BIA 10-2474 is a novel fatty acid amide hydrolase (FAAH) 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 four other subjects displayed neurological signs. As part of series of papers presenting all the toxicology data available prior to the clinical trial, we report here the preclinical toxicology studies examining once-a-day oral administration of BIA 10-2474 to male and female Wistar rats. These included a 14-day dose range finding (150, 200 and 250 mg/kg/day), a 4-week study (30, 90 and 150 mg/kg/day) and 13- and 26-week studies (both at 10, 30 and 90 mg/kg/day). The 13- and 26-week studies also included a 4-week recovery arm and a toxicokinetic arm for the parent compound, BIA 10-2474, and the two major metabolites (BIA 10-2445 and BIA 10-2583) were also measured in the 26-week study. At 150 mg/kg and below, all animals survived the scheduled treatment periods although neurological side-effects (abnormal or stiff gait, dragging of fore- or hind-limbs) were seen at 150 mg/kg in both the dose-range finding and 4-week studies. At 90 mg/kg/day, even up to 26-weeks treatment, no clinical signs were seen apart from some decreases in body weight gain. A number of consistent hematological and biochemical changes were noted which were considered related to treatment with BIA 10-2474. Morphologically, in the 4-week study, except for a slight gliosis in the hippocampus of one female at 150 mg/kg, no CNS histopathology was observed; hippocampus gliosis was not observed in subsequent studies. In the 13-week study axonal swelling was present in the medulla oblongata in about half the animals at 90 mg/kg/day and this increased to nearly all the rats at 90 mg/kg/day in the 26-week study. Additional signs seen only in the 26-week study at 90 mg/kg/day included axonal swelling of the fasiculus gracilis and vacuolar changes in the medulla oblongata and ventral commissure of the 3rd ventricle. Other findings included vacuolar degeneration in the ganglia of the GI tract, salivary glands, prostate gland, uterus, and parathyroid glands. The pituitary gland showed edema and mitotic figures in the pars nervosa. These observations outside the CNS were seen in most rats at 90 and 150 mg/kg/day independent of study duration. At 30 mg/kg/day, most of these observations were only seen in isolated cases except for the vacuolar degeneration in GI tract ganglia, which was absent at this dose after 4 weeks treatment but was present in almost all rats at 13 and 26 weeks. Hepatocellular hypertrophy and nephropathy were seen across all studies and the extent of these changes was similar in the 13- and 26-week studies. Most findings resolved after the 4-week recovery periods except for the axonal swelling seen in the medulla oblongata and spinal cord. BIA 10-2474 exposure was markedly higher than the exposure to either metabolite, BIA 10-2445 (19- to 192-fold) and BIA 10-2583 (63- to 526-fold). Exposure to metabolites differed between sexes with higher concentrations of BIA 10-2445 in females compared to males, but the inverse for BIA 10-2583. Although a No Observed Adverse Effect Level (NOAEL) of 30 mg/kg/day was concluded following the 4-week study, the histopathological findings at that dose in the 13- and 26-week studies resulted in the NOAEL being determined to be 10 mg/kg/day.

中文翻译：

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BIA 10-2474对Wistar大鼠的口服重复剂量毒性研究。

BIA 10-2474是开发用于治疗医学病症的新型脂肪酸酰胺水解酶（FAAH）抑制剂，该抑制剂可受益于内源性扁桃酰胺（AEA）水平提高，例如疼痛障碍。在I期临床试验中，一名受试者在接受BIA 10-2474的治疗后死亡，另外四名受试者表现出神经系统症状。作为介绍所有在临床试验之前可获得的所有毒理学数据的论文系列的一部分，我们在这里报告临床前毒理学研究，该研究对雄性和雌性Wistar大鼠每天口服一次BIA 10-2474。其中包括发现14天的剂量范围（150、200和250 mg / kg /天），进行4周的研究（30、90和150 mg / kg /天）以及进行13和26周的研究（均在10、30和90 mg / kg /天）。这项为期13周和26周的研究还包括母体化合物BIA 10-2474的为期4周的恢复臂和毒物代谢动力学臂，并且还对两种主要代谢物（BIA 10-2445和BIA 10-2583）进行了测定。为期26周的研究。在150 mg / kg或更低的剂量范围内，所有动物的神经系统副作用（步态异常或僵硬，前肢或后肢拖拉）均达到了预定的治疗时间，但在150 mg / kg或以下时，所有动物均幸存。 4周的研究。在每天90 mg / kg的剂量下，即使长达26周的治疗，除体重增加有所降低外，未见任何临床体征。注意到许多一致的血液和生化变化，这些变化被认为与BIA 10-2474的治疗有关。从形态上讲，在为期4周的研究中，除了一名女性以150 mg / kg的剂量存在海马轻度胶质增生外，未观察到中枢神经系统组织病理学；在随后的研究中未观察到海马神经胶质增生。在为期13周的研究中，延髓中的轴突肿胀以90 mg / kg /天的比例存在于大约一半的动物中，在26周的研究中，这种情况几乎增加了所有以90 mg / kg / day的大鼠的轴索膨胀。仅在为期26周的研究中，以90 mg / kg / day的剂量观察到的其他症状包括细小轴突的轴突肿胀，延髓的液泡变化和第三脑室的腹腔连合。其他发现包括胃肠道神经节，唾液腺，前列腺，子宫和甲状旁腺的液泡变性。垂体在神经沟中显示出水肿和有丝分裂图。在大多数大鼠中，中枢神经系统外的这些观察结果以90和150 mg / kg / day的量出现，与研究持续时间无关。以30毫克/千克/天的剂量，这些观察结果中的大多数仅在个别病例中观察到，除了胃肠道神经节中的液泡变性，在治疗4周后该剂量不存在，但在13周和26周时几乎所有大鼠中都存在。在所有研究中均观察到肝细胞肥大和肾病，在13周和26周的研究中，这些变化的程度相似。除了在延髓和脊髓中看到的轴突肿胀外，大多数发现在4周恢复期后得到解决。BIA 10-2474的暴露显着高于两种代谢物BIA 10-2445（19-至192倍）和BIA 10-2583（63-526倍）的暴露。与男性相比，女性中BIA 10-2445浓度较高的性别之间的代谢产物暴露程度不同，但BIA 10-2583则相反。