key: cord-319379-qe56u93a authors: Patil, Vaishali M.; Singhal, Shipra; Masand, Neeraj title: A systematic review on use of aminoquinolines for the therapeutic management of COVID-19: Efficacy, safety and clinical trials date: 2020-05-11 journal: Life Sci DOI: 10.1016/j.lfs.2020.117775 sha: doc_id: 319379 cord_uid: qe56u93a Recent global outbreak of the pandemic caused by coronavirus (COVID-19) emphasizes the urgent need for novel antiviral therapeutics. It can be supplemented by utilization of efficient and validated drug discovery approaches such as drug repurposing/repositioning. The well reported and clinically used anti-malarial aminoquinoline drugs (chloroquine and hydroxychloroquine) have shown potential to be repurposed to control the present pandemic by inhibition of COVID-19. The review elaborates the mechanism of action, safety (side effects, adverse effects, toxicity) and worldwide clinical trials for chloroquine and hydroxychloroquine to benefit the clinicians, medicinal chemist, pharmacologist actively involved in the management of COVID-19 infection. J o u r n a l P r e -p r o o f chronic treatment the drugs gets accumulated in tissues [95] . The selected anti-malarial drugs have been used for last 70 years. They are economic, have proven safety profile and are categorized as essential medicines by World Health Organization (WHO) [96] . Aminoquinolines have effectively reduced viral replication in Zika virus, Chikungunya virus, SARS-associated coronavirus (CoV) and MERS-CoV [97] [98] [99] [100] . Chloroquine and hydroxychloroquine has shown inhibition of SARS-CoV-2 replication [101] . Clinical trials have demonstrated the effective role of chloroquine phosphate (dose 500 mg/day) against COVID-19 [102] . The N-hydroxyethyl substituted derivative of chloroquine, hydroxychloroquine is less toxic, more soluble and has similar activity towards COVID-19 inhibition. There is continuous requirement to explore the molecular mechanism towards underlying antiviral action and clinical benefits of aminoquinolines and the toxicity profile. The detailed outcomes will help to design the randomized clinical trials [95, [103] [104] [105] [106] [107] . The present manuscript provides a systematic review of mechanism of action, efficacy, and safety of chloroquine and hydroxychloroquine for the treatment of COVID-19. For viral replication, a stable acidic pH of endosomes, lysososmes, Golgi complex of host is required. The bioaccumulation properties of both the selected aimnoquinolines explain the antiviral mechanism of their action [108] . Chloroquine increases the pH of intracellular vacuoles. In lysosomes, it alters the catalysis of the protein degradation pathways through acidic hydrolases. It also alters endosomal macromolecule synthesis and in Golgi apparatus it affects post-translational modifications. The antirheumatic response is produced by interfering with the J o u r n a l P r e -p r o o f When compared for pharmacological profile, chloroquine and hydroxychloroquine possess equivalent anti-malarial activity. The later is preferred due to lower ocular toxicity [115] . Theoretically, the antiviral activity for chloroqunie and hydroxychloroquine are similar but the reported clinical details for chloroquine are more in number [116] . Use of chloroquine is less due to some associated adverse effects and lack of availability in some countries. In patients with COVID-19 infection hydroxychloroquine is preferred as chloroquine when used in combination with lopinavir or ritonavir shows prolongation of the QT interval. Some of the other antiviral therapeutics that does not interfere with hydroxychloroquine is oseltamivir, lopinavir/ritonavir, robavirin, interferons, and immunoglobulins (intravenous) [117] . The toxicological properties reported with use of chloroquine and hydroxychloroquine are retinopathy, neuromyopathy and cardiomyopathy. Both these drugs possess affinity for melanin and affect the macular cones. The phagocytic activity of lysosomes is declined on the photoreceptors and they migrate towards central and peripheral regions as well as induces epithelial atrophy and irreversible alterations in photoreceptors [106] . In the lysosomes, hydroxychloroquine is protonated and accumulated due to its basic nature. It inhibits the activity of lysosomal phospholipases causing vacuolization of cardiac and skeletal muscle cells [118] . Prolong use of hydroxychloroquine producesi) toxicity to retina tissue which may lead to irreversible retinopathy [119] [120] ; ii) Cardiotoxicity and CNS toxicity with neuromyopathy symptoms and alterations in gastrointestinal tract [121] ; toxicity to liver cells (genetic material) [122] ; and genotoxicity [123] [124] . Studies have shown substantial increase in retinal toxicity with chronic treatment based on the hypothesis of bioaccumulation [125] . Some investigators report < 2 % incidences of retinopathy and more common in Asian patients [126] [127] . Some studies failed to report cardiac complications and neuromyopathy and may be rare after longterm treatment [128] [129] . The monitoring of side effects need to be continued even after discontinuation of treatment due to prolong half-life of chloroquine and hydroxychloroquine. The side effects (keratopathy, maculopathy) may be delayed. The current anti-COVID-19 therapeutic regimen suggests longer duration of treatment with chloroquine than that as antimalarial drug. Thus close monitoring of the adverse reactions, pharmacological effects, poisoning and toxicological mechanisms to provide help to the worldwide clinical work [110] . Table 1 for ease of access to medical fraternity. For therapeutic use of aminoquinolines (chloroquine and hydroxychoroquine) the important aspects arei) it will be administered to millions of infected patients with COVID-19, ii) It will be administered to medical workers as preventive measure, iii) during acute approach against COVID-19 higher dose will be administered as compared to use during the treatment of chronic rheumatic diseases [141] . Following points can be concluded and to be considered during the use ix) The toxicity is associated with the dose calculated by real weight and therefore dose should be suitable for patients with potential high risk of adverse effects. Cumulative dose > 203 mg/kg body weight/day is under high risk category. [142] . In the absence of sufficient clinical data, detailed information on safety, adverse effects, dose of aminoquinolines (chloroquine and hydroxychloroquine), etc. should be made available among health professionals who will dissipate it among patients. The successful application of available resources needs to be grounded in practices to minimize risk of rigorous screening and dose calculation. The species severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2 Will novel virus go pandemic or be contained? 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The work is not supported by any funding agency.