GINGIVAL OVERGROWTH: ROLE OF PHENYTOIN METABOLITES

慢性苯妥英（PHT，5，5-二苯基海因）治疗癫痫 经常出现对药物的毒性反应、结核病引起的牙龈炎 过度生长（GO），约占人口的50%。 病变 其特征在于结缔组织物质的增加 牙龈炎，这是假定发生的刺激牙龈 成纤维细胞的PHT及其代谢产物。 这种病变也容易导致 “反应者”的药物，以增加牙龈的可能性， 炎症和感染。 拟议的研究将检查儿科 接受PHT治疗的癫痫患者，并尝试将药物代谢 参数与牙龈过度生长的发生率和严重程度。 的 理论认为，酶诱导联合用药的存在增加了 将检查GO的发生率。 气相色谱和高压 将使用液相色谱（HPLC）方法测定数量， 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，因为这些代谢物来源于 潜在有毒的芳烃氧化物中间体。 牙龈的时间变化 过度生长和PHT代谢将随着患者的进展进行研究， study. 研究的第二部分将检查细胞毒性或 对-HPPH和DHD立体异构体对培养的人细胞的促有丝分裂作用 牙龈成纤维细胞体外培养。 14 C-PHT的牙龈代谢 使用HPLC技术检查成纤维细胞。 牙龈 成纤维细胞研究将提供更多的信息， 代谢物，由PHT的成纤维细胞代谢原位产生，或吸收 从血液中释放出来，发挥它们的作用， 在体内观察到的。 儿科研究将提供PHT代谢 应答者和非应答者的数据，并将尝试将 体外对PHT代谢物作用的敏感性差异。 如果儿科研究证实牙龈炎的发病率增加， 与酶诱导抗癫痫联合用药的过度生长， 可以推荐使用PHT进行抗癫痫治疗 使得GO的发生率较低。

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.