Bleavins M R, de la Iglesia F A, Munson A E, McCay J A, Stern M L, Fuchs B A, White K L
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan.
J Pharmacol Exp Ther. 1991 Apr;257(1):316-22.
CI-949 is an orally effective inhibitor of allergic mediator release as measured with in vitro and animal models. To assess the effects of CI-949 on immune function, male Fischer 344 rats were evaluated for splenic T- and B-lymphocyte populations, antibody-forming cell response to sheep red blood cells (sRBC), concanavalin A- and pokeweed mitogen-induced lymphocyte proliferation, Natural Killer cell activity and reticuloendothelial system clearance of sRBC. CI-949 was administered by gavage to rats at 25, 50 and 100 mg/kg/day for 14 consecutive days. A vehicle control and two positive controls (cyclosporine A and cyclophosphamide) were run concurrently. CI-949 at 100 mg/kg/day decreased body weight gain and was lethal to 5 of 40 rats. The deaths occurred between days 5 and 12 of study. This overtly toxic dose did not alter splenic cellularity or change the percentages of T- and B-lymphocyte subpopulations. Additionally, CI-949 did not inhibit lymphocyte proliferation or hinder clearance of sRBC by the reticuloendothelial system. Antibody-forming cell response after immunization showed a dose-related increase in the number of immunoglobulin M secreting cells. Based on the results of these assays, the immune system does not appear to be adversely affected by CI-949 even at high doses.
CI-949是一种口服有效的过敏介质释放抑制剂，这是通过体外和动物模型测定得出的。为了评估CI-949对免疫功能的影响，对雄性Fischer 344大鼠的脾T淋巴细胞和B淋巴细胞群体、对绵羊红细胞（sRBC）的抗体形成细胞反应、伴刀豆球蛋白A和商陆有丝分裂原诱导的淋巴细胞增殖、自然杀伤细胞活性以及sRBC的网状内皮系统清除能力进行了评估。CI-949以25、50和100毫克/千克/天的剂量连续14天经口灌胃给予大鼠。同时设立了赋形剂对照组和两个阳性对照组（环孢素A和环磷酰胺）。100毫克/千克/天的CI-949降低了体重增加，并且导致40只大鼠中有5只死亡。死亡发生在研究的第5天至第12天之间。这个明显有毒的剂量并没有改变脾脏细胞数量，也没有改变T淋巴细胞和B淋巴细胞亚群的百分比。此外，CI-949没有抑制淋巴细胞增殖，也没有阻碍网状内皮系统对sRBC的清除。免疫后的抗体形成细胞反应显示分泌免疫球蛋白M的细胞数量呈剂量相关增加。基于这些试验的结果，即使在高剂量下，CI-949似乎也不会对免疫系统产生不利影响。
