologia , Biópsia/veterinária , Modelos Animais de Doenças , Feminino , Glicolipídeos/imunologia , Histocitoquímica/veterinária , Antígeno de Mitsuda , Hanseníase/microbiologia , Masculino , Doenças dos Macacos/imunologiaRESUMO
INTRODUCTION: Previously we reported a 2-month clinical trial of moxifloxacin therapy in eight patients with MB leprosy (7 LL and 1 BL), finding both rapid killing of M. leprae and clinical improvement, without serious side effects or toxicities. Here we report the outcomes in two patients treated with moxifloxacin. DESIGN: Two previously untreated LL patients were treated with a single 400 mg dose of moxifloxacin, no therapy for 7 days and then daily 400 mg moxifloxacin for 48 days. Clinical response, viability of M. leprae in the skin, and side effects/toxicities were carefully monitored. RESULTS: In both patients a single dose of moxifloxacin resulted in significant killing of M. leprae (P < 0.001%). In both patients no viable M. leprae were found after 15 doses of moxifloxacin. Improvement in skin lesions occurred again remarkably rapidly and no untoward effects were noted. CONCLUSION: Loss of viable M. leprae was quite rapid, similar to that found previously only for rifampicin, patients improved rapidly, and moxifloxacin was well tolerated.
Assuntos
Compostos Aza/uso terapêutico , Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/tratamento farmacológico , Viabilidade Microbiana/efeitos dos fármacos , Mycobacterium leprae/efeitos dos fármacos , Quinolinas/uso terapêutico , Adulto , Compostos Aza/administração & dosagem , Fluoroquinolonas , Humanos , Hansenostáticos/administração & dosagem , Hanseníase Virchowiana/microbiologia , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Mycobacterium leprae/isolamento & purificação , Quinolinas/administração & dosagem , Pele/microbiologia , Pele/patologia , Resultado do TratamentoRESUMO
As a participant in a multicenter trial, we evaluated the relapse rate in 189 multibacillary (MB) leprosy patients treated with four different regimens and followed-up for as many as 12 years after the initiation of treatment. Treatment regimens included 1 year of WHO MDT (a regimen including dapsone, clofazimine, and rifampin), 2 years of WHO MDT, 1 month of daily rifampin and daily ofloxacin, and 1 year of WHO MDT plus an initial 1 month of daily rifampin and daily ofloxacin. Relapse rates after 9 and 12 years from the initiation of therapy in the three regimens that included WHO MDT were 0-3%, whereas relapses occurred in those treated with the 1-month regimen alone at a significantly greater rate (P < 0.05): 11% at 9 years and 25% at 12 years. Relapses occurred late, beginning at 5 years after the initiation of therapy, and were confined to those patients histopathologically borderline lepromatous and polar lepromatous having a high bacterial burden. Prospects for an alternative effective short-course therapy of leprosy are presented.
Assuntos
Hansenostáticos/administração & dosagem , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Adolescente , Adulto , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Tempo , Adulto JovemRESUMO
In a clinical trial of moxifloxacin in eight multibacillary leprosy patients, moxifloxacin proved highly effective. In all trial patients, a single 400-mg dose of moxifloxacin resulted in significant killing (P Assuntos
Antibacterianos/uso terapêutico
, Compostos Aza/uso terapêutico
, Hanseníase/tratamento farmacológico
, Mycobacterium leprae/efeitos dos fármacos
, Quinolinas/uso terapêutico
, Adulto
, Animais
, Antibacterianos/administração & dosagem
, Antibacterianos/farmacologia
, Compostos Aza/administração & dosagem
, Compostos Aza/farmacologia
, Fluoroquinolonas
, Pé/microbiologia
, Humanos
, Hanseníase/microbiologia
, Hanseníase/patologia
, Masculino
, Camundongos
, Pessoa de Meia-Idade
, Moxifloxacina
, Mycobacterium leprae/crescimento & desenvolvimento
, Mycobacterium leprae/patogenicidade
, Quinolinas/administração & dosagem
, Quinolinas/farmacologia
, Pele/microbiologia
, Pele/patologia
, Resultado do Tratamento
RESUMO
The World Health Organization advocates 2 leprosy treatment regimens on the basis of disease classification (as multibacillary or paucibacillary) by skin lesion count. This method, which, in the Philippines, results in a high prevalence (78%) of patients with multibacillary leprosy, was directly compared with classification using standard histopathological and microbiological criteria in 264 currently untreated patients with leprosy. Of those whose leprosy was classified as paucibacillary, 38%-51% of patients had multibacillary leprosy according to classic criteria and were thus at risk of undertreatment according to World Health Organization recommendations.
Assuntos
Hanseníase/classificação , Pele/patologia , Classificação/métodos , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/tratamento farmacológico , Hanseníase/patologia , Organização Mundial da SaúdeRESUMO
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.
Assuntos
Etionamida/uso terapêutico , Hansenostáticos/uso terapêutico , Hanseníase Virchowiana/tratamento farmacológico , Mycobacterium leprae/crescimento & desenvolvimento , Protionamida/uso terapêutico , Adolescente , Adulto , Animais , Biópsia , Criança , Relação Dose-Resposta a Droga , Etionamida/efeitos adversos , Feminino , Humanos , Hansenostáticos/efeitos adversos , Masculino , Camundongos , Pessoa de Meia-Idade , Protionamida/efeitos adversosRESUMO
In a randomized, double-blind, double-dummy controlled study, 22 men with erythema nodosum leprosum (ENL) received six capsules containing either 100 mg (group A, n = 12) or 300 mg (group B, n = 10) of thalidomide daily for one week. A six-week, four capsules per day taper followed, in which group A received 50 mg/day of thalidomide in weeks 2 and 3, then dummy capsules in weeks 4 through 7, while group B had gradual decrements every two weeks. Both regimens caused comparable improvement in 19 patients at day 7 (group A [12 of 12] versus group B [7 of 10]; P = 0.08), but slower tapering in group B showed less re-emergence of ENL through week 7 (P = 0.02, versus group A). Most patients developed new lesions soon after stopping treatment. Slower tapering from a higher initial thalidomide dose may improve clinical ENL responses, but high recurrence rates after discontinuation indicates further assessment is needed to identify better tapering regimens.
Assuntos
Eritema Nodoso/tratamento farmacológico , Hansenostáticos/administração & dosagem , Hanseníase Virchowiana/tratamento farmacológico , Talidomida/administração & dosagem , Adolescente , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Interleucina-6/sangue , Hansenostáticos/efeitos adversos , Linfócitos , Masculino , Pessoa de Meia-Idade , Neopterina/urina , Talidomida/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Monthly doses of rifampin, ofloxacin, and minocycline (ROM) are expected to be effective treatment for multi-bacillary leprosy. Patients with MB leprosy received ROM (n = 10) or World Health Organization multi-drug therapy (MDT) (n = 11). Treatment with ROM was given as 24 consecutive monthly observed doses of rifampin (600 mg), ofloxacin (400 mg), and minocycline (100 mg). Treatment with MDT was given as 24 consecutive monthly observed doses of rifampin (600 mg) and clofazimine (300 mg), and unobserved daily dapsone (100 mg) and clofazimine (50 mg). Twenty patients completed the 24-month regimens with > 99% compliance. Treatments with ROM and MDT were safe, tolerable, and caused similar improvements in lesions, bacterial indices, and histology. All MDT recipients developed clofazimine-induced pigmentation. Six ROM and nine MDT recipients assessed at five or more years after completion of treatment had no evidence of relapse. Twenty-four months of treatment with ROM is a safe, well-tolerated, and convenient regimen that may provide an alternate therapy to MDT for MB leprosy. Larger trials with sufficient follow-up would better define the role of ROM.
Assuntos
Hansenostáticos/administração & dosagem , Hanseníase/tratamento farmacológico , Minociclina/administração & dosagem , Ofloxacino/administração & dosagem , Rifampina/administração & dosagem , Adolescente , Adulto , Clofazimina/administração & dosagem , Dapsona/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
A 2-month clinical trial of pefloxacin and ofloxacin in previously untreated multibacillary patients was conducted at the Leonard Wood Memorial Leprosy Research Center, Cebu, the Philippines. Treatment with either pefloxacin or ofloxacin resulted in rapid clinical improvement, in this regard pefloxacin appearing somewhat superior. Reactions and side effects were minimal. Single doses of either agent did not result in significant killing of Mycobacterium leprae, but significant bactericidal activity was observed for all fluoroquinolone-treated patients by one week of daily therapy (n = 21), and either agent independently by 3 weeks of daily therapy. At the completion of therapy only two of 10 pefloxacin-treated patients and 0 of 11 ofloxacin-treated patients harboured any detectable viable M. leprae from active lesions, confirming previous work that these fluoroquinolones exhibit bactericidal activity in leprosy patients and more than that found previously for dapsone and clofazimine.
Assuntos
Hanseníase Virchowiana/tratamento farmacológico , Mycobacterium leprae/efeitos dos fármacos , Ofloxacino/administração & dosagem , Pefloxacina/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hanseníase Virchowiana/diagnóstico , Masculino , Filipinas , Probabilidade , Estudos Prospectivos , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Twelve patients were treated with three dose levels of minocycline for 30 days, primarily to detect the dose-related effects on Mycobacterium leprae viability, followed by another 5 months of daily minocycline for overall efficacy and persistence of clinical and antibacterial effects. Subsequently, the patients were given standard WHO/MDT chemotherapy for multibacillary leprosy. Clinical improvement was recognizable during the first month, occurring much earlier among those on minocycline 200 mg daily than those who received minocycline 100 mg daily. A similar change also was observed in one patient 11 days after three daily doses of 100 mg of minocycline. At the end of 6 months, all patients were clinically improved with a slight reduction in the average bacterial index (BI) and logarithmic index of bacilli in biopsy (LIB). The effects of minocycline on viability by mouse foot pad inoculation and palmitic acid oxidation assays were noted beginning at 10 to 14 days of daily dosing and becoming more definite after 30 days of treatment. Both tests correlated fairly well. Doses of 200 mg daily did not appear to be more efficient than minocycline 100 daily. Phenolic glycolipid-I (PGL-I) antigen determinations done on some patients during the first month remained positive and did not correlate with changes in viability results. At the end of 6 months, after 5 months of 100 mg of minocycline monotherapy, no viable organisms could be demonstrated by mouse foot pad inoculation and palmitic acid oxidation assays; assays for PGL-I antigen were all negative