Negative Interaction between Indomethacin and Exercise in Mice

Abstract

We examined the possible negative interaction of the combined use of the NSAID indomethacin (IND) and exercise in mice. Mice were assigned to one of 4 groups: Exercise 2.5 mg/kg IND (Ex-2.5), Sedentary 2.5 mg/kg IND (Sed-2.5), Exercise 5.0 mg/kg IND (Ex-5.0) and Sedentary 5.0 mg/kg IND (Sed-5.0). Mice were given IND (gavage) 1 h prior to exercise (treadmill run at 30 m/min, 8% grade for 90 min) or rest for 14 consecutive days. Run times, body weight and mortality were recorded daily. Sed-5.0 was highly toxic and caused 70% mortality compared to Sed-2.5, which was well tolerated (0% mortality) (P<0.05). While the addition of exercise had no greater effect on mortality in Ex-5.0, it increased it in the 2.5 group (52% vs. 0%; P<0.05). Run time was reduced from baseline beginning on day 2 (Ex-5.0), or day 3 (Ex-2.5) (P<0.05). Body weight (recorded in the 2.5 mg/kg groups only) was decreased from baseline in Ex-2.5 and Sed-2.5 (P<0.05), but this effect occurred earlier and was of greater magnitude in Ex-2.5. Exercise combined with IND use can lead to serious side effects in mice. Future research is needed to test the hypothesis that this effect is due to increased GI permeability and whether humans are also at risk.

Key words

NSAIDs - mortality - exercise performance

• References

• 1 Alaranta A, Alaranta H, Helenius I. Use of prescription drugs in athletes. Sports Med 2008; 38: 449-463
• 2 Camus G, Poortmans J, Nys M, Deby-Dupont G, Duchateau J, Deby C, Lamy M. Mild endotoxaemia and the inflammatory response induced by a marathon race. Clin Sci (Lond) 1997; 92: 415-422
• 3 Carmichael MD, Davis JM, Murphy EA, Brown AS, Carson JA, Mayer E, Ghaffar A. Recovery of running performance following muscle-damaging exercise: relationship to brain IL-1beta. Brain Behav Immun 2005; 19: 445-452
• 4 Cheung K, Hume P, Maxwell L. Delayed onset muscle soreness: treatment strategies and performance factors. Sports Med 2003; 33: 145-164
• 5 Davis JM, Murphy EA, Carmichael MD, Zielinski MR, Groschwitz CM, Brown AS, Gangemi JD, Ghaffar A, Mayer EP. Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage. Am J Physiol
• 6 Deguchi T, Watanabe N, Kurihara A, Igeta K, Ikenaga H, Fusegawa K, Suzuki N, Murata S, Hirouchi M, Furuta Y, Iwasaki M, Okazaki O, Izumi T. Human pharmacokinetic prediction of UDP-glucuronosyltransferase substrates with an animal scale-up approach. Drug Metab Dispos 2011; 39: 820-829
• 7 Feucht CL, Patel DR. Analgesics and anti-inflammatory medications in sports: use and abuse. Pediatr Clin North Am 2010; 57: 751-774
• 8 Harriss DJ, Atkinson G. Update – ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
• 9 Kemi OJ, Loennechen JP, Wisloff U, Ellingsen O. Intensity-controlled treadmill running in mice: cardiac and skeletal muscle hypertrophy. J Appl Physiol 2002; 93: 1301-1309
• 10 Lambert GP. Stress-induced gastrointestinal barrier dysfunction and its inflammatory effects. J Anim Sci 2009; 87: E101-E108
• 11 Lambert GP, Boylan M, Laventure JP, Bull A, Lanspa S. Effect of aspirin and ibuprofen on GI permeability during exercise. Int J Sports Med 2007; 28: 722-726
• 12 Lambert GP, Broussard LJ, Mason BL, Mauermann WJ, Gisolfi CV. Gastrointestinal permeability during exercise: effects of aspirin and energy-containing beverages. J Appl Physiol 2001; 90: 2075-2080
• 13 Lane ME, Kim MJ. Assessment and prevention of gastrointestinal toxicity of non-steroidal anti-inflammatory drugs. J Pharm Pharmacol 2006; 58: 1295-1304
• 14 McAnulty SR, Owens JT, McAnulty LS, Nieman DC, Morrow JD, Dumke CL, Milne GL. Ibuprofen use during extreme exercise: effects on oxidative stress and PGE2. Med Sci Sports Exerc 2007; 39: 1075-1079
• 15 Mottram DR. Drugs in Sports. 5^th Ed New York: Routledge; 2011
• 16 Murphy EA, Davis JM, Carmichael MD, Gangemi JD, Ghaffar A, Mayer EP. Exercise stress increases susceptibility to influenza infection. Brain Behav Immun 2008; 22: 1152-1155
• 17 Nieman DC, Dumke CL, Henson DA, McAnulty SR, Gross SJ, Lind RH. Muscle damage is linked to cytokine changes following a 160-km race. Brain Behav Immun 2005; 19: 398-403
• 18 Nieman DC, Henson DA, Dumke CL, Oley K, McAnulty SR, Davis JM, Murphy EA, Utter AC, Lind RH, McAnulty LS, Morrow JD. Ibuprofen use, endotoxemia, inflammation, and plasma cytokines during ultramarathon competition. Brain Behav Immun 2006; 20: 578-584
• 19 Peterson JM, Trappe TA, Mylona E, White F, Lambert CP, Evans WJ, Pizza FX. Ibuprofen and acetaminophen: effect on muscle inflammation after eccentric exercise. Med Sci Sports Exerc 2003; 35: 892-896
• 20 Scarpignato C, Hunt RH. Nonsteroidal antiinflammatory drug-related injury to the gastrointestinal tract: clinical picture, pathogenesis, and prevention. Gastroenterol Clin North Am 2010; 39: 433-464
• 21 Schwartz AE, Vanagunas A, Kamel PL. Endoscopy to evaluate gastrointestinal bleeding in marathon runners. Ann Intern Med 1990; 113: 632-633
• 22 Tscholl P, Junge A, Dvorak J. The use of medication and nutritional supplements during FIFA World Cups 2002 and 2006. Br J Sports Med 2008; 42: 725-730
• 23 Warden SJ. Prophylactic use of NSAIDs by athletes: a risk/benefit assessment. Physician Sportsmed 2010; 38: 132-138