Abstract
The macrolide antibiotics are a family of related 14- or 15-membered lactone ring antibiotics. There has been recent interest in the beneficial effects of these drugs as immune modulators in respiratory conditions in children. Cystic fibrosis (CF) and asthma, both of which occur in childhood, have an underlying inflammatory component and are associated with significant morbidity. The pathogenesis of both conditions is poorly understood but several molecular mechanisms have been suggested.
In CF, these mechanisms broadly involve altered chloride transport and alteration of the airway surface liquid with disordered neutrophilic inflammation. There is much evidence for a proinflammatory propensity in CF immune effector and epithelial cells and many studies indicate that macrolides modulate these inflammatory processes. Recent studies have confirmed a clinical improvement in CF following treatment with macrolides, but the exact mechanisms by which they work are unknown. Asthma is likely to represent several different phenotypes but in all of these, airway obstruction, bronchial hyperresponsiveness, and inflammation are central processes. Results from trials using macrolides have suggested an improvement in clinical outcome.
The putative mechanisms of macrolide immunomodulatory action include improvement of the primary defense mechanisms, inhibition of the bacteria-epithelial cell interaction, modulation of the signaling pathway and chemokine release, and direct neutrophil effects. Putative mechanisms of phenotypic modulation have also been proposed involving interactions with nitric oxide, endothelin-1, and bronchoconstriction, endothelial growth factors and airway remodeling, and bioactive phospholipids in both CF and asthma.
Further characterization of these effects and development of targeted designer drugs will further expand our therapeutic repertoire and lead to improved quality and quantity of life for patients with CF and asthma.
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References
FitzSimmons SC. The changing epidemiology of cystic fibrosis. J Pediatr 1993 Jan; 122(1): 1–9
Khan TZ, Wagener JS, Bost T, et al. Early pulmonary inflammation in infants with cystic fibrosis. Am J Respir Crit Care Med 1995 Apr; 151(4): 1075–82
DiMango E, Ratner AJ, Bryan R, et al. Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells. J Clin Invest 1998 Jun 1; 101(11): 2598–605
Weber AJ, Soong G, Bryan R, et al. Activation of NF-kappaB in airway epithelial cells is dependent on CFTR trafficking and Cl− channel function. Am J Physiol Lung Cell Mol Physiol 2001 Jul; 281(1): L71–8
Corvol H, Fitting C, Chadelat K, et al. Distinct cytokine production by lung and blood neutrophils from children with cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 2003 Jun; 284(6): L997–1003
Dai Y, Dean TP, Church MK, et al. Desensitisation of neutrophil responses by systemic interleukin 8 in cystic fibrosis. Thorax 1994 Sep; 49(9): 867–71
Saba S, Soong G, Greenberg S, et al. Bacterial stimulation of epithelial G-CSF and GM-CSF expression promotes PMN survival in CF airways. Am J Respir Cell Mol Biol 2002 Nov; 27(5): 561–7
Stockley RA. Role of inflammation in respiratory tract infections. Am J Med 1995 Dec 29; 99(6B): 8S–13S
Tosi MF, Zakem H, Berger M. Neutrophil elastase cleaves C3bi on opsonized pseudomonas as well as CR1 on neutrophils to create a functionally important opsonin receptor mismatch. J Clin Invest 1990 Jul; 86(1): 300–8
Meng QH, Springall DR, Bishop AE, et al. Lack of inducible nitric oxide synthase in bronchial epithelium: a possible mechanism of susceptibility to infection in cystic fibrosis. J Pathol 1998 Mar; 184(3): 323–31
Gaston B, Ratjen F, Vaughan JW, et al. Nitrogen redox balance in the cystic fibrosis airway: effects of antipseudomonal therapy. Am J Respir Crit Care Med 2002 Feb 1; 165(3): 387–90
Payne DN. Nitric oxide in allergic airway inflammation. Curr Opin Allergy Clin Immunol 2003 Apr; 3(2): 133–7
Bush A, Tiddens H, Silverman M. Clinical implications of inflammation in young children. Am J Respir Crit Care Med 2000 Aug; 162(2 Pt 2): S11–4
Payne DN, Wilson NM, James A, et al. Evidence for different subgroups of difficult asthma in children. Thorax 2001 May; 56(5): 345–50
Johansson SG, Hourihane JO, Bousquet J, et al. A revised nomenclature for allergy: an EAACI position statement from the EAACI nomenclature task force [published erratum appears in Allergy 2001 Dec; 56 (12): 1229]. Allergy 2001 Sep; 56(9): 813–24
Nicholson KG, Kent J, Ireland DC. Respiratory viruses and exacerbations of asthma in adults. BMJ 1993; 307(6910): 982–6
Johnston SL, Pattemore PK, Sanderson G, et al. Community study of role of viral infections in exacerbations of asthma in 9–11 year old children. BMJ 1995; 310(6989): 1225–9
Vuillermin P, South M, Robertson C. Parent-initiated oral corticosteroid therapy for intermittent wheezing illnesses in children. Cochrane Database Syst Rev 2006 Jul 19; 3: CD005311
Berry MA, Hargadon B, Shelley M, et al. Evidence of a role of tumor necrosis factor alpha in refractory asthma. N Engl J Med 2006 Feb 16; 354(7): 697–708
Turner H, Kinet JP. Signalling through the high-affinity IgE receptor Fc epsilonRI. Nature 1999 Nov 25; 402(6760 Suppl.): B24–30
Ammit AJ, Bekir SS, Johnson PR, et al. Mast cell numbers are increased in the smooth muscle of human sensitized isolated bronchi. Am J Respir Crit Care Med 1997 Mar; 155(3): 1123–9
Cazzola M, Polosa R. Anti-TNF-alpha and Th1 cytokine-directed therapies for the treatment of asthma. Curr Opin Allergy Clin Immunol 2006 Feb; 6(1): 43–50
Bousquet J, Chanez P, Lacoste JY, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990 Oct 11; 323(15): 1033–9
Forster R, Schubel A, Breitfeld D, et al. CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs. Cell 1999 Oct 1; 99(1): 23–33
Chanez P, Bousquet J, Couret I, et al. Increased numbers of hypodense alveolar macrophages in patients with bronchial asthma. Am Rev Respir Dis 1991 Oct; 144(4): 923–30
Fuller RW. The role of the alveolar macrophage in asthma. Respir Med 1989 May; 83(3): 177–8
Thepen T, Van Rooijen N, Kraal G. Alveolar macrophage elimination in vivo is associated with an increase in pulmonary immune response in mice. J Exp Med 1989 Aug 1; 170(2): 499–509
Bentley AM, Hamid Q, Robinson DS, et al. Prednisolone treatment in asthma: reduction in the numbers of eosinophils, T cells, tryptase-only positive mast cells, and modulation of IL-4, IL-5, and interferon-gamma cytokine gene expression within the bronchial mucosa. Am J Respir Crit Care Med 1996 Feb; 153(2): 551–6
Nickel R, Beck LA, Stellato C, et al. Chemokines and allergic disease. J Allergy Clin Immunol 1999 Oct; 104(4 Pt 1): 723–42
Dworski R, Fitzgerald GA, Oates JA, et al. Effect of oral prednisone on airway inflammatory mediators in atopic asthma. Am J Respir Crit Care Med 1994 Apr; 149(4 Pt 1): 953–9
Elwood W, Lotvall JO, Barnes PJ, et al. Effect of dexamethasone and cyclosporin A on allergen-induced airway hyperresponsiveness and inflammatory cell responses in sensitized Brown-Norway rats. Am Rev Respir Dis 1992 Jun; 145(6): 1289–94
Giembycz MA, Lindsay MA. Pharmacology of the eosinophil. Pharmacol Rev 1999 Jun; 51(2): 213–340
Birrell MA, Battram CH, Woodman P, et al. Dissociation by steroids of eosinophilic inflammation from airway hyperresponsiveness in murine airways. Respir Res 2003; 4(1): 3
Stamler DA, Edelstein MA, Edelstein PH. Azithromycin pharmacokinetics and intracellular concentrations in Legionella pneumophila-infected and uninfected guinea pigs and their alveolar macrophages. Antimicrob Agents Chemother 1994 Feb; 38(2): 217–22
Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol 2000; 50(4): 285–95
Hatipoglu U, Rubinstein I. Low-dose, long-term macrolide therapy in asthma: an overview. Clin Mol Allergy 2004; 2(1): 4
Niven AS, Argyros G. Alternate treatments in asthma. Chest 2003; 123(4): 1254–65
Nalca Y, Jansch L, Bredenbruch F, et al. Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PA01: a global approach. Antimicrob Agents Chemother 2006 May; 50(5): 1680–8
Schultz MJ, Speelman P, Zaat S, et al. Erythromycin inhibits tumor necrosis factor alpha and interleukin 6 production induced by heat-killed Streptococcus pneumoniae in whole blood. Antimicrob Agents Chemother 1998 Jul; 42(7): 1605–9
Brugiere O, Milleron B, Antoine M, et al. Diffuse panbronchiolitis in an Asian immigrant. Thorax 1996 Oct; 51(10): 1065–7
Hoiby N. Diffuse panbronchiolitis and cystic fibrosis: East meets West. Thorax 1994 Jun; 49(6): 531–2
Kobayashi H, Takeda H, Sakayori S, et al. Study on azithromycin in treatment of diffuse panbronchiolitis. Kansenshogaku Zasshi 1995 Jun; 69(6): 711–22
Takeda H, Miura H, Kawahira M, et al. Long-term administration study on TE-031 (A-56268) in the treatment of diffuse panbronchiolitis. Kansenshogaku Zasshi 1989 Jan; 63(1): 71–8
Jaffe A, Francis J, Rosenthal M, et al. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 1998 Feb 7; 351(9100): 420
Ordonez CL, Stulbarg M, Grundland H, et al. Effect of clarithromycin on airway obstruction and inflammatory markers in induced sputum in cystic fibrosis: a pilot study. Pediatr Pulmonol 2001 Jul; 32(1): 29–37
Wolter J, Seeney S, Bell S, et al. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002 Mar; 57(3): 212–6
Equi A, Balfour-Lynn IM, Bush A, et al. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet 2002 Sep 28; 360(9338): 978–84
Saiman L, Marshall BC, Mayer-Hamblett N, et al. Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. JAMA 2003 Oct 1; 290(13): 1749–56
Pirzada OM, McGaw J, Taylor CJ, et al. Improved lung function and body mass index associated with long-term use of macrolide antibiotics. J Cyst Fibros 2003 Jun; 2(2): 69–71
Clement A, Tamalet A, Le Roux E, et al. Long term effects of azithromycin in patients with cystic fibrosis: a double-blind, placebo-controlled trial. Thorax 2006; 61(10): 895–902
Jaffe A, Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatr Pulmonol 2001 Jun; 31(6): 464–73
Saiman L, Mayer-Hamblett N, Campbell P, et al. Heterogeneity of treatment response to azithromycin in patients with cystic fibrosis. Am J Respir Crit Care Med 2005 Oct 15; 172(8): 1008–12
Cystic Fibrosis Foundation home page [online]. Available from URL: http://www.cff.org [Accessed 2007 Feb 28]
Dinwiddie R. Anti-inflammatory therapy in cystic fibrosis. J Cyst Fibros 2005; 4Suppl. 2: 45–8
Kaplan MA, Goldin M. The use of triacetyloleandomycin in chronic infectious asthma. In: Welch H, Marti-Ibanez F, editors. Antibiotic annual 1958–59. New York: Interscience Publishers, Inc., 1959: 273–6
Itkin IH, Menzel ML. The use of macrolide antibiotic substances in the treatment of asthma. J Allergy 1970 Mar; 45(3): 146–62
Zeiger RS, Schatz M, Sperling W, et al. Efficacy of troleandomycin in outpatients with severe, corticosteroid-dependent asthma. J Allergy Clin Immunol 1980 Dec; 66(6): 438–46
Nelson HS, Hamilos DL, Corsello PR, et al. A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids. Am Rev Respir Dis 1993 Feb; 147(2): 398–404
Eitches RW, Rachelefsky GS, Katz RM, et al. Methylprednisolone and troleandomycin in treatment of steroid-dependent asthmatic children. Am J Dis Child 1985 Mar; 139(3): 264–8
Ball BD, Hill MR, Brenner M, et al. Effect of low-dose troleandomycin on glucocorticoid pharmacokinetics and airway hyperresponsiveness in severely asthmatic children. Ann Allergy 1990 Jul; 65(1): 37–45
Shimizu T, Kato M, Mochizuki H, et al. Roxithromycin reduces the degree of bronchial hyperresponsiveness in children with asthma. Chest 1994 Aug; 106(2): 458–61
Fost DA, Leung DY, Martin RJ, et al. Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin Immunol 1999 Jun; 103(6): 1031–5
Rosenberg SM, Gerhard H, Grunstein MM, et al. Use of TAO without methyl-prednisolone in the treatment of severe asthma. Chest 1991 Sep; 100(3): 849–50
Miyatake H, Taki F, Taniguchi H, et al. Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma. Chest 1991 Mar; 99(3): 670–3
Amayasu H, Yoshida S, Ebana S, et al. Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma. Ann Allergy Asthma Immunol 2000 Jun; 84(6): 594–8
Ackermann G, Rodloff AC. Drugs of the 21st century: telithromycin (HMR 3647): the first ketolide. J Antimicrob Chemother 2003 Mar; 51(3): 497–511
Johnston SL, Blasi F, Black PN, et al. The effect of telithromycin in acute exacerbations of asthma. N Engl J Med 2006 Apr 13; 354(15): 1589–600
Emre U, Roblin PM, Gelling M, et al. The association of Chlamydia pneumoniae infection and reactive airway disease in children. Arch Pediatr Adolesc Med 1994 Jul; 148(7): 727–32
Hahn DL, Bukstein D, Luskin A, et al. Evidence for Chlamydia pneumoniae infection in steroid-dependent asthma. Ann Allergy Asthma Immunol 1998 Jan; 80(1): 45–9
Kaneko K, Yamashiro Y, Maruyama T, et al. Chlamydia pneumoniae infection in children with persistent cough. Arch Dis Child 1999 Jun; 80(6): 581–2
Sakito O, Kadota J, Kohno S, et al. Interleukin 1 beta, tumor necrosis factor alpha, and interleukin 8 in bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis: a potential mechanism of macrolide therapy. Respiration 1996; 63(1): 42–8
Khair OA, Devalia JL, Abdelaziz MM, et al. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells. Eur Respir J 1995 Sep; 8(9): 1451–7
Tsai WC, Rodriguez ML, Young KS, et al. Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection. Am J Respir Crit Care Med 2004 Dec 15; 170(12): 1331–9
Li Y, Azuma A, Takahashi S, et al. Fourteen-membered ring macrolides inhibit vascular cell adhesion molecule 1 messenger RNA induction and leukocyte migration: role in preventing lung injury and fibrosis in bleomycin-challenged mice. Chest 2002 Dec; 122(6): 2137–45
Lin HC, Wang CH, Liu CY, et al. Erythromycin inhibits beta2-integrins (CD11b/CD18) expression, interleukin-8 release and intracellular oxidative metabolism in neutrophils. Respir Med 2000 Jul; 94(7): 654–60
Okubo Y. Macrolides reduce the expression of surface Mac-1 molecule on neutrophil. Kurume Med J 1997; 44(2): 115–23
Kawasaki S, Takizawa H, Ohtoshi T, et al. Roxithromycin inhibits cytokine production by and neutrophil attachment to human bronchial epithelial cells in vitro. Antimicrob Agents Chemother 1998 Jun; 42(6): 1499–502
Brennan S, Cooper D, Sly PD. Directed neutrophil migration to IL-8 is increased in cystic fibrosis: a study of the effect of erythromycin. Thorax 2001 Jan; 56(1): 62–4
Uriarte SM, Molestina RE, Miller RD, et al. Effect of macrolide antibiotics on human endothelial cells activated by Chlamydia pneumoniae infection and tumor necrosis factor-alpha. J Infect Dis 2002 Jun 1; 185(11): 1631–6
Labro MT, el Benna J, Babin-Chevaye C. Comparison of the in-vitro effect of several macrolides on the oxidative burst of human neutrophils. J Antimicrob Chemother 1989 Oct; 24(4): 561–72
Anderson R. Erythromycin and roxithromycin potentiate human neutrophil locomotion in vitro by inhibition of leukoattractant-activated superoxide generation and autooxidation. J Infect Dis 1989 May; 159(5): 966–73
Culic O, Erakovic V, Cepelak I, et al. Azithromycin modulates neutrophil function and circulating inflammatory mediators in healthy human subjects. Eur J Pharmacol 2002 Aug 30; 450(3): 277–89
Aoshiba K, Nagai A, Konno K. Erythromycin shortens neutrophil survival by accelerating apoptosis. Antimicrob Agents Chemother 1995 Apr; 39(4): 872–7
Mitsuyama T, Hidaka K, Furuno T, et al. Neutrophil-induced endothelial cell damage: inhibition by a 14-membered ring macrolide through the action of nitric oxide. Int Arch Allergy Immunol 1997 Oct; 114(2): 111–5
Tamaoki J, Kondo M, Kohri K, et al. Macrolide antibiotics protect against immune complex-induced lung injury in rats: role of nitric oxide from alveolar macrophages. J Immunol 1999 Sep 1; 163(5): 2909–15
Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin and clarithromycin attenuate cytokine-induced endothelin-1 expression in human bronchial epithelial cells. Eur Respir J 1998 Jul; 12(1): 57–63
Yatsunami J, Fukuno Y, Nagata M, et al. Antiangiogenic and antitumor effects of 14-membered ring macrolides on mouse B16 melanoma cells. Clin Exp Metastasis 1999 Jun; 17(4): 361–7
Yatsunami J, Tsuruta N, Hara N, et al. Inhibition of tumor angiogenesis by roxithromycin, a 14-membered ring macrolide antibiotic. Cancer Lett 1998 Sep 25; 131(2): 137–43
Fujitani Y, Trifilieff A. In vivo and in vitro effects of SAR 943, a rapamycin analogue, on airway inflammation and remodeling. Am J Respir Crit Care Med 2003 Jan 15; 167(2): 193–8
Feldman C, Anderson R, Theron A, et al. The effects of ketolides on bioactive phospholipid-induced injury to human respiratory epithelium in vitro. Eur Respir J 1999 May; 13(5): 1022–8
Lallemand JY, Stoven V, Annereau JP, et al. Induction by antitumoral drugs of proteins that functionally complement CFTR: a novel therapy for cystic fibrosis? Lancet 1997 Sep 6; 350(9079): 711–2
Gant TW, O’Connor CK, Corbitt R, et al. In vivo induction of liver P-glycoprotein expression by xenobiotics in monkeys. Toxicol Appl Pharmacol 1995 Aug; 133(2): 269–76
Tamaoki J, Isono K, Sakai N, et al. Erythromycin inhibits Cl secretion across canine tracheal epithelial cells. Eur Respir J 1992 Feb; 5(2): 234–8
Tagaya E, Tamaoki J, Kondo M, et al. Effect of a short course of clarithromycin therapy on sputum production in patients with chronic airway hypersecretion. Chest 2002 Jul; 122(1): 213–8
Advenier C, Sarria B, Naline E, et al. Contractile activity of three endothelins (ET-1, ET-2 and ET-3) on the human isolated bronchus. Br J Pharmacol 1990 May; 100(1): 168–72
Takizawa H, Desaki M, Ohtoshi T, et al. Erythromycin modulates IL-8 expression in normal and inflamed human bronchial epithelial cells. Am J Respir Crit Care Med 1997 Jul; 156(1): 266–71
Barker PM, Gillie DJ, Schechter MS, et al. Effect of macrolides on in vivo ion transport across cystic fibrosis nasal epithelium. Am J Respir Crit Care Med 2005 Apr 15; 171(8): 868–71
Equi AC, Davies JC, Painter H, et al. Exploring the mechanisms of macrolides in cystic fibrosis. Respir Med 2006 Apr; 100(4): 687–97
Engelhardt JF, Yankaskas JR, Ernst SA, et al. Submucosal glands are the predominant site of CFTR expression in the human bronchus. Nat Genet 1992 Nov; 2(3): 240–8
Basbaum CB, Jany B, Finkbeiner WE. The serous cell. Annu Rev Physiol 1990; 52: 97–113
Goldman MJ, Anderson GM, Stolzenberg ED, et al. Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 1997 Feb 21; 88(4): 553–60
Ashitani J, Mukae H, Nakazato M, et al. Elevated concentrations of defensins in bronchoalveolar lavage fluid in diffuse panbronchiolitis. Eur Respir J 1998 Jan; 11(1): 104–11
Hiratsuka T, Mukae H, Iiboshi H, et al. Increased concentrations of human beta-defensins in plasma and bronchoalveolar lavage fluid of patients with diffuse panbronchiolitis. Thorax 2003 May; 58(5): 425–30
Pamukcu A, Bush A, Buchdahl R. Effects of Pseudomonas aeruginosa colonization on lung function and anthropometric variables in children with cystic fibrosis. Pediatr Pulmonol 1995 Jan; 19(1): 10–5
Davies J, Dewar A, Bush A, et al. Reduction in the adherence of Pseudomonas aeruginosa to native cystic fibrosis epithelium with anti-asialoGM1 antibody and neuraminidase inhibition. Eur Respir J 1999 Mar; 13(3): 565–70
Schroeder TH, Lee MM, Yacono PW, et al. CFTR is a pattern recognition molecule that extracts Pseudomonas aeruginosa LPS from the outer membrane into epithelial cells and activates NF-kappa B translocation. Proc Natl Acad Sci U S A 2002 May 14; 99(10): 6907–12
Davies JC, Stern M, Dewar A, et al. CFTR gene transfer reduces the binding of Pseudomonas aeruginosa to cystic fibrosis respiratory epithelium. Am J Respir Cell Mol Biol 1997 Jun; 16(6): 657–63
Nakashio S, Susa C, Qiu S, et al. Antimicrobial activity of clarithromycin and its effect on bacterial adherence to medical material. Jpn J Antibiot 1993 Jun; 46(6): 428–36
Baumann U, Fischer JJ, Gudowius P, et al. Buccal adherence of Pseudomonas aeruginosa in patients with cystic fibrosis under long-term therapy with azithromycin. Infection 2001 Jan-Feb; 29(1): 7–11
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No sources of funding were used to assist in the preparation of this article. A. Jaffe has received a grant from Pfizer for another project. The other authors have no conflicts of interest that are directly relevant to the content of this review.
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Sharma, S., Jaffe, A. & Dixon, G. Immunomodulatory Effects of Macrolide Antibiotics in Respiratory Disease. Pediatr-Drugs 9, 107–118 (2007). https://doi.org/10.2165/00148581-200709020-00004
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DOI: https://doi.org/10.2165/00148581-200709020-00004