RESUMO
This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.518±0.029 µg/mL) and paucibacillary (0.662±0.123 µg/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDT-supervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software.
Assuntos
Clofazimina/uso terapêutico , Dapsona/uso terapêutico , Hanseníase/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Rifampina/uso terapêutico , Adulto , Análise de Variância , Catalase/sangue , Citocromo P-450 CYP2C19/metabolismo , Dapsona/sangue , Dapsona/metabolismo , Quimioterapia Combinada , Feminino , Glutationa/sangue , Corpos de Heinz/efeitos dos fármacos , Corpos de Heinz/metabolismo , Humanos , Hansenostáticos/uso terapêutico , Hanseníase/sangue , Masculino , Metemoglobina/metabolismo , Pessoa de Meia-Idade , Oxirredução , Ligação Proteica , Espécies Reativas de Oxigênio/sangue , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The physiological changes in obese subjects can modify the pharmacokinetic profiles of drugs influencing the therapeutic efficacy. METHODS: In this study, the authors compare plasma dapsone trough levels of multibacillary leprosy subjects stratified by body mass index (BMI) to evaluate if obesity plays a significant role on drug levels. The relationship between drug levels and BMI was also determined. Dapsone was measured by high-performance liquid chromatography and BMI based on World Health Organization criteria. RESULTS: At steady state, the median plasma dapsone trough level was significantly lower in obesity class 2 group, when compared with other groups, but they were similar between normal weight and preobesity groups. A weak association between drug levels and BMI was observed. CONCLUSIONS: Obesity promotes a significant reduction in plasma dapsone trough levels of subjects with multibacillary leprosy with a weak association between drug levels and BMI.
Assuntos
Índice de Massa Corporal , Dapsona/sangue , Dapsona/farmacocinética , Hansenostáticos/sangue , Hansenostáticos/farmacocinética , Hanseníase Multibacilar/sangue , Adulto , Cromatografia Líquida de Alta Pressão , Humanos , Hanseníase Multibacilar/complicações , Hanseníase Multibacilar/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicaçõesRESUMO
Dapsone has shown anti-convulsive properties in animal models of epilepsy. In the present study, we tested the safety and tolerability of dapsone as adjunctive therapy in adult patients with drug-resistant partial-onset seizures. Twenty-two adult patients with drug-resistant partial-onset seizures were included. After a 3-month baseline period, patients received dapsone 100 mg per day, for a 3-month evaluation period. Plasma concentrations of anti-epileptic drugs (AEDs) did not significantly change during the study. No alteration of mean clinical laboratory values was observed. The reported adverse events were: mild methemoglobinemia (50%), headache (31.8%), paleness (27.3%) and somnolence (4.5%).Sixteen of 22 patients reduced their seizure frequency in more than 50% as a result of dapsone treatment. Three subjects remained seizure-free during the entire dapsone treatment period. This open-label study of adjunctive dapsone therapy at 100 mg/day suggests that dapsone is safe, and well-tolerated in adults with drug-resistant partial-onset seizures.
Assuntos
Anticonvulsivantes/uso terapêutico , Dapsona/uso terapêutico , Epilepsias Parciais/tratamento farmacológico , Hansenostáticos/uso terapêutico , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/sangue , Dapsona/sangue , Interações Medicamentosas , Eletrocardiografia , Epilepsias Parciais/induzido quimicamente , Feminino , Seguimentos , Humanos , Hansenostáticos/sangue , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
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%, and in female was 2.84 ± 1.67%. 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.
Assuntos
Dapsona/sangue , Hansenostáticos/administração & dosagem , Hanseníase Multibacilar/tratamento farmacológico , Metemoglobinemia/diagnóstico , Adolescente , Adulto , Cromatografia Líquida de Alta Pressão , Clofazimina/administração & dosagem , Dapsona/administração & dosagem , Dapsona/efeitos adversos , Feminino , Humanos , Hansenostáticos/efeitos adversos , Hanseníase Multibacilar/sangue , Masculino , Metemoglobinemia/induzido quimicamente , Rifampina/administração & dosagem , Espectrofotometria , Adulto JovemRESUMO
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.
Assuntos
Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Dapsona/sangue , Hansenostáticos/administração & dosagem , Hanseníase Multibacilar/tratamento farmacológico , Metemoglobinemia/diagnóstico , Cromatografia Líquida de Alta Pressão , Clofazimina/administração & dosagem , Dapsona/administração & dosagem , Dapsona/efeitos adversos , Hansenostáticos/efeitos adversos , Hanseníase Multibacilar/sangue , Metemoglobinemia/induzido quimicamente , Rifampina/administração & dosagem , Espectrofotometria , Adulto JovemRESUMO
Dapsone (DDS) (4,4'diaminodiphenylsulfone), the drug of choice for the treatment of leprosy, frequently induces haemolytic anaemia and methaemoglobinaemia. N-hydroxylation, one of the major pathways of biotransformation, has been constantly related to the methaemoglobinaemia observed with the use of the drug. In order to determine the reversible inhibition of this toxicologic bioactivation pathway without changing the detoxification pathways of the drug or cytosolic acetylation, cimetidine (CIM), ranitidine and famotidine were administered in combination with DDS to male Wistar rats weighing 200-220 g. The animals were divided into nine groups of eight: group 1 received a single dose of 40 mg kg (-1) DDS in dimethylsulfoxide (DMSO) and groups 2-4 received the same treatment as group 1 but after the administration of a single dose of 100, 150 and 200 mg kg (-1) CIM, respectively, injected 2 h prior DDS administration. Groups 5-9 received the same treatment as group 2 but after the treatment of ranitidine (50 and 100 mg kg (-1) intraperitoneally (i.p.) in 200 microl DMSO) and famotidine (10, 50 and 100 mg kg (-1) i.p. in 200 microl DMSO), respectively. The animals were then anaesthetized with ether and blood was collected from the aorta for the determination of plasma DDS and monoacetyldapsone concentrations by HPLC and later for the determination of methaemoglobinaemia by spectrophotometry. CIM showed a higher affinity for cytochrome P-450 than famotidine and ranitidine. The results obtained showed the potentiality of the pharmacological effects of DDS with a low risk of adverse reactions, especially methaemoglobinaemia, which is dose dependent.
Assuntos
Dapsona/análogos & derivados , Dapsona/antagonistas & inibidores , Dapsona/toxicidade , Antagonistas dos Receptores H2 da Histamina/farmacologia , Hansenostáticos/antagonistas & inibidores , Hansenostáticos/toxicidade , Metemoglobinemia/induzido quimicamente , Metemoglobinemia/prevenção & controle , Animais , Biotransformação , Dapsona/sangue , Relação Dose-Resposta a Droga , Interações Medicamentosas , Famotidina/farmacologia , Masculino , Ranitidina/farmacologia , Ratos , Ratos WistarRESUMO
An original, simple, specific, and rapid high-performance liquid chromatography assay for the determination of dapsone and monoacetyldapsone in human plasma is presented. The procedure consists of extracting the drugs and the internal standard (phenacetin) from 1 mL plasma with ethyl ether at alkaline pH. A liquid chromatograph equipped with a reversed-phase 5-microm C8 analytical column was used. The drugs were eluted with a mixture of water and methanol (70:30, v/v). Flow rate and wavelength were set at 1 mL/min and 286 nm, respectively. The precision, linearity, and limit of quantitation of the method were within acceptable limits. The method was considered adequate and has been used for the determination of the acetylator phenotype in population studies.
Assuntos
Anti-Infecciosos/sangue , Dapsona/análogos & derivados , Dapsona/sangue , Acetilação , Calibragem , Cromatografia Líquida de Alta Pressão , Éter/química , Humanos , Concentração de Íons de Hidrogênio , Fenacetina/sangue , Fenótipo , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Fatores de TempoAssuntos
Controle de Qualidade , Cromatografia Líquida de Alta Pressão/estatística & dados numéricos , Cromatografia Líquida de Alta Pressão/métodos , Dapsona/análise , Dapsona/farmacocinética , Dapsona/sangue , Eletroquímica , Espectrofotometria Ultravioleta , Hanseníase/sangue , Hanseníase/tratamento farmacológico , Malária Falciparum/prevenção & controle , Saliva/químicaRESUMO
We studied dapsone pharmacokinetics in eight children with compromised immune function who were receiving three different preparations. Peak serum concentration was less than 0.25 microgram/ml after doses of an extemporaneous liquid preparation but ranged from 0.72 to 1.33 micrograms/ml after initial tablet or proprietary liquid doses and 1.48 to 2.48 microgram/ml during long-term proprietary liquid administration. Elimination followed first-order kinetics; the mean elimination half-life was 15.1 hours.