Clinical oxidative stress during leprosy multidrug therapy: impact of dapsone oxidation.

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.

Dapsone-associated Heinz body hemolytic anemia in a Cambodian woman with hemoglobin E trait.

A Cambodian woman with hemoglobin E trait (AE) and leprosy developed a Heinz body hemolytic anemia while taking a dose of dapsone (50 mg/day) not usually associated with clinical hemolysis. Her red blood cells (RBCs) had increased incubated Heinz body formation, decreased reduced glutathione (GSH), and decreased GSH stability. The pentose phosphate shunt activity of the dapsone-exposed AE RBCs was increased compared to normal RBCs. Although the AE RBCs from an individual not taking dapsone had increased incubated Heinz body formation, the GSH content and GSH stability were normal. The pentose phosphate shunt activity of the non-dapsone-exposed AE RBCs was decreased compared to normal RBCs. Thus, AE RBCs appear to have an increased sensitivity to oxidant stress both in vitro and in vivo, since dapsone does not cause hemolytic anemia at this dose in hematologically normal individuals. Given the influx of Southeast Asians into the United States, oxidant medications should be used with caution, especially if an infection is present, in individuals of ethnic backgrounds that have an increased prevalence of hemoglobin E.

Vitamin E and dapsone-induced hemolysis.

Sixteen patients, each receiving 100 mg of dapsone per day, were studied for evidence of hemolysis. Vitamin E (dl-alpha tocopherol acetate), 800 mg/day, was then administered for up to three months, and dapsone therapy was continued at the same dose. Hemolysis factors were reexamined immediately prior to cessation of vitamin E therapy. No substantial change was demonstrable for levels of hemoglobin, reticulocyte count, and haptoglobin at the end of vitamin E therapy, despite a significant rise in serum vitamin E levels. Erythrocyte survival measured in four patients before and at the end of vitamin E therapy also showed no substantial change. Erythrocyte Heinz body count, however, fell in nine of 15 patients studied, and none showed an increase in this measurement while receiving vitamin E. We conclude that in patients receiving dapsone at 100 mg/day, vitamin E therapy at 800 mg/day does not substantially ameliorate the hemolytic effect of this drug.

The haemolytic action of dapsone: the effect on red-cell glycolysis

Some aspects of red-cell matabolism were studied in blood samples taken from patients on long-term dapsone therapy. Glucose consumption by the Embden-Meyerhof pathway (EMP) was not abnormal and adenosine-triphosphate (ATP) levels lay within the normal range and were well maintained during incubation. Hexose monophosphate patchway (HMP) activity was increased above that which would be expected from the age of the red-cell population. Red-cell reduced glutathione (GSH) levels tended to be lower than normal, proportional to the dose od dapsone and GSH levels were unstable on incubation. Red-cell fractionation studies showed that the older cell fraction had lower GSH levels and more Heinz bodies but proportionally greater HMP activity than the younger cell fraction. It is suggested that the low GSH levels are probably due to the binding of GSH to sulphydryl groups in haemoglobin and possibly the red-cell membrane. The increased HMP activity in the older cells many, in part, be a compensatory mechanism.