Leflunomid methotrexat'a bağlı karaciğer toksisitesini önleyebilir mi?
Amaç:Uzun dönem methotrexat kullanımı artmış karaciğer hasarı ve fibrozis riski ile ilişkilidir. Leflunomid hastalık modifiye edici bir ilaçtır. Leflunomid nükleer faktör kappa B aktivasyonunun güçlü bir inhibitörüdür. Aynı zamanda anti-oksidan aktivitesi de vardır. Bu deneysel çalışmada methotrexat'ın neden olduğu karaciğer toksisitesinde leflunomid tedavisinin etkinliği araştırılmıştır. Gereç ve yöntem: 39 rat 4 gruba ayrılmıştır. Methotrexat'a bağlı karaciğer toksisitesi tek doz 20mg/kg methotrexat'ın periton içine injeksiyonu ile oluşturulmuştur. Ardından leflunomid 5 gün boyunca 10 mg/ kg dozda verilmiştir. Ardından serum örnekleri ve homojenize karaciğer örnekleri toplanmıştır. Serum alanin aminotransferaz, alkalin fosfataz, superoxide dismutaz, myeloperoxidaz aktivitesi, glutatyon düzeyleri çalışılmış ve histopatolojik değerlendirme yapılmıştır. Bulgular: Leflunomid tedavisi tedavi almayan gruba göre karaciğer semikantitatif skalaya bağlı histopatolojik değerlendirmede anlamlı düzelme sağlamıştır (Patolojik skor 1.1+0.7 ve 5.1+2, p
Can leflunomide prevent methotrexate induced liver toxicity?
Purpose: Long-term clinical use of methotrexate is connected with a raised risk of liver injury and fibrosis.Leflunomide is a disease-modifying drug. Leflunomide has a powerful inhibitory effect on nuclear factor kappaB activation. Leflunomide also presents antioxidant activity. In this experimental study, we aimed to investigatethe effects of leflunomide treatment on methotrexate -induced hepatotoxicity.Materials and methods: Thirty-nine rats were divided into 4 groups. A single dose of 20mg/kg methotrexatewas injected intraperitoneally for methotrexate-induced hepatotoxicity. After induction, leflunomide (10 mg/kg)was administered into the stomach for consecutive 5 days. Then, serum samples and homogenated liver tissueswere collected for analyzed serum alanine aminotransferase, alkaline phosphatase, superoxide dismutaseactivity, myeloperoxidase activity, glutathione levels and assessment of histopathology.Results: Leflunomide treatment significantly ameliorated total histopathologic score according to semiquantitativescale compared to the untreated group, (Pathological score 1.1+0.7 versus 5.1+2 respectively, p
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- Feagan BG, Alfadhli A. Methotrexate in inflammatory
bowel disease. Gastroenterol Clin North Am
2004;33:407-420
- Richard S, Guerret S, Gerard F, Tebib JG, Vignon
E. Hepatic fibrosis in rheumatoid arthritis patients
treated with methotrexate: application of a new
semi-quantitative scoring system. Rheumatology
(Oxford)2000;39:50-54.
- Beyeler C, Reichen J, Thomann SR, Lauterburg BH,
Gerber NJ. Quantitative liver function in patients with
rheumatoid arthritis treated with low dose methotrexate:
A longitudinal study. Br J Rheumatol 1997;36:338-344.
- Boffa MJ, Chalmers RJ, Haboubi NY, Shomaf M,
Mitchell DM. Sequential liver biopsies during long-term
methotrexate treatment for psoriasis: A reappraisal. Br
J Dermatol 1995;133:774-778.
- Neuman MG, Cameron RG, Haber JA, Katz GG,
Malkiewicz IM, Shear NH. Inducers of cytochrome P450
2E1 enhance methotrexate induced hepatotoxicity.
Clin Biochem 1999;32:519-536.
- Mladenovıc V, Domljan Z, Rozman B et al. Safety
and effectiveness of leflunomide in the treatment of
patients with active rheumatoid arthritis. Results of
a randomized, placebo-controlled, phase II study.
Arthritis Rheum 1995;38:1595-1603.
- MannaSK, Aggarwal BB. Immunosuppressive leflunomide
metabolite (A77 1726) blocks TNF-dependent nuclear
factor-kappa β activation and gene expression. J
Immunol. 1999;162:2095-2102.
- Bartlett RR, Anagnostopulos H, Zıelınskı T, Mattar T,
Schleyerbach R. Effects of leflunomide on immune
responses and models of inflammation. Springer
Semin Immunopathol 1993;14:381-394
- Özturk E, Demirbilek S, BegecZ, et al. Does leflunomide
attenuate the sepsis-induced acute lung injury? Pediatr
Surg Int 2008;24:899-905
- Manna SK, Mukhopadhyay A, Aggarwal BB. Leflunomide
suppresses TNF-induced cellular responses:
effects on NF-kappa B, activator protein-1, c-Jun
N-terminal protein kinase, and apoptosis. J Immunol.
2000;165:5962-5969.
- Yao HW, Li J, Chen JQ, Xu SY. Inhibitory effect of
leflunomide on hepatic fibrosis induced by CCl4
in rats.
Acta Pharmacol Sin 2004;25:915-920.
- Uraz S, Tahan V, Aygun C, et al. Role of ursodeoxycholic
acid in prevention of methotrexate-induced liver toxicity.
Dig Dis Sci 2008;53:1071-1077.
- Akerboom TP, Sies H. Assay of glutathione, glutathione
disulfide and glutathione mixed disulfides in biological
samples. Methods Enzymol 1981;77:373-382.
- Hillegass LM, Griswold DE, Brickson B, Albrightson
WC, Assessment of myeloperoxidase activity in whole
rat kidney. J Pharmacol Methods 1990;24:285-295.
- Sun Y, Oberley LW, Li Y. A simple method for
clinical assay of superoxide dismutase. Clin Chem
1988;34:497-500.
- Demling R, Lalonde C, Knox J, Youn Y, Zhu D, Daryani
R. Fluid resuscitation with deferoxamine prevents
systemic burn induced oxidant injury. J Trauma
1991;31:538-543.
- Sener G, Toklu H, Kapucu C, et al. Melatonin protects
against oxidative organ injury in a rat model of sepsis.
Surg Today 2005;35:52-59.
- Roenigk HH, Auerbach R, Weinstein GD. Use
of methotrexate in psoriasis. Arch Dermatol
1972;105:363-365.
- Alves JA, Fialho SC, Morato EF, et al. Liver toxicity is
rare in rheumatoid arthritis patients using combination
therapy with leflunomide and methotrexate. Rev Bras
Reumatol. 2011;51:141-144.
- Borg EJ, Seldenrijk CA, Timmer R. Liver cirrhosis due
to methotrexate in a patient with rheumatoid arthritis.
Neth J Med 1996;49:244-246.
- Kobayashi K, Terada C, Tsukamoto I. Methotrexateinduced apoptosis in hepatocytes after partial
hepatectomy. Eur J Pharmacol 2002;438:19-24.
- Cetinkaya A, Bulbuloglu E, Kurutas EB, Kantarceken
B. N-acetylcysteine ameliorates methotrexateinduced oxidative liver damage in rats. Med Sci Monit
2006;12:274-278.
- Cetin A, Kaynar L, Kocyigit I. et al. Role of grape seed
extract on methotrexate induced oxidative stress in rat
liver. Am J Chin Med 2008;36:861-872.
- Jahovic N, Cevik H, Sehirli AO, Yeğen BC, Sener G.
Melatonin prevents methotrexate-induced hepatorenal
oxidative injury in rats. J Pineal Res 2003;34:282-287.
- Karaman A, Iraz M, Kirimlioglu H, Karadag N, Tas E,
Fadillioglu E. Hepatic damage in biliary
-obstructed rats
is ameliorated by leflunomide treatment. Pediatr Surg
Int 2006;229:701-708.
- Imose M, Nagaki M, Kimura K, et al. Leflunomide
protects from T
-cell
-mediated liver injury in mice
through
Iinhibition of nuclear factor kappa β. Hepatology
2004;40:1160-1169.
- Latchoumycandane C, Seah QM, Tan RC, Sattabongkot
J, Beerheide W, Boelsterli UA. Leflunomide or A77 1726
protect from acetaminophen
-induced cell injury through
inhibition of JNK-mediated mitochondrial permeability
transition in immortalized human hepatocytes. Toxicol
Apol Parmacol 2006;217:125-133.
- Hall PD, Jenner MA, Ahern MJ. Hepatotoxicity in a rat
model caused by orally administered methotrexate.
Hepatology 1991;14:906-910.
- Mackay IR. Hepatoimmunology: A perspective. Immunol
Cell Biol 2002;80:36-44.
- Muriel P. NF-kappaB in liver diseases: a target for drug
therapy. J Appl Toxicol 2009;29:91-100.
- Perez-Alvarez V, Bobadilla RA, Muriel P.
Structure
-hepatoprotective activity relationship of
3,4-dihydroxycinnamic acid (caffeic acid) derivatives. J
Appl Toxicol 2001;21:527-531.
- Bruck R, Schey R, Aeed H, Hochman A, Genina O, Pines
M. A protective effect of pyrrolidine dithiocarbamate in
a rat model of liver cirrhosis. Liver Int 2004;24:169-176.
- Chávez E, Reyes-Gordillo KR, Segovia J, et al.
Resveratrol prevents fibrosis, NF-kappaB activation
and TGF-beta increases induced by chronic CCl4
treatment in rats. J Appl Toxicol 2008;28:35-43.
- Muriel P, Mourelle M. Prevention by silymarin of
membrane alterations in acute CC14 liver damage. J
Appl Toxicol 1990;10:275-279.
- Muriel P, Rivera-Espinoza Y. Beneficial drugs for liver
diseases. J Appl Toxicol 2008;28:93-103.
- Khafaga AF, El-Sayed YS. Spirulina
ameliorates methotrexate hepatotoxicity via
antioxidant, immune stimulation, and proinflammatory
cytokines and apoptotic proteins modulation.Life
Sci 2018;196:9-17.
- Mehrzadi S, Fatemi I, Esmaeilizadeh M. Ghaznavi H, Kalantar H, Goudarzi M. Hepatoprotective effect of
berberine against methotrexate induced liver toxicity in
rats. Biomed Pharmacother 2018;97:233-239.
- Bilasy SE, Essawy SS, Mandour MF, Ali EA, Zaitone
SA. Myelosuppressive and hepatotoxic potential
of leflunomide and methotrexate combination in a
rat model of rheumatoid arthritis. Pharmacol Rep
2015;67:102-114.
- Curtis JR, Beukelman T, Onofrei A, et al. Elevated liver
enzyme tests among patients with rheumatoid arthritis
or psoriatic arthritis treated with methotrexate and/or
leflunomide. Ann Rheum Dis 2010;69:43-47.