-
Pulmonary Pharmacology & Therapeutics Jun 2019Cough is a protective reflex that serves to clear the airways of excessive secretions and foreign matter and which sometimes becomes excessive, and troublesome to... (Review)
Review
Cough is a protective reflex that serves to clear the airways of excessive secretions and foreign matter and which sometimes becomes excessive, and troublesome to patients. Cough is one of the most common reasons why individuals seek medical attention. A range of drugs have been developed in the past with antitussive activity and different mechanisms of action, but there are still very few safe and effective treatments available. The poor tolerability of most available antitussives is closely related to their action on the central nervous system (CNS). An international group of experts specialized in cough met to discuss the need to identify an effective antitussive treatment with a good tolerability profile. The aim of this expert review is to increase the knowledge about the cough mechanism and the activity of levodropropizine, a peripherally acting antitussive drug.
Topics: Animals; Antitussive Agents; Cough; Drug Development; Humans; Propylene Glycols
PubMed: 30872161
DOI: 10.1016/j.pupt.2019.03.003 -
Clinical Pharmacology and Therapeutics Mar 2021Chronic cough, defined as a cough lasting > 8 weeks, is a common medical condition that exerts a substantial physical, mental, and social burden on patients. A subset... (Review)
Review
Chronic cough, defined as a cough lasting > 8 weeks, is a common medical condition that exerts a substantial physical, mental, and social burden on patients. A subset of patients with chronic cough are troubled with a cough that persists despite optimal treatment of presumed associated common and uncommon conditions (refractory chronic cough; RCC) or in which no diagnosable cause for cough can be identified despite extensive assessment (unexplained chronic cough; UCC). Many of these patients exhibit clinical features of cough hypersensitivity, including laryngeal paresthesia, hypertussia, and allotussia. Over-the-counter cough remedies are ineffective and can lead to intolerable side effects when used for RCC/UCC, and the lack of approved treatments indicated for these conditions reflects a major unmet need. An increased understanding of the anatomy and neurophysiology of protective and pathologic cough has fostered a robust clinical development pipeline of several targeted therapies for RCC/UCC. This manuscript reviews the mechanisms presumed to underly RCC/UCC together with the rationale and clinical evidence for several targeted therapies currently under clinical investigation, including transient receptor potential channel antagonists, P2X3-receptor antagonists, voltage-gated sodium channel blockers, neuromodulators, and neurokinin-1-receptor antagonists. Finally, we provide an overview of targets that have been investigated in preclinical models of cough and other airway diseases that may hold future promise for clinical studies in RCC/UCC. Development of targeted therapies with different sites of action may foster a precision medicine approach to treat this heterogeneous, underserved patient population.
Topics: Animals; Antitussive Agents; Chronic Disease; Cough; Drug Design; Humans; Molecular Targeted Therapy; Signal Transduction
PubMed: 32748976
DOI: 10.1002/cpt.2003 -
Pharmacological Reviews 2014Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal... (Review)
Review
Cough remains a serious unmet clinical problem, both as a symptom of a range of other conditions such as asthma, chronic obstructive pulmonary disease, gastroesophageal reflux, and as a problem in its own right in patients with chronic cough of unknown origin. This article reviews our current understanding of the pathogenesis of cough and the hypertussive state characterizing a number of diseases as well as reviewing the evidence for the different classes of antitussive drug currently in clinical use. For completeness, the review also discusses a number of major drug classes often clinically used to treat cough but that are not generally classified as antitussive drugs. We also reviewed a number of drug classes in various stages of development as antitussive drugs. Perhaps surprising for drugs used to treat such a common symptom, there is a paucity of well-controlled clinical studies documenting evidence for the use of many of the drug classes in use today, particularly those available over the counter. Nonetheless, there has been a considerable increase in our understanding of the cough reflex over the last decade that has led to a number of promising new targets for antitussive drugs being identified and thus giving some hope of new drugs being available in the not too distant future for the treatment of this often debilitating symptom.
Topics: Animals; Antitussive Agents; Clinical Trials as Topic; Cough; Drug Discovery; Humans; Molecular Structure; Molecular Targeted Therapy
PubMed: 24671376
DOI: 10.1124/pr.111.005116 -
Drug Discovery Today Apr 2013Acute and chronic cough represent one of the most common symptoms of medical importance but effective pharmacotherapy is, to all intents and purposes, absent. Numerous... (Review)
Review
Acute and chronic cough represent one of the most common symptoms of medical importance but effective pharmacotherapy is, to all intents and purposes, absent. Numerous initiatives targeting the recently discovered tussive pathways are in progress. Here, we review the current antitussive armamentarium and provide an update on the novel strategies and compounds in development.
Topics: Animals; Antitussive Agents; Cough; Humans
PubMed: 23159360
DOI: 10.1016/j.drudis.2012.11.004 -
Journal of the Iowa Medical Society Feb 1973
Topics: Antitussive Agents; Dose-Response Relationship, Drug; Humans; Narcotics
PubMed: 4687454
DOI: No ID Found -
Clinical Therapeutics 1997The antitussive dimemorfan phosphate was discovered through extensive screening of morphinic derivatives and was introduced in Japan in 1975. The majority of studies on... (Review)
Review
The antitussive dimemorfan phosphate was discovered through extensive screening of morphinic derivatives and was introduced in Japan in 1975. The majority of studies on dimemorfan have been published in Japanese, and this review aims to make these data more generally available. The antitussive action of dimemorfan appears to be directly on the cough center in the medulla. Dimemorfan does not induce any significant physical or psychologic dependence, and its antitussive action is not affected by the opioid-receptor blocker levallorphan. Dimemorfan is therefore considered a nonnarcotic antitussive. Studies of antitussive effects in animal models indicate that dimemorfan is up to three times more potent than codeine and is equivalent to dextromethorphan. Three major comparative clinical trials and postmarketing surveillance studies showed that dimemorfan is equally or slightly more efficacious than dextromethorphan, benproperine phosphate, or placebo for the control of coughing. Several animal and clinical studies have confirmed the efficacy and safety of dimemorfan. Dimemorfan was effective in the majority of patients. In contrast to the narcotic antitussives, dimemorfan caused no serious problems with the digestive system, such as constipation and disorders of the bile duct, caused no dependence or tolerance, and was unlikely to have clinical analgesic effects. Minor side effects, such as loss of appetite, nausea, and drowsiness, were seen in less than 10% of patients. A syrup formulation of dimemorphan that retains its efficacy and safety is also available. Overall, these data indicate that dimemorfan is an effective nonnarcotic antitussive agent with a low incidence of adverse events.
Topics: Animals; Antitussive Agents; Clinical Trials as Topic; Cough; Humans; Lethal Dose 50; Morphinans
PubMed: 9152562
DOI: 10.1016/s0149-2918(97)80111-7 -
ACS Chemical Neuroscience Jun 2023Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used... (Review)
Review
Dextromethorphan (DXM) was introduced in 1958 as the first non-opioid cough suppressant and is indicated for multiple psychiatric disorders. It has been the most used over-the-counter cough suppressant since its emergence. However, individuals quickly noticed an intoxicating and psychedelic effect if they ingested large doses. DXM's antagonism at -methyl-d-aspartate receptors (NMDAr) is thought to underly its efficacy in treating acute cough, but supratherapeutic doses mimic the activity of dissociative hallucinogens, such as phencyclidine and ketamine. In this Review we will discuss DXM's synthesis, manufacturing information, drug metabolism, pharmacology, adverse effects, recreational use, abuse potential, and its history and importance in therapy to present DXM as a true classic in chemical neuroscience.
Topics: Humans; Antitussive Agents; Dextromethorphan; Hallucinogens; Phencyclidine; Ketamine; Receptors, N-Methyl-D-Aspartate
PubMed: 37290117
DOI: 10.1021/acschemneuro.3c00088 -
Journal of Clinical Pharmacy and... Feb 1988Pholcodine has antitussive activity similar to, or somewhat greater than, that of codeine in animal test systems. The drug, which has been formulated in many combination... (Review)
Review
Pholcodine has antitussive activity similar to, or somewhat greater than, that of codeine in animal test systems. The drug, which has been formulated in many combination medications (45)--some rational and some quite irrational pharmacologically--also appears to be active in man, although the clear-cut demonstrations, unfortunately, are in artificially-induced cough models. Additional efficacy studies are needed. Preclinical toxicity studies demonstrate a generally safer profile for pholcodine than codeine, although pholcodine appears to have greater depressant effects on the respiratory and cardiovascular systems in animals. These effects have not been observed in man after administration of therapeutic doses. Pholcodine appears to be devoid of addiction liability in man. In contrast to codeine, pholcodine is not metabolised to morphine in man, a fact which may contribute to its more favourable toxicity profile, and it is metabolised and eliminated much more slowly than codeine.
Topics: Antitussive Agents; Codeine; Humans; Morpholines
PubMed: 3283158
DOI: 10.1111/j.1365-2710.1988.tb00502.x -
The New England Journal of Medicine Jul 1953
Topics: Antitussive Agents; Cough; Morphine Derivatives
PubMed: 13063699
DOI: 10.1056/NEJM195307232490402 -
Mutation Research. Genetic Toxicology... 2018Benzonatate (TESSALON) is a peripherally acting oral antitussive. It undergoes rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated...
Benzonatate (TESSALON) is a peripherally acting oral antitussive. It undergoes rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated polyethylene glycol (MPG) metabolites, which are eliminated in urine and feces. The nonclinical and clinical efficacy of Benzonatate has been demonstrated over the last 60 years, but its safety was not fully assessed. In this study, we tested the genotoxicity of Benzonatate and its major metabolite BBA in an in vitro bacterial reverse mutation and in vivo micronucleus assays. A chromosomal aberration assay was also performed on Benzonatate and BBA. In the reverse mutation assay, Benzonatate and BBA doses 1.5-5000 μg/plate ± S9 metabolic activation were used and the numbers of revertants/plate were compared to various controls. Chromosomal aberration assays with human peripheral blood lymphocytes used Benzonatate and BBA concentrations 25-2000 and 62.5-1930 μg/mL, respectively. A CByB6F1 mouse bone marrow micronucleus assay was performed as part of a 28-day oral toxicology study at up to 250 mg/kg/day. The frequencies of micronuclei in polychromatic erythrocytes in treated groups were compared with the control group. Neither Benzonatate nor BBA induced significant mutagenicity in any of the bacterial strains, with or without metabolic activation. They also did not produce any biologically relevant structural or numerical aberrations in human chromosomes. Benzonatate and its BBA and MPG metabolites rapidly produced from esterase activity did not produce any significant increase in the incidence of micronucleated polychromatic erythrocytes. In conclusion, Benzonatate and its major metabolite BBA were not mutagenic and did not cause numerical or structural chromosome alterations. While the MPG metabolite was not tested, studies on structural analogues indicated it was also unlikely to be genotoxic. This was supported by oral rodent carcinogenicity assays showing no increase in malignancies.
Topics: Adult; Animals; Antitussive Agents; Bone Marrow Cells; Butylamines; Chromosome Aberrations; Dose-Response Relationship, Drug; Escherichia coli; Female; Humans; Lymphocytes; Male; Mice; Micronuclei, Chromosome-Defective; Micronucleus Tests; Mutagenicity Tests; Salmonella typhimurium; Young Adult
PubMed: 29704989
DOI: 10.1016/j.mrgentox.2018.03.007