Study of compatibility of components of a new combined drug for treatment of alcoholic intoxication and its hepatoprotective effect on a model of alcoholic liver injury

Authors

DOI:

https://doi.org/10.15587/2519-4852.2021.249880

Keywords:

alcoholic hepatitis, effervescent powder, compatibility, physical and chemical properties, hepatoprotective effect

Abstract

The aim of the work is the development of a combined drug for use in alcohol intoxication based on the physicochemical properties and chemical compatibility of active pharmaceutical ingredients and excipients, and the study of the hepatoprotective effect in alcoholic hepatitis in rats.

Materials and methods. During the studies, physical and physicochemical methods were used, a Specord 200 spectrophotometer (Germany), analytical scales Sartorius (SARTORIUS, Germany), class A volumetric glassware and reagents that meet the requirements of the State Pharmacopoeia of Ukraine (SPhU). Alcoholic hepatitis in rats was reproduced by intragastric administration of an aqueous 40% ethanol solution at a dose of 7 ml/kg for 1 week.

Results. A new combined agent is proposed for use in alcohol intoxication in the form of an effervescent powder for the preparation of an oral solution, which contains glycine, L-glutamic acid, acetylsalicylic acid, ascorbic acid, fructose / sorbitol and sodium bicarbonate and citric acid to accelerate the dissolution of medicinal substances. To study the compatibility of the components, experimental studies of hygroscopicity, chemical interaction / chemical stability and an assessment of the redox potential of the proposed active pharmaceutical ingredients were carried out. To study the stability of the API, studies were carried out on sugaramine condensation due to the choice of amino acids and ascorbic acid in the composition of drugs. Based on the research results, it was decided to divide the API into 2 packages, separating sodium bicarbonate and glycine, which can interact with ascorbic acid / acetylsalicylic acid and ascorbic acid, respectively. In an in vivo experiment, it was found that the use of the new drug is accompanied by the normalization of the antioxidant-prooxidant status of the liver due to a likely decrease in the TBA-AP level and an increase in the RG index in the liver homogenate relative to the control group.

Conclusions. Evaluation of the physicochemical properties of API allowed us to propose a new combined drug (TS-PP) for use in alcohol intoxication in the form of an effervescent powder for the preparation of oral solution. In alcoholic hepatitis in rats, it was found that the use of the studied drug largely prevents the formation of the effects of the toxic effects of ethanol on the rat organism, which is manifested by inhibition of destruction of hepatocyte membranes, a decrease in the level of LPO products, restoration of the RG index and improvement of the protein synthesizing function of the liver due to the complex effect of amino acids and ascorbic acid contained in the product

Author Biographies

Olha Rudakova, National University of Pharmacy

Postgraduate Student,

Department of Pharmaceutical Chemistry

Lecturer

Cyclic Committee of Pharmaceutical Chemistry and Pharmacognosis

Svitlana Gubar, National University of Pharmacy

PhD, Associate Professor,

Department of Pharmaceutical Chemistry

Nataliia Smielova, National University of Pharmacy

PhD, Assistant

Department of Pharmaceutical Chemistry

Dmytro Lytkin, National University of Pharmacy

PhD, Vice-director

Educational and Scientific Institute of Applied Pharmacy

Tatiana Briukhanova, National University of Pharmacy

PhD, Assistant

Department of Biochemistry

Elena Bezchasnyuk, National University of Pharmacy

PhD, Head of Laboratory

State Research Laboratory for Quality Control of Medicines

Nataliia Bevz, National University of Pharmacy

PhD, Associate Professor

Department of Pharmaceutical Chemistry

Victoriya Georgiyants , National University of Pharmacy

Doctor of Pharmaceutical Sciences, Professor, Head of Department

Department of Pharmaceutical Chemistry

References

  1. Global status report on alcohol and health (2014). Geneva: WHO Press. Available at: https://apps.who.int/iris/bitstream/10665/112736/1/9789240692763_eng.pdf
  2. Shield, K. D., Parry, C., Rehm, J. (2006). Chronic diseases and conditions related to alcohol use. Alcohol research: current reviews, 35 (2), 155–171.
  3. Jesse, S., Bråthen, G., Ferrara, M., Keindl, M., Ben-Menachem, E., Tanasescu, R. et. al. (2016). Alcohol withdrawal syndrome: mechanisms, manifestations, and management. Acta Neurologica Scandinavica, 135 (1), 4–16. doi: http://doi.org/10.1111/ane.12671
  4. Attilia, F., Perciballi, R., Rotondo, C., Capriglione, I., Iannuzzi, S., Attilia, M. L. (2018). Alcohol withdrawal syndrome: diagnostic and therapeutic methods. Rivista di psichiatria, 53 (3), 118–122. doi: http://doi.org/10.1708/2925.29413
  5. Verster, J. C., Stephens, R., Penning, R., Rohsenow, D., McGeary, J., Levy, D. et. al. (2010). The Alcohol Hangover Research Group Consensus Statement on Best Practice in Alcohol Hangover Research. Current Drug Abuse Reviewse, 3 (2), 116–126. doi: http://doi.org/10.2174/1874473711003020116
  6. Adams, B., Ferguson, K. (2017). Pharmacologic Management of Alcohol Withdrawal Syndrome in Intensive Care Units. AACN Advanced Critical Care, 28 (3), 233–238. doi: http://doi.org/10.4037/aacnacc2017574
  7. Stefanova, A. V. (2002). Doklinicheskie issledovaniia lekarstvennykh sredstv. Kyiv: Avitsenna, 528.
  8. Mironova, A. N., Buniatian, N. D., Vasileva, A. N. et. al. (Eds.) (2012). Rukovodstvo po provedeniiu doklinicheskikh issledovanii lekarstvennykh sredstv. Part. 1. Moscow: Grif i K, 944.
  9. Pro zatverdzhennia Poriadku provedennia doklіnіchnogo vivchennia lіkarskikh zasobіv (2009). Nakaz MOZ Ukraini No. 944. 14.12.2009. Available at: https://zakon.rada.gov.ua/laws/show/z0053-10#Text
  10. Likarski zasoby. Nalezhna laboratorna praktyka (2009). Kyiv: Ministerstvo okhorony zdorovia Ukrainy, 27.
  11. Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 (2010). OJ L 276, 33–79.
  12. Kozhemiakin, Yu. M., Khromov, O. S., Filonenko, M. A., Saifetdinova, H. A. (2002). Naukovo-praktychni rekomendatsii z utrymannia laboratornykh tvaryn ta roboty z nymy. Kyiv: Avitsena, 196.
  13. Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M., Altman, D. G. (2010). Improving Bioscience Research Reporting: The ARRIVE Guidelines for Reporting Animal Research. PLoS Biology, 8 (6), e1000412. doi: http://doi.org/10.1371/journal.pbio.1000412
  14. Nair, A., Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 7 (2), 27–31. doi: http://doi.org/10.4103/0976-0105.177703
  15. Ellman, G. L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82 (1), 70–77. doi: http://doi.org/10.1016/0003-9861(59)90090-6
  16. Stalnaia, I. D., Garishvili, T. G. (1977). Metod opredeleniia malonovogo dialdegida s pomoschiu tiobarbiturovoi kisloty. Sovremennye metody v biokhimii, Moscow: Meditsina, 66–68.
  17. Khalafian, A. A. (2007). Statistica 6. Statisticheskii analiz dannykh. Moscow: OOO «Binom-Press», 512.
  18. Shokri-Kojori, E., Tomasi, D., Wiers, C. E., Wang, G.-J., Volkow, N. D. (2016). Alcohol affects brain functional connectivity and its coupling with behavior: greater effects in male heavy drinkers. Molecular Psychiatry, 22 (8), 1185–1195. doi: http://doi.org/10.1038/mp.2016.25
  19. Chourpiliadis, C., Mohiuddin, S. S. (2021). Biochemistry, Gluconeogenesis. Available at: https://www.ncbi.nlm.nih.gov/books/NBK544346/
  20. Ezequiel Leite, L., Nobre, M. J. (2012). The negative effects of alcohol hangover on high-anxiety phenotype rats are influenced by the glutamate receptors of the dorsal midbrain. Neuroscience, 213, 93–105. doi: http://doi.org/10.1016/j.neuroscience.2012.04.009
  21. Wilson, D. F., Matschinsky, F. M. (2020). Ethanol metabolism: The good, the bad, and the ugly. Medical Hypotheses, 140, 109638. doi: http://doi.org/10.1016/j.mehy.2020.109638
  22. Razvodovsky, Y. (2021). Hangover Syndrome: Pathogenesis and Treatment. International Archives of Substance Abuse and Rehabilitation, 3 (1). doi: http://doi.org/10.23937/2690-263x/1710009
  23. Marik, P. E., Liggett, A. (2019). Adding an orange to the banana bag: vitamin C deficiency is common in alcohol use disorders. Critical Care, 23 (1). doi: http://doi.org/10.1186/s13054-019-2435-4
  24. Lim, D. J., Sharma, Y., Thompson, C. H. (2018). Vitamin C and alcohol: a call to action. BMJ Nutrition, Prevention & Health, 1 (1), 17–22. doi: http://doi.org/10.1136/bmjnph-2018-000010
  25. Spoelstra-de Man, A. M. E., Elbers, P. W. G., Oudemans-van Straaten, H. M. (2018). Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury. Critical Care, 22 (1). doi: http://doi.org/10.1186/s13054-018-1996-y
  26. Royle, S., Owen, L., Roberts, D., Marrow, L. (2020). Pain Catastrophising Predicts Alcohol Hangover Severity and Symptoms. Journal of Clinical Medicine, 9 (1), 280. doi: http://doi.org/10.3390/jcm9010280
  27. Roze, M., Crucean, D., Diler, G., Rannou, C., Catanéo, C., Jonchère, C. et. al. (2021). Impact of Maltitol and Sorbitol on Technological and Sensory Attributes of Biscuits. Foods, 10 (11), 2545. doi: http://doi.org/10.3390/foods10112545
  28. Xiang, J., Liu, F., Wang, B., Chen, L., Liu, W., Tan, S. (2021). A Literature Review on Maillard Reaction Based on Milk Proteins and Carbohydrates in Food and Pharmaceutical Products: Advantages, Disadvantages, and Avoidance Strategies. Foods, 10 (9), 1998. doi: http://doi.org/10.3390/foods10091998
  29. Khoder, M., Gbormoi, H., Ryan, A., Karam, A., Alany, R. (2019). Potential Use of the Maillard Reaction for Pharmaceutical Applications: Gastric and Intestinal Controlled Release Alginate-Albumin Beads. Pharmaceutics, 11 (2), 83. doi: http://doi.org/10.3390/pharmaceutics11020083
  30. Newton, D. W. (2011). Maillard reactions in pharmaceutical formulations and human health. International Journal of Pharmaceutical Compounding, 15 (1), 32–40.
  31. Jayawardena, R., Thejani, T., Ranasinghe, P., Fernando, D., Verster, J. C. (2017). Interventions for treatment and/or prevention of alcohol hangover: Systematic review. Human Psychopharmacology: Clinical and Experimental, 32 (5), e2600. doi: http://doi.org/10.1002/hup.2600
  32. Dunn, W., Shah, V. H. (2016). Pathogenesis of Alcoholic Liver Disease. Clinics in Liver Disease, 20 (3), 445–456. doi: http://doi.org/10.1016/j.cld.2016.02.004
  33. Nagy, L. E., Ding, W.-X., Cresci, G., Saikia, P., Shah, V. H. (2016). Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes. Gastroenterology, 150 (8), 1756–1768. doi: http://doi.org/10.1053/j.gastro.2016.02.035
  34. Staudinger, H., Krisch, K., Leonhäuser, S. (1961). Role of ascorbic acid in microsomal electron transport and the possible relationship to hydroxylation reactions. Annals of the New York Academy of Sciences, 92 (1), 195–207. doi: http://doi.org/10.1111/j.1749-6632.1961.tb46119.x
  35. Defeng, W., Cederbaum, A. I. (2003). Alcohol, oxidative stress, and free radical damage. Alcohol Research & Health, 27 (4), 277–284.
  36. Cederbaum, A. I., Lu, Y., Wu, D. (2009). Role of oxidative stress in alcohol-induced liver injury. Archives of Toxicology, 83 (6), 519–548. doi: http://doi.org/10.1007/s00204-009-0432-0
  37. Cederbaum A. I. (2017). Role of Cytochrome P450 and oxidative stress in alcohol-induced liver injury. Reactive Oxygen Species, 4 (11), 303–319. doi: http://doi.org/10.20455/ros.2017.851
  38. Hausladen, A., Ruth, G. A. (2017). Glutathione. Antioxidants in higher plants. CRC Press, 1–30. doi: http://doi.org/10.1201/9781315149899-1

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Published

2021-12-30

How to Cite

Rudakova, O., Gubar, S., Smielova, N., Lytkin, D., Briukhanova, T., Bezchasnyuk, E., Bevz, N., & Georgiyants , V. (2021). Study of compatibility of components of a new combined drug for treatment of alcoholic intoxication and its hepatoprotective effect on a model of alcoholic liver injury. ScienceRise: Pharmaceutical Science, (6 (34), 91–100. https://doi.org/10.15587/2519-4852.2021.249880

Issue

No. 6 (34) (2021)

Section

Pharmaceutical Science

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Copyright (c) 2021 Olha Rudakova, Svitlana Gubar, Nataliia Smielova, Dmytro Lytkin, Tatiana Briukhanova, Elena Bezchasnyuk, Nataliia Bevz, Victoriya Georgiyants

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