Evaluation of the Impact of Repurposed Covid-19 Medications on some Biochemical Markers in Albino Wistar Rats


Authors : Obasuyi Grace Eleojo

Volume/Issue : Volume 10 - 2025, Issue 1 - January


Google Scholar : https://tinyurl.com/4hw3ueth

Scribd : https://tinyurl.com/33ez6ewn

DOI : https://doi.org/10.5281/zenodo.14716990


Abstract : The COVID-19 pandemic necessitated the rapid development and use of therapeutic drugs to combat the disease. However, concerns exist regarding the potential adverse effects of these drugs on metabolic processes like glucose homeostasis, renal function and bilirubin levels. This study aimed to evaluate the impact of chloroquine, hydroxychloroquine, ivermectin, azith romycin, lopinavir & ritonavir, zinc & selenium, which are recommended COVID- 19 drugs, on glucose metabolism, renal function (urea and creatinine levels) and bilirubin levels in Wistar rat model. About sixty (60) Wistar rats were randomly assigned to 9 treatment test groups and a control group (a total of 10 groups). The drugs were administered orally at clinically relevant doses for one month. Blood glucose, urea, creatinine and bilirubin assay was performed to assess glucose metabolism using the oxidase-peroxidase method, bilirubin by Evelyn and Malloy's method, urea and creatinine levels using urease berthe lot's and alkaline picrate method respectively. Data obtained was analyzed by the Statistical Package for Social Sciences (SPSS) software. The results showed that the group treated with hydroxychloroquine + azith romycin + lopinavir/ritonavir + ivermectin + zinc + selenium demonstrated a markedly elevated mean glucose level of 103.80 mg/dL (P = 0.001) compared to the control (83.83mg/dL), indicating a statistically significant impact on glucose metabolism. Analysis revealed no significant difference in urea and creatinine levels (p>0.05) among the different groups as p values were = 0.109 and 0.848 respectively. The hydroxychloroquine + azith romycin + lopinavir/ritonavir + ivermectin + zinc + selenium group showed markedly elevated glucose levels. The direct bilirubin of experimental animals across most treated groups was significantly elevated (p<0.05). Results also showed that total bilirubin was significantly higher (p<0.05) in animals treated with ivermectin (0.93±0.10) and Lopinavir-ritonavir (0.92±0.06) when compared to control (0.47±0.07) . In conclusion, patients who are being administered this drug combination (hydroxychloroquine + azith romycin + lopinavir/ritonavir + ivermectin + zinc + selenium) are at risk of developing diabetes mellitus and also further worsening the condition of diabetic patients. Also administration of these drugs may induce liver dysfunction, hyperbilirubinemia, drug-induced liver injury, drug-induced hepatitis and consequently jaundice. It is recommended to avoid the concurrent use of this specific drug combination unless the potential benefits outweigh the risks of hyperglycemia, the administration of these drugs adversely affected the synthetic and excretory functions of the liver and regular assessment of liver function parameters necessary.

References :

  1. Ahmed, S., Karim, M. M., Ross, A. G., Hossain, M. S., Clemens, J. D., Sumiya, M. K., Phru, C. S., Rahman, M., Zaman, K., Somani, J., Yasmin, R., Hasnat, M. A., Kabir, A., Aziz, A. B., and Khan, W. A. (2021). A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. InternationalJournalof Infectious Diseases, 103, 214–216.
  2. Albani, F., Fusina, F., Giovannini, A., Ferretti, P., Granato, A., Prezioso, C., Divizia, D., Sabaini, A., Marri, M., Mal petti, E., and Natal ini, G. (2020). Impact of Azith romycin  and/or   Hydroxychloroquine  on   Hospital   Mortality   in COVID-19. JournalofClinical Medicine, 9(9), 28-40.
  3. Al-Karmalawy,  A.A.,  Soltane,  R.,  Elmaaty,  A.A.,  Tantawy,  M.A.,  Antar,  S.A., Yahya, G., Chrouda, A., Pashameah, R.A., Mustafa, M. and Mraheil, M.A. Mostafa, A. (2021). Coronavirus disease (COVID-19) control between drug   repurposing   and   vaccination:   a   comprehensive   overview. Vaccines, 9 (11), 1317.
  4. Almazroo O.A., Miah M.K. and Venkataramanan R. (2017) Drug Metabolism in the Liver. Clinical Liver Disorders.;21(1):1-20.
  5. Alomar,  M.  J.  (2014).  Factors  affecting  the  development  of  adverse  drug reactions. Saudi PharmaceuticalJournal. 22(2): 83-94.
  6. Andersen,  K. G.,  Rambaut, A.,  Lipkin, W.  I.,  Holmes,  E. C., and Garry,  R.  F. (2020).          The     proximal origin of SARS-CoV-2.  Nature Medicine, 26(4): 450-452.
  7. Andreani, J., Le Bideau, M., Duflot, I., Jardot, P., Rolland, C., Boxberger, M., Wurtz, N., Rolain, J. M., Colson, P., La Scola, B., and Raoult, D. (2020). In vitro  testing  of  combined  hydroxychloroquine  and  azith romycin  on SARS-CoV-2  shows  synergistic  effect.  Microbial Pathogenesis,  145,104228.
  8. Ambrosino  P.,  Tarantino  L.,  Di  Minno  G.,  Paternoster  M.,  Graziano  V.  and Petitto M. (2017) The risk of venous thromboembolism in patients with cirrhosis.    A    systematic    review    and    meta-analysis. Thrombosis Haemostasis;117:139 – 148.
  9. Arabi, Y.M., Gordon, A.C., Derde, L.P.G., Nichol, A.D., Brunkhorst, F.M., Kali l, A.C.,   Alshamsi, F., Angus, D.C., Bajwa, E.K., Bauer, P.R., Belley-Cote, E., Brar, S.,       Bruzzone,      R., Burnham, E.L., Camporota, L., Coopersmith, C.M., den    Hollander, J.G., Detry, M.A., Diaz,  R.,  ...Baudouin,  S.V.  (2020).Azith romycin in hospitalized patients with COVID-19        (COALITION II): A randomized, double-blind, placebo-controlled trial. Lancet    Respiratory   Medicine,    9(6): 631-639
  10. Aronson J.K. and Ferner R.E.(2005) Clarification of terminology in drug safety. Drug Safety;28:851 –70.
  11. Bakheit, A. H., Al-Had iya, B. M., and Abd-Elgalil, A. A. (2014). Azith romycin. Profiles of Drug Substances, Excipients, and Related Methodology, 39, 1-40.
  12. Bakhsh, H. T. (2020). Hydroxychloroquine toxicity management: A literature review in COVID-19 era. Journalof Microscopy and Ultrastructure, 8(4),136-140.
  13. Bastard, J. P., Maachi, M., Lagathu, C., Kim, M. J., Caron, M., Vidal, H. and Fève, B. (2006).      Recent advances in the relationshipbetween obesity, inflammation, andinsulin resistance.      European Cytokine Network, 17(1):4-12.
  14. Batlle, D., Soler, M.J., Sparks, M.A., Hiremath, S., South, A.M., Welling, P.A.and Swaminathan, S. (2021). COVID-19 and ACE2 in Cardiovascular, Lung, and Kidney Working Group. Acute Kidney Injury in COVID-19: Emerging Evidence  of  a  Distinct  Pathophysiology.  Journal of the American Society of Nephrology, 31(7), 1380-1383.
  15. Ben-Zvi, I., Kivity, S., Langevitz, P., and Shoenfeld, Y. (2012). Hydroxychloroquine: from malaria to autoimmunity. Clinical Reviews in Alergy & Immunology, 42, 145-153.
  16. Bourgonje, A. R., Abdulle, A. E., and Timens, W. (2020). Angiotensin-converting enzyme 2 (ACE2), SARS-CoV-2, and the pathophysiology of coronavirus disease 2019 (COVID-19). The Journalof Pathology, 251(3), 228–248.
  17. Brookes,  E. M., and Power,  D. A. (2022). Elevated serum urea-to-creatinine ratio is associated with adverse inpatient clinical outcomes in non-end-stage chronic kidney disease. Scientific Reports, 12(1), 20827.
  18. Brown, S. M., Peltan, I., Kumar, N., Leither, L., Webb, B. J., Starr, N., Grissom, C. K., Buckel, W. R., Srivastava, R., Butler, A. M., Groat, D., Haaland, B., Ying, J.,   Harris,   E.,  Johnson,  S.,   Paine   III,   R.,  and  Greene,  T.  (2021). Hydroxychloroquine versus azith romycin for hospitalized patients with COVID-19: Results of a randomized, active comparator trial. Annals of the American Thoracic Society, 18(4), 590-597.
  19. Bugel, S., Larsen, E. H., Sloth, J. J., Flytlie, K., Overvad, K., Steenberg, L. C., and  Moesgaard, S. (2008). Absorption, excretion, and retention of selenium  from a high selenium yeast in men with a high intake of selenium. Food and Nutrition Research, 1, 52.
  20. Budweiser, S., Ba¸s, S., Jörres, R.A., Engelhardt, S., von Delius, S., Lenherr, K., Deerberg-Wittram,   J.   and   Bauer,   A.   (2021).   Patients’   treatment limitations  as  a predictive  factor  for  mortality  in  COVID-19:  Results from   hospitalized   patients   of   a   hotspot   region  for   SARS-CoV-2 infections. Respiratory Research, 22, 168.
  21. Bussaratid, V., Krudsood, S., Silachamroon, U., and Looareesuwan, S. (2005).  Tolerability of ivermectin in gnathostomiasis. Southeast Asian Journal ofTropical Medicine and Public Health, 36(3), 644-649.
  22. Cai  Q.,  Huang  D.,  Ou  P., Yu  H.,  Zhu  Z.  and  Xia  Z.,  (2020).  COVID-19  in  a designated infectious diseases hospital outside Hubei Province, China. Alergy;75(7):1742 – 1752.
  23. Cai Q., Huang D., Yu H., Zhu Z., Xia Z. and Su Y., (2020) COVID-19: Abnormal liver function tests. Journalof Hepatology;73(3):566 – 574.
  24. Callaway, E. (2021). Omicron's baroque mutation hierarchy. Nature, 600(7887): 15- 6.
  25. Caly, L., Druce, J. D., Catton, M. G., Jans, D. A., and Wagstaff, K. M. (2020). The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral         Research, 178: 104787: 1-4.
  26. Caly, L., Druce, J. D., Catton, M. G., Jans, D. A., and Wagstaff, K. M. (2020). The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research, 178, 780-787.
  27. Cantal uppi, V., Guglielmetti, G., Dellepiane, S., Marengo, M., Mehta, R.L. and  Ronco, C. (2020). A call to action to evaluate renal functional reserve in  patients   with   COVID-19.   American  Journal  of  Physiology-Renal Physiology, 319(5), 792-795.
  28. Cardoso,  C.  D.,  and  Bonato,  P. S.  (2005).  Enantioselective  analysis  of the metabolites  of  hydroxychloroquine  and  application  to  an  in  vitro metabolic study. Journal of Pharmaceutical and Biomedical Analysis, 37(4), 703-708.
  29. Carlson,  N.,  Nelveg-Kristensen,  K.E.,  Ballegaard,  E.,  Feldt-Rasmussen,  B.,  Hornum, M., Kamper, A.L., Gislason, G. and Torp-Pedersen, C. (2021).  Increased vulnerability to COVID-19 in chronic kidney disease. Journal of Internal Medicine, 290(1), 166-178.
  30. Cavalcanti, A. B., Zampieri, F. G., Rosa, R. G., Azevedo, L. C. P., Veiga, V. C., Avezum, A., Damiani, L. P., Marcadenti, A., Kawano-Dourado, L., Lisboa, T., Junqueira, D. L. M., de Barros E Silva, P. G. M., Tramujas, L., Abreu- Silva, E. O., Laranjeira, L. N., Soares, A. T., Echenique, L. S., Pereira, A. J., Freitas, F. G. R., Gebara, O. C. E., Dantas, V. C. S., Furtado, R. H. M., Milan, E. P., Gol in, N. A., Cardoso, F. F., Maia, I. S., Hoffmann Filho, C. R., Kormann, A. P. M., Amazonas, R. B., Bocchi de Oliveira, M. F., Serpa- Neto, A., Falavigna, M., Lopes, R. D., Machado, F. R., and Berwanger, O.; Coalition  Covid-19  Brazil  I  Investigators.  (2020).  Hydroxychloroquine with  or  without  Azith romycin  in   Mild-to-Moderate  Covid-19.   New EnglandJournalof Medicine, 383(21), 2041-2052.
  31. Cao, B., Wang, Y., Wen, D., Liu, W., Wang, J., Fan, G., Ruan, L., Song, B., Cai, Y.,  Wei, M., Li, X., Xia, J., Chen, N., Xiang, J., Yu, T., Bai, T., Xie, X., Zhang, L.,  Li, C., Yuan, Y., Chen, H., Li, H., Huang, H., Tu, S., Gong, F., Liu, Y., Wei, Y.,  Dong, C., Zhou, F., Gu, X., Xu, J., Liu, Z., Zhang, Y., Li, H., Shang, L., Wang,  K., Li, K., Zhou, X., Dong, X., Qu, Z., Lu, S., Hu, X., Ruan, S., Luo, S., Wu, J.,  Peng, L., Cheng, F., Pan, L., Zou, J., Jia, C., Wang, J., Liu, X., Wang, S., Wu, X., Ge, Q., He, J., Zhan, H., Qiu, F., Guo, L., Huang, C., Jak i, T., Hayden, F. G., Horby, P. W., Zhang, D., and Wang, C. (2020). A Trial of Lopinavir-  Ritonavir  in Adults  Hospitalized with Severe  Covid-19.  New England Journalof Medicine, 382(19), 1787– 1799.
  32. Carruthers, S. (2016). Zinc: Deficiency and toxicity. Practical Hydroponics and Greenhouses,1, 42-45.
  33. Centers for Disease Control and Prevention. (2021a). How COVID-19 Spreads. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/how-covidspreads.html
  34. Centers for Disease Control and Prevention. (2021b). Symptoms of COVID-19. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/symptoms.html
  35. Centers for Disease Control and Prevention. (2021c). Coughing and Sneezing.  https://www.cdc.gov/healthywater/hygiene/etiquette/coughing_sneezing.htm l
  36. Centers for Disease Control and Prevention. (2021d). Use Masks to Slow the Spread of COVID-19. https://www.cdc.gov/coronavirus/2019-ncov/prevent-  getting-sick/diy-cloth-face coverings.html
  37. Centers for Disease Control and Prevention. (2021e). Ventilation in Buildings. https://www.cdc.gov/coronavirus/2019-ncov/community/ventilation.html
  38. Centers for Disease Control and Prevention. (2021f). COVID-19 Vaccines. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/index.html
  39. Champney W.S. and Chittum H.S., (1995) Erythromycin inhibits the assembly of the large ribosomal subunit in growing Escherichia coli cells. Current Microbiology 30:273 –279
  40. Chary M., Barbuto A.F. and Izad mehr S. (2020) COVID-19: Therapeutics and Their Toxicities. Journalof MedicalToxicology 16: 284 –294.
  41. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., Qiu, Y., Wang J., Liu Y., Wei Y., Xia J., Yu T.,  Zhang X.  and Zhang  L.  (2020).  Epidemiological  and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. The Lancet, 395(10223), 507– 513.
  42. Chen, H., Guo, J., Wang, C., Luo, F., Yu, X., Zhang, W., Li, J., Zhao, D., Xu, D., Gong,  Q.,  Liao,  J., Yang,  H.,  Hou,  W.  and  Zhang Y.  (2020).  Clinical characteristics   and   intrauterine  vertical  transmission   potential  of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet, 395(10226), 809-815.
  43. Chen, J., Liu, D., Liu, L., Liu, P., Xu, Q., Xia, L., Ling, Y., Huang, D., Song, S., Zhang, D., Qian, Z., Li, T., Shen, Y., and Lu, H. (2020). [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang Da Xue Xue Bao Yi Xue Ban, 49(2), 215-219.
  44. Chen, N., Zhou, M., Dong, X., Qu, J., Gong, F., Han, Y., Qiu, Y., Wang, J., Liu, Y., Wei, Y., Xia, J., Yu, T., Zhang, X. and Zhang L. (2020). Epidemiological and  clinical  characteristics  of  99  cases  of  2019  novel  coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet, 395(10223),507-513.
  45. Cheng, Y., Luo, R., Wang, X., Wang, K., Zhang, N., Zhang, M., Wang, Z., Dong, L.,  Li, J., Zeng, R., Yao, Y., Ge, S. and Xu, G. (2020). The Incidence, Risk  Factors, and Prognosis of Acute Kidney Injury in Adult Patients with  Coronavirus Disease 2019. Clinical Journal ofthe American Society of Nephrology, 15(10), 1394-1402.
  46. C hey W.Y., Kosay S. and Siplet H. (1971). Observations on hepatic histology and  function  in  alcoholic  dogs.  Digest  Diseases  and Sciences  16, 825–838.
  47. Chi lvers, M., McKean, M., and Rutman, A. (2001). The effects of coronavirus on human nasal ciliated respiratory epithelium. European Respiratory Journal, 18(6), 965–970.
  48. Chou A.C. and Fitch C.D (1992): Heme polymerase: modulation by chloroquine treatment of rodent malaria. Life Sciences;51(26):2073-8.
  49. C hoy, K. T., Wong, A. Y. L., Kaewpreedee, P., Sia, S. F., Chen, D., Hui, K. P. Y.,  Chu, D. K. W., Chan, M. C. W., Cheung, P. P.-H., Huang, X., Peiris, M., and  Yen,      H.-L.      (2020).      Remdesivir,      lopinavir,      emetine,      and  homoharringtonine  inhibit  SARS-CoV-2  replication  in  vitro.  Antiviral Research, 178, 104-116.
  50. Clinton, J. W., Kiparizoska, S., Aggarwal, S., Woo, S., Davis, W. and Lewis, J. H. (2021).  Drug-induced  liver  injury:  highlights  and  controversies  in  the recent literature. Drug Safety. 2(1): 1-25.
  51. Coleman, J. E. (1998). Zinc enzymes. Current Opinion in Chemical Biology, 2(2), 222-234.
  52. Coronado, L. M., Nadovich, C. T., and Spadafora, C. (2014). Malarial hemozoin: from target to tool. Biochimica et Biophysica Acta, 1840(6), 2032-2041.
  53. Costanzo, M., De Giglio, M.A.R., and Roviello, G.N. (2020). SARS-CoV-2: Recent  reports    on    antiviral    therapies    based    on    Lopinavir/Ritonavir,  Darunavir/Umifenovir, Hydroxychloroquine, Remdesivir, Favipiravir and  other drugs for the treatment of the new coronavirus. Current Medicinal Chemistry, 27(27), 4536-4541
  54. Coronado L. M., Nadovich C. T. and Spadafora C. (2014). Malarial hemozoin: from target to tool. Biochimica etbiophysica acta, 1840(6), 2032–2041.
  55. Cousins R.J., Filer L.J., and Ziegler E.E.(1996) Present Knowledge in Nutrition. 7th  ed.  Washington  DC:  International  Life  Science  Institute  Nutrition Foundation. 18; 293 –306.
  56. Cui  J.,   Li   F.,  and  Shi  Z.L.   (2019)   Origin  and  evolution  of   pathogenic coronaviruses. Nature Reviews Microbiology 17  181  192.
  57. Crump, A., and Omura, S. (2011). Ivermectin, 'wonder drug' from Japan: the human use    perspective. Proceedings ofthe Japan Academy, Series B, 87(2):13-28.
  58. Cui,  J.,  Li,  F.,  and  Shi,  Z.  L.  (2019).  Origin  and  evolution  of  pathogenic coronaviruses. Nature Reviews Microbiology, 17(3), 181-192.
  59. Cummings,  M.J.,  Baldwin,  M.R.,  Abrams,  D.,  Jacobson,  S.D.,  Meyer,  B.J., Balough,  E.M.,  Aaron,  J.G.,  Claassen,  J.,  Rabbani,  L.E.,  Hastie,  J., Hoch man, B.R., Salazar-Schicchi, J., Yip, N.H., Brodie, D. and O'Donnell, M.R. (2020). Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in  New York City: a prospective cohort study. Lancet, 395(10239), 1763-1770.
  60. Damle, B., Vourvahis, M., Wang, E., Leaney, J., and Corrigan, B. (2020). Clinical Pharmacology  Perspectives on the Antiviral Activity of Azith romycin and Use in COVID-19. Clinical Pharmacology & Therapeutics, 108(2), 201-211.
  61. Della Porta, A., Bornstein, K., Coye, A., Montrief, T., Long, B., and Parris, M. A. (2020). Acute chloroquine and hydroxychloroquine toxicity: A review for emergency clinicians. The American Journal of Emergency Medicine, 38(10), 2209-2217.
  62. De Wit, E., van, D.N., Falzarano, D., and Munster, V.J. (2016) SARS and MERS: recent    insights    into    emerging    coronaviruses.    Nature   Reviews Microbiology, 14(8), 523-534.
  63. Descotes,  J.  (2021).  Medical  Safety  of  Ivermectin.  Expert  Review  Report. Immunosafe Consultance, 1, 120.
  64. Devaux, C. A., Rolain, J. M., Colson, P., and Raoult, D. (2020). New insights on the antiviral   effects of chloroquine against coronavirus: what to expect for COVID-19. International    JournalofAntimicrobialAgents, 55(5),   105938:1-12.
  65. Dinos G.  P., (2017). The macrolide antibiotic renaissance.  British journal of pharmacology174(18), 2967–2983.
  66. Diwaker, D., Mishra, K., and Janju, Z. (2013). Potential role of protein disulfide isomerase in viral infections. ActaVirologica, 57(3), 293–304.
  67. Doyno, C., Sobieraj, D. M., and Baker, W. L. (2021). Toxicity of chloroquine and  hydroxychloroquine  following  therapeutic  use  or  overdose.  Clinical Toxicology(Philadelphia, Pa.), 59(1), 12-23.
  68. Ducharme   J.,   and   Farinotti   R.,   (1996).   Clinical   p harmacokinetics   and  metabolism  of  chloroquine.  Focus  on  recent  advancements.  Clinical pharmacokinetics, 31(4), 257–274.
  69. Ducharme W., Zheng J. H., Cook J., Nicol M. R., Joshi, A., Rizk M.L., Sabato P. E. and   Savic,   R.   M.,   (2020).   P harmacokinetics   and   P harmacological Properties  of  Chloroquine  and  Hydroxychloroquine  in  the  Context  of COVID-19  Infection.  Clinical pharmacology and therapeutics,  108(6),1135– 1149.
  70. Ducharme,   J.,   and   Farinotti,   R.   (1996).   Clinical   p harmacokinetics   and  metabolism of chloroquine.  Focus on  recent advancements. Clinical Pharmacokinetics, 31(4), 257-274.
  71. Duran, J.  M., and Amsden,  G. W. (2020). Azith romycin:  indications for the future? Expert Opinion on Drug Delivery, 1, 489– 505.
  72. Edelstein, C.L., Venkatachalam, M A., Dong, Z. (2020). Autophagy inhibition by chloroquine  and  hydroxychloroquine  could  adversely  affect  acute kidney injury and other organ injury in critically ill patients with COVID- 19. Kidney International,98 (1), 234-235.
  73. Edwards G., Dingsdale A., Hels by N., Orme M. L. and Breckenridge A. (1988)  The relative systemic availability of ivermectin after administration as  a capsule,   tablet,   and   oral   solution.   European  Journal  of  Clinical Pharmacology; 35:681 – 684.
  74. Edwards I. R. and Aronson J. K. (2000). Adverse drug reactions: definitions, diagnosis, and management. The Lancet, 356(9237), 1255– 1259.
  75. Elmaaty, A. A., Darwish, K. M., Khattab, M., Elhady, S. S., Salah, M., Hamed, M. I. A.,  Al-Karmalawy,  A.  A.,  and  Saleh,  M.  M.  (2021).  In  a  search  for potential drug candidates for combating COVID-19: A computational study revealed salvianolic acid B as a potential therapeutic targeting 3CLpro  and  spike  proteins.  Journal of Biomolecular Structure and Dynamics, 39, 1 –28.
  76. Esson,  M.  L., and Sch rier,  R. W. (2002).  Diagnosis and treatment of acute tubular necrosis. Annals of Internal Medicine, 137(9), 744-752.
  77. Falcão  M.B.,  Pamplona  de  Góes  Cavalcanti  L.,  Filgueiras  Filho  N.M.  and Antunes  de  Brito  C.A.,  (2020)  Case  report:  Hepatotoxicity  associated with the use of hydroxychloroquine in a patient with COVID-19. American JournalofTropical Medicine and Hygiene.;102(6):1214 – 1216.
  78. Fan Z., Chen L., Li J., Cheng X., Yang J. and Tian C., (2020) Clinical features of COVID-19-related liver functional abnormality. Clinical Gastroenterology Hepatology.;18(7):1561 – 1566.
  79. Fantini, J., Cha h inian, H., and Yah i, N. (2020). Synergistic antiviral effect of hydroxychloroquine  and  azith romycin  in  combination  against  SARS- CoV-2:  What  molecular  dynamics  studies  of  virus-host  interactions reveal. InternationalJournalofAntimicrobialAgents, 56(2), 106-020.
  80. Fakree, N. K. (2015). Measurement of Serum Trace Elements (Zinc, Copper, Magnesium, and Iron) Concentrations in Pediatric Patients with Otitis Media with Effusion in Iraq. Iraqi Journal of Pharmaceutical Sciences, 24(2), 72-76.
  81. Faria, N. R., Mellan, T. A., Whittaker, C., Claro, I. M., Candido, D. D. S., Mishra, S.,           ...       and     Sabino,  E. C. (2021). Genomics and epidemiology of the P. 1 SARS- CoV-2lineage in      Manaus, Brazil. Science, 372(6544): 815-821.
  82. Feh r,  A.R.,  and  Perlman,  S.  (2015).  Coronaviruses:  an  overview  of  their replication and pathogenesis. Methods in Molecular Biology. 1282, 1-23.
  83. Fevery J. (2008).  Bilirubin  in clinical  practice: a  review.  Liver international : oficialjournal ofthe InternationalAssociationfor the Study ofthe Liver, 28(5), 592– 605.
  84. Fohner A. E., Sparreboom A., Altman R. B. and Klein T. E. (2017). P harmGKB summary: Macrolide antibiotic pathway, harmacokinetics/pharmacodynamics. genomics, 27(4), 164– 167.
  85. Pharmacogenetics and Foucquier,  J.,  &  Guedj,  M.  (2015).  Analysis  of  drug  combinations:  current methodological landscape. Pharmacology research&perspectives, 3(3).
  86. Fox   R.I.   (1993).   Mechanism   of   action   of   hydroxychloroquine   as   an antirheumatic drug. Seminars in arthritis andrheumatism, 23; 82 –91.
  87. Furst D. E. (1996). P harmacokinetics of hydroxychloroquine and chloroquine during  treatment  of  rheumatic  diseases.  Lupus5 Supplements  1, S11 –S15.
  88. Furst, D. E. (1996). P harmacokinetics of hydroxychloroquine and chloroquine during treatment of rheumatic diseases. Lupus, 5(Suppl 1), S11-S15.
  89. Gaisser, S.,  Kellenberger,  L.,  Kaja, A.  L., Weston, A. J.,  Lill,  R.  E., Wirtz,  G., Kendrew, S. G., Low, L., Sheridan, R. M., Wilkinson, B., Galloway, I. S., Stutzman-Engwall, K., McArthur, H. A., Staunton, J., and Leadlay, P. F. (2003).   Direct   production   of   ivermectin-like   drugs   after   domain exchange  in  the  avermectin  poly ketide  synthase  of  Streptomyces avermitil is  ATCC31272.  Organic and Biomolecular Chemistry,  1(16), 2840-2847.
  90. Gao, J., Tian, Z., and Yang, X. (2020). Breakthrough: Chloroquine phosphate has   shown   apparent   efficacy   in   treating   COVID-19-associated pneumonia in clinical studies. Bioscience Trends, 14(1), 72-73.
  91. Gautret,  P.,  Lagier,  J.  C.,  Parola,  P.,  Hoang, V. T.,  Meddeb,  L.,  Mailhe,  M., Doud ier, B., Courjon, J., Giordanengo, V., Vieira, V. E., Tissot Dupont, H., Honoré, S., Colson, P., Cha briè re, E., La Scola, B., Rolain, J. M., Brouqui, P., and Raoult, D. (2020). Hydroxychloroquine and azith romycin as a treatment  of  COVID-19:  Results  of  an  open-label  non-randomized clinical trial. InternationalJournal ofAntimicrobialAgents, 56(1), 1059-1069.
  92. Gautret, P., Lagier, J. C., Parola, P., Hoang, V. T., Meddeb, L., Mailhe, M., Doud ier, B., Courjon, J., Giordanengo, V., Vieira, V. E., Tissot Dupont, H., Honoré, S., Colson, P., Cha briè re, E., La Scola, B., Rolain, J. M., Brouqui, P. and Raoult D.  (2020).  Hydroxychloroquine  and  azith romycin  as  a  treatment  of COVID-19:   results   of   an   open-label   non-randomized   clinical   trial. Internationaljournalofantimicrobialagents, 56(1), 105949.
  93. General Office of  National Health Commission of the  People’s  Republic of China. (2020). Diagnosis and treatmentfor novel coronavirus (Version 5). NHC. http://www.nhc.gov.cn/xcs/zhengcwj/202002/3b09b894ac9b4204a79db5b8912d4440.shtml
  94. Giovanetti, M., Benedetti, F., Campisi, G., Ciccozzi, A., Fabris, S., Ceccarelli, G., Tambone, V., Caruso, A., Angeletti, S., Zella, D., and Ciccozzi, M. (2021). Evolution patterns of SARS-CoV-2: Snapshot on its genome variants. Biochemicaland Biophysical ResearchCommunications. 538, 88-91.
  95. Gowda, S., Desai, P. B., Kulkarni, S. S., Hull, V. V., Math, A. A., and Vernekar, S.  N. (2010). Markers of renal function tests. North American Journal of MedicalSciences, 2(4), 170.
  96. Goldfine, A. B., Bouche, C., Parker, R. A., Kim, C., Kerridge, D., Soeldner, J. S., ... and     Greenfield, M. S. (1972). Insulin andglucagon—their roles in the regulation ofglucose         production  and utilization  in  man.  Metabolism, 21(8): 643-658.
  97. Goldman J.D., Lye C.B., Hui D.S., Marks K.M., Bruno R. and Montejano R. (2020) Remdesivir  for  5  or  10  days  in  patients  with  severe  COVID-19.  New EnglandJournalof Medicine;383(19):1827 – 1837.
  98. González Canga, A., Sahagú n Prieto, A. M.,  Diez  Liébana,  M. J.,  Ferná ndez Martínez,       N., Sierra       Vega,  M.,  and  García  Vieitez,  J.  J.  (2008).  The p harmacokinetics and interactions of     ivermectin in humans — a mini-review. The AAPS    Journal, 10(1): 42-46
  99. Greenhalgh,  T.,  Jimenez,  J.  L.,  Prather,  K. A.,  Tufe kci,  Z.,  Fisman,  D.,  and Schooley,      R. (2021).      Ten  scientific   reasons   in  support   of   airborne transmission of       SARS-CoV-2. The Lancet,   397(10285): 1603-1605.
  100. Greenwood,   D.   (1995).   Conflicts   of   interest:  the   genesis   of   synthetic  antimalarial   agents   in   peace   and  war.  Journal of Antimicrobial Chemotherapy, 36 (5), 857-872, 1995
  101. Grein J., Oh magari N, S hin D., Diaz G., Asperges E. and Castagna A. (2022). Compassionate  use  of  Remdesivir  for  patients  with  severe  Covid-19. New EnglandJournalof Medicine;382(24):2327 –2336.
  102. Guan W., Ni Z. and Hu Y. (2020) Clinical Characteristics of Coronavirus Disease 2019 in China, The Journalof Emergency Medicine, 58(4), 711–712.
  103. Guan, W.J., Ni, Z.Y., Hu, Y., Liang, W.H., Ou, C.Q., He, J.X, Liu, L., Shan, H., Lei, C.L., Hui, D.S.C., Du, B., Li, L.J., Zeng, G., Yuen, K.Y., Chen, R.C., Tang, C.L., Wang, T., Chen, P.Y., Xiang, J., Li, S.Y., Wang, J.L., Liang, Z.J., Peng, Y.X., Wei, L., Liu, Y., Hu, Y.H., Peng, P, Wang, J.M., Liu, J.Y., Chen, Z., Li, G., Zheng, Z.J., Qiu, S.Q., Luo, J., Ye, C.J., Zhu, S.Y. and Zhong, N.S. (2020).   Clinical   Characteristics   of   Coronavirus   Disease   2019   in China.The New EnglandJournalof Medicine, 382(18), 1708-1720.
  104. Guerin, V.,  Levy,  P., Thomas, J.  L.,  Lardenois, T.,  Lacrosse,  P., Sarrazin,  E., Andreis,    N.    R.    and    Wonner,    M.    (2020).    Azith romycin    and Hydroxychloroquine    Accelerate    Recovery    of    Outpatients    with Mild/Moderate COVID-19. Asian Journal of Medicine and Health, 18(7),45– 55.
  105. Gulich,  M.  P., Yemchenko,  N.  L.,  Kaplinenko, V.  G.,  and  Kharchenko,  O.  O. (2023). Trace Elements Zinc and Selenium: Their Significance in the Conditions of the Covid-19 Pandemic. Mikrobiolohichnyi Zhurnal, 85(1),36-45.
  106. Gupta,  S.,  Coca,  S.G.,  Chan,  L.,  Melamed,  M.L.,  Brenner,  S.K.,  Hayek,  S.S., Sutherland, A., Puri, S., Srivastava, A., Leonberg-Yoo, A., She hata, A.M., Flythe, J.E., Rashid i, A., Schenck, E.J., Goyal, N., Hedayati, S.S., Dy, R., Bansal,  A.,  Athavale,  A.,  Nguyen,  H.B.,  Vijayan,  A.,  Charytan,  D.M., Schulze, C.E., Joo, M.J., Friedman, A.N., Zhang, J., Sosa, M.A., Judd, E., Velez, J.C.Q., Mallappallil, M., Redfern, R.E., Bansal, A.D., Neyra, J.A., Liu, K.D., Renaghan, A.D., Christov, M., Mol nar, M.Z., Sharma, S., Kamal, O., Boateng, J.O, Short, S.A.P., Admon, A.J., Sise, M.E., Wang, W., Parikh, C.R.  and  Leaf,  D.E.  (2021).  AKI  Treated  with  Renal  Replacement Therapy in Critically Ill Patients with COVID-19. Journalofthe American Society of Nephrology. 32(1), 161-176.
  107. Guseynova, S. A. (2019). Oxidative metabolism of sodium selenite in isolated human erythrocytes in vitro. Biomedicine, 3(17), 18–23.
  108. Habibzadeh, P. and Stoneman, E.K. (2020). The novel coronavirus: A bird's eye  view.     International   Journal   of    Occupational    Medicine    and Environmental Health. 11, 65-71.
  109. Hassan,  S.A.,  Sheikh,  F.N.,  Jamal,  S.,  Ezeh,  J.K.,  and  Akhtar,  A.  (2020). Coronavirus (COVID- 19): a review of clinical features, diagnosis, and treatment. Cureus 12, e7355.
  110. Hasöksüz, M., Kiliç, S. and Saraç, F. (2020) Coronaviruses and SARS-COV-2. TurkishJournalof MedicalSciences, 50, 549-556.
  111. Hanafy,  A.  S.  and  Abd-Elsalam,  S.  (2020).  Challenges  in  COVID-19  drug treatment   in  patients  with  advanced   liver  diseases:  A   hepatology perspective. WorldJournalofGastroenterology. 26(46): 7272.
  112. Hank ins, J. (2006). The role of albumin in fluid and electrolyte balance. Journal of  Infusion Nursing. 29(5): 260-265.
  113. Haroun, A. A., Bashandy, M. A., and Hussein, A. S. (2023). A Novel Study on  the Hematological and Physiological Disturbance of Ivermectin-COVID-  19 Treatment Abuse in Male Wistar Rats. Egyptian Academic Journal of BiologicalSciences. C, Physiology and Molecular Biology, 15(2), 1-10.
  114. Hegazi, A., Abet, R., Thomas, R. A., Brock, P. M., and Rotondo, L. (2021).
  115. Lopinavir/ritonavir      p harmacokinetics in HIV-positive and HIV-negative: A Systematic Review And    Meta-Analysis. Pharmaceuticals, 14(5), 441, 20.
  116. Her M., Lee Y., Jung E., Kim T. and Kim D. (2011) Liver enzyme abnormalities in systemic lupus erythematosus: a focus on toxic hepatitis. Rheumatology International;31(1):79 –84.
  117. Heuberger J., Schmidt S. and  Derendorf  H. (2013) When is  Protein  Binding Important? Journalof Pharmaceutical. Sciences; 102:3458 –3467.
  118. Heidary, F., and Gharebagh i, R. (2020). Ivermectin: a systematic review from  antiviral effects to COVID-19 complementary regimen. The Journal of Antibiotics, 73(9), 593-602.
  119. Hirsch, J.S., Ng, J.H., Ross, D.W., Sharma, P., Shah, H.H., Barnett, R.L., Hazzan, A.D.,   Fishbane,  S.   and  J haveri   K.D.   (2020).   Northwell   COVID-19 Research   Consortium;   Northwell   Nephrology   COVID-19   Research Consortium. Acute kidney injury in patients hospitalized with COVID-19. Kidney International, 98(1), 209-218.
  120. Hopper,  K., Aldrich, J., and  Haskins, S. C. (2002).  Ivermectin toxicity  in  17 collies. JournalofVeterinary Internal Medicine, 16(1), 89-94.
  121. Huang,  C.,  Wang,  Y.,  Li,  X.,  Ren,  L.,  Zhao,  J.,  Hu,  Y.  and  Cao,  B.  (2020). Clinical features of  patients infected with 2019 novel coronavirus in Wuhan, China.  The Lancet, 395(10223):    497-506.
  122. Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y, Gao, H., Guo, L., Xie, J., Wang, G., Jiang, R., Gao, Z., Jin, Q., Wang, J. and Cao, B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet, 395(10223), 497-506.
  123. Huang, M., Tang, T., Pang, P., Li, M., Ma, R., Lu, J., Shu, J., You, Y., Chen, B.,  Liang, J., Hong, Z., Chen, H., Kong, L., Qin, D., Pei, D., Xia, J., Jiang, S.,  and Shan, H. (2020). Treating COVID-19 with Chloroquine. Journal of Molecular CelBiology, 12(4), 322-325.
  124. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., Cheng Z., Yu T., Xia J., Wei Y., Wu W., Xie X., Yin W., Li H., Liu M., Xiao Y. and Cao B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet(London, England), 395(10223), 497– 506.
  125. Hur,  K.  H.,  Park,  K.,  Jung,  H.,  and  Kim,  K.  W.  (2021).  Hypoglycemia  and potential spontaneous intestinal  absorption  of   remdesivir.  Journal of Korean Medical      Science, 36(1), 10: 1-4.
  126. Huseynov, T.M.,  Gulieva,  R.T.,  and Yakhnyaeva,  F.A.  (2020). The  biological significance   of   selenium   and   its   place   in   RNA —viral   diseases. Mycoelements in medicine. 21(4), 21—31.
  127. Imamura, Y., Higashiyama, Y., Tomono, K., Izumikawa, K., Yanagihara, K., Ohno, H.,  Miyazaki, Y.,  Hirakata, Y.,  Mizuta, Y.,  Kadota, J.,  Iglewski,  B.  H.,  & Koh no,   S.   (2005).   Azith romycin   exhibits   bactericidal   effects   on Pseudomonas aeruginosa through interaction with the outer membrane. Antimicrobialagents andChemotherapy, 49(4), 1377– 1380.
  128. Jermain, B., Hanafiah, R. M., and Israf, D. A. (2020). Ivermectin targets the protein responsible for    SARS-CoV-2    maturation    in    host    cells.    Signal Biosciences, P harmaBioRxiv.
  129. Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., Zhang, B., Li, X., Zhang, L., Peng, C., Duan, Y., Yu, J., Wang, L., Yang, K., Liu, F., Jiang, R., Yang, X., You, T., Liu, X., Yang, X., Bai, F., Liu, H., Liu, X., Guddat, L. W., Xu, W., Xiao, G., Qin, C., Shi, Z., Jiang, H., Rao, Z., and Yang, H. (2020). Structure of Mpro from SARS-CoV-2 and discovery of  its  inhibitors.  Nature,  582(7811), 289-293.
  130. Kamal, A. (2014). Estimation of blood urea (BUN) and serum creatinine level in  patients of renal disorder. Indian Journal of Fundamental and Applied Life Sciences, 4(4), 199-202.
  131. Kashani,  K.,  Rosner,  M.  H.,  and  Ostermann,  M.  (2020).  Creatinine:  from  physiology   to   clinical   application.   European  Journal  of  Internal Medicine, 72, 9-14.
  132. Kesteloot,  H.  E.,  and Joossens, J. V.  (1993).  Relationship  between dietary protein intake and serum urea, uric acid and creatinine, and 24-hour urinary creatinine excretion: the BIRNH Study. Journal ofthe American Colege of Nutrition, 12(1), 42-46.
  133. Keyaerts, E., Vijgen, L., Maes, P., Neyts, J., and Van Ranst, M. (2004). In vitro inhibition   of   severe   acute   respiratory   syndrome   coronavirus   by chloroquine. Biochemical and Biophysical Research Communications, 323(1), 264-268.
  134. Kiel iszeka,  M.,  and  Lipinski,  B.  (2020).  Selenium  supplementation  in  the prevention of coronavirus infection (COVID-19). Medical Hypotheses,143, 109878.
  135. King, A.M.Q., Adams,  M.J., Carstens  E.B., and Lefkowitz,  E.J. (2012). Virus Taxonomy. Ninth Report of the International Committee on Taxonomy of Viruses. Elsevier, pp. 770–783.
  136. Kleinnijenhuis J, Quintin J, Preijers F, Benn, C.S., Joosten, L.A., Jacobs, C., van Loenhout J., Xavier, R.J., Aaby, P., van der Meer, J.W., van Crevel, R., and  Netea,  M.G.  Long-lasting  effects  of  BCG  vaccination  on  both heterologous   Th1/Th17   responses   and   innate   trained   immunity. Journalof Innate Immunity. 6(2), 152-158.
  137. K lotz  U.,  Ogbuokiri J.  E.,  Okonkwo  P.  O.  (1990)  Ivermectin  binds  avidly to  plasma          proteins.          European.         Journal        of        Clinical Pharmacology.;39:607 – 608.
  138. Koyner, J. L. (2012). Assessment and diagnosis of renal dysfunction in the ICU. Chest, 141(6), 1584-1594.
  139. Kuderer, N. M., Choueiri, T. K., Shah, D. P., Shyr, Y., Rubinstein, S. M., Rivera, D.  R., Shete, S.,  Hsu,  C. Y.,  Desai, A., de  Lima  Lopes,  G. Jr,  Grivas,  P.,  Painter, C. A., Peters, S., Thompson, M. A., Bakouny, Z., Batist, G., Bekaii  -Saab, T., Bilen, M. A., Bouganim, N., Larroya, M. B., Castellano, D., Del  Prete, S. A., Doroshow, D. B., Egan, P. C., Elkrief, A., Farmakiotis, D.,  Flora, D., Galsky, M. D., Glover, M. J., Griffiths, E. A., Gulati, A. P., Gupta,  S., Hafez, N., Halfdanarson, T. R., Hawley, J. E., Hsu, E., Kasi, A., Khaki, A.
  140. R., Lemmon, C. A., Lewis, C., Logan, B., Masters, T., McKay, R. R., Mesa, R. A.,  Morgans,  A.  K.,  Mulcahy,  M.  F.,  Panagiotou,  O. A.,  Peddi,  P., Pennell,  N. A.,  Reynolds,  K.,  Rosen,  L.  R.,  Rosovsky,  R.,  Salazar,  M., Schmidt, A., Shah, S. A., Shaya, J. A., Steinharter, J., Stockerl-Goldstein, K. E., Subbiah, S., Vinh, D. C., Wehbe, F. H., Weissmann, L. B., Wu, J. T., Wulff-Burchfield,  E., Xie, Z., Yeh, A., Yu,  P.  P., Zhou, A. Y., Zub iri,  L., Mishra,  S.,  Lyman,  G.  H.,  Rini,  B.  I.,  and  Warner,  J.  L.  and  Cancer Consortium.  (2020).  Clinical  impact  of  COVID-19  on  patients  with cancer (CCC19): a cohort study. The Lancet, 395(10241), 1907-1918.
  141. Kulkarni  A.V.,  Kumar  P.,  Tevethia  H.V.,  Premkumar  M.,  Arab  J.P.,  Candia R.(2020).     preview   with    meta-analysis:    liver    manifestations    and outcomes in COVID-19. AlimentPharmacolTher.;52(4):584 – 599.
  142. Kwiek, J. J., Haystead, T. A. J., and Rudolph, J. (2004). Kinetic mechanism of quinone   oxidoreductase   2   and   its   inhibition   by  the   antimalarial quinolines. Biochemistry, 43, 4538–4547.
  143. Lam, S., Lombardi, A. and Ouanounou, A. (2020). COVID-19: A review of the  proposed     pharmacological     treatments.     European    Journal    of Pharmacology. 886(1): 173451.
  144. Lai, C.-C., Shih, T.-P., Ko, W.-C., Tang, H.-J., and Hsueh, P.-R. (2020). Severe acute    respiratory    syndrome    coronavirus    2    (SARS-CoV-2)    and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. InternationalJournalofAntimicrobialAgents, 55, 105924.
  145. Lalak, N. J., and Morris, D. L. (1993). Azith romycin clinical p harmacokinetics. Clinical Pharmacokinetics, 25, 370–374.
  146. Lammert C., Einarsson S., Saha C., Niklasson A., Bjornsson E., and Chalasani N. (2008).   Relationship   between  daily  dose  of  oral   medications  and idiosyncratic  drug-induced  liver  injury:  search  for  signals.  Hepatology (Baltimore, Md.), 47(6), 2003–2009.
  147. Lauer S. A., Grantz K. H., Bi Q., Jones F. K., Zheng Q., Meredith H. R., Azman A.  S.,  Reich  N.  G.,  and  Lessler  J.  (2020).  The  Incubation  Period  of  Coronavirus    Disease    2019    (COVID-19)    From    Publicly    Reported  Confirmed   Cases:   Estimation   and   Application.   Annals  of  internal medicine, 172(9), 577– 582.
  148. Lefkowitz, E.J., Dempsey, D.M., Hendrickson, R.C., Orton, R.J., Siddell, S.G. and Smith, D.B. (2018). Virus taxonomy: the database of the International Committee on Taxonomy of Viruses (ICTV). Nucleic Acids Research, 46(1), 708-717.
  149. Lemke C. T., Titolo S., Von Schwedler U., Goudreau N., Mercier J. F., Ward rop E., Faucher A. M., Coulombe R., Banik S. S., Fader L., Gagnon A., Kawai S. H., Rancourt  J.,  Tremblay  M.,  Yoakim  C.,  Simoneau  B.,  Archambault  J., Sundquist W. I., and Mason S. W. (2012). Distinct effects of two HIV-1 capsid assembly inhibitor families that bind the same site within the N-terminal  domain  of  the  viral  CA  protein.  Journal of virology86(12), 6643– 6655.
  150. Liao, Z.-M., Zhang, Z.-M., and Liu, Q. (2022). Hydroxychloroquine/chloroquine and the risk of acute kidney injury in COVID-19 patients: A systematic review and meta-analysis. Renal Failure, 44(1), 415-425.
  151. Li, C.K.F. and Xu, X.N. (2010). Host immune responses to SARS coronavirus in humans. In: Lal SK (Ed.), Molecular Biology of the SARS-Coronavirus. Springer, pp259-278.
  152. Li,  G.D.  and de  Clercq,  E.,  (2020). Therapeutic options for the 2019  novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery, 19(3), 149-150.
  153. Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY,  Wong JY, Xing Miller, A., Reande lar, M. J., Fasciglione, K., Roumenova,  V. and  Li, Y.  (2020).  Correlation  between  universal  BCG vaccination  policy   and   reduced   morbidity   and   mortality   for   COVID-19:   An  epidemiological   study.   African  Journal  of  Biology  and  Medical Research, 3(2), 15-19.
  154. Li, Q., Guan, X., Wu, P., Wang, X., Zhou, L., Tong, Y., Ren, R., Leung, K.S.M., Lau, E.H.Y., Wong, J.Y., Xing, X., Xiang, N., Wu, Y., Li, C., Chen, Q., Li, D., Liu, T., Zhao, J., Liu, M., Tu, W., Chen, C., Jin, L., Yang, R., Wang, Q., Zhou, S., Wang, R., Liu, H., Luo, Y., Liu, Y., Shao, G., Li, H., Tao, Z., Yang, Y., Deng, Z., Liu, B., Ma, Z., Zhang, Y., Shi, G., Lam, T.T.Y., Wu, J.T., Gao, G.F., Cowling,  B.J.,  Yang,  B.,  Leung,  G.M.,  and  Feng,  Z.  (2020).  Early Transmission   Dynamics   in  Wuhan,   China,   of   Novel   Coronavirus-Infected  Pneumonia.The New England Journal of Medicine, 382(13),1199-1207.
  155. Lontchi-Yachen,  E.,  and  Cavayas, Y. A.  (2021).  Drugs for the treatment  of  COVID-19:     How   inflammation could induce glucose disorders. Journal of Diabetes and          Metabolic     Disorders, 20(1): 701-712.
  156. Loos,  N.  H.,  Beijnen,  J.  H.,  and  Schinkel, A.  H.  (2023). The  inhibitory  and inducing effects of ritonavir on hepatic and intestinal CYP3A and other drug-handling proteins. Biomedicine & Pharmacotherapy, 162, 114-136.
  157. Majeed, M., Nagabhushanam, K., Arumugam, S., Beede, K., and Ali, F. (2022). Zinc and selenium  metabolic  regulation  and  its  association with immune modulation in coronavirus    disease    2019    (COVID-19)- insights and perspectives. Nutrition Research      Reviews: 1-16.
  158. Mayxay,   M.,   Khanthavong,   M.,   Lindegå rdh,   N.,   Keola,   S.,   Barends,   M., Pongvongsa, T., Yapom, R., Annerberg, A., Phompida, S., Phetsouvanh, R., White, N. J., and Newton, P. N. (2004). Randomized comparison of chloroquine  plus  sulfadoxine-pyrimethamine  versus  artesunate  plus mefloquine   versus   artemether-lumefantrine   in   the   treatment   of uncomplicated  falciparum  malaria  in  the  Lao  People's  Democratic Republic. Clinical Infectious Diseases, 39(8), 1139-1147.
  159. Meece,  J.  (2020).  Caution  with   Hydroxychloroquine  and   Hypoglycemia. ADCES in Practice, 8(3), 41-41.
  160. Meini,  S.,  Pagotto, A.,  Longo,  B., Vend ramin,  I.,  Pecori,  D.,  and Tascini,  C. (2020).  Role  of  Lopinavir/Ritonavir  in  the  treatment  of  Covid-19:  a review    of    current    evidence,    guideline    recommendations,    and perspectives. JournalofClinical Medicine, 9(7), 2050.
  161. Merriman, R. B. and Peters, M. G. (2008). Approach to the patient with jaundice. Principles ofClinicalGastroenterology. 2(1): 422-441.
  162. Michiels, C., Raes, M., Toussaint, O., and Remacle, J. (1994). Importance of Se -glutathione  peroxidase,  catalase,  and  Cu/Zn-SOD  for  cell  survival against oxidative stress. Free Radical Biology and Medicine, 17(3), 235-248.
  163. Miller, A., Reande lar, M.J., Fasciglione, K., Roumenova, V., Li, Y., and Otazu, G. H  (2020)  Correlation  between  universal  BCG vaccination  policy  and reduced  morbidity  and  mortality  for  COVID-19:  An  epidemiological study. medRxiv.
  164. Mohan,  B. S. and Vinod,  N.  (2020). COVID-19: An  Insight  into SARS-CoV-2  Pandemic Originated at Wuhan City in Hubei Province of China. Journal of Infectious Diseases and Epidemiology, 6(4), 146-154.
  165. Mota  I.,  Gaspar  Â .,  Benito-Garcia  F.,  Correia  M.,  Chambel  M.,  and  Morais- Almeida  M.  Drug-induced anaphylaxis: seven-year single-center survey. European    Annals    of    Allergy    and     Clinical     Immunology.,     2018 Sep;50(5):211-216.
  166. Munster, V.J.,  Koopmans,  M., van  Doremalen,  N., van  Riel,  D. and de Wit  E. (2020).  A  Novel  Coronavirus  Emerging  in  China  -  Key  Questions  for Impact Assessment.  New England Journal of Medicine,  382(8),  692-694.
  167. Murdaugh  HV Jr, Schmidt-Nielsen  B,  Doyle  EM,  and  O'Dell  R.  (1958).  Renal  tubular   regulation   of   urea   excretion   in   man.   Journal of Applied Physiology, 13(2), 263-268.
  168. Nank ivell,  B.  J.  (2001).  Creatinine  clearance  and  the  assessment  of  renal function. Australian Prescriber, 24(1).
  169. Nardo, A. D., Sch neeweiss‐ G leixner, M., Bakail, M., Dixon, E. D., Lax, S. F. and Trauner,  M.  (2021).  Pathophysiological  mechanisms  of  liver  injury  in COVID‐ 19. Liver International. 41(1): 20-32.
  170. National  Health  Commission  of  the  People’s  Republic  of  China.  (2020). Interpretation  of  COVID-19  Treatment  Guidelines  (6th  version). Retrieved                    from                     http://www.gov.cn/zhengce/2020- 02/19/content_5480958.htm
  171. Navarro,  M.,  Camprubí,  D.,  Requena-Mendez,  A.,  Buonf rate,  D.,  Giorli,  G., Kamgno,          J. and Brito, M. (2020). Safety of high-dose ivermectin: a systematic review and meta-analysis.       The Journal of Antimicrobial Chemotherapy, 75(4): 827-834.
  172. Nitulescu, G. M., Paunescu, H., Moschos, S. A., Petrak is, D., Nitulescu, G., Ion, G.  N.  D.,  Spandidos,  D.  A.,  Niko louzak is,  T.  K.,  Drakoul is,  N.,  and Tsatsak is,   A.   (2020).   Comprehensive   analysis   of   drugs   to   treat SARS‑ CoV‑2   infection:   Mechanistic   insights   into  current   COVID‑ 19 therapies (Review). International Journal of Molecular Medicine, 46(2), 467-488.
  173. Nujić, K., Banjanac, M., Munić, V., Polančec, D., and Eraković Haber, V. (2012). Impairment  of  lysosomal  functions  by  azith romycin  and  chloroquine contributes to anti-inflammatory phenotype. Cel Immunology, 279(1), 78-86.
  174. Nutho, B., Maha lapbutr, P., Hengphasatporn, K., Pattaranggoon, N.C., Simanon, N., Shigeta, Y.,  Hannongb ua, S., and  Rungrotmongkol, T. (2020). Why are   Lopinavir   and   Ritonavir   effective   against  the   newly   emerged coronavirus 2019? Atomistic insights into the inhibitory mechanisms. Biochemistry, 59, 1769– 1779.
  175. Ochei, J., and Kolhatkar, A. (2019). Renal Function Tests and Urine Analysis, Medical  Laboratory  Science:  Theory  and  Practice  7th  edition.  Tata McGraw-Hil, pp113-121.
  176. Oldfield, V., and Plosker, G. L. (2006). Lopinavir/ritonavir: A review of its use in the management of HIV infection. Drugs, 66, 1275-1299.
  177. Ogen, Y.  (2020). Assessing  nitrogen  dioxide  (NO2)  levels  as  a  contributing  factor   to   coronavirus   (COVID-19)   fatality.   Science  of the  Total Environment, 726, 138605.
  178. Ofori-Adjei D., Ericsson O., Lindström B., and Sjöqvist F. (1986). Protein binding  of chloroquine enantiomers  and desethylchloroquine.  British journal of clinicalpharmacology, 22(3), 356–358.
  179. Okubo   Y.,   Nochioka   K.,   and   Testa   M.A.   (2019)   Nationwide   Survey   of Hospitalization Due to Pediatric Food-Induced Anaphylaxis in the United States. Pediatr Emerg Care. Nov;35(11):769-773.
  180. Olczak-Pruc,  M.,  Szarpak,  Ł .,  Navolokina,  A.,  Ch mielewski,  J.,  Panasiuk,  L., Juá rez-Vela, R., Pruc, M., Swieczkowski, D., Majer, R., Rafique, Z., and Peacock,  F.  W.  (2022).  The  effect  of  zinc  supplementation  on  the  course of COVID-19–A systematic review and meta-analysis. Annals of Agriculturaland Environmental Medicine, 29(4), 568-574.
  181. Oth man, H. M., Oth man, F. M. and Aljali, A. A. (2022). The effect of different dosages   on   hematological   and   some   biochemical   parameters   of ivermectin   after   administration   in  goats.   Libyan  Journal of  Basic Sciences. 17(1): 35-43.
  182. Pandya,  D.,  Nagrajappa,  A.  K.,  and  Ravi,  K.  S.  (2016).  Assessment  and Correlation  of  Urea  and  Creatinine  Levels  in  Saliva  and  Serum  of Patients with Chronic Kidney Disease, Diabetes, and Hypertension- A Research Study. Journal of Clinical and Diagnostic Research, 10(10),ZC58-ZC62.
  183. Parnham, M. J., Erakovic Haber, V., Giamarellos-Bourboulis, E. J., Perletti, G.,  Verleden,  G.  M.,  and  Vos,  R.  (2014).  Azith romycin:  mechanisms  of  action  and their  relevance for clinical  applications.  Pharmacology & Therapeutics, 143(2), 225-245.
  184. Peng, S., Wang, H. Y., Sun, X., Li, P., Ye, Z., Li, Q., Wang, J., Shi, X., Liu, L., Yao, Y., Zeng, R., He, F., Li, J., Ge, S., Ke, X., Zhou, Z., Dong, E., Wang, H., Xu, G., Zhang, L., and Zhao, M. H. (2020). Early versus late acute kidney injury among patients with COVID-19-a multicenter study from Wuhan, China. Nephrology Dialysis Transplantation, 35(12), 2095-2102.
  185. Planas, D., Veyer, D., Baidaliuk, A., Staropoli, I., Guivel-Benhassine, F., Rajah, M. M. and           Bruel,  T.  (2021).   Reduced  sensitivity  of  SARS-CoV-2 variant Delta to antibody     neutralization. Nature, 596(7871): 276-280.
  186. Pollard, C.A., Morran, M.P., and Nestor-Kalinoski, A.L. (2020). The COVID-19 pandemic: a global health crisis. Physiological Genomics. 52(11), 549-557.
  187. Ponomarev, A. P., Andreeva, O. G., and Uziumov, V. L. (1996). Mechanism of retaining    the stability    of    foot-and-mouth    disease    virus    during manufacturing  dried  concentrated  preparations. Voprosy Virusologii, 41(5), 218-221.
  188. Portolés, J., Marques, M., pez-Sá nchez, P., de Valdenebro, M., Muñez, E., Serrano,  M.  L.,  Malo,  R.,  García,  E.,  and  Cuervas, V.  (2020).  Chronic kidney  disease  and  acute  kidney  injury  in  the  COVID-19  Spanish outbreak. Nephrology Dialysis Transplantation, 35(8), 1353-1361.
  189. Poschet,  J.  F.,  Perkett,  E.  A.,  Timmins,  G.  S.,  and  Deretic,  V.  (2020). Azith romycin  and  ciprofloxacin  have  a  chloroquine-like  effect  on respiratory epithelial cells. Bio-archive[Preprint], 19.
  190. Prakash, A., B harti, K., and Majeed, A. B. A. (2015). Zinc: Indications in brain disorders. Fundamental& Clinical Pharmacology, 29(2), 131-149.
  191. Prasad, A. S. (1988). Zinc in growth and development and spectrum of human zinc  deficiency.  Journal of the American Colege of Nutrition, 7(5), 377–384.
  192. Prasad,  A.S.  (2008).  Clinical  immunological,  anti-inflammatory  and  anti- oxidant roles of zinc. ExperimentalGerontology, 43, 370—377.
  193. Projean D., Baune B., Farinotti R., Flinois J. P., Beaune P., Taburet A. M., and Ducharme J. (2003). In vitro metabolism of chloroquine: identification of CYP2C8,  CYP3A4,  and  CYP2D6  as  the  main  isoforms  catalyzing  N- desethylchloroquine  formation.  Drug metabolism and disposition: the biologicalfate ofchemicals, 31(6), 748–754.
  194. Rajter, J. C., Sherman, M. S., Fatteh, N., Vogel, F., Sacks, J., and Rajter, J. J. (2021).  Use  of  ivermectin  is  associated  with  lower  mortality  in hospitalized patients with coronavirus disease 2019: The Ivermectin in COVID Nineteen Study. Chest, 159(1), 85–92.
  195. Ramírez,   A.,   Van   der   Wijk,   V.,   Jurado,   P.,   and   Arellano,   C.   (2021). P harmacokinetics   and     p harmacodynamics   of   hydroxychloroquine   and chloroquine in COVID-        19. A Systematic     Review  for  The  Covid-Nma Consortium. Medrxiv.
  196. Raymond G. D., and Galambos J. T. (1971). Hepatic storage and excretion of bilirubin  in  man.  The  American journal of gastroenterology55(2), 135– 144.
  197. Razzaque,  M.S.  and  Taguchi,  T,  (2003).  Pulmonary  fibrosis:  cellular  and molecular events. Pathology International, 53(3), 133-145.
  198. Rendic,  S.,  and  Guengerich,  F.  P.  (2020).  Metabolism  and  interactions  of chloroquine  and  hydroxychloroquine  with  human  cytochrome  P450 enzymes  and  drug  transporters.  Current Drug Metabolism,  21(14),  1127-1135.
  199. Rid uan,  S.   N.,  and  Zhang,  Y.   (2021).   Recent  Advances  of  Zinc-based Antimicrobial  Materials.  Chemistry–An Asian Journal,  16(18),  2588-2595.
  200. Robert Dufour (2005) Assessment of Liver Fibrosis: Can Serum Become the Sample of Choice? ClinicalChemistry, 51(10), 1763– 1764.
  201. Roder,  P. V., Wu,  B.,  Liu, Y.,  and  Han, W.  (2016).  Pancreatic  regulation  of glucose homeostasis. Experimentaland Molecular Medicine, 48(3), 219.
  202. Roldan, Q.  E.,  Biasiotto,  G.,  Magro,  P., and Zanella,  I. (2020). The  possible mechanisms            of   action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): A role for iron homeostasis? Pharmacological Research, 158, 104-114.
  203. Roohani,  N.,  Hurrell,  R.,  Kelishad i,  R.,  and  Schul in,  R.  (2013).  Zinc  and  its  importance  for   human   health:  An   integrative   review.  Journal of Research  in  Medical  Sciences:  The  Oficial  Journal  of  Isfahan University of MedicalSciences, 18(2), 144.
  204. Roohani  N.,  Hurrell  R.,  Kelishad i  R.,  and  Schul in  R.  (2013).  Zinc  and  its  importance for human health: An integrative review. Journal of research in medical sciences:the oficial journal of Isfahan University of Medical Sciences, 18(2), 144– 157.
  205. Rosenberg, E. S., Dufort, E. M., Udo, T., Wilberschied, L. A., Kumar, J., Tesoriero, J., Weinberg, P., Kirkwood, J., Muse, A., DeHovitz, J., Blog, D. S., Hutton, B., Holtgrave, D. R., and Zucker, H. A. (2020). Association of Treatment With Hydroxychloroquine or Azith romycin With In-Hospital Mortality in Patients With COVID-19 in New York State. Journal of the American MedicalAssociation, 323(24), 2493-2502.
  206. Rostan, E. F., DeBuys, H. V., Madey, D. L., and Pinnell, S. R. (2002). Evidence  supports zinc as an  important  antioxidant for the skin.  International journalofdermatology, 41(9), 606-611.
  207. Rothe  C.,  Schunk  M.,  Soth mann  P.,  Bretzel  G.,  Froeschl  G.,  Wallrauch  C., Zimmer T., Th iel V., Janke C., Guggemos W., Seil maier M., Drosten C., Vollmar P., Zwirgl maier K., Zange S., Wölfel R., and Hoelscher M. (2020). Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. The New Englandjournalofmedicine, 382(10), 970–971.
  208. Rothe, C., Schunk, M., Soth mann, P., Bretzel, G., Froeschl, G., Wallrauch, C.,  Zimmer, T., Thiel, V., Janke, C., Guggemos, W., Seil maier, M., Drosten, C., Vollmar,  P.,  Zwirgl maier,  K.,  Zange,  S., Wölfel,  R.  and  Hoelscher,  M.
  209. (2020). Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. New England Journal of Medicine, 382(10), 970-971.
  210. Rubino, F., Amiel, S. A., Bakker, S. J. L., Luik, P. T., Riley, W., and da Silva-Xavier, G. (2020).      COVID-19,   diabetes   and   metabolic   control:   Why   is glucose control so difficult with    COVID-19 and what are the consequences for patients? Endocrinology, Diabetes and        Metabolism, 3(4), E00171.
  211. Russo,  E.,  Esposito,  P.,  Taramasso,  L.,  Magnasco,  L.,  Saio,  M.,  Briano,  F., Russo, C., Dettori, S., Vena, A., Di Biagio, A., Garibotto, G., Bassetti, M. and Viazzi, F. (2021). Kidney disease and all-cause mortality in patients  with  COVID-19   hospitalized   in  Genoa,   Northern   Italy.  Journal of Nephrology, 34(1), 173-183.
  212. Salazar, J. H. (2014). Overview of urea and creatinine. Laboratory Medicine, 45(1), e19-e20.
  213. Salter, A., Fox, R.J., Newsome, S.D., Hal per, J., Li, D.KB., Kanellis, P., Costello,  K.,  Bebo,  B.,  Rammohan,  K.,  Cutter,  G.R.  and  Cross,  A  H.  (2021).  Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a  North American Registry of Patients With Multiple Sclerosis. Journalof the American MedicalAssociation Neurology, 78(6), 699-708.
  214. Satsangi, S., Gupta, N. and Kodan, P. (2021). Current and new drugs for COVID-  19  treatment  and  its  effects  on  the  liver.  Journal of Clinical and Translational Hepatology. 9(3): 436.
  215. Savarino, A.,  Boelaert, J.  R., Cassone, A.,  Majori, G., and Cauda,  R. (2003). Effects of chloroquine on viral infections: an old drug against today's diseases? The Lancet Infectious Diseases, 3(11), 722-727.
  216. Savarino, A., Di Trani, L., Donatelli, I., Cauda, R., and Cassone, A. (2006). New insights into the antiviral effects of chloroquine. The Lancet Infectious Diseases, 6(2), 67-69.
  217. Schaer, C. A., Laczko, E., Schoedon, G., Schaer, D. J., and Valle lian, F. (2013). Chloroquine   interference   with   hemoglobin   endocytic   trafficking suppresses adaptive heme and iron homeostasis in macrophages: the paradox  of  an  antimalarial  agent.  Oxidative  Medicine and Celular Longevity, 2013, 870-878.
  218. Schrezenmeier,    E.,    and    Dörner,    T.    (2020).    Mechanisms    of    action of hydroxychloroquine and chloroquine: implications for rheumatology. Nature Reviews Rheumatology, 16(3): 155-        166.
  219. Sha khsi N, M., Namdar, P., Allami, A., Zolg had r, L., Javadi, A., Karampour, A.,  Varnaseri, M., Bijani, B., Cheraghi, F., Naderi, Y., Amini, F., Karamyan, M.,  YadYad, M. J., Jamshid ian, R., and G heibi, N. (2021). Ivermectin as an  adjunct   treatment   for   hospitalized   adult   COVID-19   patients:   A  randomized multi-center clinical trial. Asian Pacific Journal of Tropical Medicine, 14(6), 266-273.
  220. Shi, N., Guo, L., Liu, B., Bian, Y., Chen, R., Chen, S., Chen, Y., Cong, X., Dong, G., Guo, J., Hu, L., Jiang, J., Leng, L., Li, B., Li, D., Li, H., Li, J., Li, L., Liu, J., Lu, C., Lv, W., Miao, Q., Qi, W., Shi, Z., Shi, J., Shi, H., Tian, Y., Wang, B., Wang, G., Wang, J., Wang, W., Xian, Y., Xie, X., Xiong, Y., Xu, C., Xu, M., Yan, B., Yang, J., Zhang, L., Zhou, Z., and Zhu, H. (2021). Efficacy and safety of Chinese  herbal  medicine versus  Lopinavir-Ritonavir  in  adult  patients with  coronavirus  disease  2019:  A  non-randomized  controlled  trial. Phytomedicine, 81, 153-157.
  221. Shi, Y., Wang, G., Cai, X.P., Deng, J.W., Zheng, L., Zhu, H.H., Zheng, M., Yang, B., and  Chen, Z.  (2020). An overview of  COVID-19. Journal of Zhejiang University Science B, 21(5),343-360.
  222. Shiryaev S.A.,  Mesci P., and PintoA. (2017)  Repurposing of the anti-malaria drug  chloroquine  for  Zika  Virus  treatment  and  prophylaxis.  Sciences Report, 15771.
  223. Singh, D., Cho, W. C. and Upadhyay, G. (2016). Drug-induced liver toxicity and prevention by herbal antioxidants: an overview. Frontiers in Physiology. 6(1): 363.
  224. Singhal, T. (2020). A review of coronavirus disease-2019 (COVID-19). Indian Journalof Pediatrics, 87, 281-286.
  225. Sinha,   N.,   and   Balayla,   G.   (2020).   Hydroxychloroquine   and   COVID-19. Postgraduate MedicalJournal, 96(1139), 550-555.
  226. S kal ny,  A.  V.,  Rink,  L.,  Ajsuvakova,  O.  P.,  Aschner,  M.,  Gritsenko,  V.  A., A lekseenko,  S. I.,    ...and S kal naya, M. G. (2020). Zinc and respiratory tract infections: Molecular Perspectives for       COVID‑ 19  (Review).  International journal of medicine, 46(1): 17-26.
  227. S ku be, S. J., Buchner, A. M., and Pritchard Jr, M. T. (2021). Impact of COVID-19 on  metabolic      and  disease-induced  dysphagia  and  considerations  for care.   American Journal of Speech  Language  Pathology,   30(6):   2497- 2514.
  228. Sohail, M. U., Althani, A., Anwar, H., Rizzi, R., and Castellano, J. M. (2017). Role of        the      gastrointestinal tract microbiome in the kynurenine pathway: a detailed          review. Central        Nervous   System   Agents   in   Medicinal Chemistry    (Formerly Current Medicinal Chemistry Central Nervous System Agents),17(1): 45-53.
  229. Soni, S., Chaturvedi, A., and Singh, J. P. (2017). Importance of zinc in human diet. InternationalJournalof HealthScience Research, 7(8), 462-467.
  230. Special  Expert  Group  for  Control  of  the  Epidemic  of  Novel  Coronavirus Pneumonia of the Chinese Preventive Medicine Association. (2020). An update  on  the  epidemiological  characteristics  of  novel  coronavirus pneumonia (COVID-19). Chinese Journal of Epidemiology, 41(2),  139-144.
  231. Speth, R., Carrera, E., Jean-Baptiste, M., Joachim, A., and Linares, A. (2014). The concentration-dependent effects of zinc on angiotensin-converting enzyme 2 activity. FASEB Journal, 28(Suppl 1).
  232. Spinner  C.D.,  Gottlieb  R.L.,  Criner  G.J.,  Arribas  Ló pez  J.R.,  Cattelan  A.M.,  Soriano and Viladomiu A. (2020) Effect of Remdesivir vs. standard care  on  clinical  status  at  11  days  in  patients  with  moderate  COVID-19:  A  randomized   clinical   trial.   The  Journal  of  the  American  Medical Association.;324(11):1048 1057.
  233. Stegny,  M.  Y.,  Stegny,  B.  T.,  and  Goltsev,  A.  N.  (2015).  Ultrastructure  and biological  properties  of  avian  infectious  bronchitis  virus  following cryopreservation.  Problems of Cryobiology and Cryomedicine,  4(25),340–349.
  234. Sun J., Deng X., Chen X., Huang J., Huang S., and Li Y. (2020). Incidence of  adverse  drug   reactions   in  COVID-19  patients   in  China:  An  active  monitoring   study   by   hospital   pharmacovigilance   system.   Clinical Pharmacology Therapy.;108(4):791 –797.
  235. Szente Fonseca, S. N., de Queiroz Sousa, A., Wolkoff, A. G., Moreira, M. S., Pinto, B. C., Valente Takeda, C. F., Rebouças, E., Vasconcellos Abdon, A. P., Nascimento, A. L. A., and Risch, H. A. (2020). Risk of hospitalization for COVID-19 outpatients treated with various drug regimens in Brazil: Comparative  analysis.  Travel Medicine and Infectious Disease,  38, 101906.
  236. Tegally, H., Wilkinson, E., Giovanetti, M., Iranzadeh, A., Fonseca, V., Giandhari, J., ...   and deOliveira, T. (2021). Detection of a SARS-CoV-2 variant of concern in South Africa. Nature, 592(7854): 438-443.
  237. te Velthuis, A. J., van den Worm, S. H., Sims, A. C., Baric, R. S., Snijder, E. J., and  van  Hemert,  M.  J.  (2010).  Zn  (2+)  inhibits  coronavirus  and arterivirus RNA polymerase activity in vitro and zinc ionophores block the replication of these viruses in cell culture. Public Library ofScience Pathogens, 6(11), 170-176.
  238. Touret, F., Gilles, M., Barral, K., Nougairède, A., van Helden, J., Decroly, E., de Lamballerie, X., and Coutard, B. (2020). In vitro, screening of an FDA- approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. Scientific Reports, 10(1), 13093.
  239. Toews, M. L., & Bylund, D. B. (2005). P harmacologic principles for combination therapy. Proceedings ofthe American Thoracic Society, 2(4), 282–291.
  240. Tsatsak is, A., Petrak is, D., Niko louzak is, T. K., Docea, A. O., Cal ina, D., Vinceti, M.,  Goumenou,  M.,  Kostoff,  R.  N.,  Mamoula k is,  C., Aschner,  M., and Herná ndez, A.  F. (2020). COVID-19, an opportunity to reevaluate the correlation between the long-term effects of anthropogenic pollutants on viral epidemic/pandemic events and prevalence. FoodandChemical Toxicology, 141, 114-118.
  241. Tube k S. (2007) Selected zinc metabolism parameters in premenopausal and postmenopausal  women  with  moderate  and  severe  primary  arterial hypertension. BiologicalTrace Element Research.;116:249 – 56.
  242. Tyteca, D., Van Der Smissen, P., Mettlen, M., Van Bambe ke, F., Tulkens, P. M., Mingeot-Leclercq,  M.  P.,  and  Courtoy,  P.  J.  (2002).  Azith romycin,  a lysosomotropic  antibiotic,  has  distinct  effects  on  fluid-phase  and receptor-mediated endocytosis,  but does  not  impair  phagocytosis  in J774 macrophages. ExperimentalCelResearch, 281(1), 86-100.
  243. Uchino, S., Bellomo, R., and Goldsmith, D. (2012). The meaning of the blood urea  nitrogen/creatinine  ratio  in  acute  kidney  injury.  Clinical Kidney Journal, 5(2), 187-191.
  244. Uetrecht J. (2007). Idiosyncratic drug reactions: current understanding. Annual review ofpharmacology andtoxicology, 47, 513– 539.
  245. Ulrich, H., and Pillat, M. M. (2020). CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azith romycin and Stem Cell Engagement. Stem CelReviews and Reports, 16, 434–440.
  246. Van Hasselt J. G. C., & Iyengar R. (2019). Systems Pharmacology: Defining the  Interactions of Drug Combinations. Annual review of pharmacology and toxicology, 59, 21–40.
  247. Vincent  M.J.,  Bergeron  E. and  Benjannet S.  (2005)  Chloroquine  is a  potent inhibitor of SARS coronavirus infection and spread. VirolJ , 69.
  248. Volz, E., Mishra, S., Chand, M., Barrett, J. C., Johnson, R., Geide lberg, L. and Ferguson, N. M. (2021). Assessing transmissibility ofSARS-CoV-2lineage B.1.1.7 in England   Nature, 593(7858): 266-269.
  249. Wagstaff,  K.M.,  Sivakumaran,  H.,  Heaton,  S.M.,  Harrich,  D.,  and Jans,  D.A. (2012).  Ivermectin  is  a  specific  inhibitor  of  importin  a/b-mediated nuclear import able to inhibit replication of  HIV-1 and dengue virus. BiochemicalJournal, 443(3), 851–856.
  250. Walls, A. C., Park, Y. J., Tortorici, M. A., Wall, A., McGuire, A. T., and Veesler, D. (2020).          Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell,              181(2): 281-292.
  251. Wang, D., Hu, B., Hu, C., Zhu, F., Liu, X., Zhang, J., Wang, B., Xiang, H., Cheng, Z., Xiong,  Y.,  Zhao,  Y.,  Li,  Y.,  Wang,  X.  and  Peng,  Z.  (2020).  Clinical Characteristics   of   138   Hospitalized   Patients   With   2019   Novel Coronavirus-Infected Pneumonia in Wuhan, China. The Journal of the American MedicalAssociation, 323(11), 1061-1069.
  252. Wang, J. (2020). Fast identification of possible drug treatment of Coronavirus Disease -19 (COVID-19) through computational drug repurposing study. JournalofChemical Information and Modeling, 60, 3277–3286.
  253. Wax, R.S. and Christian, M.D. (2020). Practical recommendations for critical care  and  anesthesiology teams  caring  for  novel  coronavirus  (2019- nCoV) patients. Canadian JournalofAnesthesia, 67, 568-576.
  254. Wessels, J., Maywald, N., and Rink, Z. (2017). Zinc as a gatekeeper of immune function. Nutrients. 9(12), 1286.
  255. Williamson, E.J., Walker, A.J., B haskaran, K., Bacon, S., Bates, C., Morton, C.E., Curtis, H.J., Mehr kar, A., Evans, D., Inglesby, P., Cockburn, J., McDonald, H.I., MacKenna, B., Tomlinson, L., Douglas, I.J., Rentsch, C.T., Math ur, R., Wong, A.Y.S., Grieve, R., Harrison, D., Forbes, H., Schultze, A., Croker, R., Parry, J., Hester, F., Harper, S., Perera, R., Evans, S.J.W., Smeeth, L. and Goldacre, B. (2020). Factors associated with COVID-19-related death using OpenSAFELY. Nature. 584(7821), 430-436.
  256. World  Health  Organization.  (2020).  Coronavirus disease 2019 (COVID-19). Situation      Report-55.      World       Health       Organization.      WHO. https://www.who.int/emergencies/diseases/novelcoronavirus-2019/situation-reports
  257. World  Health  Organization.  (2002).  The  importance  of  pharmacovigilance: safety monitoring of medicinal products. World Health Organization
  258. World  Health  Organization.  (2020).  Clinical  management  of  severe  acute respiratory infection(SARI) when COVID-19 disease is suspected. https://www.who.int/publications/i/item/clinical-management-of-covid-19
  259. World Health Organization. (2020a). Timeline: WHO's COVID-19 response. https://www.who.int/emergencies/diseases/novel-coronavirus- 2019/interactive-timeline
  260. World    Health    Organization.    (2020a).    Transmission    of    SARS-CoV-2: Implications for       Infection        Prevention                                   Precautions. https://www.who.int/news room/commentaries/detail/transmission-of-sars- cov-2-implications-for-        infection        prevention-precautions
  261. World Health Organization. (2020b). Coronavirus disease (COVID-19). https://www.who.int/health-topics/coronavirus#tab=tab_3
  262. World Health Organization. (2020c). Hand Hygiene for All. https://www.who.int/campaigns/world-hand-hygiene-day/2020
  263. World Health Organization. (2020d). Coronavirus disease (COVID-19) advice for the public. https://www.who.int/emergencies/diseases/novel-coronavirus-  2019/advice-for-public.
  264. World Health Organization. (2020e). Cleaning and Disinfection of Environmental         Surfaces in the Context of COVID-19. https://www.who.int/publications/i/item/cleaning-and disinfection-of- environmental-surfaces-in the-context-of-covid-19
  265. World Health Organization. (2020f). Contact Tracing in the Context of COVID- 19.       https://www.who.int/publications/i/item/contact-tracing-in-the-context -of-     covid-19
  266. World Health Organization. (2021). Tracking SARS-CoV-2 variants. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/
  267. World Health Organization. (2023). WHO Coronavirus (COVID-19) Dashboard. https://covid19.who.int/
  268. Xie C.B., Jiang L.X. and Huang G. (2020) Comparison of different samples for 2019  novel  coronavirus  detection  by  nucleic  acid  amplification tests. InternationalJournalof Infectious Diseases.;93: 264 –267.
  269. Xu, Z., Shi, L., Wang. Y., Zhang, J., Huang, L., Zhang, C., Liu, S., Zhao, P., Liu, H., Zhu, L., Tai, Y., Bai, C., Gao, T., Song, J., Xia, P., Dong, J., Zhao, J. and Wang, F.S. (2020). Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet Respiratory Medicine, 8(4), 420-422.
  270. Xu X., Chen P., Wang J., Feng J., Zhou H., Li X., Zhong W. and Hao P. (2020). Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Science China. Life sciences, 63(3), 457–460.
  271. Xu Z., Shi L., Wang Y., Zhang J., Huang L., Zhang, C., Liu S., Zhao P., Liu H., Zhu L., Tai Y., Bai C., Gao T., Song J., Xia P., Dong J., Zhao J. and Wang F. S. (2020).   Pathological   findings   of   COVID-19   associated   with   acute respiratory distress syndrome. The Lancet. Respiratory medicine, 8(4), 420–422.
  272. Xue, J., Moyer, A., and Peng, B. (2014). Chloroquine is a zinc ionophore. Public Library ofScience One .9(10), 109-180.
  273. Yang, J. K., Feng, Y., Yuan, M. Y., Yuan, S. Y., Fu, H. J., Wu, B. Y. and Nawab, (2021). Plasma  glucose  levels  and  diabetes  are  independent predictors for mortality and morbidity in  patients  with  SARS- CoV-2 infection. Frontiers in Endocrinology: 12, 355.
  274. Yarijani, Z. M., and Najaf i, H. (2021). Kidney injury in COVID-19 patients, drug development and their renal complications: Review study. Biomedicine & Pharmacotherapy, 142, 111-116.
  275. Yuwen P., Chen W., Lv H., Feng C., Li Y., Zhang T., Hu P., Guo J., Tian Y., Liu L., Sun J. and Zhang Y. (2017). Albumin and surgical site infection risk in orthopaedics: a meta-analysis. BMC surgery, 17(1), 7.
  276. Zak i A. M., Van Boheemen S., Bestebroer T. M., Osterhaus A. D. and Fouch ier, R. A. (2012). Isolation of a novel coronavirus from a man with pneumonia in  Saudi Arabia. The New Englandjournalofmedicine, 367(19), 1814– 1820.
  277. Zeng, H.-L., Zhang, B., Wang, X., Yang, Q., and Cheng, L. (2021). Urinary trace elements in association with disease severity and outcome in patients with COVID-19. Environmental Research, 194, 110670.
  278. Zhang, X., Song, Y., Ci, X., An, N., Ju, Y., Li, H., Wang, X., Han, C., Cui, J., and Deng,   X.   (2008).   Ivermectin   inhibits   LPS-induced   production   of inflammatory  cytokines  and  improves  LPS-induced  survival  in  mice. Inflammation Research, 57(11), 524-529.
  279. Zhang, H., Penninger, J., and  Li, Y. (2020). Angiotensin-converting enzyme 2 (ACE2)   as   a   SARS-CoV-2   receptor:   Molecular   mechanisms   and potential therapeutic target. European Heart Journal, 46(4), 586– 590.
  280. Zheng T., Yang R. and Mei H., (2020) Pregnant women with COVID-19 and risk of adverse  birth outcomes and  maternal-fetal vertical transmission: a population-based cohort study in Wuhan, China. BMC Medicine 18; 330.
  281. Zheng, Q.L., Duan, T. and Jin, L.P. (2020). Single-cell RNA expression profiling of ACE2 and AXL in the human maternal-fetal. interface. Reproductive and Developmental Medicine, 4(1), 7-10.
  282. Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new     coronavirus     of     probable     bat     origin.     Nature.     2020 Mar;579(7798):270-273.
  283. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., Niu, P., Zhan, F., Ma, X., Wang, D., Xu, W., Wu, G., Gao, G.F. and  Tan,  W.   (2020).   China   Novel   Coronavirus   Investigating   and Research Team. A Novel Coronavirus from Patients with Pneumonia in China, 2019. New EnglandJournalof Medicine, 382(8):727-733.
  284. Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J. and Tan, W. (2020). A novel  coronavirus  from  patients  with  pneumonia  in  China,  2019.   New England       Journalof    Medicine, 382(8): 727-733.
  285. Zou L., Ruan F., Huang M., Liang L., Huang H., Hong Z., Yu J., Kang M., Song Y., Xia J., Guo Q., Song T., He J., Yen H. L., Peiris M. and Wu J. (2020). SARS- CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. The New Englandjournalofmedicine, 382(12), 1177– 1179.
  286. Zou, L., Ruan, F., Huang, M., Liang, L., Huang, H., Hong, Z., Yu, J., Kang, M., Song, Y., Xia, J., Guo, Q., Song, T., He, J., Yen, H.L., Peiris, M. and Wu, J. (2020).  SARS-CoV-2  Viral  Load  in  Upper  Respiratory  Specimens  of Infected  Patients.  New England Journal of Medicine, 382(12),  1177-1179.
  287. Zuckerman,    J.    M.    (2014).    Macrolides    and    ketolides:    azith romycin, clarith romycin,         tel ith romycin.           Infectious Disease Clinics, 28(3): 539-550.
  288. Zwerling, A.,  Behr,  M.A., Verma, A.,  Brewer,  T.F.,  Menzies,  D.,  and  Pai,  M. (2011). The BCG World Atlas: a database of global BCG vaccination policies and practices. Public Library of Science Medicine, 8(3), e1001-1012.

The COVID-19 pandemic necessitated the rapid development and use of therapeutic drugs to combat the disease. However, concerns exist regarding the potential adverse effects of these drugs on metabolic processes like glucose homeostasis, renal function and bilirubin levels. This study aimed to evaluate the impact of chloroquine, hydroxychloroquine, ivermectin, azith romycin, lopinavir & ritonavir, zinc & selenium, which are recommended COVID- 19 drugs, on glucose metabolism, renal function (urea and creatinine levels) and bilirubin levels in Wistar rat model. About sixty (60) Wistar rats were randomly assigned to 9 treatment test groups and a control group (a total of 10 groups). The drugs were administered orally at clinically relevant doses for one month. Blood glucose, urea, creatinine and bilirubin assay was performed to assess glucose metabolism using the oxidase-peroxidase method, bilirubin by Evelyn and Malloy's method, urea and creatinine levels using urease berthe lot's and alkaline picrate method respectively. Data obtained was analyzed by the Statistical Package for Social Sciences (SPSS) software. The results showed that the group treated with hydroxychloroquine + azith romycin + lopinavir/ritonavir + ivermectin + zinc + selenium demonstrated a markedly elevated mean glucose level of 103.80 mg/dL (P = 0.001) compared to the control (83.83mg/dL), indicating a statistically significant impact on glucose metabolism. Analysis revealed no significant difference in urea and creatinine levels (p>0.05) among the different groups as p values were = 0.109 and 0.848 respectively. The hydroxychloroquine + azith romycin + lopinavir/ritonavir + ivermectin + zinc + selenium group showed markedly elevated glucose levels. The direct bilirubin of experimental animals across most treated groups was significantly elevated (p<0.05). Results also showed that total bilirubin was significantly higher (p<0.05) in animals treated with ivermectin (0.93±0.10) and Lopinavir-ritonavir (0.92±0.06) when compared to control (0.47±0.07) . In conclusion, patients who are being administered this drug combination (hydroxychloroquine + azith romycin + lopinavir/ritonavir + ivermectin + zinc + selenium) are at risk of developing diabetes mellitus and also further worsening the condition of diabetic patients. Also administration of these drugs may induce liver dysfunction, hyperbilirubinemia, drug-induced liver injury, drug-induced hepatitis and consequently jaundice. It is recommended to avoid the concurrent use of this specific drug combination unless the potential benefits outweigh the risks of hyperglycemia, the administration of these drugs adversely affected the synthetic and excretory functions of the liver and regular assessment of liver function parameters necessary.

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