Chlorpheniramine Intranasal Spray to Accelerate COVID-19 Clinical Recovery in an Outpatient Setting: The ACCROS Trials

{ 'institution': [{'name': 'Research Square'}], 'indexed': { 'date-parts': [[2022, 10, 25]], 'date-time': '2022-10-25T05:06:49Z', 'timestamp': 1666674409162}, 'posted': {'date-parts': [[2022, 10, 18]]}, 'group-title': 'In Review', 'reference-count': 39, 'publisher': 'Research Square Platform LLC', 'license': [ { 'start': { 'date-parts': [[2022, 10, 18]], 'date-time': '2022-10-18T00:00:00Z', 'timestamp': 1666051200000}, 'content-version': 'unspecified', 'delay-in-days': 0, 'URL': 'https://creativecommons.org/licenses/by/4.0/'}], 'content-domain': {'domain': [], 'crossmark-restriction': False}, 'accepted': {'date-parts': [[2022, 10, 14]]}, 'abstract': '<jats:title>Abstract</jats:title>\n' ' <jats:p><jats:bold>Purpose: </jats:bold>Our group demonstrated the safety, efficacy, ' 'and antiviral effect of intranasally administered Chlorpheniramine Maleate (CPM) for treating ' 'coronavirus disease 2019 (COVID-19). Since the nasal cavity is the portal of entry for COVID ' 'pathogens, sensory and upper respiratory symptoms (URS) (e.g., cough, ageusia, anosmia, nasal ' 'congestion, etc.) are significant symptoms in the course of the disease. Intranasal therapies ' 'could alleviate the disease-induced URS faster. This study evaluated the effectiveness and ' 'safety of intranasal CPM for treating mild to moderate COVID-19-induced URS in the outpatient ' 'setting.\n' '<jats:bold>Methods: </jats:bold>The two-part <jats:bold>A</jats:bold>ccelerating ' '<jats:bold>C</jats:bold>OVID-19 <jats:bold>C</jats:bold>linical ' '<jats:bold>R</jats:bold>ecovery in an <jats:bold>O</jats:bold>utpatient ' '<jats:bold>S</jats:bold>etting (ACCROS) research study was conducted to collect evidence from ' 'a randomized, double-blinded placebo-controlled trial (ACCROS-I). Both parts enrolled ' 'patients with mild to moderate COVID-19 confirmed by reverse transcription-polymerase chain ' 'reaction. The primary endpoint in ACCROS-I was time to clinical recovery, defined as the ' 'change from baseline to day 7 in COVID-19 symptoms reported as the percent change (Δ%) in the ' 'daily symptoms score (DSS) and the severity of the disease symptoms using a visual analog ' 'scale (VAS), on a scale of 1-10 (10=worst symptoms). COVID-19 patients (n = 101) were ' 'recruited and assigned to either a 10-day CPM treatment (n=61) or placebo (PLB) (n=40) in ' 'addition to standard of care (SoC). Secondary endpoints included the incidence of ' 'hospitalization and the proportion of patients with URS on day 7. ACCROS-II data were ' 'collected from medical records of COVID-positive subjects using a standardized form. Cohorts ' 'of patients treated with CPM and SoC (CPM+Soc) were compared for the duration of general ' 'symptoms and URS. Patient information was collected as part of routine visits and telehealth ' 'consultations.\n' '<jats:bold>Results </jats:bold><jats:italic>ACCROS-I:</jats:italic> There was a statistically ' 'significant difference in the rate of clinical recovery (P&lt;0.05) in Δ%DSS (M -18.8±SEM ' '7.9%) and Δ%VAS (-8.6±5.1%), such that the CPM group reported fewer symptoms than PLB. The ' 'proportion of patients who reported sensory deficits and URS at day 7 was significantly lower ' '(P&lt;0.05) in CPM vs. PLB for ageusia (1.7% vs. 15.0%), cough (16.4% vs. 35.0%) and nasal ' 'congestion (8.1%vs.20%). None of the patients required hospitalization.\n' '<jats:italic>ACCROS-II</jats:italic>: There was a statistically significant reduction ' '(P&lt;0.05) in total days reporting URS for general symptoms of COVID-19 in CPM+SoC (5.1 ± ' '0.1) compared to SoC (11.0 ± 0.2). CPM+SoC users also showed fewer days with cough, anosmia, ' 'and ageusia. Persistent anosmia (over 29 days) was found in 3% of the patients on SoC, ' 'whereas no persistent anosmia was reported in the CPM+SoC cohort (X<jats:sup>2</jats:sup> = ' '10.18; P&lt;0.001).\n' '<jats:bold>Conclusion:</jats:bold> The result of this two-part study supports the conclusion ' 'that intranasal CPM is an antiviral agent that can be administered intranasally to treat ' 'COVID-19-induced symptoms effectively. Intranasal CPM accelerates clinical recovery and ' "reduces URS in patients with mild to moderate COVID-19. This study's important implications " 'include individuals returning to daily life faster, reducing community and individual ' 'economic burden, and decreasing healthcare utilization.\n' '<jats:bold>Trial registration:</jats:bold> ClinicalTrials.gov.; ID: NCT05449405 ACCROS-I ' 'retrospectively registered on 7/13/2022, NCT05520944 ACCROS-R retrospectively registered on ' '08/27/2022.</jats:p>', 'DOI': '10.21203/rs.3.rs-2167465/v1', 'type': 'posted-content', 'created': { 'date-parts': [[2022, 10, 18]], 'date-time': '2022-10-18T18:11:18Z', 'timestamp': 1666116678000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Chlorpheniramine Intranasal Spray to Accelerate COVID-19 Clinical Recovery in an Outpatient ' 'Setting: The ACCROS Trials', 'prefix': '10.21203', 'author': [ { 'given': 'Fernando', 'family': 'Valerio-Pascua', 'sequence': 'first', 'affiliation': [{'name': 'Hospital CEMESA Cortés'}]}, { 'given': 'Estela Jackeline Pineda', 'family': 'Mejia', 'sequence': 'additional', 'affiliation': [{'name': 'Hospital CEMESA Cortés'}]}, { 'given': 'Mari L.', 'family': 'Tesch', 'sequence': 'additional', 'affiliation': [{'name': 'Aventura Hospital Pulmonary and Critical Care Fellowship'}]}, { 'given': 'Jancy', 'family': 'Godoy', 'sequence': 'additional', 'affiliation': [{'name': 'Hospital Leonardo Martínez Valenzuela'}]}, { 'given': 'Carlos López', 'family': 'Fuentes', 'sequence': 'additional', 'affiliation': [{'name': 'Universidad Católica de Honduras'}]}, { 'given': 'Gloria B.', 'family': 'Erazo', 'sequence': 'additional', 'affiliation': [{'name': 'Universidad Católica de Honduras'}]}, { 'given': 'Marco', 'family': 'Bermúdez', 'sequence': 'additional', 'affiliation': [{'name': 'Universidad Católica de Honduras'}]}, { 'given': 'Miguel Fernando Vargas', 'family': 'Pineda', 'sequence': 'additional', 'affiliation': [{'name': 'Saint Barnabas Hospital'}]}, { 'given': 'Syed A.A.', 'family': 'Rivzi', 'sequence': 'additional', 'affiliation': [{'name': 'Hampton University School of Pharmacy'}]}, { 'given': 'Armando', 'family': 'Cabrera', 'sequence': 'additional', 'affiliation': [{'name': 'Aventura Hospital Pulmonary and Critical Care Fellowship'}]}, { 'given': 'Zeeshan', 'family': 'Chauhan', 'sequence': 'additional', 'affiliation': [{'name': 'Aventura Hospital Pulmonary and Critical Care Fellowship'}]}, { 'given': 'Scarlet', 'family': 'Grullón-Franco', 'sequence': 'additional', 'affiliation': [{'name': 'Clinica Universitaria Union Medica'}]}, { 'given': 'Jorge L.', 'family': 'Paulino-Then', 'sequence': 'additional', 'affiliation': [{'name': 'Clinica Universitaria Union Medica'}]}, { 'given': 'Natalia', 'family': 'Garcia', 'sequence': 'additional', 'affiliation': [{'name': 'Clinica Universitaria Union Medica'}]}, { 'given': 'Jeffrey D.', 'family': 'Williams', 'sequence': 'additional', 'affiliation': [{'name': 'The George Washington University'}]}, { 'given': 'Franck F.', 'family': 'Rahaghi', 'sequence': 'additional', 'affiliation': [{'name': 'Cleveland Clinic'}]}], 'member': '8761', 'reference': [ { 'issue': '6', 'key': 'ref1', 'doi-asserted-by': 'crossref', 'first-page': 'ofac138', 'DOI': '10.1093/ofid/ofac138', 'article-title': 'A Systematic Review of Coronavirus Disease 2019 Vaccine Efficacy and ' 'Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 ' 'Infection and Disease', 'volume': '9', 'author': 'Higdon MM', 'year': '2022', 'unstructured': 'Higdon, M.M., et al., A Systematic Review of Coronavirus Disease 2019 ' 'Vaccine Efficacy and Effectiveness Against Severe Acute Respiratory ' 'Syndrome Coronavirus 2 Infection and Disease. Open Forum Infect Dis, ' '2022. 9(6): p.\xa0ofac138.', 'journal-title': 'Open Forum Infect Dis'}, { 'key': 'ref2', 'volume-title': "A Pathophysiological Perspective on COVID-19's Lethal Complication: From " 'Viremia to Hypersensitivity Pneumonitis-like Immune Dysregulation', 'author': 'Sanchez-Gonzalez MA', 'year': '2020', 'unstructured': 'Sanchez-Gonzalez, M.A., et al., A Pathophysiological Perspective on ' "COVID-19's Lethal Complication: From Viremia to Hypersensitivity " 'Pneumonitis-like Immune Dysregulation. Infect Chemother, 2020.'}, { 'issue': '1', 'key': 'ref3', 'doi-asserted-by': 'crossref', 'first-page': '428', 'DOI': '10.1038/s41392-021-00849-0', 'article-title': 'SARS-CoV-2-triggered mast cell rapid degranulation induces alveolar ' 'epithelial inflammation and lung injury', 'volume': '6', 'author': 'Wu M-L', 'year': '2021', 'unstructured': 'Wu, M.-L., et al., SARS-CoV-2-triggered mast cell rapid degranulation ' 'induces alveolar epithelial inflammation and lung injury. Signal ' 'Transduction and Targeted Therapy, 2021. 6(1): p.\xa0428.', 'journal-title': 'Signal Transduction and Targeted Therapy'}, { 'key': 'ref4', 'doi-asserted-by': 'crossref', 'first-page': '633680', 'DOI': '10.3389/fphar.2021.633680', 'article-title': 'COVID-19: Famotidine, Histamine, Mast Cells, and Mechanisms', 'volume': '12', 'author': 'Malone RW', 'year': '2021', 'unstructured': 'Malone, R.W., et al., COVID-19: Famotidine, Histamine, Mast Cells, and ' 'Mechanisms. Front Pharmacol, 2021. 12: p.\xa0633680.', 'journal-title': 'Front Pharmacol'}, { 'issue': '3', 'key': 'ref5', 'doi-asserted-by': 'crossref', 'DOI': '10.3390/jcm10030459', 'article-title': 'The Association between Early-Life Gut Microbiota and Long-Term Health ' 'and Diseases', 'volume': '10', 'author': 'Sarkar A', 'year': '2021', 'unstructured': 'Sarkar, A., et al., The Association between Early-Life Gut Microbiota ' 'and Long-Term Health and Diseases. J Clin Med, 2021. 10(3).', 'journal-title': 'J Clin Med'}, { 'key': 'ref6', 'doi-asserted-by': 'crossref', 'first-page': '110622', 'DOI': '10.1016/j.mehy.2021.110622', 'article-title': 'Early multidrug treatment of SARS-CoV-2 infection (COVID-19) and ' 'reduced mortality among nursing home (or outpatient/ambulatory) ' 'residents', 'volume': '153', 'author': 'Alexander PE', 'year': '2021', 'unstructured': 'Alexander, P.E., et al., Early multidrug treatment of SARS-CoV-2 ' 'infection (COVID-19) and reduced mortality among nursing home (or ' 'outpatient/ambulatory) residents. Med Hypotheses, 2021. 153: p.\xa0' '110622.', 'journal-title': 'Med Hypotheses'}, { 'key': 'ref7', 'author': 'Ontai S', 'year': '2021', 'unstructured': 'Ontai, S., et al., Early multidrug treatment of SARS-CoV-2 (COVID-19) ' 'and decreased case fatality rates in Honduras. medRxiv, 2021: p.\xa0' '2021.07.21.21260223.'}, { 'issue': '2', 'key': 'ref8', 'article-title': 'Repurposing Drugs for Covid-19 by a Developing Country', 'volume': '6', 'author': 'Valerio Pascua F', 'year': '2022', 'unstructured': 'Valerio Pascua, F., et al., Repurposing Drugs for Covid-19 by a ' 'Developing Country. Epidemol Int J, 2022. 6(2).', 'journal-title': 'Epidemol Int J'}, { 'key': 'ref9', 'article-title': 'COVID-19: Azelastine nasal spray Reduces Virus-load In Nasal swabs ' '(CARVIN). Early intervention with azelastine nasal sprays reduces viral ' 'load in SARS-CoV-2 infected patients. First report on a double-blind ' 'placebo-controlled phase II clinical trial', 'volume': 'COVID-19', 'author': 'Klussmann JP', 'year': '2021', 'unstructured': 'Klussmann, J.P., et al., COVID-19: Azelastine nasal spray Reduces ' 'Virus-load In Nasal swabs (CARVIN). Early intervention with azelastine ' 'nasal sprays reduces viral load in SARS-CoV-2 infected patients. First ' 'report on a double-blind placebo-controlled phase II clinical trial. ' 'COVID-19, 2021.'}, { 'key': 'ref10', 'doi-asserted-by': 'crossref', 'first-page': '101989', 'DOI': '10.1016/j.pupt.2021.101989', 'article-title': 'Antihistamines and azithromycin as a treatment for COVID-19 on primary ' 'health care - A retrospective observational study in elderly patients', 'volume': '67', 'author': 'Morán Blanco JI', 'year': '2021', 'unstructured': 'Morán Blanco, J.I., et al., Antihistamines and azithromycin as a ' 'treatment for COVID-19 on primary health care - A retrospective ' 'observational study in elderly patients. Pulm Pharmacol Ther, 2021. 67: ' 'p.\xa0101989.', 'journal-title': 'Pulm Pharmacol Ther'}, { 'issue': '3', 'key': 'ref11', 'doi-asserted-by': 'crossref', 'DOI': '10.18103/mra.v10i3.2752', 'article-title': 'Intranasal Chlorpheniramine Maleate for the treatment of COVID-19: ' 'Translational and Clinical Evidence', 'volume': '10', 'author': 'Sanchez-Gonzalez MA', 'year': '2022', 'unstructured': 'Sanchez-Gonzalez, M.A., et al., Intranasal Chlorpheniramine Maleate for ' 'the treatment of COVID-19: Translational and Clinical Evidence. Medical ' 'Research Archives, 2022. 10(3).', 'journal-title': 'Medical Research Archives'}, { 'issue': '3', 'key': 'ref12', 'article-title': 'Treatment Protocol for COVID-19 Based on T2R Phenotype', 'volume': '13', 'author': 'Taha MA', 'year': '2021', 'unstructured': 'Taha, M.A., et al., Treatment Protocol for COVID-19 Based on T2R ' 'Phenotype. Viruses, 2021. 13(3).', 'journal-title': 'Viruses'}, { 'key': 'ref13', 'doi-asserted-by': 'crossref', 'first-page': '03084', 'DOI': '10.7189/jogh.11.03084', 'article-title': 'Impact of COVID-2019 on school attendance problems', 'volume': '11', 'author': 'Nathwani G', 'year': '2021', 'unstructured': 'Nathwani, G., et al., Impact of COVID-2019 on school attendance ' 'problems. J Glob Health, 2021. 11: p.\xa003084.', 'journal-title': 'J Glob Health'}, { 'issue': '2', 'key': 'ref14', 'doi-asserted-by': 'crossref', 'first-page': '2101341', 'DOI': '10.1183/13993003.01341-2021', 'article-title': 'Risk factors for post-COVID-19 condition in previously hospitalised ' 'children using the ISARIC Global follow-up protocol: a prospective ' 'cohort study', 'volume': '59', 'author': 'Osmanov IM', 'year': '2022', 'unstructured': 'Osmanov, I.M., et al., Risk factors for post-COVID-19 condition in ' 'previously hospitalised children using the ISARIC Global follow-up ' 'protocol: a prospective cohort study. European Respiratory Journal, ' '2022. 59(2): p.\xa02101341.', 'journal-title': 'European Respiratory Journal'}, { 'issue': '27', 'key': 'ref15', 'doi-asserted-by': 'crossref', 'first-page': '853', 'DOI': '10.15585/mmwr.mm6927a1', 'article-title': 'Increases in Health-Related Workplace Absenteeism Among Workers in ' 'Essential Critical Infrastructure Occupations During the COVID-19 ' 'Pandemic - United States, March-April 2020', 'volume': '69', 'author': 'Groenewold MR', 'year': '2020', 'unstructured': 'Groenewold, M.R., et al., Increases in Health-Related Workplace ' 'Absenteeism Among Workers in Essential Critical Infrastructure ' 'Occupations During the COVID-19 Pandemic - United States, March-April ' '2020. MMWR Morb Mortal Wkly Rep, 2020. 69(27): p.\xa0853–858.', 'journal-title': 'MMWR Morb Mortal Wkly Rep'}, { 'key': 'ref16', 'first-page': '1', 'article-title': 'Chlorpheniramine, an Old Drug with New Potential Clinical Applications: ' 'A Comprehensive Review of the Literature', 'volume': '17', 'author': 'Rizvi AAS', 'year': '2022', 'unstructured': 'Rizvi, A.A.S., et al., Chlorpheniramine, an Old Drug with New Potential ' 'Clinical Applications: A Comprehensive Review of the Literature. Current ' 'Reviews in Clinical and Experimental Pharmacology, 2022. 17: p.\xa01–1.', 'journal-title': 'Current Reviews in Clinical and Experimental Pharmacology'}, { 'issue': '3', 'key': 'ref17', 'doi-asserted-by': 'crossref', 'first-page': '1393', 'DOI': '10.1172/JCI72094', 'article-title': 'Bitter and sweet taste receptors regulate human upper respiratory ' 'innate immunity', 'volume': '124', 'author': 'Lee RJ', 'year': '2014', 'unstructured': 'Lee, R.J., et al., Bitter and sweet taste receptors regulate human upper ' 'respiratory innate immunity. J Clin Invest, 2014. 124(3): p.\xa0' '1393–405.', 'journal-title': 'J Clin Invest'}, { 'issue': '1', 'key': 'ref18', 'first-page': 'e20980', 'article-title': 'Molecular Modeling and Preliminary Clinical Data Suggesting Antiviral ' 'Activity for Chlorpheniramine (Chlorphenamine) Against COVID-19', 'volume': '14', 'author': 'Black S', 'year': '2022', 'unstructured': 'Black, S., Molecular Modeling and Preliminary Clinical Data Suggesting ' 'Antiviral Activity for Chlorpheniramine (Chlorphenamine) Against ' 'COVID-19. Cureus, 2022. 14(1): p.\xa0e20980.', 'journal-title': 'Cureus'}, { 'key': 'ref19', 'author': 'Mostafa A', 'year': '2020', 'unstructured': 'Mostafa, A., et al., FDA-Approved Drugs with Potent In Vitro Antiviral ' 'Activity against Severe Acute Respiratory Syndrome Coronavirus 2. ' 'Pharmaceuticals (Basel), 2020. 13(12).'}, { 'issue': '9', 'key': 'ref20', 'first-page': 'e10501', 'article-title': 'In Vitro Virucidal Effect of Intranasally Delivered Chlorpheniramine ' 'Maleate Compound Against Severe Acute Respiratory Syndrome Coronavirus ' '2', 'volume': '12', 'author': 'Westover JB', 'year': '2020', 'unstructured': 'Westover, J.B., et al., In Vitro Virucidal Effect of Intranasally ' 'Delivered Chlorpheniramine Maleate Compound Against Severe Acute ' 'Respiratory Syndrome Coronavirus 2. Cureus, 2020. 12(9): p.\xa0e10501.', 'journal-title': 'Cureus'}, { 'issue': '3', 'key': 'ref21', 'first-page': 'e14206', 'article-title': 'A Randomized Controlled Pilot Trial to Test the Efficacy of Intranasal ' 'Chlorpheniramine Maleate With Xylitol for the Treatment of Allergic ' 'Rhinitis', 'volume': '13', 'author': 'Sanchez-Gonzalez M', 'year': '2021', 'unstructured': 'Sanchez-Gonzalez, M., et al., A Randomized Controlled Pilot Trial to ' 'Test the Efficacy of Intranasal Chlorpheniramine Maleate With Xylitol ' 'for the Treatment of Allergic Rhinitis. Cureus, 2021. 13(3): p.\xa0' 'e14206.', 'journal-title': 'Cureus'}, { 'issue': '1', 'key': 'ref22', 'doi-asserted-by': 'crossref', 'first-page': '5453', 'DOI': '10.1038/s41467-020-19145-6', 'article-title': 'ACE2 localizes to the respiratory cilia and is not increased by ACE ' 'inhibitors or ARBs', 'volume': '11', 'author': 'Lee IT', 'year': '2020', 'unstructured': 'Lee, I.T., et al., ACE2 localizes to the respiratory cilia and is not ' 'increased by ACE inhibitors or ARBs. Nature Communications, 2020. 11(1): ' 'p.\xa05453.', 'journal-title': 'Nature Communications'}, { 'issue': '1', 'key': 'ref23', 'doi-asserted-by': 'crossref', 'first-page': '103', 'DOI': '10.2307/2529712', 'article-title': 'Sequential treatment assignment with balancing for prognostic factors ' 'in the controlled clinical trial', 'volume': '31', 'author': 'Pocock SJ', 'year': '1975', 'unstructured': 'Pocock, S.J. and R. Simon, Sequential treatment assignment with ' 'balancing for prognostic factors in the controlled clinical trial. ' 'Biometrics, 1975. 31(1): p.\xa0103–15.', 'journal-title': 'Biometrics'}, { 'key': 'ref24', 'author': 'FDA US', 'year': '2020', 'unstructured': 'FDA, U.S. Department of Health and Human Services Food and Drug ' 'Administration Center for Drug Evaluation and Research (CDER) Center for ' 'Biologics Evaluation and Research (CBER). Assessing COVID-19-Related ' 'Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials ' 'of Drugs and Biological Products for COVID-19 Prevention or Treatment ' 'Guidance for Industry. 2020. https://www.fda.gov/media/142143/download. ' 'Accessed 12 May 2021. 2020.'}, { 'key': 'ref25', 'author': 'Basu S', 'year': '2022', 'unstructured': 'Basu, S., et al., A model-based approach to improve intranasal sprays ' 'for respiratory viral infections. medRxiv, 2022: p.\xa0' '2022.01.26.22269854.'}, { 'issue': '1', 'key': 'ref26', 'doi-asserted-by': 'crossref', 'first-page': '6652', 'DOI': '10.1038/s41598-021-85765-7', 'article-title': 'Computational characterization of inhaled droplet transport to the ' 'nasopharynx', 'volume': '11', 'author': 'Basu S', 'year': '2021', 'unstructured': 'Basu, S., Computational characterization of inhaled droplet transport to ' 'the nasopharynx. Sci Rep, 2021. 11(1): p.\xa06652.', 'journal-title': 'Sci Rep'}, { 'key': 'ref27', 'volume-title': 'Guidance for industry. Allergic rhinitis: clinical development programs ' 'for drug products.', 'year': '2018', 'unstructured': 'U.S. Department of Health & Human Services, U.S.F.a.D.A., Guidance for ' 'industry. Allergic rhinitis: clinical development programs for drug ' 'products., U.S.F.a.D.A. U.S. Department of Health & Human Services, ' 'Editor. 2018.'}, { 'issue': '4', 'key': 'ref28', 'doi-asserted-by': 'crossref', 'first-page': '367', 'DOI': '10.1111/j.1398-9995.2006.01276.x', 'article-title': 'Visual analog scales can assess the severity of rhinitis graded ' 'according to ARIA guidelines', 'volume': '62', 'author': 'Bousquet PJ', 'year': '2007', 'unstructured': 'Bousquet, P.J., et al., Visual analog scales can assess the severity of ' 'rhinitis graded according to ARIA guidelines. Allergy, 2007. 62(4): ' 'p.\xa0367–72.', 'journal-title': 'Allergy'}, { 'issue': '2', 'key': 'ref29', 'first-page': '3', 'article-title': 'Chlorpheniramine Maleate Nasal Spray In COVID-19 Patients: Case Series', 'volume': '10', 'author': 'Torres J', 'year': '2021', 'unstructured': 'Torres, J., et al., Chlorpheniramine Maleate Nasal Spray In COVID-19 ' 'Patients: Case Series. J Clin Exp Pharmacol, 2021. 10(2): p.\xa03.', 'journal-title': 'J Clin Exp Pharmacol'}, { 'key': 'ref30', 'doi-asserted-by': 'crossref', 'first-page': '1409', 'DOI': '10.3389/fimmu.2020.01409', 'article-title': 'Beyond Anti-viral Effects of Chloroquine/Hydroxychloroquine', 'volume': '11', 'author': 'Gies V', 'year': '2020', 'unstructured': 'Gies, V., et al., Beyond Anti-viral Effects of ' 'Chloroquine/Hydroxychloroquine. Front Immunol, 2020. 11: p.\xa01409.', 'journal-title': 'Front Immunol'}, { 'key': 'ref31', 'first-page': '1', 'article-title': 'Sars-Cov-2 and risk of antiviral drug resistance', 'author': 'Vitiello A', 'year': '2021', 'unstructured': 'Vitiello, A., Sars-Cov-2 and risk of antiviral drug resistance. Ir J Med ' 'Sci, 2021: p.\xa01–2.', 'journal-title': 'Ir J Med Sci'}, { 'issue': '5', 'key': 'ref32', 'doi-asserted-by': 'crossref', 'first-page': '6008', 'DOI': '10.1096/fj.202000502', 'article-title': 'Existing bitter medicines for fighting 2019-nCoV-associated infectious ' 'diseases', 'volume': '34', 'author': 'Li X', 'year': '2020', 'unstructured': 'Li, X., et al., Existing bitter medicines for fighting ' '2019-nCoV-associated infectious diseases. Faseb j, 2020. 34(5): p.\xa0' '6008–6016.', 'journal-title': 'Faseb j'}, { 'issue': '4', 'key': 'ref33', 'doi-asserted-by': 'crossref', 'first-page': '88', 'DOI': '10.1002/lio2.26', 'article-title': 'Taste Receptors: Regulators of Sinonasal Innate Immunity', 'volume': '1', 'author': 'Carey RM', 'year': '2016', 'unstructured': 'Carey, R.M., et al., Taste Receptors: Regulators of Sinonasal Innate ' 'Immunity. Laryngoscope Investig Otolaryngol, 2016. 1(4): p.\xa088–95.', 'journal-title': 'Laryngoscope Investig Otolaryngol'}, { 'issue': '1267', 'key': 'ref34', 'article-title': 'Bitter Taste Receptors (TAS2Rs) in Human Lung Macrophages: Receptor ' 'Expression and Inhibitory Effects of TAS2R Agonists', 'volume': '10', 'author': 'Grassin-Delyle S', 'year': '2019', 'unstructured': 'Grassin-Delyle, S., et al., Bitter Taste Receptors (TAS2Rs) in Human ' 'Lung Macrophages: Receptor Expression and Inhibitory Effects of TAS2R ' 'Agonists. Frontiers in Physiology, 2019. 10(1267).', 'journal-title': 'Frontiers in Physiology'}, { 'issue': '2', 'key': 'ref35', 'first-page': '43', 'article-title': 'A hypothesis: Bitter taste receptors as a therapeutic target for the ' 'clinical symptoms of SARS-CoV-2', 'volume': '76', 'author': 'Kumar SA', 'year': '2021', 'unstructured': 'Kumar, S.A. and W. Cheng, A hypothesis: Bitter taste receptors as a ' 'therapeutic target for the clinical symptoms of SARS-CoV-2. Pharmazie, ' '2021. 76(2): p.\xa043–54.', 'journal-title': 'Pharmazie'}, { 'issue': '3', 'key': 'ref36', 'doi-asserted-by': 'crossref', 'first-page': '257', 'DOI': '10.1016/j.ejphar.2004.11.006', 'article-title': 'Comparative anticholinergic activities of 10 histamine H1 receptor ' 'antagonists in two functional models', 'volume': '506', 'author': 'Orzechowski RF', 'year': '2005', 'unstructured': 'Orzechowski, R.F., D.S. Currie, and C.A. Valancius, Comparative ' 'anticholinergic activities of 10 histamine H1 receptor antagonists in ' 'two functional models. Eur J Pharmacol, 2005. 506(3): p.\xa0257–64.', 'journal-title': 'Eur J Pharmacol'}, { 'issue': '1', 'key': 'ref37', 'doi-asserted-by': 'crossref', 'first-page': '54', 'DOI': '10.1016/0091-6749(77)90177-4', 'article-title': 'Bronchodilating activity of an H1 blocker, chlorpheniramine', 'volume': '59', 'author': 'Popa VT', 'year': '1977', 'unstructured': 'Popa, V.T., Bronchodilating activity of an H1 blocker, chlorpheniramine. ' 'J Allergy Clin Immunol, 1977. 59(1): p.\xa054–63.', 'journal-title': 'J Allergy Clin Immunol'}, { 'issue': '2', 'key': 'ref38', 'doi-asserted-by': 'crossref', 'first-page': '131', 'DOI': '10.2500/105065898781390271', 'article-title': 'Anticholinergic properties of brompheniramine, chlorpheniramine, and ' 'atropine in human nasal mucosa in vitro', 'volume': '12', 'author': 'Fang SY', 'year': '1998', 'unstructured': 'Fang, S.Y., H.M. Druce, and J.N. Baraniuk, Anticholinergic properties of ' 'brompheniramine, chlorpheniramine, and atropine in human nasal mucosa in ' 'vitro. Am J Rhinol, 1998. 12(2): p.\xa0131–3.', 'journal-title': 'Am J Rhinol'}, { 'issue': '12', 'key': 'ref39', 'doi-asserted-by': 'crossref', 'first-page': '1268', 'DOI': '10.7150/ijms.21573', 'article-title': 'Chlorpheniramine attenuates histamine-mediated aquaporin 5 ' 'downregulation in human nasal epithelial cells via suppression of NF-κB ' 'activation', 'volume': '14', 'author': 'Chang YL', 'year': '2017', 'unstructured': 'Chang, Y.L., et al., Chlorpheniramine attenuates histamine-mediated ' 'aquaporin 5 downregulation in human nasal epithelial cells via ' 'suppression of NF-κB activation. Int J Med Sci, 2017. 14(12): p.\xa0' '1268–1275.', 'journal-title': 'Int J Med Sci'}], 'container-title': [], 'original-title': [], 'link': [ { 'URL': 'https://www.researchsquare.com/article/rs-2167465/v1', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://www.researchsquare.com/article/rs-2167465/v1.html', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 10, 24]], 'date-time': '2022-10-24T04:15:00Z', 'timestamp': 1666584900000}, 'score': 1, 'resource': {'primary': {'URL': 'https://www.researchsquare.com/article/rs-2167465/v1'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 10, 18]]}, 'references-count': 39, 'URL': 'http://dx.doi.org/10.21203/rs.3.rs-2167465/v1', 'relation': {}, 'published': {'date-parts': [[2022, 10, 18]]}, 'subtype': 'preprint'}