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.

慢性苯妥英钠（PHT，5,5-二苯基氢化剂）治疗的癫痫 经常对药物产生有毒反应，PHT诱导的牙龈 大约50％的人口过度生长（GO）。 病变是 以增加结缔组织物质的增加为特征 牙龈，假设通过刺激牙龈发生 PHT及其代谢产物的成纤维细胞。 病变也容易发生 对药物的“响应者”增加了牙龈的可能性 炎症和感染。 拟议的研究将检查小儿 癫痫患者进行PHT治疗，并试图将药物代谢相关联 牙龈过度生长的发生率和严重程度的参数。 这 理论认为诱导酶的共同药物的存在增加了 将检查GO的发病率。 气色和高压 液相色谱（HPLC）方法将用于测定数字， PHT代谢物的类型和立体化学，尤其是酚类 （p-hpph）和二氢二醇（DHD）代谢物，因为它们是从中得出的 潜在有毒的氧化物中间体。 牙龈的时间变化 随着患者在患者的进展中，将研究过度生长和PHT代谢 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类的有丝分裂作用 牙龈成纤维细胞体外。 牙龈的代谢14C-PHT 将使用HPLC技术检查成纤维细胞。 牙龈 成纤维细胞研究将提供有关PHT的其他信息 代谢物，由PHT的成纤维细胞代谢原位产生或吸收 从血流中，发挥其作用，引起类似的增殖 到体内观察到的那个。 小儿研究将提供PHT代谢 响应者和非响应者中的数据，并将尝试关联 PHT代谢物在体外的敏感性差异。 0F小儿研究证实牙龈的发生率增加 与酶诱导的抗癫痫共同用途的过度生长， 可以提出利用PHT的抗癫痫疗法的建议 这样就会导致较低的发病率。