Development of Novel Therapeutics for Postsurgical Pain

术后疼痛新疗法的开发

• 批准号: 6444220
• 负责人: KENNETH W NARDUCY
• 金额: $ 43.53万
• 依托单位: ST. CHARLES PHARMACEUTICALS
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-11-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6444220
• 关键词: acetaminophen; analgesics; antipyretic; dogs; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; hepatotoxin; laboratory mouse; laboratory rat; pain; postoperative complications; sweetening agents

Acetaminophen and NSAIDs have been used routinely for treatment of pain and/or fever. This dual action is sometimes contraindicated. In many instances, pain needs to be controlled without masking symptomatic fever (e.g., during the postoperative period). These drugs can cause hepatotoxicity, particularly after ingestion of large doses or from chronic use (especially when liver function has been compromised), which can lead to death. We are exploring a series of new and proprietary derivatives of acetaminophen that have good pharmacological potency and little hepatotoxic, nephrotoxic, or antipyretic effects. In preliminary studies, the initial compounds demonstrated high analgesic activity free from antipyretic activity and hepatotoxicity. In Phase I, we further characterized these initial compounds and several other analogs/derivatives and identified a lead candidate drug. We will further test and develop this drug in Phase II for treating postoperative pain and for other analgesic treatments where acetaminophen is contraindicated. We will also use a combination of in vitro and in vivo models to evaluate additional analogs and derivatives of the Phase I lead candidate drug. We will choose second-generation candidates based on efficacy, pharmacokinetic, and toxicity evaluations. PROPOSED COMMERCIAL APPLICATION: The market for pain relievers in the US is estimated to be approaching $6 billion. Acetaminophen (marketed under the name Tylenol(TM) and other brand names) represents about 48% of that market. Although widely used, acetaminophen is not without some serious side effects. There is a clear unmet medical need for pain relievers that are effective but have a better safety profile than acetaminophen. This research is directed at developing a pain reliever that is as effective as acetaminophen but with fewer side effects. This drug would be targeted at those patients most at risk from acetaminophen toxicity, particularly those who must take pain relievers on a chronic basis, and those with postoperative pain where masking of fever by acetaminophen could delay the diagnosis of infection.

对乙酰氨基酚和非甾体抗炎药已常规用于治疗疼痛和/或发烧。这种双重作用有时是禁忌的。在许多情况下，需要在不掩盖症状发烧的情况下控制疼痛（例如，在术后期间）。这些药物可引起肝毒性，特别是在大剂量摄入或长期使用后（特别是当肝功能受损时），这可能导致死亡。我们正在开发一系列新的、专有的对乙酰氨基酚衍生物，这些衍生物具有良好的药理作用，且具有较小的肝毒性、肾毒性或解热作用。在初步研究中，最初的化合物表现出高镇痛活性，且没有解热活性和肝毒性。在第一阶段，我们进一步表征了这些初始化合物和其他几种类似物/衍生物，并确定了一种主要候选药物。我们将在第二阶段进一步测试和开发这种药物，用于治疗术后疼痛以及对乙酰氨基酚禁忌的其他镇痛治疗。我们还将结合使用体外和体内模型来评估 I 期先导候选药物的其他类似物和衍生物。我们将根据功效、药代动力学和毒性评估来选择第二代候选药物。拟议的商业应用：美国止痛药市场估计接近 60 亿美元。对乙酰氨基酚（以 Tylenol(TM) 名称和其他品牌名称销售）约占该市场的 48%。尽管广泛使用，但对乙酰氨基酚并非没有一些严重的副作用。对于有效但比对乙酰氨基酚具有更好安全性的止痛药，显然存在未满足的医疗需求。这项研究旨在开发一种与对乙酰氨基酚一样有效但副作用更少的止痛药。该药物将针对那些最容易遭受对乙酰氨基酚中毒风险的患者，特别是那些必须长期服用止痛药的患者，以及术后疼痛的患者，因为对乙酰氨基酚掩盖发烧可能会延迟感染的诊断。