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Оценка ассоциации полиморфизмов гена CYP2C8 с эффективностью и безопасностью кеторолака у пациентов с послеоперационным болевым синдромом
Оценка ассоциации полиморфизмов гена CYP2C8 с эффективностью и безопасностью кеторолака у пациентов с послеоперационным болевым синдромом
Мурадян А.А., Сычев Д.А., Благовестнов Д.А., Петров Д.И., Скукин Д.С., Епифанова И.П., Созаева Ж.А., Качанова А.А., Денисенко Н.П., Абдуллаев Ш.П., Гришина Е.А. Оценка ассоциации полиморфизмов гена CYP2C8 с эффективностью и безопасностью кеторолака у пациентов с послеоперационным болевым синдромом. Терапевтический архив. 2022;94(5):610–615.
DOI: 10.26442/00403660.2022.05.201495
DOI: 10.26442/00403660.2022.05.201495
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Аннотация
Цель. Оценить возможную ассоциацию полиморфизмов гена CYP2C8 с клинической эффективностью и безопасностью кеторолака в отношении послеоперационной боли.
Материалы и методы. В исследовании приняли участие 107 пациентов после видеолапароскопической холецистэктомии, которым в качестве послеоперационного обезболивания назначали кеторолак в дозе 30 мг х 2 мл (60 мг) внутримышечно 3 раза в день. Всех пациентов генотипировали по CYP2C8. Оценку интенсивности болевого синдрома осуществляли при помощи Визуальной аналоговой шкалы и опросника боли Мак-Гилла. Профиль нежелательных реакций оценивали по динамике показателей красной крови как возможного триггера развития желудочно-кишечных кровотечений по методике глобальной оценки тригерров (Global Trigger Tool – GTT).
Результаты. По данным Визуальной аналоговой шкалы у носителей генотипов CYP2C8*3 (rs10509681) и CYP2C8*3 (rs11572080) через 12, 24, 36, 48 ч интенсивность болевого синдрома оказалась ниже, чем у носителей дикого типа (p<0,05). По данным опросника боли Мак-Гилла статистически значимых различий в интенсивности болевого синдрома между двумя группами не обнаружено.
Заключение. У носителей генотипов CYP2C8*3 (rs10509681) и CYP2C8*3 (rs11572080) эффективность обезболивания кеторолаком выше, чем у носителей дикого типа. Носительство генотипов CYP2C8*3 (rs10509681) и CYP2С8*3 (rs10509681) не влияет на риск развития нежелательных реакций после обезболивания кеторолаком.
Ключевые слова: холецистит, кеторолак, послеоперационное обезболивание, фармакогенетика, CYP2C8
Materials and methods. The study included 107 patients after video laparoscopic cholecystectomy, who received ketorolac (30 mg 2.0 w/m 3 r/d) as postoperative pain relief. All patients were genotyped for CYP2C8. The pain syndrome was assessed using the visual analog scale, the McGill pain questionnaire. The profile of adverse reactions was assessed by the dynamics of red blood counts, as a possible trigger for the development of gastrointestinal bleeding according to the method of global assessment of triggers (Global Trigger Tool – GTT).
Results. According to visual analog scale data: in carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080) after 12, 24, 36, 48 hours the intensity of pain syndrome is lower than in carriers of the wild type (p<0.05). According to the McGill pain questionnaire, there were no statistically significant differences in pain intensity between the two groups.
Conclusion. In carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080), the effectiveness of anesthesia with ketorolac is higher than in carriers of the wild type. Carriage of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs10509681) does not affect the risk of developing adverse reactions after ketorolac anesthesia.
Keywords: cholecystitis, ketorolac, postoperative pain relief, pharmacogenetics, CYP2C8
Материалы и методы. В исследовании приняли участие 107 пациентов после видеолапароскопической холецистэктомии, которым в качестве послеоперационного обезболивания назначали кеторолак в дозе 30 мг х 2 мл (60 мг) внутримышечно 3 раза в день. Всех пациентов генотипировали по CYP2C8. Оценку интенсивности болевого синдрома осуществляли при помощи Визуальной аналоговой шкалы и опросника боли Мак-Гилла. Профиль нежелательных реакций оценивали по динамике показателей красной крови как возможного триггера развития желудочно-кишечных кровотечений по методике глобальной оценки тригерров (Global Trigger Tool – GTT).
Результаты. По данным Визуальной аналоговой шкалы у носителей генотипов CYP2C8*3 (rs10509681) и CYP2C8*3 (rs11572080) через 12, 24, 36, 48 ч интенсивность болевого синдрома оказалась ниже, чем у носителей дикого типа (p<0,05). По данным опросника боли Мак-Гилла статистически значимых различий в интенсивности болевого синдрома между двумя группами не обнаружено.
Заключение. У носителей генотипов CYP2C8*3 (rs10509681) и CYP2C8*3 (rs11572080) эффективность обезболивания кеторолаком выше, чем у носителей дикого типа. Носительство генотипов CYP2C8*3 (rs10509681) и CYP2С8*3 (rs10509681) не влияет на риск развития нежелательных реакций после обезболивания кеторолаком.
Ключевые слова: холецистит, кеторолак, послеоперационное обезболивание, фармакогенетика, CYP2C8
________________________________________________
Materials and methods. The study included 107 patients after video laparoscopic cholecystectomy, who received ketorolac (30 mg 2.0 w/m 3 r/d) as postoperative pain relief. All patients were genotyped for CYP2C8. The pain syndrome was assessed using the visual analog scale, the McGill pain questionnaire. The profile of adverse reactions was assessed by the dynamics of red blood counts, as a possible trigger for the development of gastrointestinal bleeding according to the method of global assessment of triggers (Global Trigger Tool – GTT).
Results. According to visual analog scale data: in carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080) after 12, 24, 36, 48 hours the intensity of pain syndrome is lower than in carriers of the wild type (p<0.05). According to the McGill pain questionnaire, there were no statistically significant differences in pain intensity between the two groups.
Conclusion. In carriers of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs11572080), the effectiveness of anesthesia with ketorolac is higher than in carriers of the wild type. Carriage of the genotype CYP2C8*3 (rs10509681) and CYP2C8*3 (rs10509681) does not affect the risk of developing adverse reactions after ketorolac anesthesia.
Keywords: cholecystitis, ketorolac, postoperative pain relief, pharmacogenetics, CYP2C8
Полный текст
Список литературы
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5. Kadiev E, Patel V, Rad P, et al. Role of pharmacogenetics in variable response to drugs: focus on opioids. Expert Opin Drug Metab Toxicol. 2008;4(1):77-91. DOI:10.1517/17425255.4.1.77
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8. Zhou SF, Zhou ZW, Huang M. Polymorphisms of human cytochrome P450 2C9 and the functional relevance. Toxicology. 2010;278(2):165-88. DOI:10.1016/j.tox.2009.08.013
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10. Pilotto A, Seripa D, Franceschi M, et al. Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007;133(2):465-71. DOI:10.1053/j.gastro.2007.05.025
11. Blanco G, Martínez C, Ladero JM, et al. Interaction of CYP2C8 and CYP2C9 genotypes modifies the risk for nonsteroidal anti-inflammatory drugs-related acute gastrointestinal bleeding. Pharmacogenet Genomics. 2008;18(1):37-43. DOI:10.1097/FPC.0b013e3282f305a9
12. Rodrigues AD. Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? Drug Metab Dispos. 2005;33(11):1567-75. DOI:10.1124/dmd.105.006452
13. Rollason V, Samer CF, Daali Y, Desmeules JA. Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal Anti-Inflammatory Drugs: A Review. Curr Drug Metab. 2014;15(3):326-43. DOI:10.2174/1389200215666140202214454
14. Agúndez JAG, García-Martín E, Martínez C. Genetically based impair-ment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert Opin Drug Metab Toxicol. 2009;5(6):607-20.
DOI:10.1517/17425250902970998
15. Yiannakopoulou E. Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications. Eur J Clin Pharmacol. 2013;69(7):1369-73. DOI:10.1007/s00228-013-1477-9
16. Daly AK, Aithal GP, Leathart JB, et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132(1):272-81. DOI:10.1053/j.gastro.2006.11.023
17. Yasar U, Eliasson E, Forslund-Bergengren C, et al. The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro. Eur J Clin Pharmacol. 2001;57(10):729-35. DOI:10.1007/s00228-001-0376-7
18. García-Martín E, Martínez C, Tabarés B, et al. Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther. 2004;76(2):119-27. DOI:10.1016/j.clpt.2004.04.006
19. Martínez C, García-Martín E, Blanco G, et al. The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol. 2005;59(1):62-9. DOI:10.1111/j.1365-2125.2004.02183.x
20. Arnaldo P, Thompson RE, Lopes MQ, et al. Frequencies of cytochrome P450 2B6 and 2C8 allelic variants in the Mozambican population. Malays J Med Sci. 2013;20(4):12-23.
21. Lopez-Rodriguez R, Novalbos J, Gallego-Sandin S, et al. Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers. Pharmacol Res. 2008;58(1):77-84. DOI:10.1016/j.phrs.2008.07.004
22. Menahem B, Mulliri A, Fohlen A, et al. Delayed laparoscopic cholecystectomy increases the total hospital stay compared to an early laparoscopic cholecystectomy after acute cholecystitis: an updated meta-analysis of randomized controlled trials. HPB (Oxford). 2015;17(10):857-62. DOI:10.1111/hpb.12449
2. Ladak SSJ, Chan VWS, Easty T, Chagpar A. Right Medication, Right Dose, Right Patient, Right Time, and Right Route: How Do We Sel ect the Right Patient-Controlled Analgesia (PCA) Device? Pain Manag Nurs. 2007;8(4):140-5. DOI:10.1016/j.pmn.2007.08.001
3. Kukes VG, Sychev DA, Ramenskaya GV, Ignat'ev IV. Pharmacogenetics of system of biotransformation and drugs transporters: fr om the theory to practice. Biomeditsina. 2007;6:29-47 (in Russian).
4. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7(4):257-65. DOI:10.1038/sj.tpj.6500406
5. Kadiev E, Patel V, Rad P, et al. Role of pharmacogenetics in variable response to drugs: focus on opioids. Expert Opin Drug Metab Toxicol. 2008;4(1):77-91. DOI:10.1517/17425255.4.1.77
6. Ko TM, Wong CS, Wu JY, Chen YT. Pharmacogenomics for personalized pain medicine. Acta Anaesthesiol Taiwan. 2016;54(1):24-30. DOI:10.1016/j.aat.2016.02.001
7. Flores CM, Mogil JS. The pharmacogenetics of analgesia: toward a genetically-based approach to pain management. Pharmacogenomics. 2001;2(3):177-94. DOI:10.1517/14622416.2.3.177
8. Zhou SF, Zhou ZW, Huang M. Polymorphisms of human cytochrome P450 2C9 and the functional relevance. Toxicology. 2010;278(2):165-88. DOI:10.1016/j.tox.2009.08.013
9. Martínez C, Blanco G, Ladero JM, et al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol. 2004;141(2):205-8. DOI:10.1038/sj.bjp.0705623
10. Pilotto A, Seripa D, Franceschi M, et al. Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007;133(2):465-71. DOI:10.1053/j.gastro.2007.05.025
11. Blanco G, Martínez C, Ladero JM, et al. Interaction of CYP2C8 and CYP2C9 genotypes modifies the risk for nonsteroidal anti-inflammatory drugs-related acute gastrointestinal bleeding. Pharmacogenet Genomics. 2008;18(1):37-43. DOI:10.1097/FPC.0b013e3282f305a9
12. Rodrigues AD. Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? Drug Metab Dispos. 2005;33(11):1567-75. DOI:10.1124/dmd.105.006452
13. Rollason V, Samer CF, Daali Y, Desmeules JA. Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal Anti-Inflammatory Drugs: A Review. Curr Drug Metab. 2014;15(3):326-43. DOI:10.2174/1389200215666140202214454
14. Agúndez JAG, García-Martín E, Martínez C. Genetically based impair-ment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert Opin Drug Metab Toxicol. 2009;5(6):607-20.
DOI:10.1517/17425250902970998
15. Yiannakopoulou E. Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications. Eur J Clin Pharmacol. 2013;69(7):1369-73. DOI:10.1007/s00228-013-1477-9
16. Daly AK, Aithal GP, Leathart JB, et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132(1):272-81. DOI:10.1053/j.gastro.2006.11.023
17. Yasar U, Eliasson E, Forslund-Bergengren C, et al. The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro. Eur J Clin Pharmacol. 2001;57(10):729-35. DOI:10.1007/s00228-001-0376-7
18. García-Martín E, Martínez C, Tabarés B, et al. Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther. 2004;76(2):119-27. DOI:10.1016/j.clpt.2004.04.006
19. Martínez C, García-Martín E, Blanco G, et al. The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol. 2005;59(1):62-9. DOI:10.1111/j.1365-2125.2004.02183.x
20. Arnaldo P, Thompson RE, Lopes MQ, et al. Frequencies of cytochrome P450 2B6 and 2C8 allelic variants in the Mozambican population. Malays J Med Sci. 2013;20(4):12-23.
21. Lopez-Rodriguez R, Novalbos J, Gallego-Sandin S, et al. Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers. Pharmacol Res. 2008;58(1):77-84. DOI:10.1016/j.phrs.2008.07.004
22. Menahem B, Mulliri A, Fohlen A, et al. Delayed laparoscopic cholecystectomy increases the total hospital stay compared to an early laparoscopic cholecystectomy after acute cholecystitis: an updated meta-analysis of randomized controlled trials. HPB (Oxford). 2015;17(10):857-62. DOI:10.1111/hpb.12449
2. Ladak SSJ, Chan VWS, Easty T, Chagpar A. Right Medication, Right Dose, Right Patient, Right Time, and Right Route: How Do We Sel ect the Right Patient-Controlled Analgesia (PCA) Device? Pain Manag Nurs. 2007;8(4):140-5. DOI:10.1016/j.pmn.2007.08.001
3. Кукес В.Г., Сычев Д.А., Раменская Г.В., Игнатьев И.В. Фармакогенетика системы биотрансформации и транспортеров лекарственных средств : от теории к практике. Биомедицина. 2007;6:29-47 [Kukes VG, Sychev DA, Ramenskaya GV, Ignat'ev IV. Pharmacogenetics of system of biotransformation and drugs transporters: fr om the theory to practice. Biomeditsina. 2007;6:29-47 (in Russian)].
4. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7(4):257-65. DOI:10.1038/sj.tpj.6500406
5. Kadiev E, Patel V, Rad P, et al. Role of pharmacogenetics in variable response to drugs: focus on opioids. Expert Opin Drug Metab Toxicol. 2008;4(1):77-91. DOI:10.1517/17425255.4.1.77
6. Ko TM, Wong CS, Wu JY, Chen YT. Pharmacogenomics for personalized pain medicine. Acta Anaesthesiol Taiwan. 2016;54(1):24-30. DOI:10.1016/j.aat.2016.02.001
7. Flores CM, Mogil JS. The pharmacogenetics of analgesia: toward a genetically-based approach to pain management. Pharmacogenomics. 2001;2(3):177-94. DOI:10.1517/14622416.2.3.177
8. Zhou SF, Zhou ZW, Huang M. Polymorphisms of human cytochrome P450 2C9 and the functional relevance. Toxicology. 2010;278(2):165-88. DOI:10.1016/j.tox.2009.08.013
9. Martínez C, Blanco G, Ladero JM, et al. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol. 2004;141(2):205-8. DOI:10.1038/sj.bjp.0705623
10. Pilotto A, Seripa D, Franceschi M, et al. Genetic susceptibility to nonsteroidal anti-inflammatory drug-related gastroduodenal bleeding: role of cytochrome P450 2C9 polymorphisms. Gastroenterology. 2007;133(2):465-71. DOI:10.1053/j.gastro.2007.05.025
11. Blanco G, Martínez C, Ladero JM, et al. Interaction of CYP2C8 and CYP2C9 genotypes modifies the risk for nonsteroidal anti-inflammatory drugs-related acute gastrointestinal bleeding. Pharmacogenet Genomics. 2008;18(1):37-43. DOI:10.1097/FPC.0b013e3282f305a9
12. Rodrigues AD. Impact of CYP2C9 genotype on pharmacokinetics: are all cyclooxygenase inhibitors the same? Drug Metab Dispos. 2005;33(11):1567-75. DOI:10.1124/dmd.105.006452
13. Rollason V, Samer CF, Daali Y, Desmeules JA. Prediction by Pharmacogenetics of Safety and Efficacy of Non-Steroidal Anti-Inflammatory Drugs: A Review. Curr Drug Metab. 2014;15(3):326-43. DOI:10.2174/1389200215666140202214454
14. Agúndez JAG, García-Martín E, Martínez C. Genetically based impair-ment in CYP2C8- and CYP2C9-dependent NSAID metabolism as a risk factor for gastrointestinal bleeding: is a combination of pharmacogenomics and metabolomics required to improve personalized medicine? Expert Opin Drug Metab Toxicol. 2009;5(6):607-20.
DOI:10.1517/17425250902970998
15. Yiannakopoulou E. Pharmacogenomics of acetylsalicylic acid and other nonsteroidal anti-inflammatory agents: clinical implications. Eur J Clin Pharmacol. 2013;69(7):1369-73. DOI:10.1007/s00228-013-1477-9
16. Daly AK, Aithal GP, Leathart JB, et al. Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology. 2007;132(1):272-81. DOI:10.1053/j.gastro.2006.11.023
17. Yasar U, Eliasson E, Forslund-Bergengren C, et al. The role of CYP2C9 genotype in the metabolism of diclofenac in vivo and in vitro. Eur J Clin Pharmacol. 2001;57(10):729-35. DOI:10.1007/s00228-001-0376-7
18. García-Martín E, Martínez C, Tabarés B, et al. Interindividual variability in ibuprofen pharmacokinetics is related to interaction of cytochrome P450 2C8 and 2C9 amino acid polymorphisms. Clin Pharmacol Ther. 2004;76(2):119-27. DOI:10.1016/j.clpt.2004.04.006
19. Martínez C, García-Martín E, Blanco G, et al. The effect of the cytochrome P450 CYP2C8 polymorphism on the disposition of (R)-ibuprofen enantiomer in healthy subjects. Br J Clin Pharmacol. 2005;59(1):62-9. DOI:10.1111/j.1365-2125.2004.02183.x
20. Arnaldo P, Thompson RE, Lopes MQ, et al. Frequencies of cytochrome P450 2B6 and 2C8 allelic variants in the Mozambican population. Malays J Med Sci. 2013;20(4):12-23.
21. Lopez-Rodriguez R, Novalbos J, Gallego-Sandin S, et al. Influence of CYP2C8 and CYP2C9 polymorphisms on pharmacokinetic and pharmacodynamic parameters of racemic and enantiomeric forms of ibuprofen in healthy volunteers. Pharmacol Res. 2008;58(1):77-84. DOI:10.1016/j.phrs.2008.07.004
22. Menahem B, Mulliri A, Fohlen A, et al. Delayed laparoscopic cholecystectomy increases the total hospital stay compared to an early laparoscopic cholecystectomy after acute cholecystitis: an updated meta-analysis of randomized controlled trials. HPB (Oxford). 2015;17(10):857-62. DOI:10.1111/hpb.12449
________________________________________________
2. Ladak SSJ, Chan VWS, Easty T, Chagpar A. Right Medication, Right Dose, Right Patient, Right Time, and Right Route: How Do We Sel ect the Right Patient-Controlled Analgesia (PCA) Device? Pain Manag Nurs. 2007;8(4):140-5. DOI:10.1016/j.pmn.2007.08.001
3. Kukes VG, Sychev DA, Ramenskaya GV, Ignat'ev IV. Pharmacogenetics of system of biotransformation and drugs transporters: fr om the theory to practice. Biomeditsina. 2007;6:29-47 (in Russian).
4. Kirchheiner J, Schmidt H, Tzvetkov M, et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J. 2007;7(4):257-65. DOI:10.1038/sj.tpj.6500406
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Авторы
А.А. Мурадян*1, Д.А. Сычев1, Д.А. Благовестнов1, Д.И. Петров1, Д.С. Скукин2, И.П. Епифанова1, Ж.А. Созаева1, А.А. Качанова1, Н.П. Денисенко1, Ш.П. Абдуллаев1, Е.А. Гришина1
1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
2 ГБУЗ «Научно-исследовательский институт скорой помощи им. Н.В. Склифосовского» Департамента здравоохранения г. Москвы, Москва, Россия
*andranik_muradian@mail.ru
1 Russian Medical Academy of Continuous Professional Education, Moscow, Russia;
2 Sklifosovsky Research Institute of Emergency Medicine, Moscow, Russia
*andranik_muradian@mail.ru
1 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия;
2 ГБУЗ «Научно-исследовательский институт скорой помощи им. Н.В. Склифосовского» Департамента здравоохранения г. Москвы, Москва, Россия
*andranik_muradian@mail.ru
________________________________________________
1 Russian Medical Academy of Continuous Professional Education, Moscow, Russia;
2 Sklifosovsky Research Institute of Emergency Medicine, Moscow, Russia
*andranik_muradian@mail.ru
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