Clinical trial for uniform multidrug therapy for leprosy patients in Brazil (U-MDT/CT-BR): adverse effects approach

Abstract: BACKGROUND: The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR), designed to evaluate the effectiveness of a six-months regimen, assessed the adverse effects caused by the drugs. OBJECTIVE: Describe adverse effects due to MDT in U-MDT/CT-BR, comparing the uniform regimen (U-MDT) to the current WHO regimen (R-MDT). Patients and methods: After operational classification, patients were randomly allocated to the study groups. U-MDT PB and U-MDT MB groups, received the U-MDT regimen, six doses of MB-MDT (rifampicin, dapsone and clofazimine). R-MDT PB and R-MDT MB groups, received the WHO regimens: six doses (rifampicin and dapsone) for PB and 12 doses (rifampicin, dapsone and clofazimine) for MB. During treatment, patients returned monthly for clinical and laboratorial evaluation. Patients with single lesion were not included in this trial. RESULTS: Skin pigmentation (21.7%) and xerosis (16.9%) were the most frequent complaints among 753 patients. Laboratory exams showed hemoglobin concentration lower than 10g/dL in 23.3% of the patients, glutamic oxaloacetic transaminase (GOT) above 40U/L in 29.5% and glutamic pyruvic transaminase (GPT) above 40U/L in 28.5%. Twenty-four patients (3.2%) stopped dapsone intake due to adverse effects, of whom 16.6% due to severe anemia. One case of sulfone syndrome was reported. STUDY LIMITATIONS: Loss of some monthly laboratory sample collection. CONCLUSIONS: There was no statistical difference regarding adverse effects in the R-MDT and U-MDT groups but anemia was greater in patients from R-MDT/MB group, therefore adverse effects do not represent a constraint to recommend the six-month uniform regimen of treatment for all leprosy patients.

Adverse effects of alternative therapy (minocycline, ofloxacin, and clofazimine) in multibacillary leprosy patients in a recognized health care unit in Manaus, Amazonas, Brazil / Efeitos adversos das drogas (minociclina, ofloxacina e clofazimina) utilizadas no esquema alternativo para pacientes com hanseníase multibacilar, em unidade de referência, Manaus, Amazonas, Brasil

BACKGROUND: After the introduction of the multidrug therapy, there was a decline in the coefficients of prevalence and detection of new cases of leprosy. However, the records of drug resistance and relapses are threatening factors in leprosy control. Hence, new alternative schemes and monitoring of adverse effects to avoid treatment abandonment are important considerations. OBJECTIVE: Describe the side effects of a multidrug regimen containing minocycline, ofloxacin, and clofazimine in multibacillary leprosy patients. METHODS: We conducted a prospective, descriptive, and observational study with multibacillary patients, including cases of intolerance to standard MDT and relapses. The study was carried out at Fundação Alfredo da Matta (Alfredo da Matta Foundation), in Manaus, Amazonas, from April 2010 to January 2012. The patients received alternative therapy, which consisted of daily self-administered doses of 100mg of minocycline, 400 mg of ofloxacin, and 50mg of clofazimine and a supervised monthly dose of 300mg of clofazimine for six months, followed by eighteen months of daily doses of ofloxacin 400mg, clofazimine 50mg, and a supervised monthly dose of clofazimine 300mg. Results: Twenty-one cases were included. Mild and transitory side effects occurred in 33.3% of patients. Of the total episodes, 45.9% were attributed to ofloxacin and they included abdominal pain, nausea, vomiting, headache, and insomnia; 21.6% were due to clofazimine, with 100% of patients presenting skin pigmentation. The mean time for the development of adverse effects after beginning the therapy was 15.2 days. CONCLUSION: All patients tolerated the drugs well, and compliance was satisfactory, with no serious events. Unlike other standard MDT studies ...

FUNDAMENTOS: Após introdução do esquema poliquimioterápico padrão, houve declínio nos coeficientes de prevalência e detecção de casos novos; entretanto, os registros de resistência medicamentosa e recidivas representam ameaça para o controle da hanseníase. Dessa forma, a proposição de novos esquemas alternativos e a necessidade de monitorar efeitos adversos são importantes para evitar o abandono do tratamento. OBJETIVO: Descrever efeitos adversos do esquema alternativo contendo clofazimina, ofloxacina e minociclina em pacientes com hanseníase multibacilar. MÉTODOS: Estudo prospectivo, descritivo e observacional de casos multibacilares, incluindo recidivas ou intolerância à poliquimioterapia padrão, realizado na Fundação Alfredo da Matta, Manaus, Amazonas, de abril de 2010 a janeiro de 2012. Os indivíduos receberam a terapia composta de doses diárias auto-administradas de 100mg de minociclina, 400mg de ofloxacina e 50mg de clofazimina e mensais supervisionadas de 300mg de clofazimina por seis meses, seguidas de 18 meses de doses diárias de ofloxacina 400mg, clofazimina 50 mg e supervisionadas mensais de clofazimina 300mg. Resultados: 21 pacientes foram incluídos. Efeitos adversos leves e transitórios foram observados em 33,3% dos pacientes; 45,9% foram atribuídos à ofloxacina, como dor abdominal, náuseas, vômitos, cefaléia e insônia; 21,6% foram associados à clofazimina, com relatos e observação em 100% dos pacientes de hiperpigmentação cutânea. O tempo médio de desenvolvimento das reações adversas a partir do início do esquema foi de 15,2 dias. ...

Brazilian clinical trial of uniform multidrug therapy for leprosy patients: the correlation between clinical disease types and adverse effects

This study sought to verify the correlation between leprosy types and the adverse effects of treatment drugs. This quantitative, prospective, nested study was developed at the Dona Libânia Dermatology Centre in Fortaleza, Brazil. Data were collected from November 2007-November 2008. During this period, 818 leprosy patients were diagnosed and began treatment. Forty patients with tuberculoid leprosy (TT) were selected. Twenty patients followed a standard therapy of dapsone and rifampicin and 20 were administered dapsone, rifampicin and clofazimine (U-MDT). Twenty patients with borderline lepromatous (BL) and lepromatous leprosy (LL) were also selected and treated with U-MDT. All of the subjects received six doses. With the exception of haemolytic anaemia, there was a low incidence of adverse effects in all the groups. We did not observe any differences in the incidence of haemolytic anaemia or other side effects across groups of patients with TT, BL or LL treated with U-MDT.

Methemoglobinemia and dapsone levels in patients with leprosy

The objective of this work was to determine the methemoglobinemia and correlate with dapsone levels in multibacillary leprosy patients under leprosy multi-drug therapy. Thirty patients with laboratory and clinical diagnosis of multibacillary leprosy were enrolled. Dapsone was analyzed by high performance liquid chromatography and methemoglobinemia by spectrophotometry. The mean dapsone concentrations in male was 1.42 g/mL and in female was 2.42 g/mL. The mean methemoglobin levels in male was 3.09 µg/mL; 191 percent, and in female was 2.84 ± 1.67 percent. No correlations were seen between dapsone levels and methemoglobin in male and female patients. Our results demonstrated that the dosage of dapsone in leprosy treatment does not promote a significant methemoglobinemia.

Alterações hematológicas, hemostáticas e bioquímicas induzidas pela clofazimina e claritromicina, em doses única e múltiplas, em ratos / Hematological, hemostatic and biochemical alterations induced by clofazimine and clarithromycin, in single and multiple doses, in rats

Claritromicina e clofazimina têm sido utilizadas no tratamento da hanseníase, tuberculose e infecções causadas pelo complexo Mycobacterium avium. Como os dados sobre a toxicidade de esquemas terapêuticos que incluem estes fármacos são escassos, este estudo teve como objetivo determinar os efeitos adversos destas terapias, por meio da avaliação dos parâmetros hematológicos, hemostáticos e bioquímicos. Os fármacos foram administrados em ratos machos Wistar, em monoterapia, em regime de doses única e múltipla. Claritromicina provocou aumento de leucócitos mono e polimorfonucleares. Ambos os fármacos inverteram a proporção entre células mono e polimorfonucleares e provocaram aumento do número de células polimorfonucleares e células em degeneração. Clofazimina e claritromicina prolongaram o tempo de protrombina e claritromicina também prolongou o tempo de tromboplastina parcial ativa. Claritromicina causou aumento de bilirrubinas total e direta e, ambos os fármacos, elevaram os níveis plasmáticos de gama-glutamiltransferase. Portanto, clofazimina e claritromicina induzem alterações hematológicas, hemostáticas e hepáticas.

Clarithromycin and clofazimine have been used to treat leprosy, tuberculosis and infections caused by the Mycobacterium avium complex. Since there is a scarcity of data on the toxicity of therapeutic regimens that include these drugs, this study had the aim of determining the adverse effects of these therapies, through evaluation of hematological, hemostatic and biochemical parameters. The drugs were administered to male Wistar rats, as monotherapy, in regimens of single and multiple doses. Clarithromycin caused increases in the numbers of mononuclear and polymorphonuclear leukocytes. Both of the drugs inverted the proportions between mononuclear and polymorphonuclear cells and increased the numbers of polymorphonuclear cells and degenerating cells. Clofazimine and clarithromycin prolonged the prothrombin time and clarithromycin also prolonged the activated partial thromboplastin time. Clarithromycin caused increases in total and direct bilirubin. Both of the drugs increased the plasma levels of gamma-glutamyltransferase. Therefore, clofazimine and clarithromycin induce hematological, hemostatic and hepatic changes.

Pure neural leprosy: steroids prevent neuropathy progression

Multidrug therapy (MDT), with rifampicin, dapsone, and clofazimine, treats leprosy infection but is insufficient in arresting or preventing the nerve damage that causes impairments and disabilities. This case-series study evaluates the benefits of the combined use of steroids and MDT in preventing nerve damage in patients with pure neural leprosy (PNL). In addition to MDT, 24 patients (88 percent male aged 20-79 years, median=41) received a daily morning dose of 60 mg prednisone (PDN) that was gradually reduced by 10 mg during each of the following 5 months. PNL was clinically diagnosed and confirmed by nerve histopathology or PCR. A low prevalence (8.3 percent) of reaction was observed after release from treatment. However, most of the clinical parameters showed significant improvement; and a reduction of nerve conduction block was observed in 42 percent of the patients. The administration of full-dose PDN improved the clinical and electrophysiological condition of the PNL patients, contributing to the prevention of further neurological damage.

A poliquimioterapia (PQT), com rifampicina, dapsona, e clofazimina, trata a infecção na hanseníase, mas é insuficiente para interromper ou prevenir o comprometimento neurológico que causa as incapacidades e desabilidades, nesta enfermidade. Este estudo de série de casos avalia o benefício do uso combinado de prednisona e PQT na prevenção do dano neurológico em pacientes com a forma neural pura da hanseníase (FNP). Além do PQT, 24 pacientes (88 por cento homens, com idade variando entre 20-79, mediana=41) receberam uma dose diária de 60 mg prednisona que foi reduzida gradualmente na dose de 10 mg durante cada um dos 5 meses subseqüentes. FNP foi diagnosticada clinicamente e confirmada através do estudo histopatológico ou PCR. Baixa prevalência de reação (8,3 por cento) foi observada apenas após o final do tratamento. A maioria dos parâmetros clínicos mostrou melhora significativa e redução do bloqueio de condução foi observada em 42 por cento dos pacientes. A administração de doses altas de prednisona melhora a evolução clínica e eletrofisiológica de pacientes com a FNP de hanseníase, contribuindo na prevenção de novos comprometimentos neurológicos.

Leprosy in a preschool child--a case report.

Leprosy in a preschool child appearing at the age of four years is reported due to its rarity, particularly at a time when we are hoping for its elimination. A 5-year-old female child presented with an erythematous rash over-her right buttock for last one year. Histopathological examination from the patch revealed it to be a case of indeterminate leprosy. The child responded favourably with antileprosy treatment.

Multidrug therapy in leprosy.

Leprosy is an ancient disease, which was treated by local application of chaulmoogra/hydnocarpus oil during prechemotherapeutic era. Since 1940, dapsone was the only chemotherapeutic agent used for treatment of leprosy for about three decades. Prolonged, interrupted and inadequate use of dapsone monotherapy, leads to development of dapsone-resistant cases. Usefulness of clofazimine was known in 1962. Introduction of rifampicin--a powerful bactericidal drug in 1970 has opened the avenues of multidrug therapy to treat leprosy. Multidrug therapy recommended by World Health Organisation came into practice after 1982. The regimen followed now is for duration of 6 months in paucibacillary and for the duration of 12 months in multibacillary cases. It is proven to be safe and effective. Multidrug therapy for leprosy cases is available in the form of blister calender packs and is available free of cost at all government health facilities. Although more new drugs such as ofloxacin, minocyclin, clarithromycin, etc, are known now but they are used as alternative drugs if a component of combination in multidrug therapy becomes contra-indicated. This article brings the details of various drugs used under multidrug therapy, their characteristics, side-effects, regimens and alternative drugs available for treating leprosy.

Dapsone syndrome with acute renal failure during leprosy treatment: case report

Dapsone syndrome is a rare hypersensitivity reaction to dapsone and is characterized by high fever, papular or exfoliative dermatitis, progressing to liver toxicity and generalized lymphadenopathy, resembling a mononucleosis infection. We report a patient who developed acute renal failure, as well as other complications characteristic of dapsone syndrome, during leprosy treatment. Renal involvement had not been previously described as a dapsone syndrome feature.

Chemotherapy of leprosy.

The WHO MDT regimens have proved highly successful in preventing relapse of leprosy cases. It has indirectly lad to marked reduction in prevalence of disabilities. For PB leprosy, rifampicin 600 mg monthly and 100 mg dapsone daily for a total of 6 months therapy is required. For MB leprosy clofazimine 300 mg once monthly, supervised and 50 mg daily self administered is added. For single skin lesion the current WHO recommendation is 600 mg rifampicin + 400 mg ofloxacin + 100 mg minocycline given as a single dose for adults. Dose adjustment for children and clinical information have been discussed in a nutshell. A number of trials are going on, some are yet to be completed which do offer the prospect of perhaps simplifying therapy and improving with shorter duration.

Efeitos adversos da poliquimioterapia em pacientes com hanseníase: um levantamento de cinco anos em um Centro de Saúde da Universidade Federal de Uberlândia / Adverse effects of multidrug therapy in leprosy patients: a five-year survey at a Health Center of the Federal University of Uberlândia

A implementaçäo da poliquimioterapia (PQT/OMS) - composta pelas drogas dapsona, clofazimina e rifampicina - possibilitou a cura da hanseníase, porém näo foram priorizados o manejo dos efeitos adversos pelas equipes de saúde. Objetivando determinar a magnitude dos efeitos adversos da poliquimioterapia para hanseníase e relacioná-los como possível causa de näo adesividade do paciente ao tratamento, revisou-se prontuários de 187 pacientes tratados com PQT, de 1995 a 2000, no Centro de Saúde Escola (CSE) -UFU, com registro de efeitos colaterais em 71 pacientes (37,9 por cento). Dentre os 113 efeitos adversos, 80 (70,7 por cento) relacionaram-se à dapsona, 7 (6,2 por cento) à rifampicina, 26 (20,5 por cento) à clofazimina. Esses efeitos levaram à mudança de esquema terapêutico em 28 (14,9 por cento) dos 187 pacientes ou 39,4 por cento dos 71 com efeitos adversos. Discute-se a importância de considerar os efeitos adversos da PQT na capacitaçäo das equipes de saúde para maior adesäo do paciente ao tratamento, colaborando para eliminar a hanseníase como problema de saúde pública

Efeitos adversos da poliquimioterapia em pacientes com hanseníase: um levantamento de cinco anos em um Centro de Saúde da Universidade Federal de Uberlândia / Adverse effects of multidrug therapy in leprosy patients: a five-year survey at a Health Center of the Federal University of Uberlandia

The introduction of multidrug therapy (WHO/MDT)-composed by the drugs dapsone, clofazimine and rifampicin has enabled the cure of Hansen's disease, however, the adverse effects of these drugs were not given priority by the health team. Aiming to determine MDT's adverse effects' magnitude and relate them to the non-adhesion of patients to the treatment, a study of 187 charts of patients treated with MDT from January of 1995 to May 2000, was carried out at a Health Center of the Federal University of Uberlandia. Side effects were recorded in 71 patients' charts. Among the 113 side effects found, 80 (70.7 per cent) were related to dapsone, 7 (6.2 per cent) were caused by rifampicin and 26 (20.5 per cent) were attributed to clofazimine. These effects induced 28 (14.9 per cent), patients to change the therapeutic scheme, representing 39.4 per cent from the 71 patients with adverse effects. Throughout this study, the importance is discussed of considering MDT's adverse effects when training the health team to heighten the patient's adhesion to the treatment and thereby collaborating to eliminate Hansen's disease as a public health problem.

Hanseníase: poliquimioterapia e monoterapia, Araraquara, Säo Paulo - 1990-1993 / Leprosy polichemotherapy and new therapeutics in Araraquara, Säo Paulo -1990-1993

Com o objetivo de conhecer os resultados da nova terapêutica da hanseníase por poliquimioterapia estudamos sua aplicaçäo em pacientes em Araraquara-SP no período de 1990 a 1993, do Serviço Especial de Saúde de Araraquara. Como o tratamento é de longa duraçäo, somente a partir de 1993 começamos a observar a eficiência dos resultados em relaçäo a monoterapia. Obtivemos alta por cura em 65 por cento para multibacilares e 48,5 por cento para paucibacilares e sem recidiva, enquanto para os pacientes tratados com a terapia anterior, a cura foi de 35,4 por cento. Baseado nestes resultados concluímos que é importante a poliquimioterapia na cura da hanseníase.

Lepra de Lucio en nuestro medio: presentación de un caso y consideraciones / Lucio's leprosy: a case in point

La lepra de Lucio es una rara variedad de lepra lepromatosa caracterizada por carecer de nódulos...

Síndrome de Melkersson-Rosenthal: presentación de tres casos / Melkersson-Rosenthal's syndrome: report of 3 cases

Melkersson-Rosenthal syndrome is characterized by facial or lip edema, peripheral facial palsy and scrotal tongue. We report 3 patients with the syndrome. A 17 years old male had malar and superior lip enlargement that coincided with a peripheral facial palsy. A 40 years old male with recurrent facial palsy presented with episodes of contralateral facial enlargement. A 32 years old female consulted for a hypertrophy of labia minora and majora and facial infiltration. Biopsies showed a granulomatous cheilitis in all cases. Two patients were treated with clofazimine with partial results. The female patient did not accept plastic surgery