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Antitussive Drugs—Past, Present, and Future

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Antitussive Drugs—Past, Present, and Future 1521-0081/66/2/468–512$25.00 http://dx.doi.org/10.1124/pr.111.005116 PHARMACOLOGICAL REVIEWS Pharmacol Rev 66:468–512, April 2014 Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: DAVID R. SIBLEY Antitussive Drugs—Past, Present, and Future P.V. Dicpinigaitis, A.H. Morice, S.S. Birring, L. McGarvey, J.A. Smith, B.J. Canning, and C.P. Page Albert Einstein College of Medicine and Montefiore Medical Centre, Department of Medicine, Bronx, New York (P.V.D);Centre for Cardiovascular and Metabolic Medicine, Castle Hill Hospital, Hull York Medical School, University of Hull, Hull, United Kingdom (A.H.M.); Division of Asthma, Allergy & Lung Biology, King’s College London, Denmark Hill, London, United Kingdom (S.S.B.); Centre for Infection and Immunity, Queen’s University Belfast, Belfast, United Kingdom (L.M.); Respiratory Research Group, University of Manchester, University Hospital of South Manchester, Manchester, United Kingdom (J.A.S.); Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland (B.J.C.); and Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, Franklin-Wilkins Building, London, United Kingdom (C.P.P.) Abstract ....................................................................................469 I. Cough as an Unmet Clinical Problem . ......................................................469 II. Basic Physiology of the Cough Reflex. ......................................................470 III. Drugs in Current Use for the Treatment of Cough. ..........................................472 Downloaded from A. H1-Receptor Antagonists................................................................472 B. Dextromethorphan . ..................................................................473 C. Opiates: Codeine and Morphine. ......................................................476 D. Local Anesthetics.......................................................................478 E. Caramiphen ............................................................................479 at Open University Library on January 27, 2020 F. Carbetapentane (Also Known as Pentoxyverine).........................................480 G. Chlophedianol . ........................................................................480 H. Levodropropizine .......................................................................480 IV. Other Drugs Having an Effect on Cough ....................................................482 A. Menthol and TRPM8 Agonists ..........................................................483 B. Erdosteine .............................................................................483 C. Antibiotics .............................................................................484 D. Glucocorticosteroids . ..................................................................485 E. b2-Agonists.............................................................................486 F. Muscarinic Receptor Antagonists . ......................................................487 G. Mucolytics and Expectorants............................................................488 H. Antacids/Proton Pump Inhibitors and Gastrointestinal Motility Drugs ...................489 I. Xanthines ..............................................................................491 J. Cromones ..............................................................................491 V. New Approaches to Treating Cough . ......................................................492 A. Levocloperastine........................................................................492 B. Amitriptyline. ........................................................................492 C. Novel N-Methyl-D-aspartate Receptor Antagonists. .....................................492 D. Glaucine . ..............................................................................493 E. Moguisteine ............................................................................494 F. Phosphodiesterase Inhibitors ...........................................................494 G. K+ Channel Openers. ..................................................................494 H. Cl2 Pump Inhibitors. ..................................................................495 I. Ouabain-Sensitive Na+-K+ ATPase Inhibitors . ..........................................495 J. Leukotriene Receptor Antagonists ......................................................496 K. Interferon-a ............................................................................497 L. Tropan Derivatives with High Affinity for the Nociceptin Opioid Receptor (Nociceptin) . 498 Address correspondence to: C. P. Page, King’s College London, Franklin Wilkins Building, 100 Stamford St., London, SE1 9NH, UK. E-mail: [email protected] P.V.D., A.H.M., S.S.B., L.M., J.A.S., B.C., and C.P.P. contributed equally to this work. dx.doi.org/10.1124/pr.111.005116 468 Antitussive Drugs 469 M. Selective Cannabinoid 2 Receptor Agonists..............................................498 N. Neurokinin Receptor Antagonists . ......................................................498 O. Transient Receptor Potential Vanilloid 1 Receptor Antagonists . .........................499 P. Transient Receptor Potential A1 Receptor Antagonists...................................499 Q. VRP700 . ..............................................................................500 R. GABA Receptor Agonists . ............................................................500 S. E121 ...................................................................................501 T. Gabapentin.............................................................................501 U. Thalidomide............................................................................502 V. Botulinum A Toxin . ..................................................................502 W. NaV Channel Blockers ..................................................................502 X. P2X2/3 Antagonists. ..................................................................502 VI. Clinical Trial Design for Evaluation of Antitussive Drugs....................................502 VII. Conclusions—What’s Needed................................................................503 References..................................................................................503 Abstract——Cough remains a serious unmet clinical We also reviewed a number of drug classes in various problem, both as a symptom of a range of other stages of development as antitussive drugs. Perhaps conditions such as asthma, chronic obstructive pulmo- surprising for drugs used to treat such a common nary disease, gastroesophageal reflux, and as a problem symptom, there is a paucity of well-controlled clinical initsownrightinpatientswithchroniccoughof studies documenting evidence for the use of many of the unknown origin. This article reviews our current un- drug classes in use today, particularly those available derstanding of the pathogenesis of cough and the over the counter. Nonetheless, there has been a con- hypertussive state characterizing a number of diseases siderable increase in our understanding of the cough as well as reviewing the evidence for the different reflex over the last decade that has led to a number of classes of antitussive drug currently in clinical use. For promising new targets for antitussive drugs being completeness, the review also discusses a number of identified and thus giving some hope of new drugs major drug classes often clinically used to treat cough being available in the not too distant future for the but that are not generally classified as antitussive drugs. treatment of this often debilitating symptom. I. Cough as an Unmet Clinical Problem a significant number of patients (Everett et al., 2007), even when an underlying cause has been identified Cough is an important protective reflex and a univer- (Birring et al., 2004). Cough is associated with signifi- sal symptom in health, but when persistent, it is the cantly impaired health-related quality of life (French most common reason why patients seek medical atten- et al., 1998), regardless of whether it is acute or chronic tion. In epidemiologic studies, up to 40% of the popu- (Birring et al., 2003a; Yousaf et al., 2011). Sleep dis- lation at any one time report cough (Janson et al., 2001). turbance, nausea, chest pains, and lethargy occur Upper respiratory tract infection (URTI) or the common frequently, and patients with chronic cough often cold is by far the most common cause of cough, but experience social embarrassment, urinary incontinence, postinfectious cough, unexplained chronic cough, and and low mood (Brignall et al., 2008). There is a signifi- cough due to pulmonary disorders such as asthma, cant economic cost for the individual with cough and chronic obstructive pulmonary disease (COPD), idio- society when it leads to absence from work and lost pathic pulmonary fibrosis, and lung cancer are also productivity. common. In children, the etiology of cough differs from The clinical need for nonspecific antitussive drugs is adults; viral URTI, protracted bacterial bronchitis, and reflected by the large sales of such medications: $3 asthma are frequently the cause of cough (de Jongste billion/year in the United States alone and rising in and Shields, 2003). However, it is well recognized among recent years (Footitt and Johnston, 2009) (Fig. 1). A clinicians that cough is refractory to specific therapy
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