Treatment with Paracetamol is not Associated with Increased Airway Sensitivity and Risk of Asthma in Rats

Author(s): Marco Túlio Lacerda Ribeiro, Hellen Karine Paes Porto, Daniel Fernandes de Oliveira, Patrícia Ferreira da Silva Castro, Matheus Lavorenti Rocha*.

Journal Name: Current Drug Safety

Volume 14 , Issue 2 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: Some studies have linked the use of paracetamol (PAR) with adverse effects like wheezing, exacerbation of asthma symptoms and other respiratory problems. Other studies are inconclusive or deny this correlation. This makes the association between PAR and airway hypersensitivity very controversial and still under debate.

Objective: This work investigated if chronic treatment with PAR in rats could directly affect the contraction and relaxation for different stimulus in isolated airways.

Methods: Rats were treated for 2 weeks with PAR (400 mg/Kg, v.o.). The blood was collected for biochemical analysis (alanine aminotransferase (ALT), aspartate aminotransferase (AST), TBARs reaction and glutathione) and isolated tracheal rings were prepared in organ bath to measure isometric tone after contractile and relaxant stimulus.

Results: Hepatic enzymes (ALT, AST) and lipid peroxidation were increased after PAR-treatment, while glutathione was decreased. Rats do not present any alteration in airway myocytes responsiveness, either to contractile or relaxant stimulus (i.e. cholinergic agonist, membrane depolarization, Ca2+ influx across sarcolemma, internal Ca2+ release from sarcoplasmic reticulum, Ca2+ channel blocking, β-agonist and NOmediating relaxation).

Conclusion: Despite increased oxidative stress and reduced antioxidant defense, chronic treatment with PAR does not induce airway hypersensitivity or risk of asthma in rats.

Keywords: Paracetamol, airways responsiveness, asthma, contraction, relaxation, ALT, AST, BAL.

Blieden M, Paramore LC, Shah DD, Ben-Joseph R. A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States. Expert Rev Clin Pharmacol 2014; 3: 341-8.
Hinz B, Brune K. Paracetamol and cyclooxygenase inhibition: Is there a cause for concern. Ann Rheum Dis 2012; 71: 20-5.
Zheng Z, Sheng Y, Lu B, Ji L. The therapeutic detoxification of chlorogenic acid against acetaminophen-induced liver injury by ameliorating hepatic inflammation. Chem Biol Interact 2015; 238: 93-101.
Gulmez SE, Larrey D, Pageaux GP, et al. Liver transplant associated with paracetamol overdose: Results from the seven-country SALT study. Br J Clin Pharmacol 2015; 80(3): 599-606.
Vernacchio L, Kelly JP, Kaufman DW, Mitchell AA. Medication use among children <12 years of age in the United States: Results from the Slone survey. Pediatrics 2009; 124: 446-54.
McKeever TM, Lewis SA, Smit HA, Burney P, Britton JR, Cassano PA. The association of acetaminophen, aspirin, and ibuprofen with respiratory disease and lung function. Am J Respir Crit Care Med 2005; 171: 966-71.
Beasley RW, Clayton TO, Crane J, et al. Acetaminophen use and risk of asthma, rhinoconjunctivitis, and eczema in adolescents: International study of asthma and allergies in childhood phase three. Am J Respir Crit Care Med 2011; 183: 171-8.
Nuttall SL, Khan JN, Thorpe GH, Langford N, Kendall MJ. The impact of therapeutic doses of paracetamol on serum total antioxidant capacity. J Clin Pharm Ther 2003; 28: 289-94.
Lesko SM, Louik C, Vezina RM, Mitchell AA. Asthma morbidity after the short-term use of ibuprofen in children. Pediatrics 2002; 109: E20.
Farquhar H, Stewart A, Mitchell E, et al. The role of paracetamol in the pathogenesis of asthma. Clin Exp Allergy 2010; 40: 32-41.
Liu X, Liew Z, Olsen J, et al. Association of prenatal exposure to acetaminophen and coffee with childhood asthma. Pharmacoepidemiol Drug Saf 2016; 25: 188-95.
Lourido-Cebreiro T, Salgado FJ, Valdes L, Gonzalez-Barcala FJ. The association between paracetamol and asthma is still under debate. J Asthma 2017; 54: 32-8.
Kim H, Johnson CC. The association between acetaminophen and asthma - is there anything to learn from the upper airways. Curr Opin Allergy Clin Immunol 2014; 14: 25-8.
Weatherall M, Loannides S, Braithwaite I, Beasley R. The association between paracetamol use and asthma: Causation or coincidence. Clin Exp Allergy 2015; 45: 108-13.
Sheehan WJ, Mauger DT, Paul IM, et al. Acetaminophen versus ibuprofen in young children with mild persistent asthma. N Engl J Med 2016; 18: 619-30.
Castro PFS, Andrade DL, Reis CF, et al. Relaxing effect of a new ruthenium complex nitric oxide donor on airway smooth muscle of an experimental model of asthma in rats. Clin Exp Pharmacol Physiol 2016; 43: 221-9.
Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008; 22: 659-61.
Prescott LF. Paracetamol overdosage. Pharmacological considerations and clinical management. Drugs 1983; 25: 290-314.
Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 1957; 28: 56-63.
De Castro CM, Bureau MF, Nahori MA, Dumarey CH, Vargaftig BB, Bachelet M. Modulation by dexamethasone of phospholipase A2 activities in endotoxemic guinea pigs. J Appl Physiol 1995; 79(4): 1271-7.
Abdulla A, Adams N, Bone M, et al. Guidance on the management of pain in older people. Age Ageing 2013; 42: i1-i57.
Kaufman DM, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA. Recent patterns of medication use in the ambulatory adult population of the United States - The slone survey. JAMA 2002; 287: 337-44.
Wu YL, Piao DM, Han XH, Nan JX. Protective effects of salidroside against acetaminophen-induced toxicity in mice. Biol Pharm Bull 2008; 31: 1523-9.
Ishii I, Kamata S, Hagiya Y, Abiko Y, Kasahara T, Kumagai Y. Protective effects of hydrogen sulfide anions against acetaminophen-induced hepatotoxicity in mice. J Toxicol Sci 2015; 40: 837-41.
Gamal El-din AM. Mostafa AM, Al-Shabanah OA, Al-Bekairi AM, Nagi MN. Protective effect of arabic gum against acetaminophen-induced hepatotoxicity in mice. Pharmacol Res 2003; 48: 631-5.
Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014; 43: 343-73.
Roux E, Marhl M. Role of sarcoplasmic reticulum and mitochondria in Ca2+ removal in airway myocytes. Biophys J 2004; 86: 2583-95.
Tazzeo T, Zhang Y, Keshavjee S, Janssen LJ. Ryanodine receptors decant internal Ca2+ store in human and bovine airway smooth muscle. Eur Respir J 2008; 32: 275-84.
Ellis JL. Role of soluble guanylyl cyclase in the relaxations to a nitric oxide donor and to nonadrenergic nerve stimulation in guinea pig trachea and human bronchus. J Pharmacol Exp Ther 1997; 280: 1215-8.
Ilhan M, Sahin I. Tracheal epithelium releases a vascular smooth muscle relaxant factor: Demonstration by bioassay. Eur J Pharmacol 1986; 131: 293-6.
Danielsson J, Yim P, Rinderspacher A, et al. Chloride channel blockade relaxes airway smooth muscle and potentiates relaxation by β-agonists. Am J Physiol Lung Cell Mol Physiol 2014; 307: L273-82.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [109 - 115]
Pages: 7
DOI: 10.2174/1574886314666190222194841
Price: $65

Article Metrics

PDF: 71