A STUDY TO EVALUATE EFFECTS OF ESCITALOPRAM AND CITALOPRAM ON PK OF DESIPRAMINE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 目的：多种常用抗抑郁药对细胞色素P450系统均有不同程度的抑制作用。正如我们在之前的一项研究中所证明的那样，外消旋混合物西酞普兰对CYP2D6表现出适度的抑制活性。消旋体埃西妥普兰对该同工酶的影响尚未直接与西酞普兰进行比较。本研究的目的是利用地塞帕明AUC的变化作为酶活性的指标，确定艾司匹兰与西酞普兰对CYP2D6的抑制潜力。此外，我们将利用心电描记和简易精神状态检查(MMSE)分数来比较两种药物之间地昔帕明的药效学变化。还将获得一氧化氮(NOx)的代谢终产物，以评估这些抗抑郁剂对NO产生的影响。帕罗西汀是一种对CYP2D6有很强抑制作用的SSRI，服用帕罗西汀后，NOx的平均水平显著增加。一氧化氮被认为是细胞色素P450活性降低的中介物。 研究计划：正常健康受试者将通过FLEYER从退伍军人管理局和UTHSCSA校园招募参加随机、交叉设计研究。患者将在GCRC接受筛查、基线评估和研究评估。 方法：共招募6名受试者。筛查后，受试者将接受基线评估，包括给药后T0和T2小时的地昔帕明AUC、NOx、心电描记，以及T0和T2小时的MMSE。受试者还将接受使用右美沙芬的CYP2D6活性评估和服药后4小时的尿液采集。然后，受试者将被随机分成两组，分别接受每日40毫克或10毫克的氯丙沙星或艾司匹兰治疗，共14天。第8天将重复地昔帕明AUC、NOx、心电描记、MMSE和右美沙芬挑战。然后受试者将经历一段灵活的洗脱期，然后开始第二种抗抑郁药物(地西普兰或艾司匹兰)，并重复相同的程序。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVE: Many commonly used antidepressants have varying degrees of inhibitory action on the cytochrome P450 system. The racemic mixture citalopram demonstrates modest inhibitory activity at CYP2D6, as demonstrated by our work in a previous study. The racemate escitalopram has not been directly compared with citalopram in regard to its effects on this isoenzyme. The objective of this study is to determine the inhibitory potential of escitalopram versus citalopram on CYP2D6, utilizing changes in desipramine AUC as an indicator of enzyme activity. Additionally, we will compare the pharmacodynamic changes in desipramine between the two agents utilizing ECG tracings and Mini-Mental Status Exam (MMSE) scores. Metabolic end-products of nitric oxide (NOx) will also be obtained to assess the effects of these antidepressants on NO production. Administration of paroxetine, an SSRI with potent inhibitory effects on CYP2D6, has demonstrated significant mean increase in NOx. Nitric oxide has been implicated as a mediator of decreased CYP activity. RESEARCH PLAN: Normal healthy subjects will be recruited from a VA and UTHSCSA campus via flyer to participate in the randomized, crossover design study. Patients will undergo screening, baseline assessments, and research assessments at the GCRC. METHODS: Six subjects will be recruited. After screening, subjects will undergo a baseline assessment, including desipramine AUC, NOx, ECG tracings at T0 and T2 hours post desipramine administration, and MMSE at T0 and T2 hours post. Subjects will also undergo CYP2D6 activity assessment using dextromethorphan and 4 hour post-administration urine collection. Subjects will then be randomized to receive chialopram, titrated to 40 mg daily, or escitalopram, titrated to 10 mg daily, for a total of 14 days. Desipramine AUC, NOx, ECG tracings, MMSE, and dextromethorphan challenge will be repeated on Day 8. Subjects will then undergo a flexible washout period, then begin the second antidepressant (ditalopram or escitalopram) and repeat the same procedures.