Diethylcarbamazine (DEC) does not induce nitric oxide (NO) synthesis.
Diethylcarbamazine (DEC) was discovered in 1947 as a potent therapeutic agent in lymphatic filariasis and has been a mainstay of antifilarial therapy over the past five decades (R. I. Hewitt, et al., 1947, Journal of Laboratory and Clinical Medicine 32, 1304-1313). Several hundred million doses of this drug have been administered to people. Despite its widespread and successful use over this prolonged time scale, its mechanism of action remains obscure (R. M. Maizels and D. A. Denham, 1992, Parasitology 105 Suppl. 549-560). Numerous studies suggest that DEC has no direct effect on the parasite (F. Hawking and W. Laurie, 1949, Lancet 2, 146-147) and that it exerts its action by stimulating host immune defense mechanisms (F. Hawking et al., 1948, Lancet 2, 730-731), or by activating host platelets to become microfilaricidal (J. Y. Cesbron et al., 1987, Nature 325(6104) 533-536). Recent data from two different laboratories suggest that NO may be involved in host defense against filarial parasites (T. V. Rajan et al., 1996, Infection and Immunity 64(8), 3351-3353; M. J. Taylor et al., 1996, Parasitology 112, 315-322). We investigated whether DEC stimulates the production of NO from murine macrophages or rat endothelial cells. DEC did not stimulate the synthesis or secretion of NO from either, nor did it synergize with interferon-gamma or tumor necrosis factor-alpha in the induction of inducible NO synthase (iNOS). In addition, there was no consistent increase in the output of inorganic nitrate, the end product of NO metabolism, in the urines of rats treated with DEC. These data suggest that DEC does not achieve its therapeutic efficacy through the induction of host iNOS.
Rajan
T V
TV
Department of Pathology, University of Connecticut Health Center, Farmington 06030-3105, USA.
Shultz
L D
LD
Babu
S
S
Doukas
J
J
Greiner
D
D
Porte
P
P
D000818:Animals; D002478:Cells, Cultured; D004049:Diethylcarbamazine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005369:Filaricides / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011923:Rats, Nude; D013864:Thioglycolates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
D005369:Filaricides; D009566:Nitrates; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D004049:Diethylcarbamazine