Preclinical Development of a Novel and Effective Treatment for Cough

描述(申请人提供)：症状镇咳治疗的主要药物，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，并且有很高的滥用倾向。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。最近发现的外周咳嗽受体和NMDA受体在中枢止咳机制中的作用导致观察到美金刚(MMT)，一种治疗痴呆的注册药物，在动物模型中是一种深刻的镇咳药。MMT阻断激活的NMDA离子通道，同时保留稳态的NMDA受体功能，在老年人中具有显着的临床特征，其疗效显著，没有滥用倾向和副作用。这项提案的长期目标是通过加速(505(B)2)注册途径，向FDA注册MMT作为一种安全有效的镇咳药，没有重大的滥用责任。口服MMT达到最大浓度的时间很慢(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在咳嗽方面的潜在临床应用，因为理想情况下，镇咳药应该起效迅速，并允许每天至少两次剂量。这项建议的直接目标是创建临床前数据集，以支持向FDA提交的研究性新药申请，并设计一种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的新型液体MMT配方。因此，这项建议的具体目标包括：1)开发具有改进的药代动力学(起效时间和作用持续时间)的新型MMT制剂原型，以及2)完整的机制研究，以证明MMT将比DXM或可待因更有效和更有效地抑制咳嗽。该研究战略利用了CBDM和JHMI的专业知识和资源。对于目标1，我们将筛选FDA非活性成分列表中列出的辅料，以了解它们使用体外上皮细胞单层加速MMT动力学的能力。最有希望的辅料将被组合在一起，并在体外进一步研究协同作用。最后，最有希望的组合将作为配方原型(S)应用于动物，以评估它们对MMT药代动力学的增强作用。对于目标2，MMT的镇咳作用将在豚鼠模型中进一步验证，并建立配方和非配方MMT的剂量反应曲线。MMT与其他药物(薄荷醇和氨溴索)联合使用的镇咳协同作用也将得到评估。使用体内方法，我们将评估MMT对缓激肽、辣椒素和柠檬酸诱导的咳嗽的效力、疗效和持续时间，并与地塞米松和可待因进行比较。这些研究还将用于实施具体目标1中描述的药代动力学措施。 公共卫生相关性：咳嗽是寻求初级医疗的患者最常见的症状，也是所有形式的流感、结核病和百日咳的传播机制。尽管如此，咳嗽仍然是一种安全有效的治疗方法。我们认为，引入一种安全有效的镇咳药物将减轻咳嗽带来的经济和医疗负担，并显著提高慢性咳嗽患者的生活质量。

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.