GINGIVAL OVERGROWTH: ROLE OF PHENYTOIN METABOLITES

牙龈过度生长：苯妥英代谢物的作用

• 批准号: 3220070
• 负责人: JAMES H MAGUIRE
• 金额: $ 9.24万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1989-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3220070
• 关键词: anticonvulsants; cats; child (0-11); dogs; drug adverse effect; drug metabolism; fibroblasts; gingiva hyperplasia; human subject; laboratory rat; phenytoin; stereochemistry; tissue /cell culture; urinalysis

Epileptics on chronic phenytoin (PHT, 5,5-diphenylhydantoin) therapy frequently experience a toxic reaction to the drug, PHT-induced gingival overgrowth (GO), in approximately 50% of the population. The lesion is characterized by an increase in the connective tissue substance of the gingivae, which is postulated to occur by stimulation of gingival fibroblasts by PHT and its metabolites. The lesion also predisposes "responders" to the drug to an increased likelihood of gingival inflammation and infection. The proposed studies will examine pediatric epileptic patients on PHT therapy and attempt to correlate drug metabolism parameters with the incidence and severity of gingival overgrowth. The theory that the presence of enzyme-inducing co-medications increases the incidence of GO will be examined. Gas chromatographic and high-pressure liquid chromatographic (HPLC) methods will be used to assay the number, types, and stereochemistry of PHT metabolites, particularly the phenolic (p-HPPH) and dihydrodiol (DHD) metabolites, as these are derived from potentially toxic arene oxide intermediates. Temporal changes in gingival overgrowth and PHT metabolism will be studied as patients progress in the study. A second portion of the study will examine the cytotoxic or mitogenic effects of p-HPPH and DHD stereoisomers on cultured human gingival fibroblasts in vitro. Metabolism of 14C-PHT by gingival fibroblasts will be examined with the use of HPLC techniques. The gingival fibroblast studies will provide additional information as to how PHT metabolites, generated in situ by fibroblast metabolism of PHT, or absorbed from the blood stream, exert their effects to cause a proliferation similar to that observed in vivo. The pediatric study will provide PHT metabolism data in responders and non-responders and will attempt to correlate differences in susceptibility to the actions of PHT metabolites in vitro. 0f the pediatric study confirms the increased incidence of gingival overgrowth with enzyme-inducing antiepileptic co-medication, recommendations for antiepileptic therapies utilizing PHT could be made such that a lower incidence of GO would result.

癫痫患者对慢性苯妥英钠(PHT，5，5-二苯基海因)的治疗 经常经历药物的毒性反应，PHT诱导的牙龈 过度生长(GO)，在大约50%的人口中。损伤是 以结缔组织物质增多为特征的 牙龈，被认为是通过刺激牙床而发生的 PHT及其代谢物诱导成纤维细胞。病变还易患上 对药物有反应的人患牙周炎的可能性增加 炎症和感染。拟议的研究将检查儿科 癫痫患者接受PHT治疗并尝试与药物代谢相关 参数与牙龈过度生长的发生率和严重程度有关。这个 有一种理论认为，酶诱导联合药物的存在会增加 将检查围棋的发生率。气相色谱与高压 将使用高效液相色谱(HPLC)方法来测定数量， PHT代谢物的类型和立体化学，特别是酚类 (P-HPPH)和二氢二醇(DHD)代谢物，因为这些代谢物来自 潜在有毒的芳烃氧化物中间体。牙周炎的时间变化 随着患者病情的进展，将对过度生长和PHT代谢进行研究 学习。研究的第二部分将检查细胞毒性或 P-HPPH和DHD立体异构体对培养人的促分裂作用 牙周成纤维细胞的体外培养。~(14)C-PHT在牙周的代谢 成纤维细胞将使用高效液相技术进行检测。牙周炎 成纤维细胞研究将提供更多关于PHT如何 代谢物，由PHT的成纤维细胞代谢原位产生或吸收 从血液中，发挥它们的作用，引起类似的增殖 与在体内观察到的结果相一致。这项儿科研究将提供PHT代谢 响应者和非响应者中的数据，并将尝试关联 在体外对PHT代谢物作用敏感性的差异。 一项儿科研究证实了牙龈发病率的增加 在酶诱导的抗癫痫药物联合用药下生长过度， 可以对使用PHT的抗癫痫治疗提出建议 这样，围棋的发病率就会降低。