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Oral repeated-dose toxicity studies of BIA 10-2474 in cynomolgus monkeys.
Regulatory Toxicology and Pharmacology ( IF 3.4 ) Pub Date : 2019-12-06 , DOI: 10.1016/j.yrtph.2019.104547
Klaus Weber 1 , Rüdiger Häcker 2 , Jerry F Hardisty 3 , Stephen B Harris 4 , A Wallace Hayes 5
Affiliation  

BIA 10-2474 (3-(1-(cyclohexyl(methyl)carbamoyl)-1H-imidazol-4-yl)pyridine 1-oxide) is a novel fatty acid amide hydrolase (FAAH) inhibitor developed by BIAL 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. As part of series of papers presenting all the toxicology data available prior to the clinical trial we report here the nonclinical toxicology studies performed in cynomolgus monkeys. Maximum Tolerated Dose (MTD) studies and a preliminary 14-day study by oral (capsule) administration of BIA 10-2474 established a dose between 90 and 120 mg/kg/day as a suitable high dose for a subsequent regulatory toxicity studies. An up-titration scheme was used to achieve these doses. The dose-limiting effect was the early sacrifice for ethical reasons of monkeys at doses from 125 mg/kg/day upwards. Thereafter, regulatory 4- and 13-week oral gavage toxicity studies followed by a 2- or a 4-week recovery period, respectively, were performed. In both cases a 3-4-week up-titration period was used prior to repeat dosing with the target doses. One female was euthanized during the up-titration period after receiving 9 administrations of 75 mg/kg as a result of bleeding erosion on the feet and hands and ulceration on the tongue. These signs were not seen in any other monkeys during these studies. Doses of 10, 50 or 100 mg/kg/day were administered during the 4-week study and clinical signs related to the pharmacological action of BIA 10-2474 (e.g., tremors and weakness, incoordination and loss of balance, reduction in food intake and reduced body weight) were observed in several monkeys from the intermediate and high dose. Histological alterations consisted of axonal dystrophy in the fasciculus cuneatus (dorsal medulla oblongata) characterized by swollen axons and myelin sheath edema, edema in the pars nervosa of the pituitary gland and vacuolation of Meissner's plexus ganglia in all gastrointestinal segments. All lesions recovered and a dose of 100 mg/kg/day was considered to be the NOAEL. In the 13-week oral study the monkeys received BIA 10-2474 daily by gavage at a dose of 6.25, 37.5 or 75 mg/kg/day. Similar clinical signs and histological alterations as noted in monkeys of the 28-day study were observed in monkeys at 37.5 or 75 mg/kg/day. All findings recovered, and the dose of 75 mg/kg/day was considered the NOAEL.

中文翻译:

BIA 10-2474对食蟹猴的口服重复剂量毒性研究。

BIA 10-2474(3-(1-(环己基(甲基)氨基甲酰基)-1H-咪唑-4-基)吡啶1-氧化物)是BIAL研发的用于治疗医学的新型脂肪酸酰胺水解酶(FAAH)抑制剂内毒素(AEA)水平升高而受益的疾病,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。作为介绍所有在临床试验之前可用的毒理学数据的系列论文的一部分,我们在此报告在食蟹猴中进行的非临床毒理学研究。最大耐受剂量(MTD)研究和通过口服(胶囊)施用BIA 10-2474进行的14天初步研究确定了90至120 mg / kg /天的剂量,是随后进行监管毒性研究的合适高剂量。使用滴定方案来达到这些剂量。出于伦理原因,剂量限制作用是出于猴子的早期牺牲,剂量为125 mg / kg /天以上。此后,进行了为期4周和13周的管饲管毒性试验,随后分别进行了2周或4周的恢复期研究。在这两种情况下,在重复使用目标剂量之前,都要进行3至4周的滴定期。接受9次75 mg / kg施用后,由于脚和手的出血糜烂和舌头溃疡,在调高期间对一名女性实施了安乐死。在这些研究中,没有任何其他猴子看到这些迹象。在为期4周的研究过程中,每天服用10、50或100 mg / kg的剂量,以及与BIA 10-2474的药理作用有关的临床体征(例如震颤和虚弱,在中等剂量和高剂量的几只猴子中,观察到不协调和失去平衡,食物摄入减少和体重减轻。组织学改变包括以筋膜(轴突延髓)为轴突营养不良,其特征为轴突肿胀和髓鞘鞘水肿,垂体前部神经水肿和所有胃肠道中的迈斯纳丛神经节空泡化。恢复所有病灶,将100 mg / kg /天的剂量视为NOAEL。在为期13周的口服研究中,猴子通过管饲法每天以6.25、37.5或75 mg / kg /天的剂量接受BIA 10-2474。在28天研究的猴子中,以37.5或75 mg / kg / day的猴子观察到了类似的临床体征和组织学改变。所有发现均已恢复,
更新日期:2019-12-07
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