Sagredo Onintza, Pazos M Ruth, Valdeolivas Sara, Fernandez-Ruiz Javier
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
Recent Pat CNS Drug Discov. 2012 Apr 1;7(1):41-8. doi: 10.2174/157488912798842278.
Cannabinoid pharmacology has experienced a notable increase in the last 3 decades which is allowing the development of novel cannabinoid-based medicines for the treatment of different human pathologies, for example, Cesamet® (nabilone) or Marinol® (synthetic Δ9-tetrahydrocannabinol for oral administration) that were approved in 80s for the treatment of nausea and vomiting associated with chemotherapy treatment in cancer patients and in 90s for anorexiacachexia associated with AIDS therapy. Recently, the british company GW Pharmaceuticals plc has developed an oromucosal spray called Sativex®, which is constituted by an equimolecular combination of Δ9-tetrahydrocannabinol- and cannabidiol- enriched botanical extracts. Sativex® has been approved for the treatment of specific symptoms (i.e. spasticity and pain) of multiple sclerosis patients in various countries (i.e. Canada, UK, Spain, New Zealand). However, this cannabis- based medicine has been also proposed to be useful in other neurological disorders given the analgesic, antitumoral, anti-inflammatory, and neuroprotective properties of their components demonstrated in preclinical models. Numerous clinical trials are presently being conducted to confirm this potential in patients. We are particularly interested in the case of Huntington's disease (HD), an autosomal-dominant inherited disorder caused by an excess of CAG repeats in the genomic allele resulting in a polyQ expansion in the encoded protein called huntingtin, and that affects primarily striatal and cortical neurons thus producing motor abnormalities (i.e. chorea) and dementia. Cannabinoids have been studied for alleviation of hyperkinetic symptoms, given their inhibitory effects on movement, and, in particular, as disease-modifying agents due to their anti-inflammatory, neuroprotective and neuroregenerative properties. This potential has been corroborated in different experimental models of HD and using different types of cannabinoid agonists, including the phytocannabinoids present in Sativex®, and we are close to initiate a clinical trial with this cannabis-based medicine to evaluate its capability as a disease-modifying agent in a population of HD patients. The present review will address all preclinical evidence supporting the potential of Sativex® for the treatment of disease progression in HD patients. The article presents some promising patents on the cannabinoids.
在过去三十年中，大麻素药理学取得了显著进展，这使得新型大麻素类药物得以开发，用于治疗各种人类疾病。例如，Cesamet®（纳布啡）或Marinol®（口服合成Δ9-四氢大麻酚），它们分别于20世纪80年代和90年代获批，用于治疗癌症患者化疗相关的恶心和呕吐以及艾滋病治疗相关的厌食-恶病质。最近，英国GW制药公司开发了一种名为Sativex®的口腔黏膜喷雾剂，它由富含Δ9-四氢大麻酚和大麻二酚的植物提取物等分子组合而成。Sativex®已在多个国家（如加拿大、英国、西班牙、新西兰）获批用于治疗多发性硬化症患者的特定症状（如痉挛和疼痛）。然而，鉴于其成分在临床前模型中显示出的镇痛、抗肿瘤、抗炎和神经保护特性，这种基于大麻的药物也被认为对其他神经系统疾病有用。目前正在进行大量临床试验以证实其在患者中的这种潜力。我们特别关注亨廷顿舞蹈病（HD）的情况，这是一种常染色体显性遗传性疾病，由基因组等位基因中CAG重复序列过多导致编码的亨廷顿蛋白中出现多聚谷氨酰胺扩展，主要影响纹状体和皮质神经元，从而产生运动异常（如舞蹈症）和痴呆。鉴于大麻素对运动的抑制作用，人们研究了其对缓解运动亢进症状的作用，特别是由于其抗炎、神经保护和神经再生特性，将其作为疾病修饰剂进行研究。在不同的HD实验模型中，使用不同类型的大麻素激动剂，包括Sativex®中含有的植物大麻素，已证实了这种潜力。我们即将启动一项使用这种基于大麻的药物的临床试验，以评估其在HD患者群体中作为疾病修饰剂的能力。本综述将阐述所有支持Sativex®治疗HD患者疾病进展潜力的临床前证据。本文还介绍了一些关于大麻素的有前景的专利。
