Novel drug combinations for the management of pain

一些止痛化合物的治疗用途往往受到限制，因为它们具有潜在的不良反应和 危险的副作用。然而，具有不同作用机制的镇痛剂的组合可能 增强止痛效果(协同作用)，同时减少个体剂量依赖的不良反应 组件。因此，开发具有协同作用的联合止痛药将有效地 减少每种化合物的剂量，从而在保持止痛效力的同时减少不良反应。 对乙酰氨基酚与阿片类药物(即氢可酮、可待因)的联合用药经常用于急性 和慢性疼痛管理。然而，尽管对乙酰氨基酚联合治疗有更好的疗效 中度到重度疼痛，是市场上最受欢迎的处方止痛药，它一直是 认识到即使在治疗剂量下，对乙酰氨基酚(和含有对乙酰氨基酚的混合物)也可以 会引起肝脏毒性。因此，止痛药与对乙酰氨基酚相似，但几乎没有或几乎没有 肝毒性，在这些组合中将是扑热息痛的有价值的替代品。支持的第一阶段 我们开发了一种无毒的对乙酰氨基酚类似物(SCP-1)，在其中我们探索了使用 该化合物与其他阿片类和非阿片类镇痛剂联合使用。我们的目标是确定两个SCP- 1个显示协同止痛特性的组合(一个阿片类药物和一个非阿片类药物)，并将 这是第二阶段进一步药物开发的基础。基于它们优越的协同止痛特性，SCP- 1+可待因和SCP-1+可乐定组合被确定为进一步开发的候选药物。在……下面 第二阶段支持，我们将进一步评估和筛选止痛药概况和不良反应 不同的SCP-1：可待因和SCP-1：可乐定组合比例(即配方)。这些结果将是 在第二阶段下进行关键的早期临床前GLP安全性研究的基础将在我们的 在第三阶段，我们将进行第一阶段的人体临床试验，以评估 正常人志愿者的耐受性和口服生物利用度，以及评估第二阶段人类临床试验 术后疼痛患者的联合用药情况。

The therapeutic use of some analgesic compounds are often limited because of potentially adverse and dangerous side-effects. However, combinations of analgesics with different mechanisms of action could enhance analgesic efficacy (synergy) while reducing the dose-dependent adverse effects of the individual components. The development of combination analgesics that are synergistic, therefore, would effectively reduce the dose of each compound, thus reducing the adverse effects while maintaining analgesic potency. Combinations of acetaminophen with opioids (i.e., hydrocodone, codeine) are frequently prescribed for acute and chronic pain management. However, although acetaminophen combinations have greater efficacy for moderate to severe pain and are some of the most popular prescription analgesics on the market, it has been recognized that even at therapeutic doses acetaminophen (andcombinations containing acetaminophen) can cause liver toxicity. Thus, a drug with a similar analgesic profile to acetaminophen, but with little or no hepatotoxicity, would be a valuable substitute for acetaminophen in these combinations. Phase I supported the development of a non-toxic acetaminophen analog (SCP-1) in which we explored the feasibility of using this compound in combination with other opioid and nonopioid analgesics. Our goal was to identify two SCP- 1 combinations (one opioid and one nonopioid) that displayed synergistic analgesic properties, and would be the basis for further drug development in Phase II. Based on their superior synergistic analgesic profile, SCP- 1+codeine and SCP-1+clonidine combinations were identified as candidates for further development. Under Phase II support we will evaluate and screen further the analgesic profiles and adverse side-effects of different SCP-1 : codeine and SCP-1 : clonidine combination ratios (i.e.formulations). These results will be the basis for conducting key early stage pre-clinical GLP safety studies under Phase II that will be used in our IND applications to the FDA.In Phase III we will conduct Phase I human clinical trials to evaluate tolerability and oral bioavailability in normal human volunteers, and Phase II human clinical trials to evaluate the combinations in postoperative pain patients.