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Akut lösemili çocukların idame tedavisinde kemoterapiye bağlı hepatotoksisite tedavisinde ursodeoksikolik asitin rolü

Yıl 2023, Cilt: 8 Sayı: 4, 101 - 105, 28.07.2023

Özlem Terzi Ali Ayçiçek Duygu Yıldırgan Hüseyin Avni Solgun Sibel Tekgündüz Cengiz Bayram

https://doi.org/10.22391/fppc.1186913

Öz

Giriş: Lösemi hastalarının tedavisinde kullanılan kemoterapötik ajanlar metabolize oldukları karaciğerde toksik etkilere neden olabilirler. Ursodeoksikolik asit (UDCA), ilaca bağlı karaciğer toksisitesinin tedavisinde hepatoprotektif etkisinden dolayı kullanılmaktadır. Çalışmamızda kemoterapi (KT) tedavisi devam eden lösemi tanılı çocuk hastalarda karaciğer toksisitesinin tedavisinde kullanılan ve tümör hücrelerine etkisi net olarak bilinmeyen ursodeoksikolik asidin etkinliği araştırıldı.

Yöntem: İdame tedavisi alan ve karaciğer toksisitesi gelişen pediatrik lösemi hastalarının verileri retrospektif olarak analiz edildi. Hastalar üç gruba ayrıldı ve sonuçlar karaciğer toksisitesi gelişimi açısından karşılaştırıldı. Ursodeoksikolik asit verilmeyen ve KT tedavisi kesilen hastalar Grup 1, UDCA verilen ve KT kesilen hastalar Grup 2, UDCA verilip KT' ye devam edilen hastalar Grup 3 olarak tanımlandı.

Bulgular: Çalışma grubu 119 hasta olup, bunlardan Grup 1' de 64, Grup 2' de 26 ve Grup 3' te 29 hasta yer aldı. Hastaların yaş ortalaması 6,29 ± 3,03 ve %57,1' i erkekti. Grup 1’ deki hastaların %85,9’ u, Grup 2’ deki hastaların %100’ ü, Grup 3’ teki hastaların %69,2’ sinin alanin aminotransferaz (ALT) seviyesi <100 düzeyine inerek UDCA verilmeyecek ve KT tedavisine devam edilecek duruma ulaşmıştır. Grup 1 ve Grup 2 ile Grup 1 ve Grup 3 arasında istatistiksel olarak anlamlı fark yok iken, Grup 2 ve Grup 3 arasında istatistiksel olarak anlamlı bir fark bulunmuştur (p=0,005). Hiçbir grupta bilirubin düzeyi >3 mg/dL olan hasta yoktu. Alanin aminotransferaz ve aspartat aminotransferaz değerlerinin normale dönme süreleri benzer bulundu.

Sonuç: Lösemi tanılı çocuk hastalarda kemoterapiye bağlı karaciğer toksisitesinin tedavisinde en etkili yol KT’ ye ara vermek gibi görünmektedir. Karaciğer toksisitesinin kaynağı olan KT tedavisine ara vermeden UDCA uygulamasının hastaların %69,2' sinde etkili olması dikkat çekici bulunmuştur. Ursodeoksikolik asitin bu hastalarda hepatoproteksiyondaki rolünü değerlendirmek için, daha ileri ve kapsamlı çalışmalara gerek vardır.

Anahtar kelimeler: Ursodeoksikolik asit; lösemi; kemoterapi; hepatotoksisite.

Anahtar Kelimeler

ursedeoksikolik asit lösemi kemoterapi hepatotoksisite

Kaynakça

  • 1. Sharma A, Houshyar R, Bhosale P, Choi JI, Gulati R, Lall C. Chemotherapy induced liver abnormalities: An imaging perspective. Clin Mol Hepatol. 2014 Sep;20(3):317-26. https://doi.org/10.3350/cmh.2014.20.3.317.
  • 2. Hamilton LA, Collins-Yoder A, Collins RE. Drug-induced liver injury. AACN Adv Crit Care. 2016;27(4):430-40. https://doi.org/10.4037/aacnacc2016953.
  • 3. Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J. Mercaptopurine/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol 2014;36(7):503-17. https://doi.org/10.1097/MPH.0000000000000206
  • 4. Dewitt O, Starkel P, Robin X. Thiopurine metabolism monitoring: Implications in inflammatory bowel diseases. Eur J Clin Invest 2010;40(11):1037-47. https://doi.org/10.1111/j.1365-2362.2010.02346.x.
  • 5. Perel Y, Auvrignon A, Leblanc T, Michel G, Vannier JP, Dalle JH, et al. Maintenance therapy in childhood acute myeloid leukemia. Ann Hematol 2004;83 Suppl 1:S116-9. https://doi.org/10.1007/s00277-004-0850-2
  • 6. Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Risk of liver injury among methotrexate users: A meta-analysis of randomised controlled trials. Semin Arthritis Rheum. 2015;45(2):156-62. https://doi.org/10.1016/j.semarthrit.2015.05.003
  • 7. Munnig-Schmidt E, Zhang M, Mulder CJ, Barclay ML. Late-onset rise of 6-MMP metabolites in IBD patients on azathioprine or mercaptopurine. Inflamm Bowel Dis. 2018;24(4):892-6. https://doi.org/10.1093/ibd/izx081
  • 8. Toksvang LN, Schmidt MS, Arup S, Larsen RH , Frandsen TL, Schmiegelow K, et al. Hepatotoxicity during 6-thioguanine treatment in inflammatory bowel disease and childhood acute lymphoblastic leukaemia: A systematic review. 2019;14(5):e0212157. https://doi.org/10.1371/journal.pone.0212157
  • 9. Patzke CL, Duffy AP, Duong VH, Chaer FE, Trovato JA, Baer MR, et al. Comparison of high-dose cytarabine, mitoxantrone, and pegaspargase (HAM-pegA) to high-dose cytarabine, mitoxantrone, cladribine, and filgrastim (CLAG-M) as first-line salvage cytotoxic chemotherapy for relapsed/refractory acute myeloid leukemia. J Clin Med. 2020;9(2):536. https://doi.org/10.3390/jcm9020536.
  • 10. Bachrach WH; Hofmann AF. Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Part I. Dig Dis Sci 1982;27(9):833-56. https://doi.org/10.1007/BF01391378
  • 11. Roma MG, Toledo FD, Boaglio AC, Basiglio CL, Crocenzi FA, Pozzi EJS. Ursodeoxycholic acid in cholestasis: Linking action mechanisms to therapeutic applications. Clin Sci 2011;121(12):523-44. https://doi.org/10.1042/CS20110184
  • 12. Leuschner U, Leuschner M, Sieratzki J, Kurtz W, Hübner K. Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study. Dig Dis Sci 1985;30(7):642-9. https://doi.org/10.1007/BF01308413
  • 13. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, et al. The Canadian multicentre double blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994;19(5):1149-56. https://doi.org/10.1002/hep.1840190512.
  • 14. Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology 1999;29(4):1007-12. https://doi.org/10.1002/hep.510290444
  • 15. Gong Y, Huang ZB, Christensen E, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2008;(3):CD000551. https://doi.org/10.1002/14651858.CD000551.pub2
  • 16. Reichen J. Review: Ursodeoxycholic acid does not reduce risk for mortality or liver transplantation in primary cirrhosis. ACP J Club 2008;148(1):17. https://doi.org/10.7326/ACPJC-2008-148-1-017.
  • 17. Aycicek A, Tahtakesen TN, Bayram C. The effect of ursodeoxycholic acid and n-acetyl cysteine on lymphoblast viability. BCCR J 2021;13(1):55-62. https://doi.org/10.18502/bccr.v13i1.8829.
  • 18. Lindor KD, Kowdley KV, Luketic VAC, Harrison ME, McCashland T, Befeler AS, et al. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50(3):808-14. https://doi.org/10.1002/hep.23082
  • 19. Rudolph G, Gotthardt D, Kloeters-Plachky P, Rost D, Kulaksiz H, Stiehl A. In PSC with dominant bile duct stenosis, IBD is associated with an increase of carcinomas and reduced survival. J Hepatol 2010;53(2):313-7. https://doi.org/10.1016/j.jhep.2010.02.030
  • 20. ALL IC-BFM 2009 A randomized trial of the I-BFM-SG for the management of childhood non-b acute lymphoblastic leukemia. Final Version of Therapy Protocol from August-14-2009. https://www.bialaczka.org/wp-content/uploads/2016/10/ALLIC_BFM_2009.pdf (Access Date: July 25, 2023)
  • 21. Uraz S, Tahan V, Aygun C, et al. Role of ursodeoxycholic acid in prevention of methotrexate-induced liver toxicity. Dig Dis Sci 2008;53(4):1071-7. https://doi.org/10.1007/s10620-007-9949-3
  • 22. Bordbar M, Shakibazad N, Fattahi M, et al. Effect of ursodeoxycholic acid and vitamin e in the prevention of liver injury from methotrexate in pediatric leukemia. Turk J Gastroenterol 2018;29(2):203-9. https://doi.org/10.5152/tjg.2018.17521
  • 23. Saif MM, Farid SF, Khaleel SA, Sabry NA, El-Sayed MH. Hepatoprotective efficacy of ursodeoxycholic acid in pediatrics acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2012;29(7):627-32. https://doi.org/10.3109/08880018.2012.713083
  • 24. Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM. Antioxidants and cancer therapy: A systematic review. J Clin Oncol. 2004;22(3):517-28. https://doi.org/10.1200/JCO.2004.03.086
  • 25. Moss RW. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants. Integr Cancer Ther 2006;5(1):63-82. https://doi.org/10.1177/153473540528
  • 26. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy. J Natl Cancer Inst. 2008;100(11):773-83. https://doi.org/10.1093/jnci/djn148.
  • 27. Robles-Diaz M, Nezic L, Vujic-Aleksic V. Role of ursodeoxycholic acid in treating and preventing idiosyncratic drug-induced liver injury. A systematic review. Front Pharmacol 2021;12:744488. https://doi.org/10.3389/fphar.2021.744488.

The role of ursodeoxycholic acid in the treatment of chemotherapy induced hepatotoxicity in the maintenance treatment of children with acute leukemia

Yıl 2023, Cilt: 8 Sayı: 4, 101 - 105, 28.07.2023

Özlem Terzi Ali Ayçiçek Duygu Yıldırgan Hüseyin Avni Solgun Sibel Tekgündüz Cengiz Bayram

https://doi.org/10.22391/fppc.1186913

Öz

Introduction: Chemotherapeutic agents used in the treatment of leukemia patients may cause toxic effects in the liver where they are metabolized. Ursodeoxycholic acid (UDCA) is used because of its hepatoprotective effect in the treatment of drug-induced liver toxicity. This study investigated the efficacy of UDCA use, despite the effect of UDCA on tumor cells being unknown, in the treatment of liver toxicity in pediatric patients on chemotherapy for leukemia.

Methods: Data from pediatric leukemia patients, who were on maintenance therapy and developed liver toxicity, were retrospectively analyzed. Patients were divided into three groups and the results were compared regarding development of liver toxicity. Patients who were not given UDCA and whose chemotherapy (CT) treatment was interrupted were defined as Group 1, patients who were given UDCA and whose CT was interrupted were defined as Group 2, and patients who were given UDCA and continued CT were defined as Group 3.

Results: The study cohort numbered 119 patients, of whom 64 were included in Group 1, 26 patients were in Group 2 and 29 patients were included in Group 3. The mean age of the patients was 6.29±3.03 years and 57.1% of them were male. In Group 1, alanine aminotransferase (ALT) decreased to <100 IU/L so UDCA was interrupted, and CT could be rechallenged in 85.9%, in Group 2 this proportion was 100%, and in 69.2% of patients in Group 3, respectively. While there was no significant difference between Group 1 versus Group 2 and Group 1 versus Group 3, a significant difference was found between Group 2 and Group 3 (p=0.005). There were no patients in any group with a bilirubin level of >3 mg/dL. Duration for normalization of ALT and aspartate aminotransferase levels were similar.

Conclusions: The most effective treatment for chemotherapy-induced liver toxicity in pediatric patients with leukemia seems to be to interrupt CT. It was noteworthy that UDCA administration without interruption of CT treatment, the source of the liver toxicity, was effective in 69.2% of patients. Further and comprehensive studies are needed to evaluate the role of UDCA in hepatoprotection in these patients.

Keywords: Ursodeoxycholic acid; leukemia; chemotherapy; hepatotoxicity

Anahtar Kelimeler

Ursodeoxycholic acid leukemia chemotherapy hepatotoxicity

Kaynakça

  • 1. Sharma A, Houshyar R, Bhosale P, Choi JI, Gulati R, Lall C. Chemotherapy induced liver abnormalities: An imaging perspective. Clin Mol Hepatol. 2014 Sep;20(3):317-26. https://doi.org/10.3350/cmh.2014.20.3.317.
  • 2. Hamilton LA, Collins-Yoder A, Collins RE. Drug-induced liver injury. AACN Adv Crit Care. 2016;27(4):430-40. https://doi.org/10.4037/aacnacc2016953.
  • 3. Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J. Mercaptopurine/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol 2014;36(7):503-17. https://doi.org/10.1097/MPH.0000000000000206
  • 4. Dewitt O, Starkel P, Robin X. Thiopurine metabolism monitoring: Implications in inflammatory bowel diseases. Eur J Clin Invest 2010;40(11):1037-47. https://doi.org/10.1111/j.1365-2362.2010.02346.x.
  • 5. Perel Y, Auvrignon A, Leblanc T, Michel G, Vannier JP, Dalle JH, et al. Maintenance therapy in childhood acute myeloid leukemia. Ann Hematol 2004;83 Suppl 1:S116-9. https://doi.org/10.1007/s00277-004-0850-2
  • 6. Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Risk of liver injury among methotrexate users: A meta-analysis of randomised controlled trials. Semin Arthritis Rheum. 2015;45(2):156-62. https://doi.org/10.1016/j.semarthrit.2015.05.003
  • 7. Munnig-Schmidt E, Zhang M, Mulder CJ, Barclay ML. Late-onset rise of 6-MMP metabolites in IBD patients on azathioprine or mercaptopurine. Inflamm Bowel Dis. 2018;24(4):892-6. https://doi.org/10.1093/ibd/izx081
  • 8. Toksvang LN, Schmidt MS, Arup S, Larsen RH , Frandsen TL, Schmiegelow K, et al. Hepatotoxicity during 6-thioguanine treatment in inflammatory bowel disease and childhood acute lymphoblastic leukaemia: A systematic review. 2019;14(5):e0212157. https://doi.org/10.1371/journal.pone.0212157
  • 9. Patzke CL, Duffy AP, Duong VH, Chaer FE, Trovato JA, Baer MR, et al. Comparison of high-dose cytarabine, mitoxantrone, and pegaspargase (HAM-pegA) to high-dose cytarabine, mitoxantrone, cladribine, and filgrastim (CLAG-M) as first-line salvage cytotoxic chemotherapy for relapsed/refractory acute myeloid leukemia. J Clin Med. 2020;9(2):536. https://doi.org/10.3390/jcm9020536.
  • 10. Bachrach WH; Hofmann AF. Ursodeoxycholic acid in the treatment of cholesterol cholelithiasis. Part I. Dig Dis Sci 1982;27(9):833-56. https://doi.org/10.1007/BF01391378
  • 11. Roma MG, Toledo FD, Boaglio AC, Basiglio CL, Crocenzi FA, Pozzi EJS. Ursodeoxycholic acid in cholestasis: Linking action mechanisms to therapeutic applications. Clin Sci 2011;121(12):523-44. https://doi.org/10.1042/CS20110184
  • 12. Leuschner U, Leuschner M, Sieratzki J, Kurtz W, Hübner K. Gallstone dissolution with ursodeoxycholic acid in patients with chronic active hepatitis and two years follow-up. A pilot study. Dig Dis Sci 1985;30(7):642-9. https://doi.org/10.1007/BF01308413
  • 13. Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, et al. The Canadian multicentre double blind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 1994;19(5):1149-56. https://doi.org/10.1002/hep.1840190512.
  • 14. Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology 1999;29(4):1007-12. https://doi.org/10.1002/hep.510290444
  • 15. Gong Y, Huang ZB, Christensen E, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2008;(3):CD000551. https://doi.org/10.1002/14651858.CD000551.pub2
  • 16. Reichen J. Review: Ursodeoxycholic acid does not reduce risk for mortality or liver transplantation in primary cirrhosis. ACP J Club 2008;148(1):17. https://doi.org/10.7326/ACPJC-2008-148-1-017.
  • 17. Aycicek A, Tahtakesen TN, Bayram C. The effect of ursodeoxycholic acid and n-acetyl cysteine on lymphoblast viability. BCCR J 2021;13(1):55-62. https://doi.org/10.18502/bccr.v13i1.8829.
  • 18. Lindor KD, Kowdley KV, Luketic VAC, Harrison ME, McCashland T, Befeler AS, et al. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology 2009;50(3):808-14. https://doi.org/10.1002/hep.23082
  • 19. Rudolph G, Gotthardt D, Kloeters-Plachky P, Rost D, Kulaksiz H, Stiehl A. In PSC with dominant bile duct stenosis, IBD is associated with an increase of carcinomas and reduced survival. J Hepatol 2010;53(2):313-7. https://doi.org/10.1016/j.jhep.2010.02.030
  • 20. ALL IC-BFM 2009 A randomized trial of the I-BFM-SG for the management of childhood non-b acute lymphoblastic leukemia. Final Version of Therapy Protocol from August-14-2009. https://www.bialaczka.org/wp-content/uploads/2016/10/ALLIC_BFM_2009.pdf (Access Date: July 25, 2023)
  • 21. Uraz S, Tahan V, Aygun C, et al. Role of ursodeoxycholic acid in prevention of methotrexate-induced liver toxicity. Dig Dis Sci 2008;53(4):1071-7. https://doi.org/10.1007/s10620-007-9949-3
  • 22. Bordbar M, Shakibazad N, Fattahi M, et al. Effect of ursodeoxycholic acid and vitamin e in the prevention of liver injury from methotrexate in pediatric leukemia. Turk J Gastroenterol 2018;29(2):203-9. https://doi.org/10.5152/tjg.2018.17521
  • 23. Saif MM, Farid SF, Khaleel SA, Sabry NA, El-Sayed MH. Hepatoprotective efficacy of ursodeoxycholic acid in pediatrics acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2012;29(7):627-32. https://doi.org/10.3109/08880018.2012.713083
  • 24. Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM. Antioxidants and cancer therapy: A systematic review. J Clin Oncol. 2004;22(3):517-28. https://doi.org/10.1200/JCO.2004.03.086
  • 25. Moss RW. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants. Integr Cancer Ther 2006;5(1):63-82. https://doi.org/10.1177/153473540528
  • 26. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy. J Natl Cancer Inst. 2008;100(11):773-83. https://doi.org/10.1093/jnci/djn148.
  • 27. Robles-Diaz M, Nezic L, Vujic-Aleksic V. Role of ursodeoxycholic acid in treating and preventing idiosyncratic drug-induced liver injury. A systematic review. Front Pharmacol 2021;12:744488. https://doi.org/10.3389/fphar.2021.744488.
Toplam 27 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Çocuk Sağlığı ve Hastalıkları
Bölüm Araştırma Makalesi (Original Article)
Yazarlar

Özlem Terzi 0000-0002-8449-4778

Ali Ayçiçek 0000-0001-8951-4750

Duygu Yıldırgan 0000-0003-3511-0755

Hüseyin Avni Solgun 0000-0001-6811-4600

Sibel Tekgündüz 0000-0003-4937-1681

Cengiz Bayram 0000-0003-2153-0628

Yayımlanma Tarihi 28 Temmuz 2023
Gönderilme Tarihi 11 Ekim 2022
Kabul Tarihi 15 Mayıs 2023
Yayımlandığı Sayı Yıl 2023Cilt: 8 Sayı: 4

Kaynak Göster

APA Terzi, Ö., Ayçiçek, A., Yıldırgan, D., Solgun, H. A., vd. (2023). The role of ursodeoxycholic acid in the treatment of chemotherapy induced hepatotoxicity in the maintenance treatment of children with acute leukemia. Family Practice and Palliative Care, 8(4), 101-105. https://doi.org/10.22391/fppc.1186913
AMA Terzi Ö, Ayçiçek A, Yıldırgan D, Solgun HA, Tekgündüz S, Bayram C. The role of ursodeoxycholic acid in the treatment of chemotherapy induced hepatotoxicity in the maintenance treatment of children with acute leukemia. Fam Pract Palliat Care. Temmuz 2023;8(4):101-105. doi:10.22391/fppc.1186913
Chicago Terzi, Özlem, Ali Ayçiçek, Duygu Yıldırgan, Hüseyin Avni Solgun, Sibel Tekgündüz, ve Cengiz Bayram. “The Role of Ursodeoxycholic Acid in the Treatment of Chemotherapy Induced Hepatotoxicity in the Maintenance Treatment of Children With Acute Leukemia”. Family Practice and Palliative Care 8, sy. 4 (Temmuz 2023): 101-5. https://doi.org/10.22391/fppc.1186913.
EndNote Terzi Ö, Ayçiçek A, Yıldırgan D, Solgun HA, Tekgündüz S, Bayram C (01 Temmuz 2023) The role of ursodeoxycholic acid in the treatment of chemotherapy induced hepatotoxicity in the maintenance treatment of children with acute leukemia. Family Practice and Palliative Care 8 4 101–105.
IEEE Ö. Terzi, A. Ayçiçek, D. Yıldırgan, H. A. Solgun, S. Tekgündüz, ve C. Bayram, “The role of ursodeoxycholic acid in the treatment of chemotherapy induced hepatotoxicity in the maintenance treatment of children with acute leukemia”, Fam Pract Palliat Care, c. 8, sy. 4, ss. 101–105, 2023, doi: 10.22391/fppc.1186913.
ISNAD Terzi, Özlem vd. “The Role of Ursodeoxycholic Acid in the Treatment of Chemotherapy Induced Hepatotoxicity in the Maintenance Treatment of Children With Acute Leukemia”. Family Practice and Palliative Care 8/4 (Temmuz 2023), 101-105. https://doi.org/10.22391/fppc.1186913.
JAMA Terzi Ö, Ayçiçek A, Yıldırgan D, Solgun HA, Tekgündüz S, Bayram C. The role of ursodeoxycholic acid in the treatment of chemotherapy induced hepatotoxicity in the maintenance treatment of children with acute leukemia. Fam Pract Palliat Care. 2023;8:101–105.
MLA Terzi, Özlem vd. “The Role of Ursodeoxycholic Acid in the Treatment of Chemotherapy Induced Hepatotoxicity in the Maintenance Treatment of Children With Acute Leukemia”. Family Practice and Palliative Care, c. 8, sy. 4, 2023, ss. 101-5, doi:10.22391/fppc.1186913.
Vancouver Terzi Ö, Ayçiçek A, Yıldırgan D, Solgun HA, Tekgündüz S, Bayram C. The role of ursodeoxycholic acid in the treatment of chemotherapy induced hepatotoxicity in the maintenance treatment of children with acute leukemia. Fam Pract Palliat Care. 2023;8(4):101-5.
 Kapak Resmi İndir

Family Practice and Palliative Care      ISSN 2458-8865       E-ISSN 2459-1505