key: cord-0728061-tqj2s9qf authors: Choudhary, Renuka; Sharma, Anil K. title: Potential use of hydroxychloroquine, ivermectin and azithromycin drugs in fighting COVID-19: trends, scope and relevance date: 2020-04-22 journal: New Microbes New Infect DOI: 10.1016/j.nmni.2020.100684 sha: 4a58abcf7971920a4aee6b6994578851c30f6c72 doc_id: 728061 cord_uid: tqj2s9qf Abstract Alarming situation has been caused due to the emergence of COVID-19 infection around the world. There is an urgency of developing a therapeutic strategy in order to control the spread of COVID-19. Towards that initiative, potential drugs like hydroxychloroquine, ivermectin and azithromycin have been tested by diverse group of researchers worldwide for their potential against novel coronavirus. The present report presents together the comprehensive knowledge derived from the major researches about the above drugs altogether in context of the current health emergency around the world. Hydroxychloroquine and ivermectin were known to act by creating the acidic environment and inhibiting the importin (IMPα/β1) mediated viral import. Azithromycin was found to act similar to the hydroxychloroquine as an acidotropic lipophilic weak base. All the three categories of drugs seemed to potentially act against novel coronavirus infection. However, their efficacies need to be studied in detail individually and in combination in-vivo in order to combat COVID-19 infection. and Azithromycin [6] , have shown therapeutic effects against novel coronavirus infection. However, it was not reported that which drug has better efficacy in comparison to other or a combination of them can give life saving results. Therefore, the present report has been able to provide the comprehensive view of combining the knowledge of these drugs altogether in the context of current health emergency around the world. The first category of drug was Chloroquine and its safer derivative hydroxychloroquine which may act as a therapeutic agent against COVID-19 infection. Earlier both have been used widely for the treatment of rheumatoid arthritis and systemic lupus erythematosus. Chloroquine was initially used for the treatment of malaria, but Plasmodium falciparum substantially developed resistance against it. With the subsequent development of new antimalarials, this drug is now being used for the prophylaxis of malaria. In 1946, by the introduction of hydroxyl group into chloroquine, a derivative was produced known as Hydroxychloroquine and was found to have less acute poisoning than the former one [7] . Both the drugs otherwise, share a similar mechanism of action and structure. These drugs tend to increase the pH within intracellular vacuoles and act as weak base. In addition, they are known to alter processes such as protein degradation by acidic hydrolases in the lysosome, assembly of macromolecules in the endosomes, and post translation modification of proteins in the Golgi apparatus [8] . Over the past few decades this drug has received wider attention, as a potential antiviral drug. Chang and his colleagues in 2014 revealed that hydroxychloroquine activates the host anti-viral innate immunity [9] . This drug accumulates in the cellular organelles creating acidic environment to Another study revealed that ivermectin which is a broad spectrum anti-parasitic drug demonstrated its efficacy against COVID-19 which comes as a second line of drug [5] . Ivermectin is FDA approved drug, known to have wide-spectrum antiviral activity against number of viruses under in vitro conditions [10, 11, 12 and 13] . SARS-CoV-2 (causative agent of COVID-19) is a single stranded RNA virus (positive sense) which is closely related to SARS conditions revealed that it can inhibit the viral replication. The single treatment of this drug was able to reduce the virus up to 5,000-fold in culture within 48h. However, no further reduction was reported with further increase in time period i.e up to 72h. Moreover, no toxicity was seen with the drug at any point of time [5] . Mechanism by which ivermectin responded against the CoV-19 virus is not known and was believed to be working similarly as it acted on other viruses. It was known to inhibit the nuclear import of viral and host proteins. Integrase protein of viruses and the importin (IMP) α/β1 heterodimer was responsible for IN nuclear import which further increases the infection (Figure 2) . As most of the RNA viruses are dependent upon IMPα/β1 during infection, Ivermectin acts on it and inhibits the import with the increase in antiviral response [5 and 14] . Third category of therapeutic drug is Azithromycin, which is a class of antibiotics known as macrolide, used to treat infections like bronchitis, pneumonia and MAC (Mycobacterium avium complex) infection. With the spread of the SARS-CoV-2 viral pneumonia, which started in Wuhan, China, many countries of the world started developing countermeasures in order to decrease the spread of the disease. Researchers found that apart from hydroxychloroquine, another FDA approved drug known as Azithromycin was shown to have therapeutic effects against COVID-19 in a study done by a research group at New Mexico University. The researchers were able to prove that azithromycin acted as an acidotropic lipophilic weak base which modulate the pH of endosomes and trans-Golgi network (Figure 2) . This further led to in vitro effects on intracellular organelles similar to the one as conferred by hydroxychloroquine [15] . This further indicates that this antimicrobial drug has an immense therapeutic value as far as the treatment of COVID-19 patients is concerned. Clinical trials need to be carried out with this drug as it can act as a prophylaxis for declining the infection rate. These drugs have been shown to have a potential broad-spectrum antiviral response in vitro against many viruses including coronaviruses. However, hydroxychloroquine has been found to be associated with dangerous side-effects in the past if the dosage is not carefully controlled. There have been many cases of chloroquine poisoning reported in Nigeria and the USA as well. Due to sudden rapid increase in demand of the above broad-spectrum drugs, may lead to significant shortage for patients who rely on these drugs to treat their other disorders like malaria, rheumatoid arthritis among others. Therefore, adequate buffer stocks should be maintained for these drugs to overcome potential scarcity of the above-mentioned drugs. All three categories of drugs seem to act against novel coronavirus infection. However, further research using large cohort of samples with randomized controlled clinical trials are urgently required for each drug alone and in-combination in order to find a concrete solution against COVID-19 infection. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro In vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Hydroxychloroquine and azithromycin as a treatment of COVID19: results of an open-label non-randomized clinical trial The FDA-approved Drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells Review of side effects and toxicity of chloroquine Mechanism of action of hydroxychloroquine as an antirheumatic drug Hydroxychloroquine activates host antiviral innate immunity Evaluation of cytotoxicity and antiviral activity of ivermectin against Newcastle disease virus Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import Kehn-Hall K. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan Equine Encephalitis Virus replication Inhibitors of nuclear transport Azithromycin and ciprofloxacin have a chloroquine-like effect on respiratory epithelial cells The authors express sincere thanks to the Chancellor, Maharishi Markandeshwar deemed to be University, Mullana for providing necessary facilities for writing on pandemic research. The author has no conflict of interest to declare.