DOI QR코드

DOI QR Code

Montelukast as an add-on therapy in bronchopulmonary dysplasia

기관지폐 이형성증의 추가 치료제로서의 Montelukast

  • Kim, He Min (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Song, Ji Eun (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Lee, Soon Min (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Park, Min Soo (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Park, Kook In (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Namgung, Ran (Department of Pediatrics, Yonsei University College of Medicine) ;
  • Lee, Chul (Department of Pediatrics, Yonsei University College of Medicine)
  • 김혜민 (연세대학교 의과대학 소아과학교실) ;
  • 송지은 (연세대학교 의과대학 소아과학교실) ;
  • 이순민 (연세대학교 의과대학 소아과학교실) ;
  • 박민수 (연세대학교 의과대학 소아과학교실) ;
  • 박국인 (연세대학교 의과대학 소아과학교실) ;
  • 남궁란 (연세대학교 의과대학 소아과학교실) ;
  • 이철 (연세대학교 의과대학 소아과학교실)
  • Received : 2008.07.31
  • Accepted : 2008.11.11
  • Published : 2009.02.15

Abstract

Purpose : Inflammation plays a potential role in the pathogenesis of bronchopulmonary dysplasia (BPD). Strategies for preventing BPD include respiratory management, antioxidants, nutritional treatment, and others such as anti-inflammatory agents. We aimed to assess the safety, tolerability, and efficacy of montelukast (MK), a cysteinyl leukotriene 1 receptor antagonist, as an add-on therapy in BPD. Methods : In addition to currently available standard measures such as oxygen supplementation, bronchodilators, nutritional support, and/or diuretics, montelukast was administered to 15 preterm infants with BPD. MK was given orally (1 mg/kg/d) for a mean period of 12 weeks. We compared safety and efficacy parameters with historical controls. Results : All 15 patients survived, and no differences were found in the incidence of adverse reactions between the 2 groups. The ventilation index was significantly improved after 2 weeks in MK group compared with historical controls. There were no significant differences in other respiratory parameters (MAP, oxygen dependency, and ventilator dependency) between the groups, but the MK group showed trends of greater improvement. Conclusion : Administration of MK 1 mg/kg/d was well tolerated in preterm BPD patients as an add-on therapy. We demonstrated that after 2 weeks of MK administration of 1 mg/kg/d, MK had beneficial therapeutic effects on BPD patients as an add-on to the standard therapy. Further multicenter randomized controlled clinical trials are needed to confirm the efficacy and safety of MK as a useful supplement to standard therapy for BPD patients.

목적 : 기도 및 폐 간질의 염증은 기관지폐 이형성증의 중요한 기전으로 알려져 있다. 염증매개 물질의 하나인 cysteinyl leukotrienes는 기관지 수축, 점액 분비, 부종을 일으켜 폐에 손상을 준다. 저자들은 기관지폐 이형성증 환자의 추가 치료제로서 montelukast의 안전성 및 효과를 연구하고자 하였다. 방법 : 2007년 3월부터 2008년 1월까지 연세대학교 의과대학 영동세브란스병원 및 신촌세브란스병원 신생아 중환자실에 입원하여 montelukast를 복용한 15명의 기관지폐 이형성증 환자를 montelukast 군으로 지정하였으며 2005년 5월부터 2007년 2월까지 영동세브란스병원 및 신촌세브란스병원 신생아 중환자실에 입원하여 montelukast를 복용하지 않은 15명의 기관지폐 이형성증 환아들을 대조군으로 지정하였다. montelukast는 1 mg/kg/d를 하루에 두번 나누어 구강으로 복용하게 하였으며 평균적으로 12주 동안 복용하였고 기존의 기관지폐 이형성증 치료의 추가 치료제로 사용하였다. 결과 : Montelukast 군은 15명 모두 생존하였으며 특이 이상 반응 없었고 생체징후, 혈액검사 모두 정상 소견 보였으며 montelukast 복용 2주 후부터 ventilator index가 대조군에 비해 유의한 감소를 보였다. 다른 호흡 지표들도 대조군에 비해 더 감소하였으나 통계학적으로 의미는 없었다. 결론 : 본 연구 대상 환아 중에서는 기관지폐 이형성증의 기존치료에 추가로 사용된 montelukast에 특이 이상 반응이 없었으며, 대부분 well-tolerable한 것으로 나타났다. 또한 1 mg/kg/d의 montelukast는 치료 2주째부터 기계적 환기의 기간을 줄여 주어 기관지폐 이형성증의 추가 치료제로써 효과가 있음이 확인되었다. 그러나 montelukast 치료 및 예방의 효과 및 안전성을 확립하기 위해서는 더 많은 수의 환아를 대상으로 대규모의 다기관 무작위 대조 연구가 시행되어야 할 것으로 여겨진다.

Keywords

References

  1. Bancalari E, Claure N. Definitions and diagnostic criteria for bronchopulmonary dysplasia. Semin Perinatol 2006;30:164-70 https://doi.org/10.1053/j.semperi.2006.05.002
  2. Ehrenkranz RA, Walsh MC, Vohr BR, Jobe AH, Wright LL, Fanaroff AA, et al. Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia. Pediatrics 2005;116:1353-60 https://doi.org/10.1542/peds.2005-0249
  3. Bancalari E, Claure N, Sosenko IR. Bronchopulmonary dysplasia: changes in pathogenesis, epidemiology and definition. Semin Neonatol 2003;8:63-71 https://doi.org/10.1016/S1084-2756(02)00192-6
  4. Groneck P, Gtze-Speer B, Oppermann M, Eiffert H, Speer CP. Association of pulmonary inflammation and increased microvascular permeability during the development of bronchopulmonary dysplasia: a sequential analysis of inflammatory mediators in respiratory fluids of high-risk preterm neonates. Pediatrics 1994;93:712-8
  5. Speer CP. Inflammatory mechanisms in neonatal chronic lung disease. Eur J Pediatr 1999;158:18-22 https://doi.org/10.1007/s004310051002
  6. Speer CP. Pre- and postnatal inflammatory mechanisms in chronic lung disease of preterm infants. Paediatr Respir Rev 2004;5:241-4 https://doi.org/10.1016/S1526-0542(04)90045-0
  7. Denis D, Fayon MJ, Berger P, Molimard M, De Lara MT, Roux E, et al. Prolonged moderate hyperoxia induces hyperresponsiveness and airway inflammation in newborn rats. Pediatr Res 2001;50:515-9 https://doi.org/10.1203/00006450-200110000-00015
  8. Hosford GE, Koyanagi KS, Leung WI, Olson DM. Hyperoxia increases protein mass of 5-lipoxygenase and its activating protein, flap, and leukotriene B(4) output in newborn rat lungs. Exp Lung Res 2002;28:671-84 https://doi.org/10.1080/01902140260426751
  9. Sheikh S, Null D, Gentile D, Bimle C. Skoner D, McCoy K. Urinary leukotrine E(4) excretion during the first month of life and subsequent bronchopulmonary dysplasia in premature infants. Chest 2001;119:1749-54 https://doi.org/10.1378/chest.119.6.1749
  10. Espinosa K, BossY, Stankova J, Rola-Pleszczynski M. CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4. J Allergy Clin Immunol 2003;111:1032-40 https://doi.org/10.1067/mai.2003.1451
  11. Nathan RA, Kemp JP. Efficacy of antileukotriene agents in asthma management. Ann Allergy Asthma Immunol 2001; 86:9-17 https://doi.org/10.1016/S1081-1206(10)62306-X
  12. Devillier P, Baccard N, Advenier C. Leukotrienes, leukotriene receptor antagonists and leukotriene synthesis inhibitors in asthma: an update. Part I: synthesis, receptors and role of leukotrienes in asthma. Phamacol Res 1999;40:3-13 https://doi.org/10.1006/phrs.1998.0458
  13. Rosewich M, Rose MA, Eickmeier O, Travaci M, Kitz R, Zielen S. Montelukast as add-on therapy to beta-agonists and late airway response. Eur Respir J 2007;30:56-61 https://doi.org/10.1183/09031936.00063106
  14. Holgate ST, Peters-Golden M, Panettieri RA, Henderson WR. Roles of cysteinyl leukotrienes in airway inflammation, smooth muscle function, and remodeling. J Allergy Clinl Immunol 2003;111:18-34 https://doi.org/10.1067/mai.2003.25
  15. Drazen JM. Leukotrienes as mediators of airway obstruction. Am J Respir Crit Care Med 1998;158:193-200
  16. Van Marter LJ. Strategies for preventing bronchopulmonary dysplasia. Curr Opin Pediatr 2005;17:174-80 https://doi.org/10.1097/01.mop.0000158732.64293.1c
  17. Charafeddine L, D'Angio CT, Phelps DL. Atypical chronic lung disease patterns in neonates. Pediatrics 1999;103:759-65 https://doi.org/10.1542/peds.103.4.759
  18. Baveja R, Christou H. Pharmacological strategies in the prevention and management of bronchopulmonary dysplasia. Semin Perinatol 2006;30:209-18 https://doi.org/10.1053/j.semperi.2006.05.008
  19. Knorr B, Maganti L, Ramakrishnan R, Tozzi CA, Migoya E, Kearns G. Pharmacokinetics and safety of montelukast in children aged 3 to 6 months. J Clin Pharmacol 2006;46:620-7 https://doi.org/10.1177/0091270006288324
  20. Bisgaard H. A randomized trial of montelukast in respiratory syncytial virus postbronchiolitis. Am J Respir Crit Care Med 2003;167:379-83 https://doi.org/10.1164/rccm.200207-747OC
  21. Park MS, Rieger-Fackeldey E, Schanbacher BL, Cook AC, Bauer JA, Rogers LK, et al. Altered expressions of fibroblast growth factor receptors and alveolarization in neonatal mice exposed to 85% oxygen. Pediatr Res 2007;62:652-7 https://doi.org/10.1203/PDR.0b013e318159af61