Safety of Herbal Medicines: Clinical and Pharmacological Aspects
https://doi.org/10.30895/2312-7821-2020-8-4-165-177
Abstract
Herbal medicines make up a large part of all medicinal products in the Russian market. Complex combinations of biologically active substances that are used as components in herbal medicines not only determine their therapeutic efficacy, but can also cause adverse reactions. The aim of this review was to analyse data on adverse effects of herbal medicines, and reasons and mechanisms behind their development. Special attention should be given to hepatotoxic and nephrotoxic effects of biologically active substances that are used as components in herbal medicines, because liver and kidney failure may lead to life-threatening conditions. The paper addresses hepatic adverse effects, including sinusoidal obstruction syndrome, caused by toxic biologically active substances of the pyrrolizidine alkaloids group. The paper summarises data on herbal medicines and toxic biologically active substances causing acute kidney injury and chronic kidney disease. It analyses potential clinically significant interactions that may occur during co-use of herbal and other types of medicines due to their pharmacokinetic and pharmacodynamic interactions. Further research involving collection, systematisation, and analysis of adverse effects of herbal medicines used alone or in combination with other medicinal products is needed to improve the safety of pharmacotherapy.
Keywords
About the Authors
O. A. DemidovaRussian Federation
Olga A. Demidova, Cand. Sci. (Pharm.).
8/2 Petrovsky Blvd, Moscow 127051
V. V. Arkhipov
Russian Federation
Vladimir V. Arkhipov, Dr. Sci. (Med.), Professor.
8/2 Petrovsky Blvd, Moscow 127051
M. V. Zhuravleva
Russian Federation
Marina V. Zhuravleva, Dr. Sci. (Med.), Professor.
8/2 Petrovsky Blvd, Moscow 127051
T. A. Alexandrova
Russian Federation
Tatiana V. Alexandrova, Cand. Sci. (Med.).
8/2 Petrovsky Blvd, Moscow 127051
A. A. Alexandrov
Russian Federation
Alexey A. Alexandrov.
8/2 Petrovsky Blvd, Moscow 127051
References
1. Sambukova TV, Ovchinnikov BV, Ganapolskii VP, Yatmanov AN, Shabanov PD. Prospects for phytopreparations use in modem pharmacology. Obzory po klinicheskoy farmakologii i lekarstvennoy terapii = Reviews on Clinical Pharmacology and Drug Therapy. 2017;15(2):56–63 (In Russ.) https://doi.org/10.17816/RCF15256-63
2. Boyko NN, Bondarev AV, Zhilyakova ET, Pisarev DI, Novikov OO. Phytodrugs, analysis of Russian Federation pharmaceutical market. Nauchnyj rezul’tat. Meditsina i farmatsiya = Research Result. Medicine and Pharmacy. 2017;3(4):30–8 (In Russ.) https://doi.org/10.18413/2313-8955-2017-3-4-30-38
3. Mironov AN, Sakaeva IV, Sakanyan EI, Korsun LV, Mochikina OA. Current approaches to standartization of herbal substasnce. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2013;(2):52–6 (In Russ.)
4. Akamova AV, Nemyatykh OD, Narkevich IA. Multiple view marketing analysis of the Russian plant-based drugs market. Razrabotka i registratsiya lekarstvennykh sredstv = Development and Registration of Medicines. 2017;4(21):276–80 (In Russ.)
5. Izzo AA, Hoon‐Kim S, Radhakrishnan R, Williamson EM. A critical approach to evaluating clinical efficacy, adverse evants and drug intervactions of herbal remedies. Phytother Res. 2016;30(5):691–700. https://doi.org/10.1002/ptr.5591
6. Shih EV, Bulaev VM, Demidova OA, Sokova EA. The interaction of biologically active substances of medicinal herbal preparations with other pharmacotherapeutic agents. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2016;(4):48–52 (In Russ.)
7. Sakanyan EI, Shemeryankina TB, Malkina YuK, Lyakina MN, Postoyuk NA. Modern approaches to herbal preparations efficacy and safety assessment in Russia and abroad. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya = The Bulletin of the Scientific Centre for Expert Evaluation of Medicinal Products. 2015;(1):35–9 (In Russ.)
8. De Smet PAGM. Health risks of herbal remedies: an update. Clin Pharmacol Ther. 2004;76(1):1–17. https://doi.org/10.1016/j.clpt.2004.03.005
9. Posadzki P, Watson LK, Ernst E. Adverse effects of herbal medicines: an overview of systematic reviews. Clin Med. 2013;13(1):7–12. https://doi.org/10.7861/clinmedicine.13-1-7
10. Di Lorenzo C, Ceschi A, Kupferschmidt H, Lüde S, De Souza Nascimento E, Dos Santos A, et al. Adverse effects of plant food supplements and botanical preparations: a systematic review with critical evalution of causality. Br J Clin Pharmacol. 2015;79(4):578–92. https://doi.org/10.1111/bcp.1251
11. Samylina IA, Bulaev VM. Safety concerns for medicinal plants containing endogenous toxic substances. Farmatsiya = Pharmacy. 2009;(3):6–8 (In Russ.)
12. Krepkova LV, Bortnikova VV, Sokolskaya TA. Some aspects of the toxicological study of medical products based on herbal raw materials. Fundamental’nye issledovaniya = Basic Research. 2013;(9):256–8 (In Russ.)
13. Nedelcheva A, Kostova N, Sidjimov A. Pyrrolizide alkaloids in Tussilago farfara from Bulgaria. Biotechnology & Biotechnologocal Equipment. 2015;29(S1):S1–S7. https://doi.org/10.1080/13102818.2015.1047149
14. Ekor M. The growing use of herbal medicines: issues relating to adverse reactions and challenges in monitoring safety. Front Pharmacol. 2014;(4):177. https://doi.org/10.3389/fphar.2013.00177
15. Calitz C, du Plessis L, Gouws C, Steyn D, Steenekamp J, Muller C, Hamman S. Herbal hepatotoxicity: current status, examples, and challenges. Expert Opin Drug Metab Toxicol. 2015;11(10):1551–65. https://doi.org/10.1517/17425255.2015.1064110
16. Navarro VJ, Khan I, Björnsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements. Hepatology. 2017;65(1):363–73. https://doi.org/10.1002/hep.28813
17. Byeon JH, Kil JH, Ahn YC, Son CG. Systematic review of published data on herb induced liver injury. J Ethnopharmacol. 2019;233:190–6. https://doi.org/10.1016/j.jep.2019.01.006
18. Shen T, Liu Y, Shang J, Xie Q, Li J, Yan M, et al. Incidence and etiology of drug-induced liver injury in mainland China. Gastroenterology. 2019;156(8):2230–41.e11. https://doi.org/10.1053/j.gastro.2019.02.002
19. Navarro VJ, Lucena MI. Hepatotoxicity induced by herbal and dietary supplements. Semin Liver Dis. 2014;34(2):172–93. https://doi.org/10.1055/s-0034-1375958
20. Teschke R, Eickhoff A. Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps. Front Pharmacol. 2015;6:72. https://doi.org/10.3389/fphar.2015.00072
21. Larrey D. Complementary and alternative medicine hepatotoxicity. In: Andrade RJ, ed. Hepatotoxicity. Permanyer publications; 2007. P. 125–135.
22. Larrey D, Faure S. Herbal medicine hepatotoxicity: a new step with development of specific biomarkers. J Hepatology. 2011;54(4):599–601. https://doi.org/10.1016/j.jhep.2010.12.003
23. Bunchorntavakul C, Reddy KR. Review article: herbal and dietary supplement hepatotoxicity. Aliment Pharmacol Ther. 2013;37(1):3–17. https://doi.org/10.1111/apt.12109
24. Bulaev VM, Shih EV, Sychev DA. Safety and efficacy of medicinal plants. Moscow: Practical medicine; 2013 (In Russ.)
25. He S, Zhang C, Zhou P, Zhang X, Ye T, Wang R, et al. Herb induced liver injury: phylogenetic relationship, structure-toxicity relationship and herb-ingredient network analysis. Int J Mol Sci. 2019;20(15):3633. https://doi.org/10.3390/ijms20153633
26. Adamczak A, Opala B, Gryszczyńska A, Buchwald W. Content of pyrrolizide alkaloids in the leaves of coltsfoot (Tussilago farfara L.) in Poland. Acta Societatis Botanicorum Poloniae. 2013;82(4):289–93. https://doi.org/10.5586/asbp.2013.028
27. Serment OC, Olaru OT, Gutu CM, Nitulescu GM, Ilie M, Negres S, et al. Toxicity of plant extracts containing pyrrolizide alkaloids using alternative invertebrate models. Mol Med Rep. 2018;17(6):7757–63. https://doi.org/10.3892/mmr.2018.8795
28. Fu PP, Xia Q, Lin G, Chou MW. Pyrrolizidine alkaloids — genotoxicity, metabolism enzymes, metabolic activation, and mechanisms. Drug Metab Rev. 2004;36(1):1–55. https://doi.org/10.1081/dmr-120028426
29. Dai N, Yu YC, Ren TH, Wu JG, Jiang Y, Shen LG, Zhang J. Gynura root induces hepatic veno-occlusive disease: a case report and review of the literature. World J Gastroenterol. 2007;13(10):1628–31. https://doi.org/10.3748/wjg.v13.i10.1628
30. Helmy A. Review article: updates in the pathogenesis and therapy of hepatic sinusoidal obstruction syndrome. Aliment Pharmacol Ther. 2006;23(1):11–25. https://doi.org/10.1111/j.1365-2036.2006.02742.x
31. Yang MB, Ruan JQ, Fu PP, Lin G. Cytotoxicity of pyrrolizidine alkaloids in human hepatic parenchymal and sinusoidal endothelial cells: firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity. Chem Biol Interact. 2016;243:119–26. https://doi.org/10.1016/j.cbi.2015.09.011
32. Ruan J, Gao H, Li N, Xue J, Chen J, Ke C, et al. Blood pyrrole-protein adducts—a biomarker of pyrrolizidine alkaloid-induced liver injury in humans. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2015;33(4):404–21. https://doi.org/10.1080/10590501.2015.1096882
33. Gao H, Ruan J, Chen J, Li N, Ke CQ, Ye Y, et al. Blood pyrrole-protein adducts as a diagnostic and prognostic indexin pyrrolizidine alkaloid-hepatic sinusoidal obstruction syndrome. Drug Des Devel Ther. 2015;9:4861–8. https://doi.org/10.2147/DDDT.S87858
34. Yang M, Ruan J, Gao H, Li N, Ma J, Xue J, et al. First evidence of pyrrolizidine alkaloid N-oxide-induced hepatic sinusoidal obstruction syndrome in humans. Arch Toxicol. 2017;91(12):3913–25. https://doi.org/10.1007/s00204-017-2013-y
35. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: drug-induced liver injury. J Hepatol. 2019;70(6):1222–61. https://doi.org/10.1016/j.jhep.2019.02.014
36. Gao L, Schmitz HJ, Merz KH, Schrenk D. Characterization of the cytotoxicity of selected Chelidonium alkaloids in rat hepatocytes. Toxicol Lett. 2019;311:91–7. https://doi.org/10.1016/j.toxlet.2019.04.031
37. Wu C, Wang Y, Xu M, Liu Y, Di X. Intracellular accumulation as an cytotoxicity to screen hepatotoxic components of Chelidonium majus L. by LC–MS/MS. Molecules. 2019;24(13):2410. https://doi.org/10.3390/molecules24132410
38. Zhou P, Gross S, Liu JH, Yu BY, Feng LL, Nolta J, et al. Flavokawain B, the hepatotoxic constituent from kava root, induces GSH-sensitive oxidative stress through modulation of IKK/NF-kappaB and MAPK signaling pathways. FASEB J. 2010;24(12):4722–32. https://doi.org/10.1096/fj.10.163311
39. Haouzi D, Lekéhal M, Moreau A, Moulis C, Feldmann G, Robin MA, et al. Cytochrome P450-generated reactive metabolites cause mitochondrial permeability transition, caspase activation, and apoptosis in rat hepatocytes. Hepatology. 2000;32(2):303–11. https://doi.org/10.1053/jhep.2000.9034
40. Rader JI, Delmonte P, Trucksess MW. Recent studies on selected botanical dietary supplement ingredients. Anal Bioanal Chem. 2007;389(1):27–35. https://doi.org/10.1007/s00216-007-1254-7
41. Choen DL, Toro YD. A case of valerian-associated hepatotoxicity. J Clin Gastroenterol. 2008;42(8):961–2. https://doi.org/10.1097/MCG.0b013e3180500348
42. Vassiliadis T, Anagnostis P, Patsiaoura K, Giouleme O, Katsinelos P, Mpoumponaris A, Eugenidis N. Valeriana hepatotoxicity. Sleep Med. 2009;10(8):935. https://doi.org/10.1016/j.sleep.2008.09.009
43. Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Sarganas G, et al. Drug-induced liver injury: results from the hospital-based Berlin case-control surveillance study. Br J Clin Pharmacol. 2015;79(6):988–99. https://doi.org/10.1111/bcp.12565
44. Wu Y, Sun L, Zeng F, Wu S. A conjugated-polymer-based ratiometric nanoprobe for evaluating in vivo hepatotoxicity induced by herbal medicine via MSOT imaging. Photoacoustics. 2019;13:6–17. https://doi.org/10.1016/j.pacs.2018.11.002
45. Ma X, Peng JH, Hu YY. Chinese herbal medicin-induced liver injury. J Clin Transl Hepatol. 2014;2(3):170–5. https://doi.org/10.14218/JCTH.2014.00009
46. Chau TN, Cheuny WI, Ngan T, Lin J, Lee KWS, Poon WT, et al. Causality assessment of herb-ibduced liver injury using multidisciplinary approach and the Roussel Uclaf Causality assessment Method (RUCAM). Clin Toxicol. 2011;49(1):34–9. https://doi.org/10.3109/15563650.2010.537662
47. Teschke R, Schwarzenboeck A, Hennermann K. Kava hepatotoxicity: a clinical cases and critical analysis of 26 suspected cases. Eur J Gastroenterol Hepatol. 2008;20(12):1182–93. https://doi.org/10.1097/MEG.0b013e3283036768
48. Bagins CI, Derag G, Baumelou A, Le Quintrec M, Vanherweghem JL. Herbs and the kidney. Am J Kidney Dis. 2004;44(1):1–11. http://dx.doi.org/10.1053/j.ajkd.2004.02.009
49. Jain A, Olivero JJ. Herbal nephropathy. Methodist Debakey Cardiovasc J. 2019;15(3):228–30.
50. Arlt VM, Stiborova M, Schmeiser HH. Aristolochic acids as a probable human cancer in herbal remedies: a review. Mutagenesis. 2002;17(4):265–77. https://doi.org/10.1093/mutage/17.4.265
51. Jadot I, Declèves AE, Nortier J, Caron N. Decleves an integrated view of Aristolochic acid nephropathy: update of the literature. In J Mol Sci. 2017;18(2):297. https://doi.org/10.3390/ijms18020297
52. Stiborová M, Hudeček J, Frei E, Schmeiser HH. Contribution of biotransformation enzymes to the development of renal injury and urothelial cancer caused by aristolochic acid: urgent questions, difficult answers. Interdisc Toxicol. 2008;1(1):8–12. https://doi.org/10.2478/v10102-010-0023-1
53. Sun M, Zhang J, Zheng C, Liu Y, Lin F, Xu F, Chen C. Analysis of potential risk factors for cancer incidence in patients with aristolochic acid nephropathy from Wenzhou, China. Renal Failure. 2015;37(2):209–13. https://doi.org/10.3109/0886022X.2014.990347
54. Leung EMK, Chan W. Camparison of DNA and RNA adduct formation: significantly higher levels of RNA than DNA modificantions in the internal organs of aristolochic acid-dosed rats. Chem Res Toxicol. 2015;28(2):248–55. https://doi.org/10.1021/tx500423m
55. Li YY, Lu XY, Wang QQ, Zhang YD, Zhang JB, Fan XH. Potential hepatic and renal biflavonoids from Ginkgo biloba. Chin J Nat Med. 2019;17(9):672–81. https://doi.org/10.1016/S1875-5364(19)30081-0
56. Liew ZH, Lee KG. Liquorice-induced severe hypokalaemic rhabdomyolysis with acute kidney injury. Ann Acad Med Singapore. 2017;46(9):354–5.
57. Yase H, Foh T, Mizuno Y, Harada E. Severe hypokalemia, rhabdomyolysis, muscle paralysis and respiratory impairment in a hypertensive patient taking herbal medicines containing licorice. Intern Med. 2007;46(9):575–8. https://doi.org/10.2169/internalmedicine.46.6316
58. Batyushin MM, Sadovnichaya NA, Rudenko LI, Povilaitite PE. Clinical case of nephropathy caused by the reception of the Agrimonia eupatoria. Vestnik Urologii = Urology Herald. 2013;(3):30–8 (In Russ.) https://doi.org/10.21886/2308-6424-2013-0-3-30-38
59. Nayeri A, Wu S, Adams E, Tanner C, Meshmans S, Saini I, Reid W. Acute calcincurin inhibitor nephrotoxicity secondary to turmeric intake: a case report. Transplant Proc. 2017;49(1):198–200. https://doi.org/10.1016/j.transproceed.2016.11.029
60. Carbajal R, Yisfalem A, Pradhan N, Baumstein D, Chaudhari A. Case report: boldo (Peumus boldus) and tacrolimus interaction in a renal transplant patient. Transplant Proc. 2014;46(7):2400–2. https://doi.org/10.1016/j.transproceed.2014.01.021
61. Nowack R, Nowak B. Herbal teas interfere with cyclosporin levels in renal transplant patients. Nephrol Dial Transplant. 2005;20(11):2554–6. https://doi.org/10.1093/ndt/gfi003
62. Burdman EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol. 2003;23(5):465–76. https://doi.org/10.1016/s0270-9295(03)00090-1
63. Egashira K, Sasaki H, Higuchi S, Ieiri I. Food-drug interaction of tacrolimus with pomelo, ginger and turmeric juice in rats. Drug Metab Pharmacokinet. 2012;27(2):242–7. https://doi.org/10.2133/dmpk.dmpk-11-rg-105
64. Zhang W, Lim LY. Effects of spice constituents on P-glycoprotein-mediated transplant and CYP3A4-mediated metabolism in vitro. Drug Metab Dispos. 2008;36(7):1283–90. https://doi.org/10.1124/dmd.107.019737
65. Chen XW, Sneed KB, Pan SY, Cao C, Kanwar JR, Chew H, et al. Herb-drug interactions and mechanistic and clinical considerations. Curr Drug Metab. 2012;13(5):640–51. https://doi.org/10.2174/1389200211209050640
66. Cho HJ, Yoon IS. Pharmacokinetic interactions of herbs with cytochrome P450 and P-glycoprotein. Evid Based Complement Alternat Med. 2015;2015:736431. https://doi.org/10.1155/2015/736431
67. Ramos-Esquivel A, Viquez-Jaikel A, Fernandez K. Potential drug-drug and herb-drug interactions in patients with cancer: a prospective study of medication surveillance. J Oncol Pract. 2017;13(17):e613–e622. https://doi.org/10.1200/JOP.2017.020859
68. Gribakina AO, Kolyvanov GB, Litvin AA, Viglinskaya AO, Zherdev VP. pharmacokinetic interaction of drugs, the metabolisable cytochrome P450 isoenzyme CYP2C9. Farmakokinetika i farmakodinamika = Pharmacokinetics and Pharmacodynamics. 2016;(1):21–32 (In Russ.)
69. Gorski JC, Huang SM, Pinto A, Hamman MA, Hilligoss JK, Zaheer NA, et al. The effect of echinacea (Echinacea purpurea root) on cytochrome P450 activity in vivo. Clin Pharmacol Ther. 2004;75(1):89–100. https://doi.org/10.1016/j.clpt.2003.09.013
70. Bossaer JB, Odle BL. Probable etoposide interaction with Echinacea. J Diet Suppl. 2012;9(2):90–5. https://doi.org/10.3109/19390211.2012.682643
71. Strippoli S, Lorusso V, Albano A, Guida M. Herbal-drug interaction induced rhabdomyolisis in a liposarcoma patient receving trabectedin. BMC Complement Altern Med.2013;13:199. https://doi.org/10.1186/1472-6882-13-199
72. Braunlich M, Christensen H, Johannesen S, Slimestad R, Wangensteen H, Malterud KE, Barsett H. In vitro inhibition of cytochrome P4503A4 by Aronia melanocarpa constituents. Planta Med. 2013;79(2):137–41. https://doi.org/10.1055/s-0032-1328055
73. Van Strater ACP, Bogers JPAM. Interaction of St. John’s wort (Hypericum perforatum) with clozapine. Int Clin Psychopharmacol. 2012;27(2):121–4. https://doi.org/10.1097/YIC.0b013e32834e8afd
74. Hussaarts KGAM, Hurkmans DP, Hoop EO, van Harten LJ, Berghuis S, van Alphen RJ. Impact of curcumin (with or without piperine) on the pharmacokinetics of tamoxifen. Cancers (Basel). 2019;11(3):403. https://doi.org/10.3390/cancers11030403
75. Muellers SC, Majcher-Peszynska J, Uehleke B, Klamnt S, Mundkowski RG, Miekisch W, et al. The extent of induction of CYP3A by St. John’s wort varies among products and is linked to hyperforin dose. Eur J Clin Pharmacol. 2006;62(1):29–36. https://doi.org/10.1007/s00228-005-0061-3
76. Muellers SC, Majcher-Peszynska J, Mundkowsk RF, Uehleke B, Klamnt S, Sievers H, et al. No clinically relevant CYP3A4 induction after St. John’s wort with low hyperforin content in healthy volunteers. Eur J Clin Pharmacol. 2009;65(1):81–7. https://doi.org/10.1007/s00228-008-0554-y
77. Arold G, Donath F, Maurer A, Diefenbach K, Dauer S, Henneicke-von Zepelin HH, et al. No revelant interaction with alprazolam, caffeine, tolbutamide and digoxin by treatment with a low-hyperforin St. John’s wort extract. Planta Med. 2005;71(4):331–7. https://doi.org/10.1055/s-2005-864099
78. Mai I, Bauer S, Perloff E, Johne A, Uehleke B, Frank B, et al. Hyperforin content determines the magnitude of the St. John’s wort-cyclosporine drug interaction. Clin Pharmacol Ther. 2004:76(4):330–40. https://doi.org/10.1016/j.clpt.2004.07.004
79. Yin OQP, Tomlinson B, Waye MMY, Chow AHL, Chow MSS. Pharmacogenetics and herb-drug interactions: experiense with Ginkgo biloba and omeprazole. Pharmacogenetics. 2004;14(12):841–50. https://doi.org/10.1097/00008571-200412000-00007
80. Moses GM, McGuire TM. Drug interactions with complementary medicines. Aust Prescr. 2010;33(6):177–80. https://doi.org/10.18773/austprescr.2010.084
81. Hodges PJ, Kam PCA. The peri-operative implications of herbal medicines. Anaesthesia. 2002;57(9):889–99. https://doi.org/10.1046/j.1365-2044.2002.02781.x
82. Diamond BJ, Baley MR. Ginkgo biloba: indications, mechanisms and safety. Psychiatr Clin North Am. 2013;36(1):73–83. https://doi.org/10.1016/j.psc.2012.12.006
83. Mai I, Störmer E, Bauer S, Krüger H, Budde K, Roots I. Impact of St Jobn`s wort treatment on the pharmacokinetics of tacrolimus and mycophenolic acid in renal transplant patients. Nephrol Dial Transplant. 2003;18(4):819–22. https://doi.org/10.1093/ndt/gfg002
84.
Supplementary files
Review
For citations:
Demidova O.A., Arkhipov V.V., Zhuravleva M.V., Alexandrova T.A., Alexandrov A.A. Safety of Herbal Medicines: Clinical and Pharmacological Aspects. Safety and Risk of Pharmacotherapy. 2020;8(4):165-177. (In Russ.) https://doi.org/10.30895/2312-7821-2020-8-4-165-177