Efficacy of Quinine Sulfate in Patients with Mild-To-Moderate COVID-19: A Randomized Controlled Trial

Irma Rahayu Latarissa, Melisa Intan Barliana, Anna Meiliana, Ida Paulina Sormin, Erizal Sugiono, Cissy Bana Kartasasmita, Irmansyah Irmansyah, Keri Lestari

Abstract


BACKGROUND: Before WHO revoked the emergency use authorization for Chloroquine (CQ) and Hydroxychloroquine (HCQ) because of their side effects, it was suggested to use these two drugs for COVID-19 therapy. In addition, another derivate of quinine, namely Quinine Sulfate (QS), showed good in silico and in vitro antiviral activity against SARS-CoV-2. Prior the WHO revocation, this study was conducted to evaluate the efficacy of QS in mild-to-moderate COVID-19 patients.

METHODS: This was an adaptive, controlled, multicenter, randomized, double-blind clinical trial involving mild-to-moderate COVID-19 patients in Indonesia. The participants were divided into 2 groups: the control group (standard COVID-19 treatment + placebo) and the treatment group (standard COVID-19 treatment + QS). The primary outcome was the efficacy of QS based on clinical status using a 7-point ordinal scale. The secondary outcomes were the efficacy of QS in terms of the incidence and duration of oxygen supplementation, incidence of mechanical ventilation, and length of stay.

RESULTS: No significant difference in the efficacy parameters studied was found between the control group and the treatment group. The difference in the mean oxygen saturation was also measured and the results showed a significant difference where the treatment group had higher mean oxygen saturation than the control group (p=0.001).

CONCLUSION: Although not significant, the treatment group showed better therapy outcomes compared to the control group.

KEYWORDS: clinical trials, efficacy, quinine, chloroquine, hydroxychloroquine


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References


Johns Hopkins University & Medicine [Internet]. COVID-19 Map - Johns Hopkins Coronavirus Resource Center [cited 2023 Jan 30]. Available from: https://coronavirus.jhu.edu/.

Liu Q, Wang Z. Perceived stress of the COVID-19 pandemic and adolescents’ depression symptoms: The moderating role of character strengths. Pers Individ Dif 2021; 182: 111062, CrossRef.

Konishi T. Progressing adaptation of SARS-CoV-2 to humans. Chem-Bio Inform J. 2022; 22: 1-12, CrossRef.

Konishi T. Continuous mutation of SARS-CoV-2 during migration via three routes at the beginning of the pandemic. PeerJ. 2022; 10: e12681, CrossRef.

World Health Organization [Internet[. Tracking SARS-CoV-2 variants 2021 [cited 2022 Nov 10]. Available from: https://www.who.int/.

Tandirogang N, Fitriany E, Mardania N, Jannah M, Dilan BFN, Ratri SR, et al. Neutralizing antibody response by inactivated SARS-CoV-2 vaccine on healthcare workers. Mol Cell Biomed Sci. 2023; 7(1): 18-27, CrossRef.

Wan EYF, Chui CSL, Wang Y, Ng VWS, Yan VKC, Lai FTT, et al. Herpes zoster related hospitalization after inactivated (CoronaVac) and mRNA (BNT162b2) SARS-CoV-2 vaccination: A self-controlled case series and nested case-control study. Lancet Reg Health West Pac. 2022; 21: 100393, CrossRef.

Higdon MM, Wahl B, Jones CB, Rosen JG, Truelove SA, Baidya A, et al. A systematic review of coronavirus disease 2019 vaccine efficacy and effectiveness against severe acute respiratory syndrome coronavirus 2 infection and disease. Open Forum Infect Dis. 2022; 9(6): ofac138, CrossRef.

Gruell H, Vanshylla K, Tober-Lau P, Hillus D, Schommers P, Lehmann C, et al. mRNA booster immunization elicits potent neutralizing serum activity against the SARS-CoV-2 omicron variant. Nat Med. 2022; 28: 477-80, CrossRef.

Stowe J, Andrews N, Kirsebom F, Ramsay M, Bernal JL. Effectiveness of COVID-19 vaccines against omicron and delta hospitalisation, a test negative case-control study. Nat Commun. 2022; 13(1): 5736, CrossRef.

Willett BJ, Grove J, Maclean OA, Wilkie C, Logan N, De Lorenzo G, et al. The hyper-transmissible SARS-CoV-2 Omicron variant exhibits significant antigenic change, vaccine escape and a switch in cell entry mechanism. MedRxiv. 2022; 2022: preprint, CrossRef.

Australian Government Department Health [Internet]. COVID-19 Omicron Variant 2022 [cited 2022 Nov 10]. Available from: https://www.health.gov.au/.

Ministry of Health, Labour and Welfare of Japan [Internet]. Number of new positive cases and vaccination coverage nationwide 2022 [cited 2022 Nov 10]. Abailable from: https://www.mhlw.go.jp/.

Kuhlmann C, Mayer CK, Claassen M, Maponga T, Burgers WA, Keeton R, et al. Breakthrough infections with SARS-CoV-2 omicron despite mRNA vaccine booster dose. Lancet. 2022; 399(10325): 625-6, CrossRef.

Wisnivesky JP, Govindarajulu U, Bagiella E, Goswami R, Kale M, Campbell KN, et al. Association of vaccination with the persistence of post-COVID symptoms. J Gen Intern Med. 2022; 37(7): 1748-53, CrossRef.

Bar-On YM, Goldberg Y, Mandel M, Bodenheimer O, Amir O, Freedman L, et al. Protection by a Fourth Dose of BNT162b2 against omicron in Israel. N Engl J Med. 2022; 386(18): 1712-20, CrossRef.

Achan J, Talisuna AO, Erhart A, Yeka A, Tibenderana JK, Baliraine FN, et al. Quinine, an old anti-malarial drug in a modern world: Role in the treatment of malaria. Malar J. 2011: 10: 144, CrossRef.

Jomsky M. Could low-dose quinine prevent or treat coronavirus infection? EC Pharmacol Toxicol. 2020; 8(4): 62-4, CrossRef.

Malakar S, Sreelatha L, Dechtawewat T, Noisakran S, Yenchitsomanus P thai, Chu JJH, et al. Drug repurposing of quinine as antiviral against dengue virus infection. Virus Res. 2018; 255: 171-8, CrossRef.

Marois I, Cloutier A, Meunier I, Weingartl HM, Cantin AM, Richter M V. Inhibition of influenza virus replication by targeting broad host cell pathways. PLoS One. 2014; 9(10): e110631, CrossRef.

Mehra MR, Desai SS, Ruschitzka F, Patel AN. RETRACTED: Hydroxychloroquine or chloroquine with or without a macrolide for treatment of COVID-19: a multinational registry analysis. Lancet. 2020: S0140-6736(20)31180-6, CrossRef.

Latarissa IR, Barliana MI, Meiliana A, Lestari K. Potential of quinine sulfate for covid-19 treatment and its safety profile: Review. Clin Pharmacol. 2021; 13: 225-34, CrossRef.

Lestari K, Sitorus T, Instiaty, Megantara S, Levita J. Molecular docking of quinine, chloroquine and hydroxychloroquine to angiotensin converting enzyme 2 (ACE2) receptor for discovering new potential COVID-19 antidote. J Adv Pharm Educ Res.2020; 10(2): 1-4, article.

Große M, Ruetalo N, Layer M, Hu D, Businger R, Rheber S, et al. Quinine inhibits infection of human cell lines with sars-cov-2. Viruses. 2021; 13(4): 647, CrossRef.

Covid19.go.id [Internet] Pedoman Tatalaksana COVID-19 edisi 4 [updated 2022 Feb 3; cited 2022 Oct 4] Available from: https://covid19.go.id/.

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe covid-19. N Engl J Med. 2020; 382(19): 1787-99, CrossRef.

Gachelin G, Garner P, Ferroni E, Tröhler U, Chalmers I. Evaluating Cinchona bark and quinine for treating and preventing malaria. J R Soc Med. 2017; 110(1): 31-40, CrossRef.

Marella A, Tanwar OP, Saha R, Ali MR, Srivastava S, Akhter M, et al. Quinoline: A versatile heterocyclic. Saudi Pharm J. 2013; 21(1): 1-12, CrossRef.

Chen YL, Fang KC, Sheu JY, Hsu SL, Tzeng CC. Synthesis and antibacterial evaluation of certain quinolone derivatives. J Med Chem. 2001; 44(14): 2374-7, CrossRef.

Edmont D, Rocher R, Plisson C, Chenault J. Synthesis and evaluation of quinoline carboxyguanidines as antidiabetic agents. Bioorg Med Chem Lett. 2000; 10(16): 1831-4, CrossRef.

Gendrot M, Andreani J, Boxberger M, Jardot P, Fonta I, Le Bideau M, et al. Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation. Travel Med Infect Dis. 2020; 37: 101873, CrossRef.

Nugraha RV, Ridwansyah H, Ghozali M, Khairani AF, Atik N. Traditional herbal medicine candidates as complementary treatments for COVID-19: A review of their mechanisms, pros and cons. Evid Based Complement Alternat Med. 2020: 2020: 2560645, CrossRef.

Große M, Ruetalo N, Businger R, Rheber S, Setz C, Rauch P, et al. Evidence that quinine exhibits antiviral activity against SARS-CoV-2 infection in vitro. Preprints. 2020: 2020; 2020070102, article.

Hamming I, Timens W, Bulthuis MLC, Lely AT, Navis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004; 203(2): 631-7, CrossRef.

Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med. 2020; 14(2): 185-92, CrossRef.

Barrow E, Nicola AV, Liu J. Multiscale perspectives of virus entry via endocytosis. Virol J. 2013;10: 177, CrossRef.

Sun Y, Tien P. From endocytosis to membrane fusion: Emerging roles of dynamin in virus entry. Crit Rev Microbiol. 2013; 39(2): 166-79, CrossRef.

Bray PG, Mungthin M, Hastings IM, Biagini GA, Saidu DK, Lakshmanan V, et al. PfCRT and the trans-vacuolar proton electrochemical gradient: Regulating the access of chloroquine to ferriprotoporphyrin IX. Mol Microbiol. 2006; 62(1): 238-51, CrossRef.

Colson P, Rolain JM, Lagier JC, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight COVID-19. Int J Antimicrob Agents. 2020; 55(4):105932, CrossRef.

Jackson CB, Farzan M, Chen B, Choe H. Mechanisms of SARS-CoV-2 entry into cells. Nat Rev Mol Cell Biol. 2022; 23(1): 3-20, CrossRef.

Pan S, Sharma P, Shah SD, Deshpande DA. Bitter taste receptor agonists alter mitochondrial function and induce autophagy in airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2017; 313(1): L154-65, CrossRef.

Sharma P, Yi R, Nayak AP, Wang N, Tang F, Knight MJ, et al. Bitter taste receptor agonists mitigate features of allergic asthma in Mice. Sci Rep. 2017; 7: 46166, CrossRef.

Khan MA, Khan ZA, Charles M, Pratap P, Naeem A, Siddiqui Z, et al. Cytokine storm and mucus hypersecretion in COVID-19: Review of mechanisms. J Inflamm Res. 2021; 14: 175-89, CrossRef.

Kumar SS, Binu A, Devan AR, Nath LR. Mucus targeting as a plausible approach to improve lung function in COVID-19 patients. Med Hypotheses. 2021: 156: 110680, CrossRef.




DOI: https://doi.org/10.18585/inabj.v15i6.2543

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