BIOAVAILABILITY AND PHARMACOTHERAPEUTICS OF PROMETHAZINE IN HUMAN SUBJECTS

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。 空间运动病(SMS)通常在太空中用异丙嗪(PMZ)治疗。地面上注射PMZ(50毫克肌肉注射)的常见副作用是嗜睡和认知能力受损。坊间报道表明，这些影响在太空中不存在或不太明显。这表明，PMZ对人体的利用度(生物利用度)和/或身体对PMZ的反应(药效学)在太空飞行过程中可能会发生变化。在太空进行临床研究的机会有限。这是一项地面研究，需要改进或回答有关太空飞行期间的诊断和治疗以及飞行后康复的具体问题。 我们将使用新的稳定同位素技术评估PMZ肌肉注射(IM)、口服片剂和直肠栓剂在正常受试者卧床和卧床(ABR)条件下的生物利用度。在给受试者注射三种剂量的PMZ后，我们将测量嗜睡、认知能力和唾液流率，并将它们与药物在血液中的浓度进行比较。我们将比较和对比PMZ在正常和ABR条件下的生物利用度，以检查ABR期间药物吸收和利用度的变化，并评估这些变化是否类似于微重力环境中预期的变化。这项研究的结果将验证批准的飞行中调查的方法，该药物正在等待显现的机会。这些数据还将提供关于PMZ的动力学和治疗指数及其对机组人员疲劳和太空表现的影响的迫切需要的信息。

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. Space motion sickness (SMS) is often treated in space with promethazine (PMZ). Common side effects of PMZ administration (50 mg intramuscular) on the ground are drowsiness and impaired cognitive performance. Anecdotal reports indicate that these effects are absent or less pronounced in space. This suggests that the availability of PMZ to the body (bioavailability) and/or the response of the body to PMZ (pharmacodynamics) may change during space flight. Opportunities for clinical research in space are limited. This is a ground-based research needed to improve, or answer specific questions about, diagnosis and therapy during space flight, and post-flight rehabilitation. We will estimate the bioavailability of an intramuscular injection (IM), oral tablet, and rectal suppository of PMZ in normal subjects during ambulatory and antiorthostatic bed rest (ABR) conditions using novel stable isotope techniques. After three IM doses of PMZ are administered to subjects, we will measure drowsiness, cognitive performance, and salivary flow rate, and will compare them with concentrations of the drug in the blood. We will compare and contrast the bioavailability of PMZ during normal and ABR conditions to examine changes in drug absorption and availability during ABR and evaluate whether these changes may be similar to those anticipated in a microgravity environment. Results of this study will validate methods for an approved in-flight investigation with this medication awaiting an opportunity for manifestation. These data will also provide the much-needed information on the dynamics and therapeutic index of PMZ and their implications on crew fatigue and performance in space.