Mauler Frank, Horváth Ervin, De Vry Jean, Jäger Rainer, Schwarz Thomas, Sandmann Steffen, Weinz Corinna, Heinig Roland, Böttcher Michael
Bayer HealthCare PH-R-EU CNS, Aprather Weg 18a, D-42096 Wuppertal, Germany.
CNS Drug Rev. 2003 Winter;9(4):343-58. doi: 10.1111/j.1527-3458.2003.tb00259.x.
Traumatic brain injury (TBI) is the most common cause of mortality and morbidity in adults under 40 years of age in industrialized countries. Worldwide the incidence is increasing, about 9.5 million people are hospitalized per year due to TBI, and the death rate is estimated to be more than one million people per year. Recently BAY 38-7271 has been characterized as a structurally novel, selective and highly potent cannabinoid CB1/CB2 receptor agonist in vitro and in vivo with pronounced neuroprotective efficacy in a rat traumatic brain injury model, showing a therapeutic window of at least 5 h. Furthermore, neuroprotective efficacy was also found in models of transient and permanent occlusion of the middle cerebral artery and brain edema models as well. In this article we review the in vitro and in vivo pharmacology of BAY 38-7271, the results from acute and subacute toxicity studies, pharmacokinetics and drug metabolism in animals and healthy male volunteers. In phase I studies BAY 38-7271 was safe and well tolerated when administered by i.v. infusion for either 1 or 24 h. As the doses of BAY 38-7271 in animals needed for maximal neuroprotective efficacy were significantly lower than those inducing typical cannabinoid-like side effects, it is to be expected that the compound will offer a novel therapeutic approach with a favorable therapeutic window for the treatment of TBI or cerebral ischemia.
创伤性脑损伤（TBI）是工业化国家40岁以下成年人死亡和发病的最常见原因。在全球范围内，其发病率正在上升，每年约有950万人因TBI住院，估计死亡率超过每年100万人。最近，BAY 38-7271在体外和体内被鉴定为一种结构新颖、选择性高且强效的大麻素CB1/CB2受体激动剂，在大鼠创伤性脑损伤模型中具有显著的神经保护作用，显示出至少5小时的治疗窗。此外，在大脑中动脉短暂和永久性闭塞模型以及脑水肿模型中也发现了神经保护作用。在本文中，我们综述了BAY 38-7271的体外和体内药理学、急性和亚急性毒性研究结果、动物和健康男性志愿者的药代动力学和药物代谢。在I期研究中，BAY 38-7271通过静脉输注给药1或24小时时安全且耐受性良好。由于实现最大神经保护作用所需的BAY 38-7271动物剂量显著低于诱导典型大麻素样副作用的剂量，预计该化合物将为治疗TBI或脑缺血提供一种具有良好治疗窗的新型治疗方法。
