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.