Dapsone-Induced Hemolytic Anemia

Abstract

Dapsone, an old drug introduced and used almost exclusively for the treatment of leprosy, is now utilized in an increasing number of therapeutic situations. However, its hemotoxicity is potentially severe and is often dose limiting. Effective countermeasures, based on resolution of the mechanisms underlying dapsone-induced hemotoxicity, could significantly enhance the therapeutic value of the drug. In studies on rat red cells, we have established that the N-hydroxy metabolites of dapsone, DDS-NOH and MADDS-NOH, are direct-acting hemolytic agents, that they are formed in amounts sufficient to account for the hemotoxicity of the parent drug, and that the action of these toxic metabolites in the red cell induces premature sequestration by the spleen. Incubation of rat red cells with hemolytic concentrations of arylhydroxylamines leads to the generation of hydroxyl, glutathiyl, and hemoglobinthiyl radicals, and the formation of protein-glutathione mixed disulfides. Disulfide-linked adducts are also formed between membrane skeletal proteins and hemoglobin monomers, as well as between the monomeric hemoglobin units forming dimers, trimers, tetramers, and pentamers. Profound morphological changes are seen with change from normal discoidocity to an extreme nonspherocytic enchinocyte shape. Parallel studies with human red cells indicate that the response of human cells is qualitatively similar but that there are notable differences in regard to skeletal membrane effects. A working hypothesis for the mechanism underlying dapsone hemolytic activity is proposed.

Complications Related to Dapsone Use for Pneumocystis Jirovecii Pneumonia Prophylaxis in Solid Organ Transplant Recipients

“…Dapsone, a synthetic sulfone that inhibits folate synthesis, was first used in the late 1940s after its discovery as a potent anti-leprosy agent (1,2). In the 1980s, it was shown to be effective prophylaxis against Pneumocystis jirovecii (PCP) infections in patients infected with Human Immunodeficiency Virus (HIV) (3).…”

Protective role of vitamin E on the oxidative stress in Hansen's disease (Leprosy) patients

“…These free radical scavengers (antioxidants) are compartmentalized in cytoplasm and subcellular organelles guard the cells and biomolecules against the injurious effect of ROS (Yu, 1994). Besides the deleterious effects of ROS, the drugs used in MDT during the mode of action also generate ROS and favor the accumulation of intraneural ceroid pigments, lipofuscin pigments under the skin, induce hemolysis of red blood cells and damage DNA in single cells (McDougall & Jones, 1981;Job et al, 1990;Jallow et al, 1995;Kalaiselvi et al, 2002). Recent evidences reveal the role of ROS in causing T cell hypo-responsiveness, defective T-cell signaling pathway and apoptosis in leprosy (Cemerski et al, 2002;Walsh et al, 2004).…”

Participation of metabolic activation of 2,4,6-trinitrotoluene to 4-hydroxylamino-2,6-dinitrotoluene in hematotoxicity

“…We also found that HADNT causes oxidation of globin sulfhydryls and heme release; as a consequence, aggregation of Hb and hemolysis appears to occur. We speculate that TNTinduced decrease in the Ht value is due to an increased removal of the damaged erythrocytes caused by HADNT in the spleen because Jollow et al (1995) reported that the N-hydroxy metabolites of dapsone induce the premature sequestration of the damaged cells by the spleen.…”