Development of Novel Therapeutics for Postsurgical Pain

对乙酰氨基酚和非甾体抗炎药已被常规用于治疗疼痛和/或发烧。这种双重行为有时是禁忌的。在许多情况下，需要在不掩盖症状发热的情况下控制疼痛(例如，在术后期间)。这些药物可能会导致肝脏毒性，特别是在大剂量摄入或长期使用后(特别是在肝功能受损的情况下)，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效力，而且几乎没有肝、肾毒性或解热作用。在初步研究中，最初的化合物表现出高的止痛活性，没有解热和肝毒性。在第一阶段，我们进一步对这些初始化合物和其他几个类似物/衍生物进行了表征，并确定了一种主要的候选药物。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禁止使用对乙酰氨基酚的止痛治疗。我们还将使用体外和体内模型相结合的方法来评估I期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估来选择第二代候选药物。拟议的商业应用：据估计，美国止痛药市场的规模接近60亿美元。扑热息痛(以Tylenol(TM)和其他品牌名称销售)约占该市场的48%。对乙酰氨基酚虽然被广泛使用，但也有一些严重的副作用。显然，医学上对止痛药的需求尚未得到满足，这些止痛药有效，但安全性比对乙酰氨基酚更好。这项研究旨在开发一种止痛药，它与对乙酰氨基酚一样有效，但副作用更少。这种药物将针对那些最有可能受到对乙酰氨基酚中毒的患者，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，在这些患者中，对乙酰氨基酚掩盖发烧可能会推迟感染的诊断。

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.