BIA 10-2474 is a novel fatty acid amide hydrolase inhibitor developed for the treatment of medical conditions which would benefit from enhanced levels of endogenous anandamide (AEA) such as pain disorders. During a Phase I clinical trial one subject died after receiving BIA 10-2474 and others displayed neurological signs. We describe here the toxicology studies in beagle dogs that supported phase I testing of BIA 10-2474 in humans. A Maximum Tolerated Dose (MTD) study using once-a-day oral (capsule) application of BIA 10-2474 was first conducted to establish suitable dose levels for subsequent studies. Based on these results, 100 mg/kg/day was considered to be the MTD. The 4-week oral (capsule) toxicity study with a 3-week recovery period for BIA 10-2474 was therefore carried out at 20, 50 or 100 mg/kg/day. There were no changes recorded at 50 mg/kg/day and this was considered the oral No Observed Effect Level (NOEL) for four-week once-a-day capsule administration to Beagle dogs. At 100 mg/kg/day, the dose-limiting findings consisted of clinical symptoms including tremor, loss of balance, abnormal gait, decreased motor activity, weakness, vomits, salivation increase and miosis, increased severity of thymic atrophy/involution, and moderate acute, focal/multifocal bronchopneumonia in lungs of three animals. In a 13-week oral (capsule) toxicity study in the Beagle dog with a 6-week recovery period, using the same dose levels, clinical signs were recorded during treatment with BIA 10-274 at 50 and 100 mg/kg/day. The most frequent signs included difficulty breathing, respiratory sounds (with or without auscultation) and cough. Incoordination of the hind limbs with absence of correction reflex were also observed on some occasions. As a result, the 50 and 100 mg/kg/day doses were reduced to 35 and 50 mg/kg/day respectively on day 37. Because of the continued signs, the doses in both groups were further reduced to 20 mg/kg/day from day 77. Under the conditions of this study and given the severe signs recorded in groups treated at 100-50-20 and 50-35-20 mg/kg/day and only very occasional presence of signs in the group treated for the 13-week period at 20 mg/kg/day (abnormal respiratory sounds once in two animals), the dose of 20 mg/kg/day was considered the No Observed Adverse Effect Level (NOAEL).

中文翻译：

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BIA 10-2474对比格犬的口服重复剂量毒性研究。

BIA 10-2474是开发用于治疗医学疾病的新型脂肪酸酰胺水解酶抑制剂，该疾病可受益于内源性Anandamide（AEA）水平的提高，例如疼痛疾病。在I期临床试验中，一名受试者在接受BIA 10-2474感染后死亡，其他受试者则表现出神经系统症状。我们在这里描述了比格犬的毒理学研究，这些研究支持了人类对BIA 10-2474的I期测试。首先进行了每日一次的BIA 10-2474口服（胶囊）应用最大耐受剂量（MTD）研究，以建立适合后续研究的剂量水平。根据这些结果，将100 mg / kg /天视为MTD。因此，以20、50或100 mg / kg /天的剂量进行了为期4周的BIA 10-2474口服（胶囊）毒性研究，恢复期为3周。没有记录到50 mg / kg / day的变化，这被认为是对Beagle犬口服4周每天一次的口服无观察到的作用水平（NOEL）。在100 mg / kg / day时，剂量限制的发现包括临床症状，包括震颤，失去平衡，步态异常，运动活动减少，虚弱，呕吐，流涎增加和瞳孔缩小，胸腺萎缩/复旧的严重程度增加以及中度三只动物的肺部有急性，局灶性/多灶性支气管肺炎。在具有6周恢复期的比格犬的13周口服（胶囊）毒性研究中，使用相同的剂量水平，在以50和100 mg / kg / day的BIA 10-274治疗期间记​​录了临床体征。最常见的体征包括呼吸困难，呼吸音（有或没有听诊）和咳嗽。在某些情况下，还观察到后肢不协调而没有矫正反射的情况。结果，第37天的50和100 mg / kg /天剂量分别降低到35和50 mg / kg /天。由于持续的体征，两组的剂量进一步降低到20 mg / kg /天。从第77天起，在本研究的条件下，考虑到以100-50-20 mg / kg / kg和50-35-20 mg / kg /天治疗的组记录到了严重的体征，并且治疗组中仅偶尔出现体征以20 mg / kg /天的剂量持续13周（两只动物一次呼吸异常），将20 mg / kg /天的剂量视为未观察到不良反应水平（NOAEL）。