Preclinical Development of a Novel and Effective Treatment for Cough

描述（由申请人提供）：对症止咳治疗的主要药物右美沙芬（DXM）和可待因在大多数对照临床试验中并不比安慰剂好，并且有很高的滥用风险。在过去的几十年里，由于缺乏对咳嗽机制的了解，阻碍了新疗法的发现。最近外周咳嗽受体和NMDA受体在中枢咳嗽门控机制中的作用的发现，导致观察到美金刚（MMT），一种用于治疗痴呆的注册药物，在动物模型中具有深刻的止咳作用。MMT阻断激活的NMDA离子通道，同时保持NMDA受体的稳态功能，并且在老年人中具有显著的疗效和无滥用风险和副作用的临床特征。该提案的长期目标是通过加速（505(b)2）注册途径，在FDA注册MMT作为安全有效的止咳药，无重大滥用责任。口服MMT达到最大浓度的时间非常慢（TMAX ~ 4 ~ 6小时），半衰期很长（T1/2 ~ 60 ~ 80小时）。这些特性极大地限制了MMTs在咳嗽中的潜在临床应用，因为理想情况下，止咳药应该具有快速起效，并且允许每天至少两次给药。该提案的近期目标是创建临床前数据集，以支持向FDA提交新药研究申请，并设计一种新型液体MMT配方，具有增强的药代动力学，特别是更快的起效和更短的作用时间。因此，本提案的具体目标包括：1)开发具有改善药代动力学（起效时间和作用持续时间）的新型MMT配方原型；2)完成机制研究，以证明MMT比DXM或可待因更有效，更有效地抑制咳嗽。该研究策略结合了CBDM和JHMI的专业知识和资源。对于Aim 1，我们将筛选FDA非活性成分清单中列出的辅料，以评估其使用体外上皮细胞单层加速MMT动力学的能力。最有希望的赋形剂将被联合使用，并在体外进一步研究其协同作用。最后，最有希望的组合将作为配方原型进行动物试验，以评估其对MMT药代动力学的增强作用。对于Aim 2， MMT的止咳作用将在豚鼠模型中进一步验证，并建立配方和未配方MMT的剂量反应曲线。还将评估MMT与其他药物（薄荷醇和氨溴索）联合使用的止咳协同作用。通过体内实验方法，我们将评估MMT对缓激肽、辣椒素和柠檬酸致咳嗽的效价、疗效和作用时间，并与DXM和可待因进行比较。这些研究也将用于执行具体目标1中描述的药代动力学测量。

DESCRIPTION (provided by applicant): The mainstays of symptomatic antitussive therapy, dextromethorphan (DXM) and codeine, are no better than placebo in the majority of controlled clinical trials and have high abuse liability. A lack of knowledge regarding the mechanisms of cough has hindered the discovery of new treatments over the past few decades. Recent discoveries of peripheral cough receptors and of the role of NMDA receptors in central cough gating mechanisms have led to the observation that memantine (MMT), a registered drug for the treatment of dementia, is a profound antitussive in animal models. MMT blocks activated NMDA ion channels while preserving homeostatic NMDA receptor function and has a clinical profile in the elderly that is remarkable for its efficacy and the absence of abuse liability and side effects. The long term objective of this proposal is to register MMT with the FDA as a safe and effective antitussive that is free of significant abuse liability, via an accelerated (505(b)2) registration pathway. Oral MMT has a very slow time to maximum concentration (TMAX ~ 4 - 6 hrs) and a long half-life (T1/2 ~ 60 - 80 hrs). These properties greatly limit MMTs potential clinical utility in cough, as an antitussive should ideally have a rapid onset of action and allow for at least twice daily dosing. The immediate goals of this proposal are to create preclinical data sets to support an Investigational New Drug application to the FDA and to design a novel liquid MMT formulation with enhanced pharmacokinetics, specifically faster onset and shorter duration of action. Therefore, the Specific Aims for this proposal include: 1) develop novel MMT formulation prototypes with improved pharmacokinetics (time to onset and duration of effect), and 2) complete mechanistic studies to demonstrate that MMT will be more potent and more effective at inhibiting cough than DXM or codeine. The research strategy utilizes the combined expertise and resources of CBDM and JHMI. For Aim 1, we will screen excipients listed in the FDA Inactive Ingredient List for their ability to accelerate MMT kinetics using in vitro epithelial cell monolayers. The most promising excipients will be combined and further investigated in vitro for synergies. Finally, the most promising combinations will be administered, as formulation prototype(s), to animals in order to assess their enhancement of MMT pharmacokinetics. For Aim 2, the antitussive effect of MMT will be further validated in the guinea pig model and a dose response curve established for both formulated and unformulated MMT. Antitussive synergy of MMT in combination with other agents (menthol and ambroxol) will also be evaluated. Using in vivo methods, we will evaluate the potency, efficacy and duration of action of MMT against bradykinin, capsaicin and citric acid-induced cough, compared to DXM and codeine. These studies will also be utilized to perform the pharmacokinetic measures that are described in Specific Aim 1. PUBLIC HEALTH RELEVANCE: Cough is the most common presenting symptom in patients seeking primary medical care and a mechanism of transmission of all forms of influenza, tuberculosis and pertussis. Despite this, cough remains a condition for which safe and effective treatments do not exist. We propose that the introduction of a safe and effective antitussive will reduce the economic and healthcare burdens of cough, and significantly improve the quality of life for those suffering from chronic cough.