Antitussive effects of memantine in guinea pigs.
BACKGROUND
The treatment of cough is a significant clinical unmet need because there is little evidence that current therapies are effective. Based on evidence supporting a role for N-methyl D-aspartate receptors (NMDARs) in cough, we hypothesized that memantine, a low-affinity, uncompetitive NMDAR channel blocker in routine use for the treatment of Alzheimer disease, could be an effective, well-tolerated, antitussive therapy. The aim of this study was to establish preclinical evidence that memantine has antitussive effects.


METHODS
We studied the influence of memantine on experimentally induced coughing in response to citric acid and bradykinin inhalation in guinea pigs. We also compared the potency and efficacy of memantine as an antitussive to other NMDAR antagonists, dextromethorphan and ketamine, and to the γ-aminobutyric acid class B receptor agonist baclofen.


RESULTS
Compared with control subjects, 10 mg/kg memantine significantly reduced the cumulative number of coughs evoked by both citric acid (median, 24.0 [interquartile range (IQR), 13.0-25.5] vs 1.5 [IQR, 0.3-10.3] coughs; P = .012) and bradykinin aerosols (median, 16.0 [IQR, 9.5-18.5] vs 0.0 [IQR, 0-0.75] coughs; P = .002). Memantine 10 mg/kg produced a similar reduction in the cumulative number of coughs to baclofen 3 mg/kg and demonstrated comparatively greater cough suppression than 30 mg/kg dextromethorphan or 30 mg/kg ketamine. This dose of memantine produced no sedative or respiratory depressive effects.


CONCLUSIONS
This study illustrates that memantine has marked antitussive effects in guinea pigs, most likely mediated through NMDAR channel blockade. Memantine, therefore, has the potential to be a safe, effective, and well-tolerated antitussive agent.
Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD; Respiratory Research Group, The University of Manchester, University Hospital of South Manchester, Manchester, England.
Jaclyn A
JA
Smith
Respiratory Research Group, The University of Manchester, University Hospital of South Manchester, Manchester, England.
Emma C Y
ECY
Hilton
Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD.
Loren
L
Saulsberry
Department of Medicine, Division of Allergy and Clinical Immunology, Johns Hopkins Asthma and Allergy Center, Baltimore, MD. Electronic address: bjc@jhmi.edu.
Brendan J
BJ
Canning
D000818:Animals; D000996:Antitussive Agents / Q000494:pharmacology*; D001418:Baclofen / Q000494:pharmacology; D001920:Bradykinin; D019343:Citric Acid; D003371:Cough / Q000139:chemically induced / Q000188:drug therapy; D003915:Dextromethorphan / Q000494:pharmacology; D006168:Guinea Pigs; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D008559:Memantine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000032:analysis; D012701:Serotonin / Q000494:pharmacology
D000996:Antitussive Agents; D019343:Citric Acid; D012701:Serotonin; D016202:N-Methylaspartate; D007649:Ketamine; D008464:Mecamylamine; D003915:Dextromethorphan; D001418:Baclofen; D001920:Bradykinin; D008559:Memantine