Development of Novel Therapeutics for Postsurgical Pain

对乙酰氨基酚和NSAID已常规用于治疗疼痛和/或发热。这种双重作用有时是禁忌的。在许多情况下，需要在不掩盖症状性发热的情况下控制疼痛（例如，术后期间）。这些药物可引起肝毒性，特别是在摄入大剂量或长期使用后（特别是当肝功能受损时），可导致死亡。我们正在探索一系列新的和专有的对乙酰氨基酚衍生物，具有良好的药理效力和肝，肾毒性小，或解热作用。在初步研究中，初始化合物表现出高镇痛活性，无解热活性和肝毒性。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，用于治疗术后疼痛和其他对乙酰氨基酚禁忌的镇痛治疗。我们还将使用体外和体内模型的组合来评估I期先导候选药物的其他类似物和衍生物。我们将根据疗效、药代动力学和毒性评价选择第二代候选药物。拟议的商业应用：美国的止痛药市场估计接近60亿美元。对乙酰氨基酚（以Tylenol（TM）和其他品牌名称销售）占该市场的48%左右。虽然被广泛使用，但醋氨酚并非没有一些严重的副作用。对于有效但安全性优于对乙酰氨基酚的止痛药，存在明显未满足的医疗需求。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。这种药物将针对那些最有可能受到对乙酰氨基酚毒性影响的患者，特别是那些必须长期服用止痛药的患者，以及那些术后疼痛的患者，其中对乙酰氨基酚掩盖发烧可能会延迟感染的诊断。

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.