Development of Drinabant for Treatment of Acute Cannabinoid Overdose

急性大麻素过量（ACO）是由大量大麻素化合物的消耗引起的。这些包括德尔塔-9-四氢大麻酚（THC），大麻植物中天然存在的精神活性化合物，以及其他合成大麻素（SC）化合物。虽然sc在化学上与THC不同，但THC和sc通过结合和激活大脑中的大麻素受体（主要是CB-1受体）来引发精神活性作用。SCs最初是作为研究CB受体的研究工具而开发的，据报道，SCs在激活CB-1受体方面比四氢大麻酚更有效。食用食品的一个关键问题是，与吸烟相比，通过肠道吸收THC/SC的时间被推迟了。随后的高发作延迟导致一些人过量食用这些食品。因为很难衡量一种食物中含有多少THC/SC，这种过量消费很快就会导致过量服用。据报道，ACO的症状持续数小时至数天，导致一些人需要紧急医疗护理，甚至住院治疗。使用SCs的人需要紧急医疗护理的可能性是吸食大麻的人的30倍。

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.