Furst Sylvia M, Khan K Nasir, Komocsar Wendy J, Mennear John
Pfizer Inc., Worldwide Safety Sciences, Ann Arbor, Michigan 48108, USA.
J Immunotoxicol. 2005 Jul 1;2(3):161-70. doi: 10.1080/15476910500290567.
Results from earlier experiments in our laboratories revealed that both selective and non-selective inhibitors of cyclooxygenase-2 possess little potential for decreasing in vitro phagocytosis by rat macrophages or canine neutrophils, and no potential for decreasing in vivo phagocytosis by the intact murine immune system. We have also demonstrated that pharmacologically relevant doses and concentrations of these drugs do not reduce canine complement activation, superoxide anion generation, leukocytic chemotaxis or transmigration of leukocytes through endothelial monolayers. We now report the results of immunotoxicology studies to assess the effects of the drugs on cell-mediated immunity. Male and female Sprague-Dawley rats were administered daily oral gavage doses of naproxen (10 mg/kg), SC-791 (2.5 mg/kg), or SC-245 (17 mg/kg) for 28 consecutive days or treated with cyclophosphamide or anti-asialo GM1 antibody as positive immunomodulatory controls (for T-dependent antibody response and natural killer cell assay, respectively). All rats, except those treated with GM1 antibody or used in toxicokinetic analyses, were immunized on study day 25 with sheep red blood cells to induce a primary T-dependent antibody response. The doses of test agents were chosen to be either supra-pharmacologic or limited by anticipated systemic toxicity. Hematologic changes consistent with gastrointestinal (GI) blood loss due to mild GI mucosal toxicity were seen with naproxen and SC-791. Both positive control agents produced anticipated immunomodulatory effects confirming the validity of the assay system. In the antibody-forming cell assay, naproxen, SC-791 and SC-245 were without effects on splenic cellularity, splenocyte viability or the number of sheep red blood cell antibody-forming cells. Cyclophosphamide reduced both splenic cellularity and antibody-forming cell counts. In the natural killer cell assay, naproxen, SC-791 and SC-245 were all without effects on natural killer cell activity, while anti-asialo antibody reduced natural killer cell activity up to 85%. In considering the sum total of scientific information relative to the immunotoxicological potential of non-selective and selective cyclooxygenase-2 inhibitors, we conclude that, although high (supra-pharmacologic) concentrations of these drugs may induce some in vitro immunomodulatory effects on the innate immune system, the findings are of doubtful predictive significance with respect to human health implications.
我们实验室早期实验的结果显示，环氧化酶 -2 的选择性和非选择性抑制剂在降低大鼠巨噬细胞或犬中性粒细胞的体外吞噬作用方面几乎没有潜力，在降低完整小鼠免疫系统的体内吞噬作用方面也没有潜力。我们还证明，这些药物在药理学相关剂量和浓度下不会降低犬补体激活、超氧阴离子生成、白细胞趋化性或白细胞通过内皮单层的迁移。我们现在报告免疫毒理学研究的结果，以评估这些药物对细胞介导免疫的影响。将雄性和雌性斯普拉格 - 道利大鼠连续 28 天每日经口灌胃给予萘普生（10 mg/kg）、SC - 791（2.5 mg/kg）或 SC - 245（17 mg/kg），或用环磷酰胺或抗去唾液酸 GM1 抗体作为阳性免疫调节对照进行处理（分别用于 T 依赖性抗体反应和自然杀伤细胞测定）。除了用 GM1 抗体处理的大鼠或用于毒代动力学分析的大鼠外，所有大鼠在研究第 25 天用绵羊红细胞免疫，以诱导初次 T 依赖性抗体反应。选择的受试药物剂量要么是超药理剂量，要么受到预期全身毒性的限制。萘普生和 SC - 791 出现了与轻度胃肠道黏膜毒性导致的胃肠道失血一致的血液学变化。两种阳性对照药物都产生了预期的免疫调节作用，证实了检测系统的有效性。在抗体形成细胞测定中，萘普生、SC - 791 和 SC - 245 对脾细胞数量、脾细胞活力或绵羊红细胞抗体形成细胞数量均无影响。环磷酰胺降低了脾细胞数量和抗体形成细胞计数。在自然杀伤细胞测定中，萘普生、SC - 791 和 SC - 245 对自然杀伤细胞活性均无影响，而抗去唾液酸抗体使自然杀伤细胞活性降低高达 85%。综合考虑与非选择性和选择性环氧化酶 -2 抑制剂免疫毒理学潜力相关的全部科学信息，我们得出结论，尽管这些药物的高（超药理）浓度可能对先天免疫系统产生一些体外免疫调节作用，但这些发现对于人类健康影响的预测意义值得怀疑。
