Araştırma Makalesi
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Yıl 2020, Cilt 39, Sayı 1, 54 - 60, 29.07.2020
https://doi.org/10.30782/jrvm.665878

Öz

Kaynakça

  • Wolff A. Uber Grundgesetze der Immunitat. Bakteriol. 1904;37:390–7.
  • Raetz CR. Bacterial endotoxins: extraordinary lipids that activate eucaryotic signal transduction. J Bacteriol. 1993 Sep;175(18):5745–53.
  • Nowak M, Gaines G, Rosenberg J, Minter R, Bahjat F, Rectenwald J, et al. LPS-induced liver injury in d -galactosamine-sensitized mice requires secreted TNF-α and the TNF-p55 receptor. Am J Physiol - Regul Intergrative Comp Physiol. 2000;278:R1202–9.
  • Hamesch K, Borkham-Kamphorst E, Strnad P, Weiskirchen R. Lipopolysaccharide-induced inflammatory liver injury in mice. Lab Anim. 2015 Apr 2;49(1_suppl):37–46.
  • Exley AR, Leese T, Holliday MP, Swann RA, Cohen J. Endotoxaemia and serum tumour necrosis factor as prognostic markers in severe acute pancreatitis. Gut. 1992 Aug 1;33(8):1126–8.
  • Cawello W. Clinical Pharmacokinetic and Pharmacodynamic Profile of Lacosamide. Clin Pharmacokinet. 2015 Sep 9;54(9):901–14.
  • de Biase S, Gigli GL, Valente M, Merlino G. Lacosamide for the treatment of epilepsy. Expert Opin Drug Metab Toxicol. 2014 Mar 30;10(3):459–68.
  • Clapham DE. Calcium signaling. Cell. 1995 Jan 27;80(2):259–68.
  • Dong Z, Saikumar P, Weinberg JM, Venkatachalam MA. CALCIUM IN CELL INJURY AND DEATH. Annu Rev Pathol Mech Dis. 2006 Feb;1(1):405–34.
  • ZIPFEL GJ, BABCOCK DJ, LEE J-M, CHOI DW. Neuronal Apoptosis After CNS Injury: The Roles of Glutamate and Calcium. J Neurotrauma. 2000 Oct;17(10):857–69.
  • Nikolaeva MA, Mukherjee B, Stys PK. Na+-Dependent Sources of Intra-Axonal Ca2+ Release in Rat Optic Nerve during In Vitro Chemical Ischemia. J Neurosci. 2005 Oct 26;25(43):9960–7.
  • Ballard-Croft C, Carlson D, Maass DL, Horton JW. Burn trauma alters calcium transporter protein expression in the heart. J Appl Physiol. 2004 Oct;97(4):1470–6.
  • Banasiak K., Burenkova O, Haddad G. Activation of voltage-sensitive sodium channels during oxygen deprivation leads to apoptotic neuronal death. Neuroscience. 2004 Jan;126(1):31–44.
  • Choi DW. Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci. 1995 Feb;18(2):58–60.
  • Vornov JJ, Thomas AG, Jo D. Protective effects of extracellular acidosis and blockade of sodium/hydrogen ion exchange during recovery from metabolic inhibition in neuronal tissue culture. J Neurochem. 1996 Dec;67(6):2379–89.
  • Mentzer RM, Lasley RD, Jessel A, Karmazyn M. Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection. Ann Thorac Surg. 2003 Feb;75(2):S700-8.
  • Baptiste DC, Fehlings MG. Update on the treatment of spinal cord injury. In: Progress in brain research. 2007. p. 217–33.
  • Luna G. Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology. 3rd editio. New York: McGraw Hill Book Co; 1968. 32–34 p.
  • Harry D, Anand R, Holt S, Davies S, Marley R, Fernando B, et al. Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic rat. Hepatology. 1999 Nov;30(5):1198–205.
  • Li G, Liu Y, Tzeng N, Cui G, Block ML, Wilson B, et al. Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol. 2005 Jan 15;69(2):233–40.
  • Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong J-S, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007 Apr 1;55(5):453–62.
  • Bossù P, Cutuli D, Palladino I, Caporali P, Angelucci F, Laricchiuta D, et al. A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-α and IL-18. J Neuroinflammation. 2012 Dec 29;9(1):671.
  • Caroff M, Karibian D. Structure of bacterial lipopolysaccharides. Carbohydr Res. 2003 Nov 14;338(23):2431–47.
  • Ajuwon OR, Oguntibeju OO, Marnewick JL. Amelioration of lipopolysaccharide-induced liver injury by aqueous rooibos (Aspalathus linearis) extract via inhibition of pro-inflammatory cytokines and oxidative stress. BMC Complement Altern Med. 2014 Dec 13;14(1):392.
  • Hill AG, Hill GL. Metabolic response to severe injury. Br J Surg. 1998 Jul;85(7):884–90.
  • Leung KL, Lai PB, Ho RL, Meng WC, Yiu RY, Lee JF, et al. Systemic cytokine response after laparoscopic-assisted resection of rectosigmoid carcinoma: A prospective randomized trial. Ann Surg. 2000 Apr;231(4):506–11.
  • Wortel CH, van Deventer SJ, Aarden LA, Lygidakis NJ, Büller HR, Hoek FJ, et al. Interleukin-6 mediates host defense responses induced by abdominal surgery. Surgery. 1993 Sep;114(3):564–70.
  • Requintina PJ, Oxenkrug GF. Differential effects of lipopolysaccharide on lipid peroxidation in F344N, SHR rats and BALB/c mice, and protection of melatonin and NAS against its toxicity. Ann N Y Acad Sci. 2003 May;993:325–33; discussion 345-9.
  • Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81–128.
  • Lynn WA, Cohen J. Adjunctive therapy for septic shock: a review of experimental approaches. Clin Infect Dis. 1995 Jan;20(1):143–58.
  • Venugopal SK, Devaraj S, Jialal I. Macrophage Conditioned Medium Induces the Expression of C-Reactive Protein in Human Aortic Endothelial Cells. Am J Pathol. 2005 Apr;166(4):1265–71.
  • Teshima S, Rokutan K, Takahashi M, Nikawa T, Kishi K. Induction of heat shock proteins and their possible roles in macrophages during activation by macrophage colony-stimulating factor. Biochem J. 1996 Apr 15;315 ( Pt 2(Pt 2):497–504.
  • Rai R, Richardson C, Flecknell P, Robertson H, Burt A, Manas DM. Study of Apoptosis and Heat Shock Protein (HSP) Expression in Hepatocytes Following Radiofrequency Ablation (RFA). J Surg Res. 2005 Nov;129(1):147–51.
  • Hartman D, Gething MJ. Normal protein folding machinery. EXS. 1996;77:3–24.
  • Wang J, Wei Y, Li X, Cao H, Xu M, Dai J. The identification of heat shock protein genes in goldfish (Carassius auratus) and their expression in a complex environment in Gaobeidian Lake, Beijing, China. Comp Biochem Physiol Part C Toxicol Pharmacol. 2007 Apr;145(3):350–62.
  • Padmini E, Usha Rani M. Impact of seasonal variation on HSP70 expression quantitated in stressed fish hepatocytes. Comp Biochem Physiol Part B Biochem Mol Biol. 2008 Nov;151(3):278–85.
  • Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures. Epilepsia. 2007 Jul;48(7):1308–17.
  • Gutiérrez-Grobe Y, Bahena-Gonzalez JA, Herrera-Gomar M, Mendoza-Diaz P, García-López S, González-Chon O. Acute Liver Failure Associated with Levetiracetam and Lacosamide Combination Treatment for Unspecified Epileptic Disorder. Case Rep Emerg Med. 2013;2013:1–3.
  • Sunwoo J-S, Byun J-I, Lee SK. A case of lacosamide-induced hepatotoxicity. Int J Clin Pharmacol Ther. 2015 Jun 1;53(06):471–3.
  • Zaccara G, Perucca P, Loiacono G, Giovannelli F, Verrotti A. The adverse event profile of lacosamide: A systematic review and meta-analysis of randomized controlled trials. Epilepsia. 2013 Jan;54(1):66–74.
  • Wiemuth D, Gründer S. A single amino acid tunes Ca2+ inhibition of brain liver intestine Na+ channel (BLINaC). J Biol Chem. 2010 Oct 1;285(40):30404–10.
  • Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. In: Handbook of clinical neurology. 2014. p. 417–32.
  • Alvarez V, Rossetti AO. Monotherapy or Polytherapy for First-Line Treatment of SE? J Clin Neurophysiol. 2016 Feb;33(1):14–7.
  • Vidaurre J, Gedela S, Yarosz S. Antiepileptic Drugs and Liver Disease. Pediatr Neurol. 2017 Dec;77:23–36.

Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology

Yıl 2020, Cilt 39, Sayı 1, 54 - 60, 29.07.2020
https://doi.org/10.30782/jrvm.665878

Öz

Bacterial lipopolysaccharides (LPS) generally increase the pathogenicity of the agent. This study aimed to examine the hepatic pathology and possible prophylactic effects of lacosamide (LCM) in a LPS-induced sepsis rat model. Overall, 24 1-year-old female Wistar Albino rats were divided into three groups: Group I (control), Group II (LPS group: 5 mg/kg LPS intraperitoneally, single dose), and Group III (LCM group: 40 mg/kg LCM intraperitoneally once daily for 3 days plus 5 mg/kg LPS 30 min after the last LCM treatment). Animals were euthanized 6 hours after LPS administration. Blood and liver samples collected during necropsy were analyzed biochemically, pathologically, and immunohistochemically. LPS caused a significant increase in serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, and alkaline phosphatase levels. Histopathological analysis revealed numerous neutrophil leucocyte infiltrations, slight hemorrhages in the liver, and degenerative or necrotic changes in hepatocytes. Increased expressions of malondialdehyde, C-reactive protein, heat shock protein-70, interleukin-1β, and tumor necrosis factor-α were observed in the LPS administered group. LCM ameliorated the biochemical, histopathological, and immunohistochemical findings. The present study results revealed that LCM ameliorated the LPS-induced liver damage in the rat models as evidenced by the biochemical and pathological findings.

Kaynakça

  • Wolff A. Uber Grundgesetze der Immunitat. Bakteriol. 1904;37:390–7.
  • Raetz CR. Bacterial endotoxins: extraordinary lipids that activate eucaryotic signal transduction. J Bacteriol. 1993 Sep;175(18):5745–53.
  • Nowak M, Gaines G, Rosenberg J, Minter R, Bahjat F, Rectenwald J, et al. LPS-induced liver injury in d -galactosamine-sensitized mice requires secreted TNF-α and the TNF-p55 receptor. Am J Physiol - Regul Intergrative Comp Physiol. 2000;278:R1202–9.
  • Hamesch K, Borkham-Kamphorst E, Strnad P, Weiskirchen R. Lipopolysaccharide-induced inflammatory liver injury in mice. Lab Anim. 2015 Apr 2;49(1_suppl):37–46.
  • Exley AR, Leese T, Holliday MP, Swann RA, Cohen J. Endotoxaemia and serum tumour necrosis factor as prognostic markers in severe acute pancreatitis. Gut. 1992 Aug 1;33(8):1126–8.
  • Cawello W. Clinical Pharmacokinetic and Pharmacodynamic Profile of Lacosamide. Clin Pharmacokinet. 2015 Sep 9;54(9):901–14.
  • de Biase S, Gigli GL, Valente M, Merlino G. Lacosamide for the treatment of epilepsy. Expert Opin Drug Metab Toxicol. 2014 Mar 30;10(3):459–68.
  • Clapham DE. Calcium signaling. Cell. 1995 Jan 27;80(2):259–68.
  • Dong Z, Saikumar P, Weinberg JM, Venkatachalam MA. CALCIUM IN CELL INJURY AND DEATH. Annu Rev Pathol Mech Dis. 2006 Feb;1(1):405–34.
  • ZIPFEL GJ, BABCOCK DJ, LEE J-M, CHOI DW. Neuronal Apoptosis After CNS Injury: The Roles of Glutamate and Calcium. J Neurotrauma. 2000 Oct;17(10):857–69.
  • Nikolaeva MA, Mukherjee B, Stys PK. Na+-Dependent Sources of Intra-Axonal Ca2+ Release in Rat Optic Nerve during In Vitro Chemical Ischemia. J Neurosci. 2005 Oct 26;25(43):9960–7.
  • Ballard-Croft C, Carlson D, Maass DL, Horton JW. Burn trauma alters calcium transporter protein expression in the heart. J Appl Physiol. 2004 Oct;97(4):1470–6.
  • Banasiak K., Burenkova O, Haddad G. Activation of voltage-sensitive sodium channels during oxygen deprivation leads to apoptotic neuronal death. Neuroscience. 2004 Jan;126(1):31–44.
  • Choi DW. Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci. 1995 Feb;18(2):58–60.
  • Vornov JJ, Thomas AG, Jo D. Protective effects of extracellular acidosis and blockade of sodium/hydrogen ion exchange during recovery from metabolic inhibition in neuronal tissue culture. J Neurochem. 1996 Dec;67(6):2379–89.
  • Mentzer RM, Lasley RD, Jessel A, Karmazyn M. Intracellular sodium hydrogen exchange inhibition and clinical myocardial protection. Ann Thorac Surg. 2003 Feb;75(2):S700-8.
  • Baptiste DC, Fehlings MG. Update on the treatment of spinal cord injury. In: Progress in brain research. 2007. p. 217–33.
  • Luna G. Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology. 3rd editio. New York: McGraw Hill Book Co; 1968. 32–34 p.
  • Harry D, Anand R, Holt S, Davies S, Marley R, Fernando B, et al. Increased sensitivity to endotoxemia in the bile duct-ligated cirrhotic rat. Hepatology. 1999 Nov;30(5):1198–205.
  • Li G, Liu Y, Tzeng N, Cui G, Block ML, Wilson B, et al. Protective effect of dextromethorphan against endotoxic shock in mice. Biochem Pharmacol. 2005 Jan 15;69(2):233–40.
  • Qin L, Wu X, Block ML, Liu Y, Breese GR, Hong J-S, et al. Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. Glia. 2007 Apr 1;55(5):453–62.
  • Bossù P, Cutuli D, Palladino I, Caporali P, Angelucci F, Laricchiuta D, et al. A single intraperitoneal injection of endotoxin in rats induces long-lasting modifications in behavior and brain protein levels of TNF-α and IL-18. J Neuroinflammation. 2012 Dec 29;9(1):671.
  • Caroff M, Karibian D. Structure of bacterial lipopolysaccharides. Carbohydr Res. 2003 Nov 14;338(23):2431–47.
  • Ajuwon OR, Oguntibeju OO, Marnewick JL. Amelioration of lipopolysaccharide-induced liver injury by aqueous rooibos (Aspalathus linearis) extract via inhibition of pro-inflammatory cytokines and oxidative stress. BMC Complement Altern Med. 2014 Dec 13;14(1):392.
  • Hill AG, Hill GL. Metabolic response to severe injury. Br J Surg. 1998 Jul;85(7):884–90.
  • Leung KL, Lai PB, Ho RL, Meng WC, Yiu RY, Lee JF, et al. Systemic cytokine response after laparoscopic-assisted resection of rectosigmoid carcinoma: A prospective randomized trial. Ann Surg. 2000 Apr;231(4):506–11.
  • Wortel CH, van Deventer SJ, Aarden LA, Lygidakis NJ, Büller HR, Hoek FJ, et al. Interleukin-6 mediates host defense responses induced by abdominal surgery. Surgery. 1993 Sep;114(3):564–70.
  • Requintina PJ, Oxenkrug GF. Differential effects of lipopolysaccharide on lipid peroxidation in F344N, SHR rats and BALB/c mice, and protection of melatonin and NAS against its toxicity. Ann N Y Acad Sci. 2003 May;993:325–33; discussion 345-9.
  • Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med. 1991;11(1):81–128.
  • Lynn WA, Cohen J. Adjunctive therapy for septic shock: a review of experimental approaches. Clin Infect Dis. 1995 Jan;20(1):143–58.
  • Venugopal SK, Devaraj S, Jialal I. Macrophage Conditioned Medium Induces the Expression of C-Reactive Protein in Human Aortic Endothelial Cells. Am J Pathol. 2005 Apr;166(4):1265–71.
  • Teshima S, Rokutan K, Takahashi M, Nikawa T, Kishi K. Induction of heat shock proteins and their possible roles in macrophages during activation by macrophage colony-stimulating factor. Biochem J. 1996 Apr 15;315 ( Pt 2(Pt 2):497–504.
  • Rai R, Richardson C, Flecknell P, Robertson H, Burt A, Manas DM. Study of Apoptosis and Heat Shock Protein (HSP) Expression in Hepatocytes Following Radiofrequency Ablation (RFA). J Surg Res. 2005 Nov;129(1):147–51.
  • Hartman D, Gething MJ. Normal protein folding machinery. EXS. 1996;77:3–24.
  • Wang J, Wei Y, Li X, Cao H, Xu M, Dai J. The identification of heat shock protein genes in goldfish (Carassius auratus) and their expression in a complex environment in Gaobeidian Lake, Beijing, China. Comp Biochem Physiol Part C Toxicol Pharmacol. 2007 Apr;145(3):350–62.
  • Padmini E, Usha Rani M. Impact of seasonal variation on HSP70 expression quantitated in stressed fish hepatocytes. Comp Biochem Physiol Part B Biochem Mol Biol. 2008 Nov;151(3):278–85.
  • Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures. Epilepsia. 2007 Jul;48(7):1308–17.
  • Gutiérrez-Grobe Y, Bahena-Gonzalez JA, Herrera-Gomar M, Mendoza-Diaz P, García-López S, González-Chon O. Acute Liver Failure Associated with Levetiracetam and Lacosamide Combination Treatment for Unspecified Epileptic Disorder. Case Rep Emerg Med. 2013;2013:1–3.
  • Sunwoo J-S, Byun J-I, Lee SK. A case of lacosamide-induced hepatotoxicity. Int J Clin Pharmacol Ther. 2015 Jun 1;53(06):471–3.
  • Zaccara G, Perucca P, Loiacono G, Giovannelli F, Verrotti A. The adverse event profile of lacosamide: A systematic review and meta-analysis of randomized controlled trials. Epilepsia. 2013 Jan;54(1):66–74.
  • Wiemuth D, Gründer S. A single amino acid tunes Ca2+ inhibition of brain liver intestine Na+ channel (BLINaC). J Biol Chem. 2010 Oct 1;285(40):30404–10.
  • Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. In: Handbook of clinical neurology. 2014. p. 417–32.
  • Alvarez V, Rossetti AO. Monotherapy or Polytherapy for First-Line Treatment of SE? J Clin Neurophysiol. 2016 Feb;33(1):14–7.
  • Vidaurre J, Gedela S, Yarosz S. Antiepileptic Drugs and Liver Disease. Pediatr Neurol. 2017 Dec;77:23–36.

Ayrıntılar

Birincil Dil İngilizce
Konular Veteriner Hekimlik
Bölüm Research Articles
Yazarlar

Özlem ÖZMEN
MEHMET AKİF ERSOY ÜNİVERSİTESİ, VETERİNER FAKÜLTESİ
0000-0002-1835-1082
Türkiye


Volkan İPEK (Sorumlu Yazar)
MEHMET AKİF ERSOY ÜNİVERSİTESİ, VETERİNER FAKÜLTESİ
0000-0001-5874-7797
Türkiye

Yayımlanma Tarihi 29 Temmuz 2020
Yayınlandığı Sayı Yıl 2020, Cilt 39, Sayı 1

Kaynak Göster

Bibtex @araştırma makalesi { jrvm665878, journal = {Journal of Research in Veterinary Medicine}, issn = {}, eissn = {2667-6745}, address = {Bursa Uludağ Üniversitesi Veteriner Fakültesi Gorukle-Bursa-Türkiye}, publisher = {Bursa Uludağ Üniversitesi}, year = {2020}, volume = {39}, pages = {54 - 60}, doi = {10.30782/jrvm.665878}, title = {Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology}, key = {cite}, author = {Özmen, Özlem and İpek, Volkan} }
APA Özmen, Ö. & İpek, V. (2020). Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology . Journal of Research in Veterinary Medicine , 39 (1) , 54-60 . DOI: 10.30782/jrvm.665878
MLA Özmen, Ö. , İpek, V. "Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology" . Journal of Research in Veterinary Medicine 39 (2020 ): 54-60 <https://dergipark.org.tr/tr/pub/jrvm/issue/56195/665878>
Chicago Özmen, Ö. , İpek, V. "Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology". Journal of Research in Veterinary Medicine 39 (2020 ): 54-60
RIS TY - JOUR T1 - Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology AU - Özlem Özmen , Volkan İpek Y1 - 2020 PY - 2020 N1 - doi: 10.30782/jrvm.665878 DO - 10.30782/jrvm.665878 T2 - Journal of Research in Veterinary Medicine JF - Journal JO - JOR SP - 54 EP - 60 VL - 39 IS - 1 SN - -2667-6745 M3 - doi: 10.30782/jrvm.665878 UR - https://doi.org/10.30782/jrvm.665878 Y2 - 2020 ER -
EndNote %0 Journal of Research in Veterinary Medicine Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology %A Özlem Özmen , Volkan İpek %T Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology %D 2020 %J Journal of Research in Veterinary Medicine %P -2667-6745 %V 39 %N 1 %R doi: 10.30782/jrvm.665878 %U 10.30782/jrvm.665878
ISNAD Özmen, Özlem , İpek, Volkan . "Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology". Journal of Research in Veterinary Medicine 39 / 1 (Temmuz 2020): 54-60 . https://doi.org/10.30782/jrvm.665878
AMA Özmen Ö. , İpek V. Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology. J Res Vet Med. 2020; 39(1): 54-60.
Vancouver Özmen Ö. , İpek V. Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology. Journal of Research in Veterinary Medicine. 2020; 39(1): 54-60.
IEEE Ö. Özmen ve V. İpek , "Effects of Lacosamide in Rats with Lipopolysaccharide Induced Hepatic Pathology", Journal of Research in Veterinary Medicine, c. 39, sayı. 1, ss. 54-60, Tem. 2020, doi:10.30782/jrvm.665878