- Email: [email protected]
Immunomodulatory properties of macrolides: Overview and historical perspective
Immunomodulatory Properties of Macrolides: Overview and Historical Perspective Bruce K. Rubin, MD, MEngr
T
he macrolide antibiotics have distinct antibacterial and anti-inflammatory properties. Interest in the clinical benefit of macrolides for the treatment of chronic inflammatory diseases of the airways has grown with increasing evidence of their effectiveness in treating these disorders. Macrolides reduce inflammation associated with diffuse panbronchiolitis (DPB), asthma, cystic fibrosis, chronic bronchitis, and chronic sinusitis.
STRUCTURE AND EFFECTIVENESS OF MACROLIDES The immunomodulatory effects of the macrolide antibiotics appear to be related to their structure. The 14- and 15-member macrolides, including erythromycin, clarithromycin, roxithromycin, and azithromycin possess anti-inflammatory properties. However, 16-member ring macrolides, such as josamycin, do not have immunomodulatory properties. Differences between the immunomodulatory properties of these macrolides are thought to be due, in part, to the presence of sugar moieties attached to the ring system of the 14- and 15member macrolides.1–3 Differences between the sugar moieties may also affect the ability of the drug to inhibit the development of virulence factors such as type IV fimbrae that are critical in transforming Pseudomonas from the planktonic phenotype to biofilm colonies.4
IMMUNOMODULATORY EFFECTS OF MACROLIDES Macrolides inhibit the production of proinflammatory cytokines, including interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor–␣, and inhibit the expression of transcription factors, including nuclear factor–B and activator protein–1.5,6 IL-8 is a chemoattractant for neutrophils, and studies show that the concentration of IL-8 in bronchoalveolar lavage fluid from patients with DPB correlates with the number of neutrophils.7,8 These changes have also been shown in patients with chronic sinusitis, asthma, and cystic fibrosis.6,9 –25 Macrolides also inhibit neutrophil elastase and reactive oxygen radicals26,27; they suppress the expression of neutrophil adhesion molecules and selectins,28,29 thus de-
From the Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. Reprints are not available. Correspondence should be addressed to Bruce K. Rubin, MD, MEngr, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1081. 2S
© 2004 by Elsevier Inc. All rights reserved.
creasing infiltration of inflammatory cells into the airway epithelium. Macrolides reduce mucus hypersecretion by inhibiting mucin gene expression and by reducing local airway inflammation.30
HISTORY OF MACROLIDE USE FOR THE TREATMENT OF CHRONIC AIRWAY DISEASE Steroid-Sparing Effects of Macrolides As early as the 1960s, the immunomodulatory effects of macrolides were observed in patients with corticosteroiddependent asthma who were treated with troleandomycin.31 Initially, the benefit of troleandomycin therapy was thought to be due to inhibition of steroid metabolism or direct effects on mucus secretion.32–35 Other studies had reported the effectiveness of troleandomycin in subjects with steroid-dependent asthma as well as in those with chronic bronchitis.36 Since these initial reports, a number of studies evaluating the effectiveness of troleandomycin have shown that it can decrease corticosteroid use and improve the symptoms and pulmonary function of children and adults with asthma.37– 41 Some patients who receive concomitant troleandomycin and corticosteroid therapy are able to discontinue steroids completely without worsening their asthma.42 These data suggest that troleandomycin probably has immunomodulatory activity for the treatment of asthma. Use of Macrolides in Treatment of DPB Most of the clinical studies of the immunomodulatory properties of macrolides have been in patients with DPB, an airway disease characterized by chronic sinusitis, persistent cough, increased sputum, and progressive loss of pulmonary function leading to respiratory failure and death. Since the first report of the effectiveness of erythromycin in persons with DPB, a large number of studies have shown the effectiveness of the 14- and 15-member macrolides for the treatment of this disease.43– 49 Macrolide therapy improves pulmonary function, reduces mucus hypersecretion, and reduces airway inflammation in patients with DPB.50 Macrolide therapy has significantly increased the 5-year survival rate from 26% in untreated DPB patients to ⬎90% in patients receiving macrolides.51 The dramatic response of patients with this disease to macrolide therapy and the similarities among DPB and other airway diseases have spurred research on the use of macrolides for treatment of patients with other chronic inflammatory airway diseases such as cystic fibrosis and chronic bronchitis. 1548-2766/04/$22.00 doi:10.1016/j.amjmed.2004.07.021
A Symposium: Macrolides: Overview and Historical Perspective/Rubin
CLINICAL TRIALS In clinical trials that evaluated the benefits of macrolide therapy in patients with cystic fibrosis,20,25,52–57 both children and adults who received a macrolide had improved pulmonary function and improved quality of life. Limited data available from studies of patients with chronic bronchitis suggest that macrolides reduce the frequency of acute exacerbations.58 Several studies show that macrolides reduce nasal secretion and size of nasal polyps in patients with chronic sinusitis.14,59,60
8.
9.
10.
CONCLUSION Macrolide antibiotics have been widely used as immunomodulatory therapy in Japan and Korea for at least 10 years. With recent studies in cystic fibrosis and as additional information becomes available on the effectiveness of long-term, low-dose macrolides for the therapy of chronic respiratory diseases, it is anticipated that use will increase in North America and Europe. If effective immunomodulatory agents without antibacterial properties (and thus without the risk of antimicrobial resistance) are developed and if macrolides are found to be effective for the treatment of chronic diseases such as coronary artery disease, cancer, inflammatory bowel disease, inflammatory arthritis, and atopic dermatitis, their use could increase dramatically. Currently, North American physicians are reluctant to prescribe antibiotics chronically and insurance companies in the United States often refuse to pay for antibiotics used as immunomodulatory drugs.
11.
12.
13.
14.
15.
16.
17.
REFERENCES 1. Abdelghaffar H, Vazifeh D, Labro MT. Erythromycin A-derived macrolides modify the functional activities of human neutrophils by altering the phospholipase D-phosphatidate phosphohydrolase transduction pathway: L-cladinose is involved both in alterations of neutrophil functions and modulation of this transductional pathway. J Immunol. 1997; 159:3995–4005. 2. Abdelghaffar H, Mtairag EM, Labro MT. Effects of dirithromycin and erythromycylamine on human neutrophil degranulation. Antimicrob Agents Chemother. 1994;38:1548 –1554. 3. Abdelghaffar H, Vazifeh D, Labro MT. Comparison of various macrolides on stimulation of human neutrophil degranulation in vitro. J Antimicrob Chemother. 1996;38:81–93. 4. Nagino K, Kobayashi H. Influence of macrolides on mucoid alginate biosynthetic enzyme from Pseudomonas aeruginosa. Clin Microbiol Infect. 1997;3:432–439. 5. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-B and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 2000;267:124 –128. 6. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-B transcription factors. J Antimicrob Chemother. 2002;49:745–755. 7. Fujii T, Kadota J, Morikawa T, et al. Inhibitory effect of erythromycin on interleukin 8 production by 1 alpha,25-
18.
19.
20.
21.
22.
23.
24.
25.
November 8, 2004
dihydroxyvitamin D3-stimulated THP-1 cells. Antimicrob Agents Chemother. 1996;40:1548 –1551. Sakito O, Kadota J, Kohno S, Abe K, Shirai R, Hara K. 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;63:42–48. Xiao W, Yu H, Zheng C. The imbalance of Th1/Th2 cytokine expression in peripheral blood mononuclear cell from asthmatic patients and the effect of erythromycin on these cytokines [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi. 2000;23:347–350. 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;12:57–63. Nakajima T, Yoshizawa I, Kawano Y, Noma T. Suppressive effect of roxithromycin on the induction of IL-2 responsiveness by DF-stimulated lymphocytes from patients with bronchial asthma [in Japanese]. Arerugi. 1996;45:554 –561. Nakahara H, Higashida A, Nogami J, et al. Effect of roxithromycin on cytokine production by peripheral monocytes derived from patients with bronchial asthma [in Japanese]. Jpn J Antibiot. 1997;50(Suppl A):113–115. Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121:1782–1788. Yamada T, Fujieda S, Mori S, Yamamoto H, Saito H. Macrolide treatment decreased the size of nasal polyps and IL-8 levels in nasal lavage. Am J Rhinol. 2000;14:143–148. 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;156: 266 –271. Nonaka M, Pawankar R, Saji F, Yagi T. Effect of roxithromycin on IL-8 synthesis and proliferation of nasal polyp fibroblasts. Acta Otolaryngol Suppl. 1998;539:71–75. MacLeod CM, Hamid QA, Cameron L, Tremblay C, Brisco W. Anti-inflammatory activity of clarithromycin in adults with chronically inflamed sinus mucosa. Adv Ther. 2001;18:75–82. Fujita K, Shimizu T, Majima Y, Sakakura Y. Effects of macrolides on interleukin-8 secretion from human nasal epithelial cells. Eur Arch Otorhinolaryngol. 2000;257:199 –204. Suzuki H, Asada Y, Ikeda K, Oshima T, Takasaka T. Inhibitory effect of erythromycin on interleukin-8 secretion from exudative cells in the nasal discharge of patients with chronic sinusitis. Laryngoscope. 1999;109:407–410. Ordonez CL, Stulbarg M, Grundland H, Liu JT, Boushey HA. Effect of clarithromycin on airway obstruction and inflammatory markers in induced sputum in cystic fibrosis: a pilot study. Pediatr Pulmonol. 2001;32:29 –37. Cunningham S, McColm JR, Mallinson A, Boyd I, Marshall TG. Duration of effect of intravenous antibiotics on spirometry and sputum cytokines in children with cystic fibrosis. Pediatr Pulmonol. 2003;36:43–48. 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;56:62–64. Konno S, Asano K, Kurokawa M, Ikeda K, Okamoto K, Adachi M. Antiasthmatic activity of a macrolide antibiotic, roxithromycin: analysis of possible mechanisms in vitro and in vivo. Int Arch Allergy Immunol. 1994;105:308 –316. Wallwork B, Coman W, Feron F, Mackay-Sim A, Cervin A. Clarithromycin and prednisolone inhibit cytokine production in chronic rhinosinusitis. Laryngoscope. 2002;112:1827–1830. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term THE AMERICAN JOURNAL OF MEDICINE威
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azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002;360:978 – 984. Kadota J, Iwashita T, Matsubara Y, et al. Inhibitory effect of erythromycin on superoxide anion production by human neutrophils primed with granulocyte-colony stimulating factor. Antimicrob Agents Chemother. 1998;42:1866 –1867. Oishi K, Sonoda F, Kobayashi S, et al. Role of interleukin-8 (IL-8) and an inhibitory effect of erythromycin on IL-8 release in the airways of patients with chronic airway diseases. Infect Immun. 1994;62:4145–4152. Mukae H, Kadota J, Ashitani J, et al. Elevated levels of soluble adhesion molecules in serum of patients with diffuse panbronchiolitis. Chest. 1997;112:1615–1621. Isono K, Tamaoki J, Nishimura K, Takeyama R, Nagai A. Effects of macrolide antibiotics on neutrophil infiltration into the airway mucosa and ICAM-1 expression [in Japanese]. Jpn J Antibiot. 1998;51(Suppl):34 –37. Shimizu T, Shimizu S, Hattori R, Gabazza EC, Majima Y. In vivo and in vitro effects of macrolide antibiotics on mucus secretion in airway epithelial cells. Am J Respir Crit Care Med. 2003;168:581–587. Itkin IH, Menzel ML. The use of macrolide antibiotic substances in the treatment of asthma. J Allergy. 1970;45:146 – 162. Fost DA, Leung DY, Martin RJ, Brown EE, Szefler SJ, Spahn JD. Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy. J Allergy Clin Immunol. 1999;103:1031–1035. LaForce CF, Szefler SJ, Miller MF, Ebling W, Brenner M. Inhibition of methylprednisolone elimination in the presence of erythromycin therapy. J Allergy Clin Immunol. 1983;72: 34 –39. Szefler SJ, Brenner M, Jusko WJ, Spector SL, Flesher KA, Ellis EF. Dose- and time-related effect of troleandomycin on methylprednisolone elimination. Clin Pharmacol Ther. 1982; 32:166 –171. Nelson HS, Hamilos DL, Corsello PR, Levesque NV, Buchmeier AD, Bucher BL. A double-blind study of troleandomycin and methylprednisolone in asthmatic subjects who require daily corticosteroids. Am Rev Respir Dis. 1993;147: 398 –404. Spector S, Katz F, Farr R. Troleandomycin: effectiveness in steroid-dependent asthma and bronchitis. J Allergy Clin Immunol. 1974;54:367–379. Kamada AK, Hill MR, Ikle DN, Brenner AM, Szefler SJ. Efficacy and safety of low-dose troleandomycin therapy in children with severe, steroid-requiring asthma. J Allergy Clin Immunol. 1993;91:873–882. Flotte TR, Loughlin GM. Benefits and complications of troleandomycin (TAO) in young children with steroid-dependent asthma. Pediatr Pulmonol. 1991;10:178 –182. Zeiger RS, Schatz M, Sperling W, Simon RA, Stevenson DD. Efficacy of troleandomycin in outpatients with severe, corticosteroid-dependent asthma. J Allergy Clin Immunol. 1980;66:438 –446. Wald JA, Friedman BF, Farr RS. An improved protocol for the use of troleandomycin (TAO) in the treatment of steroidrequiring asthma. J Allergy Clin Immunol. 1986;78(Pt 1):36 – 43. Siracusa A, Brugnami G, Fiordi T, Areni S, Severini C, Marabini A. Troleandomycin in the treatment of difficult asthma. J Allergy Clin Immunol. 1993;92:677–682. Rosenberg SM, Gerhard H, Grunstein MM, Schramm CM. Use of TAO without methylprednisolone in the treatment of severe asthma. Chest. 1991;100:849 –850.
4S November 8, 2004 THE AMERICAN JOURNAL OF MEDICINE威
43. Kudoh S, Uetake T, Hagiwara K, et al. Clinical effects of low-dose long-term erythromycin chemotherapy on diffuse panbronchiolitis [in Japanese]. Nihon Kyobu Shikkan Gakkai Zasshi. 1987;25:632–642. 44. Kadota J, Mukae H, Ishii H, et al. Long-term efficacy and safety of clarithromycin treatment in patients with diffuse panbronchiolitis. Respir Med. 2003;97:844 –850. 45. Brugiere O, Milleron B, Antoine M, Carette MF, Philippe C, Mayaud C. Diffuse panbronchiolitis in an Asian immigrant. Thorax. 1996;51:1065–1067. 46. Nagai H, Shishido H, Yoneda R, Yamaguchi E, Tamura A, Kurashima A. Long-term low-dose administration of erythromycin to patients with diffuse panbronchiolitis. Respiration. 1991;58:145–149. 47. Ichikawa Y, Ninomiya H, Koga H, et al. Erythromycin reduces neutrophils and neutrophil-derived elastolytic-like activity in the lower respiratory tract of bronchiolitis patients. Am Rev Respir Dis. 1992;146:196 –203. 48. Shirai R, Abe K, Yoshinaga M, et al. Analysis of cases allowed to cease erythromycin therapy for diffuse panbronchiolitis— comparative study between patients with cessation of the therapy and patients continuing the therapy [in Japanese]. Kansenshogaku Zasshi. 1997;71:1155–1161. 49. Kobayashi H, Takeda H, Sakayori S, et al. Study on azithromycin in treatment of diffuse panbronchiolitis [in Japanese]. Kansenshogaku Zasshi. 1995;69:711–722. 50. Ichikawa Y, Hotta M, Sumita S, Fujimoto K, Oizumi K. Reversible airway lesions in diffuse panbronchiolitis: detection by high-resolution computed tomography. Chest. 1995;107:120 –125. 51. Kudoh S, Azuma A, Yamamoto M, Izumi T, Ando M. Improvement of survival in patients with diffuse panbronchiolitis treated with low-dose erythromycin. Am J Respir Crit Care Med. 1998;157(Pt 1):1829 –1832. 52. Southern KW, Barker PM, Solis A. Macrolide antibiotics for cystic fibrosis. Cochrane Database Syst Rev. 2003;3: CD002203. 53. Pirzada O, Taylor C. Long-term macrolide antibiotics improve pulmonary function in cystic fibrosis. Pediatr Pulmonol. 1999;28(Suppl 19):263. 54. 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;29:7–11. 55. Anstead M, Kuhn R, LH H. Effect of chronic azithromycin on lung function in cystic fibrosis. Pediatr Pulmonol. 1999; 28(Suppl 19):283. 56. Jaffe A, Francis J, Rosenthal M, Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis [letter]. Lancet. 1998;351:420. 57. Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J. Effect of long-term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax. 2002;57:212–216. 58. Suzuki T, Yanai M, Yamaya M, et al. Erythromycin and common cold in COPD. Chest. 2001;120:730 –733. 59. Rubin BK, Druce H, Ramirez OE, Palmer R. Effect of clarithromycin on nasal mucus properties in healthy subjects and in patients with purulent rhinitis. Am J Respir Crit Care Med. 1997;155:2018 –2023. 60. Cervin A, Kalm O, Sandkull P, Lindberg S. One-year lowdose erythromycin treatment of persistent chronic sinusitis after sinus surgery: clinical outcome and effects on mucociliary parameters and nasal nitric oxide. Otolaryngol Head Neck Surg. 2002;126:481–489.
Volume 117 (9A)
T
he macrolide antibiotics have distinct antibacterial and anti-inflammatory properties. Interest in the clinical benefit of macrolides for the treatment of chronic inflammatory diseases of the airways has grown with increasing evidence of their effectiveness in treating these disorders. Macrolides reduce inflammation associated with diffuse panbronchiolitis (DPB), asthma, cystic fibrosis, chronic bronchitis, and chronic sinusitis.
STRUCTURE AND EFFECTIVENESS OF MACROLIDES The immunomodulatory effects of the macrolide antibiotics appear to be related to their structure. The 14- and 15-member macrolides, including erythromycin, clarithromycin, roxithromycin, and azithromycin possess anti-inflammatory properties. However, 16-member ring macrolides, such as josamycin, do not have immunomodulatory properties. Differences between the immunomodulatory properties of these macrolides are thought to be due, in part, to the presence of sugar moieties attached to the ring system of the 14- and 15member macrolides.1–3 Differences between the sugar moieties may also affect the ability of the drug to inhibit the development of virulence factors such as type IV fimbrae that are critical in transforming Pseudomonas from the planktonic phenotype to biofilm colonies.4
IMMUNOMODULATORY EFFECTS OF MACROLIDES Macrolides inhibit the production of proinflammatory cytokines, including interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor–␣, and inhibit the expression of transcription factors, including nuclear factor–B and activator protein–1.5,6 IL-8 is a chemoattractant for neutrophils, and studies show that the concentration of IL-8 in bronchoalveolar lavage fluid from patients with DPB correlates with the number of neutrophils.7,8 These changes have also been shown in patients with chronic sinusitis, asthma, and cystic fibrosis.6,9 –25 Macrolides also inhibit neutrophil elastase and reactive oxygen radicals26,27; they suppress the expression of neutrophil adhesion molecules and selectins,28,29 thus de-
From the Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. Reprints are not available. Correspondence should be addressed to Bruce K. Rubin, MD, MEngr, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1081. 2S
© 2004 by Elsevier Inc. All rights reserved.
creasing infiltration of inflammatory cells into the airway epithelium. Macrolides reduce mucus hypersecretion by inhibiting mucin gene expression and by reducing local airway inflammation.30
HISTORY OF MACROLIDE USE FOR THE TREATMENT OF CHRONIC AIRWAY DISEASE Steroid-Sparing Effects of Macrolides As early as the 1960s, the immunomodulatory effects of macrolides were observed in patients with corticosteroiddependent asthma who were treated with troleandomycin.31 Initially, the benefit of troleandomycin therapy was thought to be due to inhibition of steroid metabolism or direct effects on mucus secretion.32–35 Other studies had reported the effectiveness of troleandomycin in subjects with steroid-dependent asthma as well as in those with chronic bronchitis.36 Since these initial reports, a number of studies evaluating the effectiveness of troleandomycin have shown that it can decrease corticosteroid use and improve the symptoms and pulmonary function of children and adults with asthma.37– 41 Some patients who receive concomitant troleandomycin and corticosteroid therapy are able to discontinue steroids completely without worsening their asthma.42 These data suggest that troleandomycin probably has immunomodulatory activity for the treatment of asthma. Use of Macrolides in Treatment of DPB Most of the clinical studies of the immunomodulatory properties of macrolides have been in patients with DPB, an airway disease characterized by chronic sinusitis, persistent cough, increased sputum, and progressive loss of pulmonary function leading to respiratory failure and death. Since the first report of the effectiveness of erythromycin in persons with DPB, a large number of studies have shown the effectiveness of the 14- and 15-member macrolides for the treatment of this disease.43– 49 Macrolide therapy improves pulmonary function, reduces mucus hypersecretion, and reduces airway inflammation in patients with DPB.50 Macrolide therapy has significantly increased the 5-year survival rate from 26% in untreated DPB patients to ⬎90% in patients receiving macrolides.51 The dramatic response of patients with this disease to macrolide therapy and the similarities among DPB and other airway diseases have spurred research on the use of macrolides for treatment of patients with other chronic inflammatory airway diseases such as cystic fibrosis and chronic bronchitis. 1548-2766/04/$22.00 doi:10.1016/j.amjmed.2004.07.021
A Symposium: Macrolides: Overview and Historical Perspective/Rubin
CLINICAL TRIALS In clinical trials that evaluated the benefits of macrolide therapy in patients with cystic fibrosis,20,25,52–57 both children and adults who received a macrolide had improved pulmonary function and improved quality of life. Limited data available from studies of patients with chronic bronchitis suggest that macrolides reduce the frequency of acute exacerbations.58 Several studies show that macrolides reduce nasal secretion and size of nasal polyps in patients with chronic sinusitis.14,59,60
8.
9.
10.
CONCLUSION Macrolide antibiotics have been widely used as immunomodulatory therapy in Japan and Korea for at least 10 years. With recent studies in cystic fibrosis and as additional information becomes available on the effectiveness of long-term, low-dose macrolides for the therapy of chronic respiratory diseases, it is anticipated that use will increase in North America and Europe. If effective immunomodulatory agents without antibacterial properties (and thus without the risk of antimicrobial resistance) are developed and if macrolides are found to be effective for the treatment of chronic diseases such as coronary artery disease, cancer, inflammatory bowel disease, inflammatory arthritis, and atopic dermatitis, their use could increase dramatically. Currently, North American physicians are reluctant to prescribe antibiotics chronically and insurance companies in the United States often refuse to pay for antibiotics used as immunomodulatory drugs.
11.
12.
13.
14.
15.
16.
17.
REFERENCES 1. Abdelghaffar H, Vazifeh D, Labro MT. Erythromycin A-derived macrolides modify the functional activities of human neutrophils by altering the phospholipase D-phosphatidate phosphohydrolase transduction pathway: L-cladinose is involved both in alterations of neutrophil functions and modulation of this transductional pathway. J Immunol. 1997; 159:3995–4005. 2. Abdelghaffar H, Mtairag EM, Labro MT. Effects of dirithromycin and erythromycylamine on human neutrophil degranulation. Antimicrob Agents Chemother. 1994;38:1548 –1554. 3. Abdelghaffar H, Vazifeh D, Labro MT. Comparison of various macrolides on stimulation of human neutrophil degranulation in vitro. J Antimicrob Chemother. 1996;38:81–93. 4. Nagino K, Kobayashi H. Influence of macrolides on mucoid alginate biosynthetic enzyme from Pseudomonas aeruginosa. Clin Microbiol Infect. 1997;3:432–439. 5. Desaki M, Takizawa H, Ohtoshi T, et al. Erythromycin suppresses nuclear factor-B and activator protein-1 activation in human bronchial epithelial cells. Biochem Biophys Res Commun. 2000;267:124 –128. 6. Kikuchi T, Hagiwara K, Honda Y, et al. Clarithromycin suppresses lipopolysaccharide-induced interleukin-8 production by human monocytes through AP-1 and NF-B transcription factors. J Antimicrob Chemother. 2002;49:745–755. 7. Fujii T, Kadota J, Morikawa T, et al. Inhibitory effect of erythromycin on interleukin 8 production by 1 alpha,25-
18.
19.
20.
21.
22.
23.
24.
25.
November 8, 2004
dihydroxyvitamin D3-stimulated THP-1 cells. Antimicrob Agents Chemother. 1996;40:1548 –1551. Sakito O, Kadota J, Kohno S, Abe K, Shirai R, Hara K. 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;63:42–48. Xiao W, Yu H, Zheng C. The imbalance of Th1/Th2 cytokine expression in peripheral blood mononuclear cell from asthmatic patients and the effect of erythromycin on these cytokines [in Chinese]. Zhonghua Jie He He Hu Xi Za Zhi. 2000;23:347–350. 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;12:57–63. Nakajima T, Yoshizawa I, Kawano Y, Noma T. Suppressive effect of roxithromycin on the induction of IL-2 responsiveness by DF-stimulated lymphocytes from patients with bronchial asthma [in Japanese]. Arerugi. 1996;45:554 –561. Nakahara H, Higashida A, Nogami J, et al. Effect of roxithromycin on cytokine production by peripheral monocytes derived from patients with bronchial asthma [in Japanese]. Jpn J Antibiot. 1997;50(Suppl A):113–115. Kraft M, Cassell GH, Pak J, Martin RJ. Mycoplasma pneumoniae and Chlamydia pneumoniae in asthma: effect of clarithromycin. Chest. 2002;121:1782–1788. Yamada T, Fujieda S, Mori S, Yamamoto H, Saito H. Macrolide treatment decreased the size of nasal polyps and IL-8 levels in nasal lavage. Am J Rhinol. 2000;14:143–148. 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;156: 266 –271. Nonaka M, Pawankar R, Saji F, Yagi T. Effect of roxithromycin on IL-8 synthesis and proliferation of nasal polyp fibroblasts. Acta Otolaryngol Suppl. 1998;539:71–75. MacLeod CM, Hamid QA, Cameron L, Tremblay C, Brisco W. Anti-inflammatory activity of clarithromycin in adults with chronically inflamed sinus mucosa. Adv Ther. 2001;18:75–82. Fujita K, Shimizu T, Majima Y, Sakakura Y. Effects of macrolides on interleukin-8 secretion from human nasal epithelial cells. Eur Arch Otorhinolaryngol. 2000;257:199 –204. Suzuki H, Asada Y, Ikeda K, Oshima T, Takasaka T. Inhibitory effect of erythromycin on interleukin-8 secretion from exudative cells in the nasal discharge of patients with chronic sinusitis. Laryngoscope. 1999;109:407–410. Ordonez CL, Stulbarg M, Grundland H, Liu JT, Boushey HA. Effect of clarithromycin on airway obstruction and inflammatory markers in induced sputum in cystic fibrosis: a pilot study. Pediatr Pulmonol. 2001;32:29 –37. Cunningham S, McColm JR, Mallinson A, Boyd I, Marshall TG. Duration of effect of intravenous antibiotics on spirometry and sputum cytokines in children with cystic fibrosis. Pediatr Pulmonol. 2003;36:43–48. 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;56:62–64. Konno S, Asano K, Kurokawa M, Ikeda K, Okamoto K, Adachi M. Antiasthmatic activity of a macrolide antibiotic, roxithromycin: analysis of possible mechanisms in vitro and in vivo. Int Arch Allergy Immunol. 1994;105:308 –316. Wallwork B, Coman W, Feron F, Mackay-Sim A, Cervin A. Clarithromycin and prednisolone inhibit cytokine production in chronic rhinosinusitis. Laryngoscope. 2002;112:1827–1830. Equi A, Balfour-Lynn IM, Bush A, Rosenthal M. Long term THE AMERICAN JOURNAL OF MEDICINE威
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A Symposium: Macrolides: Overview and Historical Perspective/Rubin
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