zdorПроблемы здоровья и экологииHealth and Ecology Issues2220-09672708-6011Gomel State Medical University10.51523/2708-6011.2014-11-4-5zdor-1545Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEWS AND LECTURESЛЕФЛУНОМИД: ТОКСИЧЕСКИЕ ОСОБЕННОСТИ (обзор литературы)ВоловиковаО. Н.VolovikovaO. N.noemail@neicon.ruМихайловаЕ. И.MikhailovaE. I.noemail@neicon.ruДундароваГ. Г.DundarovaG. G.noemail@neicon.ruКарпенкоЕ. Э.KarpenkoE. E.noemail@neicon.ruГомельский государственный медицинский университетGomel State Medical UniversityГомельская областная клиническая больница Гомельская городская клиническая больница № 1Gomel Regional Clinical Hospital Gomel City Clinical Hospital No.1201428122014043034Copyright © Воловикова О.Н., Михайлова Е.И., Дундарова Г.Г., Карпенко Е.Э., 20142014Воловикова О.Н., Михайлова Е.И., Дундарова Г.Г., Карпенко Е.Э.Volovikova O.N., Mikhailova E.I., Dundarova G.G., Karpenko E.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.gsmu.by/jour/article/view/1545

С недавнего времени в лечении ревматоидного артрита начали активно использовать новый иммуносупрессивный препарат - лефлуномид. По своей эффективности он не уступает давно известному базисному препарату - метотрексату. В большинстве случаев лефлуномид хорошо переносится. Однако у части пациентов он способен вызывать зачастую тяжелые побочные эффекты. Наиболее распространенными нежелательными эффектами лефлуномида являются желудочно-кишечные расстройства, потеря веса, артериальная гипертензия, инфекции кожи, нейро- и гематотоксичность. При длительной терапии он оказывает гепатотоксические и тератогенные эффекты. В 2010 г. Управление по контролю за продуктами и лекарствами (FDA) рекомендовало внести в инструкцию к лекарственному средству предупреждение «черный ящик», что означает, что клинические исследования показали, что лефлуномид обладает значительным риском развития серьезных и даже опасных для жизни побочных эффектов.

The new immunosuppressive drug Leflunomide has been used in the treatment of rheumatoid arthritis recently. By its efficiency Leflunomide is not inferior to the long known basic drug - Methotrexate. In most cases, Leflunomide is well tolerated. However, it can cause severe side effects in some patients. The most common adverse effects of Leflunomide are gastrointestinal disorders, weight loss, hypertension, skin infections, neuro-and hematotoxicity. Long-term therapy with Leflunomide has hepatotoxic and teratogenic effects. In 2010, the Food and Drug Administration (FDA) recommended to label the drug as a «black box» in the instructions, which means that clinical studies have shown that Leflunomide has a significant risk for serious and even life-threatening side effects.

лефлуномидревматоидный артриттоксичностьLeflunomiderheumatoid arthritistoxicityReferencesPrakash, A. Leflunomide: a review of its use in active rheumatoid arthritis / A. Prakash, B. Jarvis // Drugs. - 1999. - № 58. - P. 1137-1164.Prakash, A. Leflunomide: a review of its use in active rheumatoid arthritis / A. Prakash, B. Jarvis // Drugs. - 1999. - № 58. - P. 1137-1164.Gugenberger, C. Persistent diarrhea and loss of weight during therapy with leflunomide / C. Gugenberger, P. Donner, A. Naami // Dtsch. Med. Wochenschr. - 2008. - № 133. - P. 1730-1732.Gugenberger, C. Persistent diarrhea and loss of weight during therapy with leflunomide / C. Gugenberger, P. Donner, A. Naami // Dtsch. Med. Wochenschr. - 2008. - № 133. - P. 1730-1732.Bakhleca, Y. A. Cyclooxygenase-2 and its regulation in inflammation / Y. A. Bakhleca, R. M. Botting // Mediators Inflamm. - 1996. - № 5. - P. 305-323.Bakhleca, Y. A. Cyclooxygenase-2 and its regulation in inflammation / Y. A. Bakhleca, R. M. Botting // Mediators Inflamm. - 1996. - № 5. - P. 305-323.Kumar, V. Basic Pathology / V. Kumar, N. Fausto, A. Abbas // Saunders. - 2004. - № 7. - P. 632-666.Kumar, V. Basic Pathology / V. Kumar, N. Fausto, A. Abbas // Saunders. - 2004. - № 7. - P. 632-666.Internet website [Electronic recourse]. - Mode of access: 12.09.2013.Internet website [Electronic recourse]. - Mode of access: 12.09.2013.Mehta, V. Leflunomide / V. Mehta, S. Kisalay, C. Balachandran // Indian. J. Dermatol. Venereol. Leprol. - 2009. - № 75. - P. 422-424.Mehta, V. Leflunomide / V. Mehta, S. Kisalay, C. Balachandran // Indian. J. Dermatol. Venereol. Leprol. - 2009. - № 75. - P. 422-424.Gupta, R. Risk of hepatotoxicity with add on Leflunomide in a patient / R. Gupta, J. Bhatia, S. K. Gupta // Arzneimettelforschung. - 2011. - № 61. - P. 312-316.Gupta, R. Risk of hepatotoxicity with add on Leflunomide in a patient / R. Gupta, J. Bhatia, S. K. Gupta // Arzneimettelforschung. - 2011. - № 61. - P. 312-316.Leflunomide induced acute hepatitis / C. Sevilla-Mantilla [еt al.] // Dig. Liv. Disease. - 2004. - № 36. - P. 82-84.Leflunomide induced acute hepatitis / C. Sevilla-Mantilla [еt al.] // Dig. Liv. Disease. - 2004. - № 36. - P. 82-84.Hepatic cytochrome P450s attenuate the cytotoxicity induced by Leflunomide and its active metabolite A771726 in primary cultured rat hepatocyte / S. Qiang [еt al.] // Toxicol. Sci. - 2011. - № 122. - P. 579-586.Hepatic cytochrome P450s attenuate the cytotoxicity induced by Leflunomide and its active metabolite A771726 in primary cultured rat hepatocyte / S. Qiang [еt al.] // Toxicol. Sci. - 2011. - № 122. - P. 579-586.Jonathan, S. C. Leflunomide-Associated Weight Loss in Rheumatoid Arthritis / S. C. Jonathan, S. Nancy, H. Simon // Arthritis Rheum. - 2001. - № 44. - P. 1048-1051.Jonathan, S. C. Leflunomide-Associated Weight Loss in Rheumatoid Arthritis / S. C. Jonathan, S. Nancy, H. Simon // Arthritis Rheum. - 2001. - № 44. - P. 1048-1051.Leflunomide and hypertension / B. Rozman [еt al.] // Ann. Rheum. Dis. - 2002. - № 61. - P. 567-569.Leflunomide and hypertension / B. Rozman [еt al.] // Ann. Rheum. Dis. - 2002. - № 61. - P. 567-569.Yuyuan, L. Leflunomide-induced acute liver failure: a case report / L. Yuyuan, Z. Xuqing // J. Med. Coll. PLA. - 2010. - № 25. - P. 62-64.Yuyuan, L. Leflunomide-induced acute liver failure: a case report / L. Yuyuan, Z. Xuqing // J. Med. Coll. PLA. - 2010. - № 25. - P. 62-64.Mehta, V. Lefunomide / V. Mehta, S. Kisalay, C. Balachandran // Indian J. Dermatol. Venereol. Leprol. - 2009. - № 75. - P. 422-424.Mehta, V. Lefunomide / V. Mehta, S. Kisalay, C. Balachandran // Indian J. Dermatol. Venereol. Leprol. - 2009. - № 75. - P. 422-424.Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial / J. S. Smolen [еt al.] // Lancet. - 1999. - № 353. - P. 259-266.Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial / J. S. Smolen [еt al.] // Lancet. - 1999. - № 353. - P. 259-266.Sullivan, J. R. The drug hypersensitivity syndrome: What is the pathogenesis? / J. L. Sullivan, N. H. Shear // Arch. Dermatol. - 2001. - № 137. - P. 357-364.Sullivan, J. R. The drug hypersensitivity syndrome: What is the pathogenesis? / J. L. Sullivan, N. H. Shear // Arch. Dermatol. - 2001. - № 137. - P. 357-364.Sandra, R. K. Idiosyncratic drug reaction; The reactive metabolite syndrome / R. K. Sandra, J. Vetrechi, N. H. Shear // Lancet. - 2000. - № 356. - P. 1587-1591.Sandra, R. K. Idiosyncratic drug reaction; The reactive metabolite syndrome / R. K. Sandra, J. Vetrechi, N. H. Shear // Lancet. - 2000. - № 356. - P. 1587-1591.Wise, D. M. Suppressed Wound Healing In a Patient with Rheumatoid Arthritis Taking Leflunomide (Arava) / D. M. Wise // J. Permanente. - 2011. - № 15. - P. 70-74.Wise, D. M. Suppressed Wound Healing In a Patient with Rheumatoid Arthritis Taking Leflunomide (Arava) / D. M. Wise // J. Permanente. - 2011. - № 15. - P. 70-74.Peripheral neuropathy associated with leflunomide: is there a risk patient profile? / K. Martin [еt al.] // Pharmacoepidemiol Drug Saf. - 2007. - № 16. - P. 74-78.Peripheral neuropathy associated with leflunomide: is there a risk patient profile? / K. Martin [еt al.] // Pharmacoepidemiol Drug Saf. - 2007. - № 16. - P. 74-78.Bharatdwaj, A. Peripheral neuropathy in patients on leflunomide / A. Bharatdwaj, N. Haroon / Rheumatology. - 2004. - № 43. - P. 934-939.Bharatdwaj, A. Peripheral neuropathy in patients on leflunomide / A. Bharatdwaj, N. Haroon / Rheumatology. - 2004. - № 43. - P. 934-939.Chan, A. T. Y. Leflunomide induced vasculitis a dose response relationship / A. T. Y. Chan, A. Bradlow, J. Mcnally // Rheumatology. - 2003. - № 42. - P. 492-493.Chan, A. T. Y. Leflunomide induced vasculitis a dose response relationship / A. T. Y. Chan, A. Bradlow, J. Mcnally // Rheumatology. - 2003. - № 42. - P. 492-493.Barak, A. Leflunomide (Arava)-induced cystoid macular oedema / A. Barak, L. S. Morse, I. Schwab // Rheumatology. - 2004. - № 43. - P. 246-248.Barak, A. Leflunomide (Arava)-induced cystoid macular oedema / A. Barak, L. S. Morse, I. Schwab // Rheumatology. - 2004. - № 43. - P. 246-248.Camras, C. B. Latanoprost may trigger the biosynthesis of endogenous prostaglandins in early postoperative pseudophakias / C. B. Camras // Arch. Ophthalmol. - 1999. - № 117. - P. 1265-1266.Camras, C. B. Latanoprost may trigger the biosynthesis of endogenous prostaglandins in early postoperative pseudophakias / C. B. Camras // Arch. Ophthalmol. - 1999. - № 117. - P. 1265-1266.WHO Drug Information. Leflunomide: haematologic, hepatic and respiratory reactions. - 2002. - № 16. - P. 205-268.WHO Drug Information. Leflunomide: haematologic, hepatic and respiratory reactions. - 2002. - № 16. - P. 205-268.Wǖsthof, M. Severe aplastic anaemia following leflunomide therapy / M. Wǖsthof // Rheumatology. - 2010. - № 49. - P. 1016-1017.Wǖsthof, M. Severe aplastic anaemia following leflunomide therapy / M. Wǖsthof // Rheumatology. - 2010. - № 49. - P. 1016-1017.Toyokawa, Y. Pancytopenia, including macrocytic anemia, associated with leflunomide in a rheumatoid arthritis patient / Y. Toyokawa, I. Kingzetsu, C. Yasuda // Mod. Rheumatol. - 2007. - № 17. - P. 436-440.Toyokawa, Y. Pancytopenia, including macrocytic anemia, associated with leflunomide in a rheumatoid arthritis patient / Y. Toyokawa, I. Kingzetsu, C. Yasuda // Mod. Rheumatol. - 2007. - № 17. - P. 436-440.Brent, R. L. Teratogen Update: Reproductive Risks of Leflunomide (Arava™); A Pyrimidine Synthesis Inhibitor: Counseling Women Taking Leflunomide Before or During Pregnancy and Men Taking Leflunomide Who Are Contemplating Fathering a Child / R. L. Brent // Teratology. - 2001. - № 63. - P. 106-112.Brent, R. L. Teratogen Update: Reproductive Risks of Leflunomide (Arava™); A Pyrimidine Synthesis Inhibitor: Counseling Women Taking Leflunomide Before or During Pregnancy and Men Taking Leflunomide Who Are Contemplating Fathering a Child / R. L. Brent // Teratology. - 2001. - № 63. - P. 106-112.Leflunomide: assessment of teratogenic risk in the first trimester of pregnancy / C. C. Sorní [еt al.] // Hospital Pharmacy. - 2005. - № 29. - P. 265-268.Leflunomide: assessment of teratogenic risk in the first trimester of pregnancy / C. C. Sorní [еt al.] // Hospital Pharmacy. - 2005. - № 29. - P. 265-268.Internet website [Electronic recourse] - Mode of access: http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety Alertsfor Human MedicalProducts/ucm218912.htm. - Date of access: 12.09.2013.Internet website [Electronic recourse] - Mode of access: http://www.fda.gov/Safety/MedWatch/SafetyInformation/Safety Alertsfor Human MedicalProducts/ucm218912.htm. - Date of access: 12.09.2013.Inhibiting the Teratogenicity of the Immunosuppressant Leflunomide in Mice by Supplementation of Exogenous Uridine / R. Fukushima [еt al.] // Toxicol Sci. - 2009. - № 108. - P. 419-426.Inhibiting the Teratogenicity of the Immunosuppressant Leflunomide in Mice by Supplementation of Exogenous Uridine / R. Fukushima [еt al.] // Toxicol Sci. - 2009. - № 108. - P. 419-426.The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase / J. P. Davis [et al.] // Biochemistry. - 1996. - № 35. - P. 1270-1273.The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase / J. P. Davis [et al.] // Biochemistry. - 1996. - № 35. - P. 1270-1273.Herrmann, M. Cell cycle control of the de novo pyrimidine synthesis inhibitor leflunomide through the p53 and p21 pathways / M. Herrmann, C. G. Grangou, B. Kirschbaum // Arthritis Rheum. - 1997. - № 40. - P. 177-179.Herrmann, M. Cell cycle control of the de novo pyrimidine synthesis inhibitor leflunomide through the p53 and p21 pathways / M. Herrmann, C. G. Grangou, B. Kirschbaum // Arthritis Rheum. - 1997. - № 40. - P. 177-179.Ito, S. Interstitial lung disease associated with leflunomide / S. Ito, T. Sumida // Intern. Med. - 2004. - № 43. - P. 1103-1104.Ito, S. Interstitial lung disease associated with leflunomide / S. Ito, T. Sumida // Intern. Med. - 2004. - № 43. - P. 1103-1104.Kamata, Y. Rheumatoid arthritis complicated with acute interstitial pneumonia induced by leflunomide as an adverse reaction / Y. Kamata, H. Nara, T. Kamimura // Intern Med. - 2004. - № 43. - P. 1201-1204.Kamata, Y. Rheumatoid arthritis complicated with acute interstitial pneumonia induced by leflunomide as an adverse reaction / Y. Kamata, H. Nara, T. Kamimura // Intern Med. - 2004. - № 43. - P. 1201-1204.Chikura, B. Clinical expression of leflunomide-induced pneumonitis / B. Chikura, S. Lane, J. K. Dawson // Rheumatology. - 2009. - № 48. - P. 1065-1068.Chikura, B. Clinical expression of leflunomide-induced pneumonitis / B. Chikura, S. Lane, J. K. Dawson // Rheumatology. - 2009. - № 48. - P. 1065-1068.Increased risk of tuberculosis in patients with rheumatoid arthritis / L. Carmona [et al.] // J. Rheumatol. - 2003. - № 30. - P. 1436-1439.Increased risk of tuberculosis in patients with rheumatoid arthritis / L. Carmona [et al.] // J. Rheumatol. - 2003. - № 30. - P. 1436-1439.Cannon, G. W. Leflunomide / G. W. Cannon, J. M. Kremer // Rheum. Dis. Clin. North. Am. - 2004. - № 30. - P. 295-309.Cannon, G. W. Leflunomide / G. W. Cannon, J. M. Kremer // Rheum. Dis. Clin. North. Am. - 2004. - № 30. - P. 295-309.Bieber, J. Consideration of the risk and treatment of tuberculosis in patients who have rheumatoid arthritis and receive biologic treatments / J. Bieber, A. Kavanaugh // Rheum. Dis. Clin. North Am. - 2004. - № 30. - P. 257-270.Bieber, J. Consideration of the risk and treatment of tuberculosis in patients who have rheumatoid arthritis and receive biologic treatments / J. Bieber, A. Kavanaugh // Rheum. Dis. Clin. North Am. - 2004. - № 30. - P. 257-270.

The authors declare that there are no conflicts of interest present.