Chang Jane C F, Ciaccio Paul, Schroeder Patricia, Wright Lindsay, Westwood Russell, Berg Anna-Lena
AstraZeneca R&D, Wilmington, DE 19850, USA.
AstraZeneca R&D, Wilmington, DE 19850, USA ; Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, MA 02421, USA.
J Toxicol Pathol. 2014 Apr;27(1):31-42. doi: 10.1293/tox.2013-0033. Epub 2014 Apr 30.
AZD3783, a cationic amphiphilic drug and a potent inhibitor of the 5-hydroxytryptamine (5-HT1B) receptor, was explored as a potential treatment for depression. To support clinical trials, repeat dose toxicity studies in rats and dogs were conducted. Here we report toxicity findings in dogs after dosing from 1 to 3 months. In the 1-month study, there were minimal neuronal vacuolation in the brain, a marked increase in liver enzymes accompanied by hepatocellular degeneration/necrosis and phospholipidosis (PLD), and PLD/cholecystitis in the gallbladder of animals dosed at 47 mg/kg/day. In the 3-month study, neurotoxicity resulted in euthanasia of one animal dosed at 30 mg/kg/day after 86 days. Extensive pathologic changes were seen in all animals in retina epithelium (inclusion bodies), brain (neuronal vacuolation, degeneration, or necrosis and nerve fiber degeneration), spinal ganglia (vacuolation, degeneration, or necrosis), as well as sciatic and optic nerves (degeneration). Pigment-laden macrophages were observed in the lung, kidney, liver, gallbladder, bone marrow, gastrointestinal tract, and lymphoid tissues. Also seen were vitrel and retinal hemorrhage in the eyes. A brain concentration and pathology study showed that the concentration of AZD3783 in the brain was approximately 4 times higher than in the plasma after 4 weeks of dosing, however, they were similar in all regions examined, and did not correlate with areas with pathologic findings. Our findings with AZD3783 in dogs have not been reported previously with other CNS compounds that effect through serotonergic pharmacology.
AZD3783是一种阳离子两亲性药物，也是5-羟色胺（5-HT1B）受体的强效抑制剂，被作为抑郁症的一种潜在治疗方法进行研究。为支持临床试验，在大鼠和狗身上进行了重复剂量毒性研究。在此我们报告给药1至3个月后狗的毒性研究结果。在为期1个月的研究中，给药剂量为47 mg/kg/天的动物大脑中出现了轻微的神经元空泡化，肝酶显著升高，伴有肝细胞变性/坏死和磷脂蓄积症（PLD），胆囊中出现了PLD/胆囊炎。在为期3个月的研究中，神经毒性导致一只给药剂量为30 mg/kg/天的动物在86天后实施安乐死。所有动物的视网膜上皮（包涵体）、大脑（神经元空泡化、变性或坏死以及神经纤维变性）、脊髓神经节（空泡化、变性或坏死）以及坐骨神经和视神经（变性）均出现了广泛的病理变化。在肺、肾、肝、胆囊、骨髓、胃肠道和淋巴组织中观察到了含色素巨噬细胞。眼睛中还出现了玻璃体和视网膜出血。一项大脑浓度和病理学研究表明，给药4周后，AZD3783在大脑中的浓度比血浆中约高4倍，然而，在所检查的所有区域中浓度相似，且与有病理发现的区域无关。我们关于AZD3783在狗身上的研究结果此前尚未在通过血清素能药理学起作用的其他中枢神经系统化合物中报道过。
