Research Article

The Potential of Melatonin and N-Acetylcysteine on Remdesivir Induced Liver Injury in Covid 19 Patients

Seyedmohammad Karimi1, Mohammad Darvishi2*, Mohammad Barati3, Ramin Hamidi Frahani4, Mohammad Hassan Kazemi5

1Researcher and General practitioner, Infectious Diseases Research Center, Aja University of Medical Sciences, Tehran, Iran; 2Faculty of Aerospace and Subaquatic Medicine, AJA University of Medical Sciences, Tehran, Iran; 3Infectious Diseases Research Center, AJA University of Medical Sciences, Tehran, Iran; 4Department of Infectious diseases, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran; 5Department of Medical Epidemiology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran.

Received | September 24, 2022; Accepted | February 01, 2023; Published | February 13, 2023

*Correspondence | Mohammad Darvishi, Faculty of Aerospace and Subaquatic Medicine, AJA University of Medical Sciences, Tehran, Iran; Email: [email protected]

Citation | Karimi S, Darvishi M, Barati M, Frahani RH, Kazemi MH (2023). The potential of melatonin and N-acetylcysteine on remdesivir induced liver injury in Covid 19 patients. Adv. Anim. Vet. Sci. 11(3):404-409.

DOI | https://dx.doi.org/10.17582/journal.aavs/2023/11.3.404.409

ISSN (Online) | 2307-8316

Copyright: 2023 by the authors. Licensee ResearchersLinks Ltd, England, UK.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

INTRODUCTION

In December 2019, an acute respiratory illness broke out in Wuhan, China (Yuki et al., 2020; Hassanzadeh Khanmiri et al., 2022; Widoyo et al., 2022). The disease spread rapidly and infected more than 470 million people and caused more than 6 million deaths by March 2022 (WHO, 2021; Karimi et al., 2021; Ijaz et al., 2021; Hatami et al., 2022). The disease named novel covid19 and caused by SARS CoV-2 virus, which belongs to the coronaviridae family and causes a range from asymptomatic to fever, cough, dyspnea, pneumonia and death (Sharma et al., 2021). Four stages are known for the disease: The first stage includes an upper respiratory tract infection, the second stage is the onset of shortness of breath and pneumonia, in the third stage cytokine storm occurs, and the fourth stage will be recovery or death. Depending on the stage of the disease and the patient’s clinical condition, several drugs are used for treatment, including antivirals and immunomodulatory drugs (Stasi et al., 2020).

Remdesivir is the first FDA-approved drug for treating covid19 patients that originally developed for the treatment of Ebola virus. It is a nucleotide analogue with broad-spectrum antiviral properties that its effectiveness in treating hospitalized covid-19 patients has been observed in several clinical trials (Lamb, 2020).

In a meta-analysis performed by Elsawah et al. (2021) it was observed that treatment with Remdesivir increase recovery rates on day 14 by 50% in patients with severe cases and reduced mortality rate by 36% in all hospitalized patients.

Despite the benefits of Remdesivir, its hepatic adverse effect should be considered. There is some evidence that the use of Remdesivir can causes liver injury and a low to moderate increase in liver enzymes. Therefore, routinly it is recommended that liver enzymes be checked serially and if the liver enzymes increase more than 10 times injection should be discontinued (Zampino et al., 2020; Aleem et al., 2021).

Melatonin (N-acetyl 5-methoxytryptamine) is a hormone synthesized from the amino acid tryptophan, which in addition to regulating the circadian rhythms, has protective effects on liver diseases and injuries caused by drugs, alcohol and chemical contaminants by preventing oxidative damage, improving mitochondrial physiology, and suppressing liver fibrosis (Zhang et al., 2017; Stacchiotti et al., 2019).

NAC is derived from the amino acid cystein that neutralizes oxygen free radicals and has antioxidant properties. It acts as a glutathione substitute and, in direct combination with active metabolites, stores cytoplasmic and mitochondrial glutathione reserves as a sulfate source and prevents liver damage (Moosa et al., 2021; Walayat et al., 2021).

Since it is important to administer Remdesivir without any side effects for covid-19 patients, we decided to conduct this clinical trial to evaluate the propable role of melatonin and NAC to protect the liver.

Materials and Methods

Study design

This randomized, double-blind, placebo-controlled clinical trial study was conducted on hospitalized patients diagnosed with covid-19 in Besat Hospital, Tehran, Iran, in 2022. This study was reviewed and approved by the Ethics Committee of AJA University of Medical Sciences and was performed after obtaining informed consent from all patients (Clinical Trial Registration Code: IRCT20210926052586N2).

Patients

70 patients were enrolled. All patients were over 18 years of old, have positive SARS-CoV-2 PCR test, hospitalized, and have indication to receive Remdesivir. Liver disease and inability to receive oral medication were considered as exclusion criteria.

Randomization and intervention

Patients were randomly divided into two groups of 35 each. Both groups received 200 mg of Remdesivir on the first day of hospitalization and then 100 mg daily for up to four doses. During this period, the first group (experimental group) received N-acetylcysteine 600 mg teblet twice daily and melatonin 6 mg tablet at bedtime. The second group (placebo group) just received a placebo with the same appearance.

Extraction of data

AST, ALT, ALP, CBC and Cr of all patients were serially evaluated on the day 1, 3 and 6 of hospitalization. The chief complaint, severity of the disease at the time of admission and the patients underlying disease were assessed. Moreover, demographic datas such as age, gender and BMI were extracted from medical records.

Statistical analysis

Data were entered SPSS version 26. At first, all datas normality were examined with Kolmogorov–Smirnov test. Then, based on the variable, Mann-Whitney test, Chi-square test and independent t-test were used for analysis of data. P-value of less than 0.05 was considered statistically significant.

RESULTS and Discussion

As shown in Table 1, the mean age of participants in the case and control groups was 63.40±16.39 and 55.17±21.98, respectively (P=0.068). Also, there was no significant difference between the two groups in term of gender of patients (P= 0.641). The mean BMI in the case and control groups was 27.70±4.45 and 26.28±3.28 that was not significantly different (0.130).

Moreover, as demonstrated in Table 1, based on the WHO classification (13), no significant difference were observed between the two groups in term of the severity of the disease (P=0.217).

 

Table 1: Comparison of two groups in terms of age, gender, BMI and disease severity.

Variable	Intervention (n=35)	Placebo (n=35)	P value a
Age (years), Mean±SD	63.41±16.39	55.17±21.98	0.068
Gender, n (%) Men Female	15 (44.1) 19 (55.9)	18 (50.0) 18 (50.0)	0.641
BMI (kg/m2), Mean±SD	27.70±4.45	26.28±3.28	0.130
Severity, n (%) Mild Moderate Severe	21 (61.8) 5 (14.7) 8 (23.5)	27 (75.0) 6 (16.7) 3 (8.3)	0.217

 

As shown in Table 2, on day 3 of enrolment the AST and ALP level of patients in intervention group decreased compared to the placebo group, but the difference was not statistically significant (P:0.903 and P:0.858). Also, the ALT and CBC level in the intervention group patinets increased less than the control group but there was no significant difference (P:0.191 and P:0.518).

As Table 3 shows, on day 6 of enrolment the AST and ALP level of patients who received Melatonin and NAC numerically decreased more than the placebo group, but the difference was not significant (P:0.242 and P:0.110). Also, the level of ALT and CBC in subjects who received intervention increased less than the placebo group but no significant difference was observed between them (P:0.100 and P:0.055).

Remdesivir is a broad-spectrum antiviral drug that has been reported causes liver injury in some patients with covid19 who have received it. It is metabolised in the liver to form remdesivir triphosphate, this metabolite is a nucleotide analogue that competes with ATP and inhibits RNA-dependent RNA polymerase which is essential for viral replication. Therefore, it seems that this drug can causes liver injury by the mechanism of hepatocytes mitochondrial damage (Wong et al., 2021).

 

Melatonin and NAC are two substances that with their antioxidant and anti-inflammatory effects have important role in reducing liver toxicity caused by medications (Zhang et al., 2017; Stacchiotti et al., 2019).

NAC has an antioxidant function by acting as a glutathione precursor, which is a potential antioxidant, also by breaking down thiol proteins and releasing free thiols that have antioxidant activity. Moreover, NAC sometimes acts as a direct antioxidant for some oxidants such as NO2 and HOX when glutathione and cysteine stores are depleted (Aldini et al., 2018).

 

Table 2: AST, ALT, ALP, CBC change after 3 days of enrolment.

Variable	Intervention			Placebo			P value
	Day 1	Day 3	Change	Day 1	Day 3	Change
AST (IU/μL), Mean ± SD	40.03±20.37	38.21±22.15	-1.82	41.14±19.37	39.78±15.34	-1.36	0.903
ALT (IU/μL), Mean±SD	31.56±21.22	38.82±24.77	7.26	33.33±14.68	41.78±21.84	8.44	0.191
ALP (IU/μL), Mean ± SD	163.18±49.41	158.82±66.66	-4.35	162.50±34.76	159.61±26.65	-2.89	0.858
CBC (cells/μL), Mean ± SD	6539.12± 3504.16	7855.88 ±3041.25	1316.76	6472.22 ±2859.73	8305.56± 3255.45	1833.33	0.518

 

Table 3: Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), complete blood count (CBC) chang after 6 days of enrolment.

Variable	Intervention			Placebo			P value
	Day 1	Day 6	Change	Day 1	Day 6	Change
AST(IU/μL), Mean±SD	40.03±20.37	34.30±13.90	-5.73	41.14±19.37	39.89±14.97	-1.25	0.242
ALT(IU/μL), Mean±SD	31.56±21.22	40.18±21.70	8.61	33.33±14.68	46.60±19.21	13.26	0.100
ALP(IU/μL), Mean±SD	163.18±49.41	151.91±62.47	-11.26	162.50±34.76	161.94±41.09	-0.56	0.110
CBC (cells/μL), Mean±SD	6539.12± 3504.16	8316.47 ±2898.02	1777.35	6472.22 ±2859.73	9677.78 ±3734.34	3205.56	0.055

 

On the other hand, melatonin’s functions as an antioxidant include: direct free radical scavenging, stimulation of antioxidative enzymes, increasing the efficiency of mitochondrial oxidative phosphorylation, reducing electron leakage and augmenting the efficiency of other antioxidants (Reiter et al., 2003).

In this double-blind, case control clinical trial, we examined the efficacy oral NAC and Melatonin in dose of 1200mg and 6mg daily in the management of Remdesivir liver injury in COVID-19 patients. The results of our study showed that the use of NAC and Melatonin along with Remdesivir in Covid 19 patients, can slows down the elevation of liver enzymes level. However, this was not statistically significant.

In a clinical trial that was reported by Cichoz-Lach et al, demonstrated that adding of Melatonin to treatment regimen of patients with NASH cannot sigificantly decrease AST, ALP or ALP level (Cichoz-Lach et al., 2010). In contrast Chojnacki et al. (2017) showed that for patient taking Atorvastatin 20mg daily for hyperlipidemia receiving daily dose of 10mg of Melatonin orally can reduce Liver enzymes compared to Placebo group. Also, in a study by Pakravan et al. (2017) was found that administration of Melatonin in a duration of 6 weeks in patients with NAFLD can reduce AST significantly compared to the placebo group but ALT level was not changed significantly.

Gokcimen et al. (2007) in an animal intervention study after histopathological examination found that N-acetylcysteine had no protective effect on the liver in doxorubicin induced hepatotoxicity. In contrast, Baniasadi et al. (2010) showed that receiving 600mg NAC orally twice a day can protect liver against anti TB drug induced damage. Moreover, Carother et al. (2020) showed that IV administration of NAC with discontinuation of Remdesivir can have important role in reduction of AST and ALT and improved acute liver failure due to Remdesivir infusion.

Conclusions and Recommendations

The limitation of our study was that, it was conducted at a single centre with a relatively small sample size. And also, it was difficult to distinguish whether the increase in patients’ liver enzymes was due to the injection of remedsivir or Covid-19 disease itself. In conclusion, in this clinical trial of oral administration of melatonin and NAC doses of 6mg and 1200mg in patients with Covid-19, no significant difference in either the CBC level or liver enzymes decline after 6 days of enrolment was observed.

ACKNOWLEDGEMENTS

Thanks to the staff of the Infectious Diseases Department of Besat Hospital for their kind contribution.

Novelty Statement

To administer Remdesivir without any side effects for covid-19 patients, we decided to conduct this clinical trial to evaluate the role of melatonin and NAC to protect the liver.

AUTHOR’S CONTRIBUTION

This study was performed due to the widespread prevalence of covid19 in our region and the fact that so far almost no study has been done to find a way to reduce the hepatotoxicity caused by Ramed Sivir. All authors read and approved the final manuscript.

Ethical approved

IR.AJAUMS.REC.1400.306

Funding/support

AJA University of medical sciences.

Informed consent

Informed consent was obtained from all patients before the study.

Conflict of interest

The authors have declared no conflict of interest.

REFERENCES

Aldini G, Altomare A, Baron G, Vistoli G, Carini M, Borsani L, Sergio F (2018). N-Acetylcysteine as an antioxidant and disulphide breaking agent: The reasons why. Free Radic. Res., 52(7): 751-762. https://doi.org/10.1080/10715762.2018.1468564

Aleem A, Mahadevaiah G, Shariff N, Kothadia JP (2021). Hepatic manifestations of COVID-19 and effect of remdesivir on liver function in patients with COVID-19 illness. Proc. (Bayl Univ. Med. Cent.). 34(4): 473-477. https://doi.org/10.1080/08998280.2021.1885289

Aleksandrovna KL, Danilovich KE, Koloskov DA (2022). Environmental investment, the main condition for the COVID-19 post-pandemic recovery of Russian economy and transition to sustainable economic growth. Caspian J. Environ. Sci., 20(5): 1069-1082.

Baharvand-Ahmadi B, Bahmani M, Naghdi N, Saki K, Baharvand A, Rafieian-Kopaei M (2015). Medicinal plants used to treat infectious and non-infectious diseases of skin and skin appendages in city of Urmia, northwest Iran. Der Pharm. Lett., 7(11): 189-196.

Bahmani M, Jalilian A, Salimikia I, Shahsavari S, Abbasi N (2020). Phytochemical screening of two Ilam native plants Ziziphus nummularia (Burm. f.) Wight and Arn. And Ziziphus spina-christi (Mill.) Georgi using HS-SPME and GC-MS spectroscopy. Plant Sci. Today, 7(2): 275-280.

Bahmani M (2019). Synthesis and evaluation of the antibacterial effect of titanium dioxide nanoparticles in comparison with ampicillin, colistin, and ertapenem on Staphylococcus aureus. J. Pharm. Negat. Results, 10(1): 16-20.

Baniasadi S, Eftekhari P, Tabarsi P, Fahimi F, Raoufy MR, Masjedi MR, Velayati AA (2010). Protective effect of N-acetylcysteine on antituberculosis drug-induced hepatotoxicity. Eur. J. Gastroenterol. Hepatol., 22(10): 1235-1238. https://doi.org/10.1097/MEG.0b013e32833aa11b

Carothers C, Birrer K, Vo M (2020). Acetylcysteine for the treatment of suspected remdesivir-associated acute liver failure in COVID-19: A case series. Pharmacotherapy, 40(11): 1166-1171. https://doi.org/10.1002/phar.2464

Chojnacki C, Błońska A, Chojnacki J (2017). The effects of melatonin on elevated liver enzymes during statin treatment. Biomed. Res. Int., pp. 3204504. https://doi.org/10.1155/2017/3204504

Cichoz-Lach H, Celinski K, Konturek PC, Konturek SJ, Slomka M (2010). The effects of L-tryptophan and melatonin on selected biochemical parameters in patients with steatohepatitis. J. Physiol. Pharmacol., 61(5): 577-580.

Elsawah HK, Elsokary MA, Abdallah MS, El-Shafie AH (2021). Efficacy and safety of remdesivir in hospitalized Covid-19 patients: Systematic review and meta-analysis including network meta-analysis. Rev. Med. Virol., 31(4): e2187. https://doi.org/10.1002/rmv.2187

Gokcimen A, Cim A, Tola HT, Bayram D, Kocak A, Özgüner F, Ayata A (2007). Protective effect of N-acetylcysteine, caffeic acid and vitamin E on doxorubicin hepatotoxicity. Hum. Exp. Toxicol., 26(6): 519-525. https://doi.org/10.1177/0960327107076885

Hassanzadeh-Khanmiri H, Amer MA, Yousif RS, Jasim SA, Kzar HH, Lafta MH, Turki JA, Romero PRM, Darvishi M (2022). SARS-CoV2 neuroinvasive potential in respiratory failure in COVID-19 patients. Caspian J. Environ. Sci., pp. 1-6.

Hatami A, Hajiloo A, Bayati R, Kakavand P, Nasrollahi AH, Yarahmadi AH, Nourmohammadi MJ, Asadi H (2022). Public COVID-19 vaccination acceptance: A narrative review of correlated factors. Adv. Life Sci., 9(2): 143-150.

Heryadi DY, Tannady H, Rembulan GD, Rofatin B, Sundari RS (2023). Changes in behavior and welfare of organic rice farmers during the COVID-19 pandemic. Caspian J. Environ. Sci., pp. 1-7.

Ijaz S, Afzal M, Naeem T, Zaid N, Gillani SF, Saeed A, Rehman K, Haseeb S, Najeeb M (2021). Knowledge, attitude, practices (KAP) and psychological impact of COVID-19 among Pakistani population a quick cross- sectional online study. Adv. Life Sci., 8(3): 287-292.

Karimi E, Abbasi S, Abbasi N (2019). Thymol polymeric nanoparticle synthesis and its effects on the toxicity of high glucose on OEC cells: involvement of growth factors and integrin‐linked kinase. Drug Design, Dev. Ther., 25: 2513-2532.

Karimi M, Gholami-Ahangaran M (2021). A brief report on current evidence of traditional chinese medicine in the treatment of patients infected with SARS-CoV-2. Plant Biotechnol. Persa, 3(1): 34-36. https://doi.org/10.52547/pbp.3.1.1

Lamb YN (2020). Remdesivir: First approval. Drugs, 80(13): 1355-1363. https://doi.org/10.1007/s40265-020-01378-w

Moosa MS, Maartens G, Gunter H, Allie S, Chughlay MF, Setshedi M (2021). A randomized controlled trial of intravenous N-acetylcysteine in the management of anti-tuberculosis drug-induced liver injury. Clin. Infect. Dis., 73(9): e3377-e83. https://doi.org/10.1093/cid/ciaa1255

WHO (2021). Living guidance for clinical management of COVID-19: Living guidance, 23 November 2021. World Health Organization.

Pakravan H, Ahmadian M, Fani A, Aghaee D, Brumanad S, Pakzad B (2017). The effects of melatonin in patients with nonalcoholic fatty liver disease: A randomized controlled trial. Adv. Biomed. Res., pp. 6. https://doi.org/10.4103/2277-9175.204593

Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z (2003). Melatonin as an antioxidant: Biochemical mechanisms and pathophysiological implications in humans. Acta Biochim. Pol., 50(4): 1129-1146. https://doi.org/10.18388/abp.2003_3637

Samarghandian S, Asadi-Samani M, Farkhondeh T, Bahmani M (2016). Assessment the effect of saffron ethanolic extract (Crocus sativus L.) on oxidative damages in aged male rat liver. Der. Pharm. Lett., 8(3): 283-290.

Sharma A, Ahmad FI, Lal SK (2021). COVID-19: A review on the novel coronavirus disease evolution, transmission, detection, control and prevention. Viruses, 13(2): 202. https://doi.org/10.3390/v13020202

Stacchiotti A, Grossi I, García-Gómez R, Patel GA, Salvi A, Lavazza A, De Petro G, Monsalve M, Rezzani R (2019). Melatonin effects on non-alcoholic fatty liver disease are related to MicroRNA-34a-5p/Sirt1 axis and autophagy. Cells, 8(9): 1. https://doi.org/10.3390/cells8091053

Stasi C, Fallani S, Voller F, Silvestri C (2020). Treatment for COVID-19: An overview. Eur. J. Pharmacol., 889: 173644. https://doi.org/10.1016/j.ejphar.2020.173644

Walayat S, Shoaib H, Asghar M, Kim M, Dhillon S (2021). Role of N-acetylcysteine in non-acetaminophen-related acute liver failure: An updated meta-analysis and systematic review. Ann. Gastroenterol., 34(2): 235-240. https://doi.org/10.20524/aog.2021.0571

WHO Coronavirus (COVID-19) Dashboard| WHO coronavirus (COVID-19) dashboard with vaccination data [Internet]. WHO Coronavirus (COVID-19) Dashboard

WHO Coronavirus (COVID-19) dashboard with vaccination data. [cited 2022 Apr 2]. Available from: https://covid19.who.int/.

Widoyo H, Mohammed ZY, Ramírez-Coronel AA, Iswanto AH, Thattarauthodiyil U, Alkhayyat SA, Karimi M, Bahmani M, Eftekhari Z (2022). Herbal therapy in Covid-19: A systematic review of medicinal plants effective against Covid-19. Caspian J. Environ. Sci., pp. 1-10.

Wong CK, Au IC, Cheng WY, Man KK, Lau KT, Mak LY, Lui SL, Chung MS, Xiong X, Lau EH, Cowling BJ (2021). Remdesivir use and risks of acute kidney injury and acute liver injury among patients hospitallised with COVID-19: A self-controlled case series study. Aliment. Pharmacol. Ther. n/a(n/a),2, 2021. https://doi.org/10.1111/apt.16894

Yuki K, Fujiogi M, Koutsogiannaki S (2020). COVID-19 pathophysiology: A review. Clin. Immunol., 215: 108427. https://doi.org/10.1016/j.clim.2020.108427

Zampino R, Mele F, Florio LL, Bertolino L, Andini R, Galdo M, De Rosa R, Corcione A, Durante-Mangoni E (2020). Liver injury in remdesivir-treated COVID-19 patients. Hepatol. Int., 14(5): 881-883. https://doi.org/10.1007/s12072-020-10077-3

Zhang JJ, Meng X, Li Y, Zhou Y, Xu DP, Li S, Li HB (2017). Effects of melatonin on liver injuries and diseases. Int. J. Mol. Sci., 18(4): 673. https://doi.org/10.3390/ijms18040673