Treatment of SLE with Ajulemic Acid, a Non-Psychoactive Cannabinoid Derivative

描述(申请人提供)：肌肉骨骼症状，如关节炎、肌腱炎和滑囊炎，在系统性红斑狼疮(SLE)中非常常见。这些症状引起的疼痛和残疾可能是严重的，目前SLE肌肉骨骼疼痛的治疗方案包括非类固醇抗炎药物(NSAIDs)、麻醉性止痛和皮质类固醇。其中每一种都受到重大潜在毒性的限制，包括非类固醇类药物的胃肠道出血和肾毒性，麻醉剂和骨质疏松症的嗜睡、便秘和恶心，骨坏死、糖尿病、白内障和皮质类固醇的动脉粥样硬化。阿魏酸(AJA)是从一类大麻素类化合物中提取的，它保留了止痛和抗炎的特性，但没有四氢大麻酚(THC；大麻)特有的精神药物作用。在动物研究和人类慢性神经性疼痛的临床试验中，AJA已被证明具有有效的止痛作用，而没有精神作用。AJA的抗炎作用也已在动物模型、人体受试者和人炎性细胞的体外研究中得到证实。到目前为止，共有123名受试者(健康人和神经病理性疼痛患者)接受了AJA治疗，没有严重的副作用。这项IIa期临床试验的总体目的是评估AJA对有轻到中度肌肉骨骼疼痛的SLE患者的安全性，并确定将提供最大益处和最小毒性的AJA最佳剂量。临床改善将通过评估SLE疾病活动性和疼痛程度的变化来确定。研究还计划评估AJA对循环炎症细胞的作用机制。根据我们实验室已经完成的临床前研究，我们预计AJA将减少外周血细胞中某些促炎蛋白的表达，并增加其他增强炎症消退的蛋白的表达。

DESCRIPTION (provided by applicant): Musculoskeletal symptoms, such as arthritis, tendonitis and bursitis, are very common in Systemic Lupus Erythematosus (SLE). Pain and disability from these symptoms can be significant and current treatment options for musculoskeletal pain in SLE include non-steroidal anti-inflammatory medications (NSAIDS), narcotic analgesia and corticosteroids. Each of these is limited by significant potential toxicitie including gastrointestinal bleeding and kidney toxicity in the case of NSAIDS, somnolence, constipation and nausea for narcotics and osteoporosis, osteonecrosis, diabetes, cataracts and atherosclerosis for corticosteroids. Ajulemic acid (AjA) is derived from a class of cannabinoids that retain analgesic and anti-inflammatory properties without the psychotropic effects characteristic of tetrahydrocannabinol (THC; marijuana). AjA has been shown to have potent pain- relieving effects, without psychotropic effects, in animal studies and a clinical trial in human subjects with chronic neuropathic pain. Anti-inflammatory effects of AjA have also been demonstrated in animal models as well as in human subjects and in vitro studies of human inflammatory cells. Thus far, a total of 123 subjects (healthy individuals and patients with neuropathic pain) have received AjA with no serious side effects. The overall purpose of this Phase IIa clinical trial is to evaluate the safety of AjA in SLE patients with mild to moderate musculoskeletal pain and to determine an optimum dose of AjA that will provide maximum benefit and minimal toxicity. Clinical improvement will be determined by assessment of SLE disease activity and changes in pain scales. Studies are also planned to evaluate the mechanisms of action of AjA on circulating inflammatory cells. Based on pre- clinical studies already completed in our laboratory, we expect that AjA will decrease the expression of certain pro-inflammatory proteins in peripheral blood cells and increase the expression of other proteins that enhance the resolution of inflammation.