Development of Drinabant for Treatment of Acute Cannabinoid Overdose

急性大麻素过量(ACO)是由于大量摄入大麻素化合物造成的。这些化合物包括大麻植物中天然存在的精神活性化合物--三角洲-9-四氢大麻酚(THC)，以及其他合成大麻素(SC)化合物。尽管SCs在化学上与THC不同，但THC和SCs通过结合和激活大脑中的大麻素(CB)受体，主要是CB-1受体而产生精神活性效应。干细胞最初是作为研究CB受体的研究工具而开发的，据报道，在激活CB-1受体方面，干细胞比THC更有效和有效。食用食品的一个关键问题是，与吸烟相比，THC/SC在肠道中的吸收延迟。随后高潮开始的延迟导致一些人过度食用这些食物。因为很难衡量一个人的食物中含有多少THC/SC，这种过度消费很快就会导致服药过量。据报道，ACO的症状从几个小时到几天不等，导致一些人需要紧急医疗护理，甚至住院。使用SC的人需要紧急医疗护理的可能性大约是吸食大麻的人的30倍。 治疗假说是，CB-1拮抗剂可以通过取代与CB-1受体结合的激动剂(THC或SC)来逆转ACO的临床表现。先前的临床研究表明，口服CB-1拮抗剂(饮酒剂、苏利那班)可以阻断吸入THC的药效作用。口服饮酒起效慢，因此在急性过量情况下服用是不切实际的。为了改善药物动力学，主要合作者提出了一种非肠道给药途径(静脉或肌肉注射)，这种途径更适合在紧急医疗环境下治疗ACO。 布里奇斯的科学家们已经发起了一项临床前开发活动，以推动饮酒进入临床评估。一种注射制剂的开发和剂量范围的毒理学研究正在进行中。计划的活动包括支持研究新药(IND)申请所需的药代动力学和毒理学研究。

Acute cannabinoid overdose (ACO) results from the consumption of large quantities of cannabinoid compounds. These include delta-9-tetrahydrocannabinol (THC), the naturally occurring psychoactive compound in Cannabis plants, as well as other synthetic cannabinoid (SC) compounds. Although SCs are chemically distinct from THC, THC and SCs elicit psychoactive effects through the binding and activation of cannabinoid (CB) receptors in the brain, principally the CB-1 receptor. Initially developed as research tools to study CB receptors, SCs are reported to be more potent and efficacious than THC at activating CB-1 receptors. A critical issue with edibles is that absorption of the THC/SC through the gut is delayed compared to smoking. The subsequent delay in the onset of a high leads some to overconsume these edibles. Because it can be difficult to gauge how much THC/SC is contained in an individual edible, this overconsumption can quickly result in an overdose. Symptoms of ACO have been reported to last anywhere from several hours to days, leading some individuals to require emergency medical attention or even hospitalization. Individuals using SCs are about 30 times more likely to require emergency medical care than for smoked marijuana. The therapeutic hypothesis is that a CB-1 antagonist can reverse the clinical manifestations of ACO by replacing the agonist (THC or SC) bound to CB-1 receptors. Prior clinical studies have demonstrated that oral administration of CB-1 antagonists (drinabant, surinabant) can block the pharmacodynamic effects of inhaled THC. Orally administered drinabant has a slow onset, making it impractical to administer in the acute overdose setting. To improve the pharmacokinetics, the lead collaborators have proposed a parenteral route of administration (intravenous or intramuscular injection) that would be more amenable to treating ACO in the emergency medical setting. BrIDGs scientists have initiated a preclinical development campaign to advance drinabant to clinical evaluation. Development of an injectable formulation and dose range finding toxicology studies are underway . Planned activities include the pharmacokinetic and toxicology studies needed to support an Investigational New Drug (IND) application.