Rajan T V, Shultz L D, Babu S, Doukas J, Greiner D, Porte P
Department of Pathology, University of Connecticut Health Center, Farmington 06030-3105, USA.
Exp Parasitol. 1998 Mar;88(3):217-22. doi: 10.1006/expr.1998.4247.
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.
1947年发现二乙碳酰嗪（DEC）是治疗淋巴丝虫病的一种有效治疗剂，在过去五十年里一直是抗丝虫治疗的主要药物（R.I.休伊特等人，1947年，《实验室与临床医学杂志》32卷，1304 - 1313页）。已经给数亿人使用过这种药物。尽管在如此长的时间里它得到了广泛且成功的应用，但其作用机制仍不清楚（R.M.梅泽尔斯和D.A.德纳姆，1992年，《寄生虫学》105增刊，549 - 560页）。大量研究表明，DEC对寄生虫没有直接作用（F.霍金和W.劳里，1949年，《柳叶刀》2卷，146 - 147页），它通过刺激宿主免疫防御机制发挥作用（F.霍金等人，1948年，《柳叶刀》2卷，730 - 731页），或者通过激活宿主血小板使其具有杀微丝蚴作用（J.Y.塞斯布龙等人，1987年，《自然》325(6104) 533 - 536页）。来自两个不同实验室的最新数据表明，一氧化氮（NO）可能参与宿主对丝虫寄生虫的防御（T.V.拉詹等人，1996年，《感染与免疫》64(8)卷，3351 - 3353页；M.J.泰勒等人，1996年，《寄生虫学》112卷，315 - 322页）。我们研究了DEC是否刺激小鼠巨噬细胞或大鼠内皮细胞产生NO。DEC既不刺激二者产生或分泌NO，在诱导诱导型一氧化氮合酶（iNOS）方面也不与干扰素 - γ或肿瘤坏死因子 - α协同作用。此外，用DEC处理的大鼠尿液中，作为NO代谢终产物的无机硝酸盐产量没有持续增加。这些数据表明，DEC并非通过诱导宿主iNOS来实现其治疗效果。
