Screening of subjects took place between 21 and 3 days 4SC-202 mouse before first study drug administration. Enrolled subjects were randomized to treatment sequences A/B or B/A. Treatment A consisted of almorexant 200 mg once daily on day 1–10 and a single dose of 25 mg warfarin co-administered on day 5; treatment B consisted of a single dose of 25 mg warfarin on day 1. A 2-week washout period between learn more treatments was respected. A dose of 200 mg almorexant was chosen because it was expected to be well tolerated
and it was the highest dose investigated in phase III trials. Study drugs were administered in the morning to subjects in the fasted state, with breakfast served 2 h thereafter. During both treatments, subjects were confined to the study
center from approximately 12 h prior to warfarin administration until 144 h thereafter. Because of the sleep-promoting properties of almorexant, subjects stayed in the clinic under supervision for approximately 5 h after its intake on days 1–4 of treatment A. After this 5-h observation period, a physician determined whether the subject was fully alert and could be allowed to go home or whether there were any residual effects that could be attributed to a sleep-promoting drug (e.g., muscular weakness, dizziness, fatigue, or somnolence). Subjects were not to drive a car or engage in activities that required operating vehicles check details or dangerous machinery. From screening until the end-of-study examination, which was performed 144 h after warfarin administration in the second treatment period, subjects had to refrain from excessive physical exercise and strenuous sports activities and were not allowed to consume cranberries, grapefruit, cranberry juice, or grapefruit juice. Although no effect of grapefruit juice on the pharmacodynamics
of warfarin could be shown [17], cranberry juice increased the international normalized ratio (INR) [18]. This study was conducted in full conformity with the Declaration of Helsinki and its amendments. The protocol was approved by an independent ethics committee (Ethics Committee of the Medical University, Graz, Austria). Each subject provided written informed consent Tacrolimus (FK506) prior to any study procedure. 2.2 Inclusion and Exclusion Criteria Eligible subjects were healthy males aged between 18 and 45 years who had a body mass index between 18 and 28 kg/m2 at screening. Subjects were judged to be healthy based on medical history, physical examination, ECG, vital signs, and clinical laboratory tests. Subjects were not enrolled if they had a history of hemorrhagic disease, frequent nasal, hemorrhoidal, or gingival bleeding, an activated partial thromboplastin time >40 s, an INR >1.15, a low (<150 × 109) or high (>400 × 109) platelet count, or had been treated with any medication (including over-the-counter and herbal medicines) within 2 weeks prior to screening. 2.