The effect of vitamin C on bronchoconstriction and respiratory symptoms caused by exercise: a review and statistical analysis

Allergy, Asthma & Clinical Immunology

Harri Hemilä¹ 

[1] Department of Public Health, POB 41 University of Helsinki, Mannerheimintie 172, FIN-00014 Helsinki, Finland

关键词: The lungs;    Randomized controlled trial;    Prostaglandin;    Meta-analysis;    Forced expiratory flow rates;    Exercise-induced asthma;    Histamine;    Cough;    Ascorbic acid;    Anti-asthmatic agents;   

Others  :  1083792
DOI  :  10.1186/1710-1492-10-58

 received in 2014-05-01, accepted in 2014-11-01,  发布年份 2014

【 摘 要 】

Physical activity increases oxidative stress and therefore the antioxidant effects of vitamin C administration might become evident in people undertaking vigorous exercise. Vitamin C is involved in the metabolism of histamine, prostaglandins, and cysteinyl leukotrienes, all of which appear to be mediators in the pathogenesis of exercise-induced bronchoconstriction (EIB). Three studies assessing the effect of vitamin C on patients with EIB were subjected to a meta-analysis and revealed that vitamin C reduced postexercise FEV₁ decline by 48% (95% CI: 33% to 64%). The correlation between postexercise FEV₁ decline and respiratory symptoms associated with exercise is poor, yet symptoms are the most relevant to patients. Five other studies examined subjects who were under short-term, heavy physical stress and revealed that vitamin C reduced the incidence of respiratory symptoms by 52% (95% CI: 36% to 65%). Another trial reported that vitamin C halved the duration of the respiratory symptoms in male adolescent competitive swimmers. Although FEV₁ is the standard outcome for assessing EIB, other outcomes may provide additional information. In particular, the mean postexercise decline of FEF₅₀ is twice the decline of FEV₁. Schachter and Schlesinger (1982) reported the effect of vitamin C on exercise-induced FEF₆₀ levels in 12 patients suffering from EIB and their data are analyzed in this paper. The postexercise FEF₆₀ decline was greater than 60% for five participants and such a dramatic decline indicates that the absolute postexercise FEF₆₀ level becomes an important outcome in its own right. Vitamin C increased postexercise FEF₆₀ levels by 50% to 150% in those five participants, but had no significant effect in the other seven participants. Thus, future research on the effects of vitamin C on EIB should not be restricted to measuring only FEV₁. Vitamin C is inexpensive and safe, and further study on those people who have EIB or respiratory symptoms associated with exercise is warranted.

【 授权许可】

   
2014 Hemilä; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Anderson SD, Kippelen P: Airway injury as a mechanism for exercise-induced bronchoconstriction in elite athletes. J Allergy Clin Immunol 2008, 122:225-235. http://www.ncbi.nlm.nih.gov/pubmed/18554705 webcite. http://dx.doi.org/10.1016/j.jaci.2008.05.001 webcite
• [2]Weiler JM, Anderson SD, Randolph C: Pathogenesis, prevalence, diagnosis, and management of exercise-induced bronchoconstriction. Ann Allergy Asthma Immunol 2010, 105(6):S1-S47. http://dx.doi.org/10.1016/j.anai.2010.09.021 webcite
• [3]Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, Storms WW, Weiler JM, Cheek FM, Wilson KC, Anderson SD: An official American thoracic society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2013, 187:1016-1027. http://www.ncbi.nlm.nih.gov/pubmed/23634861 webcite. http://dx.doi.org/10.1164/rccm.201303-0437ST webcite
• [4]De Baets F, Bodart E, Dramaix-Wilmet M, Van Daele S, de Bilderling G, Masset S, Vermeire P, Michel O: Exercise-induced respiratory symptoms are poor predictors of bronchoconstriction. Pediatr Pulmonol 2005, 39:301-305. http://www.ncbi.nlm.nih.gov/pubmed/15678500 webcite. http://dx.doi.org/10.1002/ppul.20185 webcite
• [5]Thomas S, Wolfarth B, Wittmer C, Nowak D, Radon K, GA2LEN-Olympic study-Team: Self-reported asthma and allergies in top athletes compared to the general population - results of the German part of the GA2LEN-Olympic study 2008. Allergy Asthma Clin Immunol 2010, 6:31. http://dx.doi.org/10.1186/1710-1492-6-31 webcite BioMed Central Full Text
• [6]Rundell KW, Wilber RL, Szmedra L, Jenkinson DM, Mayers LB, Im J: Exercise-induced asthma screening of elite athletes: field versus laboratory exercise challenge. Med Sci Sports Exerc 2000, 32:309-316. http://www.ncbi.nlm.nih.gov/pubmed/10694112 webcite. http://dx.doi.org/10.1097/00005768-200002000-00010 webcite
• [7]Rundell KW, Im J, Mayers LB, Wilber RL, Szmedra L, Schmitz HR: Self-reported symptoms and exercise-induced asthma in the elite athlete. Med Sci Sports Exerc 2001, 33:208-213. http://www.ncbi.nlm.nih.gov/pubmed/11224807 webcite. http://dx.doi.org/10.1097/00005768-200102000-00006 webcite
• [8]Hallstrand TS, Moody MW, Wurfel MM, Schwartz LB, Henderson WR, Aitken ML: Inflammatory basis of exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2005, 172:679-686. http://www.ncbi.nlm.nih.gov/pubmed/15947280 webcite. http://dx.doi.org/10.1164/rccm.200412-1667OC webcite
• [9]Shin HW, Schwindt CD, Aledia AS, Rose-Gottron CM, Larson JK, Newcomb RL, Cooper DM, George SC: Exercise-induced bronchoconstriction alters airway nitric oxide exchange in a pattern distinct from spirometry. Am J Physiol Regul Integr Comp Physiol 2006, 291:R1741-R1748. http://www.ncbi.nlm.nih.gov/pubmed/16840654 webcite. http://dx.doi.org/10.1152/ajpregu.00178.2006 webcite
• [10]Chinellato I, Piazza M, Peroni D, Sandri M, Chiorazzo F, Boner AL, Piacentini G: Bronchial and alveolar nitric oxide in exercise-induced bronchoconstriction in asthmatic children. Clin Exp Allergy 2012, 42:1190-1196. http://www.ncbi.nlm.nih.gov/pubmed/22805466 webcite. http://dx.doi.org/10.1111/j.1365-2222.2012.03973.x webcite
• [11]Baumann JM, Rundell KW, Evans TM, Levine AM: Effects of cysteine donor supplementation on exercise-induced bronchoconstriction. Med Sci Sports Exerc 2005, 37:1468-1473. http://www.ncbi.nlm.nih.gov/pubmed/16177596 webcite. http://dx.doi.org/10.1249/01.mss.0000177479.57468.15 webcite
• [12]Barreto M, Villa MP, Olita C, Martella S, Ciabattoni G, Montuschi P: 8-Isoprostane in exhaled breath condensate and exercise-induced bronchoconstriction in asthmatic children and adolescents. Chest 2009, 135:66-73. http://dx.doi.org/10.1378/chest.08-0722 webcite
• [13]Powers SK, Nelson WB, Hudson MB: Exercise-induced oxidative stress in humans: cause and consequences. Free Radic Biol Med 2011, 51:942-950. http://www.ncbi.nlm.nih.gov/pubmed/21167935 webcite. http://dx.doi.org/10.1016/j.freeradbiomed.2010.12.009 webcite
• [14]Ashton T, Young IS, Peters JR, Jones E, Jackson SK, Davies B, Rowlands CC: Electron spin resonance spectroscopy, exercise, and oxidative stress: an ascorbic acid intervention study. J Appl Physiol 1999, 87:2032-2036. http://www.ncbi.nlm.nih.gov/pubmed/10601146 webcite
• [15]Davison GW, Ashton T, Davies B, Bailey DM: In vitro electron paramagnetic resonance characterization of free radicals: relevance to exercise-induced lipid peroxidation and implications of ascorbate prophylaxis. Free Radic Res 2008, 42:379-386. http://dx.doi.org/10.1080/10715760801976618 webcite
• [16]Sánchez-Quesada JL, Jorba O, Payés A, Otal C, Serra-Grima R, González-Sastre F, Ordóñez-Llanos J: Ascorbic acid inhibits the increase in low-density lipoprotein (LDL) susceptibility to oxidation and the proportion of electronegative LDL induced by intense aerobic exercise. Coron Artery Dis 1998, 9:249-255. http://www.ncbi.nlm.nih.gov/pubmed/9710684 webcite. http://dx.doi.org/10.1097/00019501-199809050-00002 webcite
• [17]Silvestro A, Scopacasa F, Oliva G, de Cristofaro T, Iuliano L, Brevetti G: Vitamin C prevents endothelial dysfunction induced by acute exercise in patients with intermittent claudication. Atherosclerosis 2002, 165:277-283. http://www.ncbi.nlm.nih.gov/pubmed/12417278 webcite. http://dx.doi.org/10.1016/S0021-9150(02)00235-6 webcite
• [18]Goldfarb AH, Patrick SW, Bryer S, You T: Vitamin C supplementation affects oxidative-stress blood markers in response to a 30-minute run at 75% VO2max. Int J Sport Nutr Exerc Metab 2005, 15:279-290. http://www.ncbi.nlm.nih.gov/pubmed/16131698 webcite
• [19]Shanklin DR, O’Dell TE: Ascorbic acid and the lung. Nature 1966, 210:1329-1331. http://dx.doi.org/10.1038/2101329a0 webcite
• [20]Castranova V, Wright JR, Colby HD, Miles PR: Ascorbate uptake by isolated rat alveolar macrophages and type II cells. J Applied Physiol 1983, 54:208-214. http://www.ncbi.nlm.nih.gov/pubmed/6826406 webcite
• [21]Skoza L, Snyder A, Kikkawa Y: Ascorbic acid in bronchoalveolar wash. Lung 1983, 161:99-109. http://www.ncbi.nlm.nih.gov/pubmed/6221162 webcite. http://dx.doi.org/10.1007/BF02713848 webcite
• [22]Slade R, Crissman K, Norwood J, Hatch G: Comparison of antioxidant substances in bronchoalveolar lavage cells and fluid from humans, guinea pigs, and rats. Exp Lung Res 1993, 19:469-484. http://www.ncbi.nlm.nih.gov/pubmed/8370346 webcite. http://dx.doi.org/10.3109/01902149309064358 webcite
• [23]Wiester MJ, Tepper JS, Winsett DW, Crissman KM, Richards JH, Costa DL: Adaptation to ozone in rats and its association with ascorbic acid in the lung. Fundam Appl Toxicol 1996, 31:56-64. http://www.ncbi.nlm.nih.gov/pubmed/8998953 webcite. http://dx.doi.org/10.1006/faat.1996.0075 webcite
• [24]Wiester MJ, Winsett DW, Richards JH, Jackson MC, Crissman KM, Costa DL: Ozone adaptation in mice and its association with ascorbic acid in the lung. Inhal Toxicol 2000, 12:577-590. http://www.ncbi.nlm.nih.gov/pubmed/10880145 webcite. http://informahealthcare.com/doi/abs/10.1080/08958370050030958 webcite
• [25]Arad ID, Forman HJ, Fisher AB: Ascorbate efflux from guinea pig and rat lungs: effect of starvation and O2 exposure. J Lab Clin Med 1980, 96:673-681. http://www.ncbi.nlm.nih.gov/pubmed/6252268 webcite
• [26]Leung HW, Morrow PE: Interaction of glutathione and ascorbic acid in guinea pig lungs exposed to nitrogen dioxide. Res Commun Chem Pathol Pharmacol 1981, 31:111-118. http://www.ncbi.nlm.nih.gov/pubmed/7255866 webcite
• [27]Matzen RN: Effect of vitamin C and hydrocortisone on the pulmonary edema produced by ozone in mice. J Appl Physiol 1957, 11:105-109. http://www.ncbi.nlm.nih.gov/pubmed/13462928 webcite
• [28]Mittler S: Protection against death due to ozone poisoning. Nature 1958, 181:1063-1064. http://www.ncbi.nlm.nih.gov/pubmed/13541362 webcite. http://dx.doi.org/10.1038/1811063a0 webcite
• [29]Brown LA, Harris FL, Jones DP: Ascorbate deficiency and oxidative stress in the alveolar type II cell. Am J Physiol 1997, 273:L782-L788. http://www.ncbi.nlm.nih.gov/pubmed/9357853 webcite. http://ajplung.physiology.org/content/273/4/L782 webcite
• [30]Mudway IS, Stenfors N, Blomberg A, Helleday R, Dunster C, Marklund SL, Frew AJ, Sandström T, Kelly FJ: Differences in basal airway antioxidant concentrations are not predictive of individual responsiveness to ozone. Free Radic Biol Med 2001, 31:962-974. http://www.ncbi.nlm.nih.gov/pubmed/11595381 webcite. http://dx.doi.org/10.1016/S0891-5849(01)00671-2 webcite
• [31]Glick D, Hosoda S: Ascorbic acid in normal mast cells and macrophages and in neoplastic mast cells. Proc Soc Exp Biol Med 1965, 119:52-56. http://www.ncbi.nlm.nih.gov/pubmed/14297882 webcite
• [32]Ortner MJ: The oxidation of endogenous ascorbic acid during histamine secretion by rat peritoneal mast cells. Exp Cell Res 1980, 129:485-487. http://dx.doi.org/10.1016/0014-4827(80)90521-2 webcite
• [33]Dawson W, West GB: The influence of ascorbic acid on histamine metabolism in guinea-pigs. Br J Pharmacol 1965, 24:725-734. http://dx.doi.org/10.1111/j.1476-5381.1965.tb01628.x webcite
• [34]Chatterjee IB, Gupta SD, Majumder AK, Nandi BK, Subramanian N: Effect of ascorbic acid on histamine metabolism in scorbutic guinea-pigs. J Physiol 1975, 251:271-279. http://www.ncbi.nlm.nih.gov/pubmed/52707 webcite. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1348426 webcite
• [35]Johnston CS, Huang SN: Effect of ascorbic acid nutriture on blood histamine and neutrophil chemotaxis in guinea pigs. J Nutr 1991, 121:126-130. http://jn.nutrition.org/content/121/1/126 webcite
• [36]Nandi BK, Subramanian N, Majumder AK, Chatterjee IB: Effect of ascorbic acid on detoxification of histamine under stress conditions. Biochem Pharmacol 1974, 23:643-647. http://www.ncbi.nlm.nih.gov/pubmed/4132605 webcite. http://dx.doi.org/10.1016/0006-2952(74)90629-7 webcite
• [37]Clemetson CA: Histamine and ascorbic acid in human blood. J Nutr 1980, 110:662-668. http://www.ncbi.nlm.nih.gov/pubmed/7365537 webcite. http://jn.nutrition.org/content/110/4/662 webcite
• [38]Johnston CS, Retrum KR, Srilakshmi JC: Antihistamine effects and complications of supplemental vitamin C. J Am Diet Assoc 1992, 92:988-989. http://www.ncbi.nlm.nih.gov/pubmed/1640045 webcite
• [39]Johnston CS, Solomon RE, Corte C: Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults. J Am Coll Nutr 1996, 15:586-591. http://www.ncbi.nlm.nih.gov/pubmed/8951736 webcite. http://dx.doi.org/10.1080/07315724.1996.10718634 webcite
• [40]Hagel AF, Layritz CM, Hagel WH, Hagel HJ, Hagel E, Dauth W, Kressel J, Regnet T, Rosenberg A, Neurath MF, Molderings GJ, Raithel M: Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases. Naunyn Schmiedebergs Arch Pharmacol 2013, 386:789-793. http://dx.doi.org/10.1007/s00210-013-0880-1 webcite. http://www.ncbi.nlm.nih.gov/pubmed/23666445 webcite
• [41]Guirgis HM: The regulatory role of vitamin C on the adrenal function and resistance to histamine aerosol in the scorbutic guinea-pig. J Pharm Pharmacol 1965, 17:674-675. http://dx.doi.org/10.1111/j.2042-7158.1965.tb07586.x webcite
• [42]Dawson W, Hemsworth BA, Stockham MA: Actions of sodium ascorbate on smooth muscle. Br J Pharmacol Chemother 1967, 31:269-275. http://dx.doi.org/10.1111/j.1476-5381.1967.tb01997.x webcite
• [43]Brink C, Ridgway P, Douglas JS: Regulation of guinea pig airways in vivo by endogenous prostaglandins. Pol J Pharmacol Pharm 1978, 30:157-166. http://www.ncbi.nlm.nih.gov/pubmed/673926 webcite
• [44]Mohsenin V, Tremml PG, Rothberg KG, Souhrada M, Douglas JS: Airway responsiveness and prostaglandin generation in scorbutic guinea pigs. Prostaglandins Leukot Essent Fatty Acids 1988, 33:149-155. http://www.ncbi.nlm.nih.gov/pubmed/3186781 webcite
• [45]Zuskin E, Lewis AJ, Bouhuys A: Inhibition of histamine-induced airway constriction by ascorbic acid. J Allergy Clin Immunol 1973, 51:218-226. http://dx.doi.org/10.1016/0091-6749(73)90141-3 webcite
• [46]Sipahi E, Ercan ZS: The mechanism of the relaxing effect of ascorbic acid in guinea pig isolated tracheal muscle. Gen Pharmacol 1997, 28:757-760. http://dx.doi.org/10.1016/S0306-3623(96)00277-7 webcite
• [47]Yeadon M, Wilkinson D, Darley-Usmar V, O’Leary VJ, Payne AN: Mechanisms contributing to ozone-induced bronchial hyperreactivity in guinea-pigs. Pulm Pharmacol 1992, 5:39-50. http://dx.doi.org/10.1016/0952-0600(92)90016-A webcite
• [48]Puglisi L, Berti F, Bosisio E, Longiave D, Nicosia S: Ascorbic acid and PGF2α antagonism on tracheal smooth muscle. Adv Prostaglandin Tromboxane Res 1976, 1:503-506. http://www.ncbi.nlm.nih.gov/pubmed/998441 webcite
• [49]Rothberg KG, Hitchcock M: Effects of ascorbic acid deficiency on the in vitro biosynthesis of cyclooxygenase metabolites in guinea pig lungs. Prostaglandins Leukot Med 1983, 12:137-147. http://dx.doi.org/10.1016/0262-1746(83)90077-X webcite
• [50]Ogilvy CS, DuBois AB, Douglas JS: Effects of ascorbic acid and indomethacin on the airways of healthy male subjects with and without induced bronchoconstriction. J Allergy Clin Immunol 1981, 67:363-369. http://dx.doi.org/10.1016/0091-6749(81)90081-6 webcite
• [51]Tecklenburg SL, Mickleborough TD, Fly AD, Bai Y, Stager JM: Ascorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma. Respir Med 2007, 101:1770-1778. http://www.ncbi.nlm.nih.gov/pubmed/17412579 webcite. http://dx.doi.org/10.1016/j.rmed.2007.02.014 webcite
• [52]Schock BC, Koostra J, Kwack S, Hackman RM, Van Der Vliet A, Cross CE: Ascorbic acid in nasal and tracheobronchial airway lining fluids. Free Radic Biol Med 2004, 37:1393-1401. http://www.ncbi.nlm.nih.gov/pubmed/15454278 webcite. http://dx.doi.org/10.1016/j.freeradbiomed.2004.07.023 webcite
• [53]Behndig AF, Blomberg A, Helleday R, Kelly FJ, Mudway IS: Augmentation of respiratory tract lining fluid ascorbate concentrations through supplementation with vitamin C. Inhal Toxicol 2009, 21:250-258. http://dx.doi.org/10.1080/08958370802474736 webcite
• [54]Hemilä H: Vitamin C may alleviate exercise-induced bronchoconstriction: a meta-analysis. BMJ Open 2013, 3:e002416. http://dx.doi.org/10.1136/bmjopen-2012-002416 webcite
• [55]Hemilä H: Vitamin C should be tested against exercise-induced bronchoconstriction. Am J Respir Crit Care Med 2013, 188:1370. http://dx.doi.org/10.1164/rccm.201307-1205LE webcite
• [56]Schachter EN, Schlesinger A: The attenuation of exercise-induced bronchospasm by ascorbic acid. Ann Allergy 1982, 49:146-151. http://www.ncbi.nlm.nih.gov/pubmed/7114587 webcite
• [57]Cohen HA, Neuman I, Nahum H: Blocking effect of vitamin C in exercise-induced asthma. Arch Pediatr Adolescent Med 1997, 151:367-370. http://dx.doi.org/10.1001/archpedi.1997.02170410041005 webcite
• [58]Murphy JD, Ferguson CS, Brown KR, Harms CA: The effect of dietary antioxidants on lung function in exercise induced asthma [abstract]. Med Sci Sports Exerc 2002, 34(5):S155.
• [59]McFadden ER Jr: Resurrection men and the FEF25-75. J Allergy Clin Immunol 2010, 126:535-536. http://dx.doi.org/10.1016/j.jaci.2010.06.035 webcite
• [60]Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF Jr, Szefler SJ, Taussig L, Bacharier LB, Morgan W: Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values. J Allergy Clin Immunol 2010, 126:527-534. http://www.ncbi.nlm.nih.gov/pubmed/20638110 webcite. http://dx.doi.org/10.1016/j.jaci.2010.05.016 webcite
• [61]Haas F, Axen K, Schicchi JS: Use of maximum expiratory flow-volume curve parameters in the assessment of exercise-induced bronchospasm. Chest 1993, 103:64-68. http://www.ncbi.nlm.nih.gov/pubmed/8417938 webcite. http://dx.doi.org/10.1378/chest.103.1.64 webcite
• [62]Custovic A, Arifhodzic N, Robinson A, Woodcock A: Exercise testing revisited. The response to exercise in normal and atopic children. Chest 1994, 105:1127-1132. http://www.ncbi.nlm.nih.gov/pubmed/8162737 webcite. http://dx.doi.org/10.1378/chest.105.4.1127 webcite
• [63]Fonseca-Guedes CH, Cabral AL, Martins MA: Exercise-induced bronchospasm in children: comparison of FEV1 and FEF25-75% responses. Pediatr Pulmonol 2003, 36:49-54. http://www.ncbi.nlm.nih.gov/pubmed/12772223 webcite. http://dx.doi.org/10.1002/ppul.10309 webcite
• [64]Bar-Yishay E, Amirav I, Goldberg S: Comparison of maximal midexpiratory flow rate and forced expiratory flow at 50% of vital capacity in children. Chest 2003, 123:731-735. http://www.ncbi.nlm.nih.gov/pubmed/12628870 webcite. http://dx.doi.org/10.1378/chest.123.3.731 webcite
• [65]Hemilä H: Vitamin C and common cold incidence: a review of studies with subjects under heavy physical stress. Int J Sports Med 1996, 17:379-383. http://dx.doi.org/10.1055/s-2007-972864 webcite. Available at: http://hdl.handle.net/10250/7983 webcite
• [66]Hemilä H, Chalker E: Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2013, 1:CD000980. http://dx.doi.org/10.1002/14651858.CD000980.pub4 webcite
• [67]Peters EM, Goetzsche JM, Grobbelaar B, Noakes TD: Vitamin C supplementation reduces the incidence of postrace symptoms of upper-respiratory-tract infection in ultramarathon runners. Am J Clin Nutr 1993, 57:170-174. http://www.ncbi.nlm.nih.gov/pubmed/8185726 webcite. http://ajcn.nutrition.org/content/57/2/170 webcite
• [68]Peters EM, Goetzsche JM, Joseph LE, Noakes TD: Vitamin C as effective as combinations of anti-oxidant nutrients in reducing symptoms of upper respiratory tract infection in ultramarathon runners. S Afr J Sports Med 1996, 11:23-27.
• [69]Moolla ME: The Effect of Supplemental Anti-Oxidants on the Incidence and Severity of Upper Respiratory Tract Infections in Ultra-Marathon Runners. South Africa: University of Cape Town; 1996. [MSc Thesis]
• [70]Sabiston BH, Radomski MW: Health Problems and Vitamin C in Canadian Northern Military Operations. DCIEM Report no. 74-R-1012. Downsview, Ontario, Canada: Defence and Civil Institute of Environmental Medicine; 1974:1-10. Available at: http://www.mv.helsinki.fi/home/hemila/CC/Sabiston_1974_ch.pdf webcite (accessed 18 Nov 2014)
• [71]Ritzel G: Critical analysis of the role of vitamin C in the treatment of the common cold [in German]. Helv Med Acta 1961, 28:63-68. Translation at: http://www.mv.helsinki.fi/home/hemila/T3.pdf webcite (accessed 18 Nov 2014)
• [72]Kippelen P, Anderson SD: Airway injury during high-level exercise. Br J Sports Med 2012, 46:385-390. http://dx.doi.org/10.1136/bjsports-2011-090819 webcite
• [73]Eccles R: Is the common cold a clinical entity or a cultural concept? Rhinology 2013, 51:3-8. http://www.ncbi.nlm.nih.gov/pubmed/23441305 webcite
• [74]Spence L, Brown WJ, Pyne DB, Nissen MD, Sloots TP, McCormack JG, Locke AS, Fricker PA: Incidence, etiology, and symptomatology of upper respiratory illness in elite athletes. Med Sci Sports Exerc 2007, 39:577-586. http://www.ncbi.nlm.nih.gov/pubmed/17414793 webcite. http://dx.doi.org/10.1249/mss.0b013e31802e851a webcite
• [75]Arruda E, Pitkäranta A, Witek TJ, Doyle CA, Hayden FG: Frequency and natural history of rhinovirus infections in adults during autumn. J Clin Microbiol 1997, 35:2864-2868. http://www.ncbi.nlm.nih.gov/pubmed/9350748 webcite. http://jcm.asm.org/content/35/11/2864 webcite
• [76]Constantini NW, Dubnov-Raz G, Eyal BB, Berry EM, Cohen AH, Hemilä H: The effect of vitamin C on upper respiratory infections in adolescent swimmers: a randomized trial. Eur J Pediatr 2011, 170:59-63. http://www.ncbi.nlm.nih.gov/pubmed/20689965 webcite. http://dx.doi.org/10.1007/s00431-010-1270-z webcite
• [77]Bougault V, Boulet LP: Airway dysfunction in swimmers. Br J Sports Med 2012, 46:402-406. http://dx.doi.org/10.1136/bjsports-2011-090821 webcite
• [78]Wenzel SE: Asthma: defining of the persistent adult phenotypes. Lancet 2006, 368:804-813. http://www.ncbi.nlm.nih.gov/pubmed/16935691 webcite. http://dx.doi.org/10.1016/S0140-6736(06)69290-8 webcite
• [79]Lötvall J, Akdis CA, Bacharier LB, Bjermer L, Casale TB, Custovic A, Lemanske RF Jr, Wardlaw AJ, Wenzel SE, Greenberger PA: Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol 2011, 127:355-360. http://dx.doi.org/10.1016/j.jaci.2010.11.037 webcite
• [80]Akaike T: Role of free radicals in viral pathogenesis and mutation. Rev Med Virol 2001, 11:87-101. http://dx.doi.org/10.1002/rmv.303 webcite
• [81]Castro SM, Guerrero-Plata A, Suarez-Real G, Adegboyega PA, Colasurdo GN, Khan AM, Garofalo RP, Casola A: Antioxidant treatment ameliorates respiratory syncytial virus-induced disease and lung inflammation. Am J Respir Crit Care Med 2006, 174:1361-1369. http://www.ncbi.nlm.nih.gov/pubmed/17008643 webcite. http://dx.doi.org/10.1164/rccm.200603-319OC webcite
• [82]Hemilä H: Vitamin C and common cold-induced asthma: a systematic review and statistical analysis. Allergy Asthma Clin Immunol 2013, 9:46. http://dx.doi.org/10.1186/1710-1492-9-46 webcite BioMed Central Full Text
• [83]Fogarty A, Lewis SA, Scrivener SL, Antoniak M, Pacey S, Pringle M, Britton J: Oral magnesium and vitamin C supplements in asthma: a parallel group randomized placebo-controlled trial. Clin Exp Allergy 2003, 33:1355-1359. http://www.ncbi.nlm.nih.gov/pubmed/14519140 webcite. http://dx.doi.org/10.1046/j.1365-2222.2003.01777.x webcite
• [84]Heart Protection Study Collaborative Group: MRC/BHF heart protection study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002, 360:23-33. http://www.ncbi.nlm.nih.gov/pubmed/12114037 webcite. http://dx.doi.org/10.1016/S0140-6736(02)09328-5 webcite
• [85]Fogarty A, Lewis SA, Scrivener SL, Antoniak M, Pacey S, Pringle M, Britton J: Corticosteroid sparing effects of vitamin C and magnesium in asthma: a randomised trial. Respir Med 2006, 100:174-179. http://www.ncbi.nlm.nih.gov/pubmed/16338599 webcite. http://dx.doi.org/10.1016/j.rmed.2005.03.038 webcite
• [86]Goodwin JS, Tangum MR: Battling quackery: attitudes about micronutrient supplements in American Academic medicine. Arch Intern Med 1998, 158:2187-2191. http://dx.doi.org/10.1001/archinte.158.20.2187 webcite
• [87]Richards E: The politics of therapeutic evaluation: the vitamin C and cancer controversy. Soc Stud Sci 1988, 18:653-701. http://dx.doi.org/10.1177/030631288018004004 webcite
• [88]Louhiala P, Hemilä H: Can CAM treatments be evidence-based? Focus Altern Complement Ther 2014, 19:84-89. http://dx.doi.org/10.1111/fct.12110 webcite
• [89]Hemilä H, Herman ZS: Vitamin C and the common cold: a retrospective analysis of Chalmers’ review. J Am Coll Nutr 1995, 4:116-123. http://dx.doi.org/10.1080/07315724.1995.10718483 webcite. Available at: http://hdl.handle.net/10138/42358 webcite
• [90]Hemilä H: Vitamin C supplementation and common cold symptoms: problems with inaccurate reviews. Nutrition 1996, 12:804-809. http://dx.doi.org/10.1016/S0899-9007(96)00223-7 webcite. Available at: http://hdl.handle.net/10250/7979 webcite
• [91]Kaur B, Rowe BH, Arnold E: Vitamin C supplementation for asthma. Cochrane Database Syst Rev 2009, 1:CD000993. http://dx.doi.org/10.1002/14651858.CD000993.pub3 webcite
• [92]Hemilä H: Feedback to Cochrane review on vitamin C and asthma. 2009. http://hdl.handle.net/10138/38500 webcite
• [93]Hemilä H: Vitamin C and exercise-induced bronchoconstriction: further problems in the Cochrane review “vitamin C for asthma”. 2013. http://hdl.handle.net/10138/40816 webcite