Novel drug combinations for the management of pain

用于治疗疼痛的新型药物组合

• 批准号: 7054738
• 负责人: KENNETH W NARDUCY
• 金额: $ 53.57万
• 依托单位: ST. CHARLES PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7054738
• 关键词: Absence of pain sensation; Acetaminophen; Acute; Adverse effects; Analgesics; Animals; Biological Assay; Biological Availability; Canis familiaris; Cardiovascular system; Clinical Trials; Clonidine; Codeine; Condition; Dependence; Development; Doctor of Philosophy; Dose; Drug Combinations; Drug Formulations; Formalin; Funding; Glutathione; Goals; Hepatotoxicity; Human; Human Volunteers; Hydrocodone; Individual; Lead; Liver; Marketing; Modeling; Mus; Opioid; Oral; Oxycodone; Pain; Pain management; Patients; Pharmaceutical Preparations; Phase; Plasma; Postoperative Pain; Property; Range; Rattus; Research Personnel; SCP 1; Safety; Staging; Testing; Therapeutic; Therapeutic Uses; Time; Toxic effect; Tramadol; Transaminases; United States Food and Drug Administration; Xylazine; analog; base; chronic pain; drug development; non-opioid analgesic; novel; pre-clinical; preference; prescription document; prescription procedure; programs; sedative

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.

一些镇痛化合物的治疗用途常常受到限制，因为可能存在不良反应和副作用。 危险的副作用。然而，具有不同作用机制的镇痛药的组合可能会 增强镇痛功效（协同作用），同时减少个体剂量依赖性不良反应 成分。因此，开发具有协同作用的组合镇痛药将有效地 减少每种化合物的剂量，从而减少副作用，同时保持镇痛效力。 对乙酰氨基酚与阿片类药物（即氢可酮、可待因）的组合经常用于治疗急性发作 和慢性疼痛管理。然而，尽管对乙酰氨基酚联合用药具有更大的功效 中度至重度疼痛，是市场上最受欢迎的处方镇痛药之一， 认识到即使在治疗剂量下，对乙酰氨基酚（以及含有对乙酰氨基酚的组合）也可以 引起肝毒性。因此，一种与对乙酰氨基酚具有相似镇痛作用但几乎没有或没有镇痛作用的药物 肝毒性，将是这些组合中对乙酰氨基酚的有价值的替代品。第一阶段支持 开发无毒的对乙酰氨基酚类似物（SCP-1），其中我们探索了使用的可行性 该化合物与其他阿片类和非阿片类镇痛药联合使用。我们的目标是识别两个 SCP- 1 种组合（一种阿片类药物和一种非阿片类药物）显示出协同镇痛特性，并且将 为二期进一步药物开发奠定基础。基于其卓越的协同镇痛作用，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镇痛特性和不良副作用 不同的 SCP-1：可待因和 SCP-1：可乐定组合比例（即制剂）。这些结果将是 第二阶段进行关键早期临床前 GLP 安全性研究的基础，该研究将用于我们的 向FDA申请IND申请。在III期我们将进行I期人体临床试验来评估 正常人类志愿者的耐受性和口服生物利用度，以及 II 期人体临床试验来评估 术后疼痛患者的组合。