Antidiabetic effects of inosine

描述(摘自申请者摘要)：炎症性胰岛细胞 新发1型糖尿病的损伤是一种自身免疫组织损伤， 可能从造成胰岛损伤的恶性状态“切换”到 一种良性状态，很少或根本没有β细胞损伤。后者 这个过程涉及对免疫系统的适当刺激，并通过 通过免疫反应的发展，这可能需要数周或 可能要几个月才能完全有效。所需要的是一种治疗方法 在所需时间内控制急性胰岛损伤的干预措施 新城疫“蜜月期”恶性免疫反应的调节 这种疾病。我们现在提供的新数据表明，可能存在一种战略 这既可以阻止蜜月期间对胰岛的破坏，也可以 也可用于预防胰岛移植后复发 糖尿病患者。这一策略涉及到使用消炎药 嘌呤，肌苷，以阻止持续的炎症性胰岛β细胞损伤，而 自身免疫反应正从恶性转变为良性 州政府。我们最近的数据表明，出乎意料的是，无毒的 嘌呤肌苷具有多种抗炎和免疫调节作用。 肌苷抑制促炎症细胞因子的产生 胰岛细胞损伤，包括肿瘤坏死因子-α、白介素1、白介素12、巨噬细胞炎症 蛋白-1-α和干扰素-γ。此外，肌苷还提高了黄瓜的产量。 抗炎细胞因子IL-10。肌苷肠内注射给药 链脲佐菌素-糖尿病大鼠显著延缓糖尿病和糖尿病的发展 降低患糖尿病的动物比例。这些影响是 与胰腺胰岛素含量的显著保存和 对胰岛内细胞因子产生的有益调节。在当前 应用方面，我们建议利用糖尿病的NOD模型进行进一步的研究 确定肌苷抑制糖尿病发展的有效性，并 建立干预治疗窗口。鉴于肌苷是一种 经批准的非处方药营养补充剂，并有良好的记录 人类的安全性，我们设想了一条加速的临床前和临床路径 如果肌苷证实在NOD模型中有效，则开发。 建议的商业应用： 一种安全有效的自身免疫性糖尿病治疗方法的市场估计在&gt； 在美国每年10亿美元。

DESCRIPTION (Scanned from the Applicant's Abstract): Inflammatory islet cell injury in new-onset Type 1 diabetes is a form of autoimmune tissue injury that may be "switched" from the malignant state responsible for islet damage to a benign condition where little or no beta-cell damage occurs. This latter process involves appropriate stimulation of the immune system and is mediated by the development of an immune response that is likely to take weeks or possibly months to be completely effective. What is required is a therapeutic intervention that will control acute islet damage during the time needed for the adjustment of the malignant immune response during the "honeymoon" phase of the disease. We now present new data which suggest that there may be a strategy that could both arrest islet damage during the honeymoon phase, and which could also be used to prevent recurrent disease when islets are transplanted to diabetic individuals. This strategy involves the use of the anti-inflammatory purine, inosine, to arrest ongoing inflammatory islet beta-cell damage, while the autoimmune response is being converted from the malignant to the benign state. Our recent data have demonstrated that unexpectedly, the non-toxic purine inosine exerts multiple anti-inflammatory and immunomodulatory effects. Inosine suppresses the production of pro-inflammatory cytokines implicated in islet-cell injury, including TNF-alpha, IL-1, IL-12, macrophage-inflammatory protein-1-alpha, and IFN-gamma. Further, inosine enhanced the production of the anti-inflammatory cytokine IL-10. Enteral administration of inosine to streptozotocin-diabetic rats markedly delays the development of diabetes and reduces the proportion of animals that develop diabetes. These effects are associated with a significant preservation of pancreatic insulin content and a beneficial modulation of intraislet cytokine production. In the current application, we propose further studies, using the NOD model of diabetes, to establish the efficacy of inosine in suppressing diabetes development and to establish the therapeutic window of intervention. Given that inosine is an approved over-the-counter nutritional supplement and has an excellent record of safety in man, we envision an accelerated path of preclinical and clinical development, if inosine confirms to be effective in the NOD model. PROPOSED COMMERCIAL APPLICATION: The market for a safe and effective therapy for autoimmune diabetes is estimated at > $1 billion in the US per annum.