Effects of sulfamethoxazole and trimethoprim on human neutrophil and lymphocyte functions in vitro: in vivo effects of co-trimoxazole

Abstract

Tetrazolium reduction, glycolysis, hexose monophosphate shunt activity, myeloperoxidase-mediated protein iodination, hydrogen peroxide production, and degranulation were assessed. The effects on lymphocyte mitogen-induced transformation were also evaluated. It was found that the test agents individually and in combination at high concentrations (>100 ,ig/ml) caused the inhibition of neutrophil postphagocytic myeloperoxidase-mediated protein iodination, which was related to the interference with H202 formation as the enzyme per se was unaffected. Both agents caused the inhibition of lymphocyte transformation at high concentrations (>100 ug/ml). In vivo studies before and after the ingestion of co-trimoxazole by three individuals showed no inhibition of any of the neutrophil functions tested. The inhibition of lymphocyte transformation was observed in one individual after the ingestion ofthe chemotherapeutic agent. These findings indicate that the concentrations which inhibit neutrophil H202 production and lymphocyte transformation in vitro are not attainable in vivo.Combinations of sulfonamides and trimethoprim (TMP) are now widely used in treating various infections. Conventional therapeutic concentrations are without effect on human folate metabolism (4). On the other hand, combinations of the sulfonamides, sulfadiazine, and sulfamethoxazole (SMX) with TMP may have immunosuppressive effects. Ghilchick et al. (6) have reported that TMP per se had an immunosuppressive effect and a prolonged allograft survival in mice. The inhibition of antibody synthesis in animals after the ingestion of co-trimoxazole, the combined SMX-TMP chemotherapeutic agent, has been reported (2, 3). The depressed uptake of tritiated thymidine by mitogen-stimulated lymphocytes after the ingestion of co-trimoxazole by humans has been reported (5). However, Kobayashi et al. (7) failed to detect any subsequent impairment of leukocyte function in seven children with chronic granulomatous disease receiving prophylactic SMX-TMP (Bactrim; Hoffinann-LaRoche, Inc., Nutley, N.J.).The present study was undertaken to investigate extensively the effects of SMX and TMP individually and in combination (SMX-TMP) on neutrophil motility, phagocytosis, postphagocytic metabolic activity, and lymphocyte mitogen-induced transformation in vitro. In a further series of experiments, neutrophil and lymphocyte functions were evaluated before and after the ingestion of co-trimoxazole by three normal adult volunteers. MATERIALS AND METHODSChemotherapeutic agents. The individual drugs were tested at a final concentration range of 6.25 to 200 ,g/ml. The proportions in the SMX-TMP combination were those used in certain commercial preparations: the ratio of SMX to TMP was 5:1. The concentration ranges were 6.25 to 200 ,ug of SMX per ml and 1.05 to 40 ,g of TMP per ml. The drugs were dissolved in the appropriate suspending medium according to the cell function being assessed.Neutrophil functions: studies of motility. Neutrophils were obtained from heparinized venous blood (...

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Generalized Wegener's Granulomatosis Responding to Sulfamethoxazole-trimethoprim Monotherapy.

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