Uncontrolled mass use of hydroxychloroquine

Tugolbai Tagaev*1, Sagynali Mamatov2, Farida Imanalieva2, Vityala Yethindra3, Altynai Zhumabekova4, Aizhan Bazarbaeva5, Yogesh Parihar6 1Department of Pathology, International Higher School of Medicine, International University of Kyrgyzstan, Bishkek-720054, Kyrgyzstan 2Department of Hospital Internal Medicine, Occupational Pathology with a Course of Hematology, I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek-720020, Kyrgyzstan 3International Higher School of Medicine, International University of Kyrgyzstan, Bishkek-720054, Kyrgyzstan 4Gynecologist, Clinical Maternity Hospital No. 2, Bishkek-720010, Kyrgyzstan 5I.K. Akhunbaev Kyrgyz State Medical Academy, Bishkek-720020, Kyrgyzstan 6International Higher School of Medicine, International University of Kyrgyzstan, Bishkek-720054, Kyrgyzstan


INTRODUCTION
In addition to being an antimalarial drug, hydroxychloroquine (HCQ) also exhibits antiin lammation and immunomodulation by regulating the production of TNFα, interferons, and some cytokines (Weber and Levitz, 2000;Müller-Calleja et al., 2017). HCQ inhibits replication in a variety of viruses (Miller and Lenard, 1981). Even anti-viral properties mechanisms are not well known, HCQ is a weak base that accumulates in lysosomes, modi ies their pH, and interferes with some enzymes. Thus, HCQ can inhibit the pH-dependent entry of some viruses into host cells, or even block the enveloped viruses replication by inhibition the glycosylation of envelope proteins (Savarino et al., 2006). These in vitro anti-viral effects suggest the potential use of HCQ in the treating viral infections, against which there are no effective drugs, or against which drugs exist but cannot be seen globally, mostly in low-income countries (Savarino et al., 2003).

RISKS OF UNCONTROLLED MASS USE
In the lack of con irmed ef icacy, the initial potential risk is not to expose patients to adverse effects. The common side effects are abdominal pain or diarrhoea, which seen in almost 10% of patients as well as pruritus and rashes. Headache, dizziness, and tinnitus have also been reported. Additionally, adverse psychiatric effects ranging from anxiety disorders and insomnia to psychotic decompensations are even reported. Psychotic side effects, such as hallucinations and delusions, are frequent than depression. Serious psychiatric effects resulting from HCQ treatment are infrequent within the structure of conventional prescription. Because of the anxiety-provoking nature of the coronavirus disease 2019 (COVID-19) pandemic, and the desire to limit the spread of the disease, the prevalence of these undesirable effects is likely to increase.
HCQ also induces adverse cardiac effects due to its inhibitory effect on the human ether-a-go-go-related gene (hERG) potassium (K + ) channels, which repolarize phase 3 cardiomyocyte action potentials in potassium ef lux. This effect increases the risk of a prolonged corrected QT interval (QTc) on a surface electrocardiogram (ECG) (Borsini et al., 2012). Although this toxicity is dose-dependent and, cases of serious arrhythmias are shown at therapeutic doses. Risk factors for QTc prolongation that can facilitate such arrhythmias include a slow heart rate (<55 bpm) and female sex (Drici and Clément, 2001) as well as hypokalemia in combination with other drugs that lengthen the QTc.
Hypokalemia often occurs in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), possibly due to the particular tropism of SARS-CoV-2 concerning Angiotensin-converting enzyme 2 (ACE2) (French Society of Pharmacology and Therapeutics, 2020). Additionally, diarrhoea and vomiting may accompany the infection. It is important to check serum K+ levels and rectify any hypokalemia before HCQ treatment, which can itself cause diarrhoea. Relatively, the combination of azithromycin, which causes QT prolongation, with HCQ, justi ies reinforced monitoring with ECGs, mostly, initiation of therapy and within 3-4 h after the administration of the irst dose. It should then be monitored two times a week for the treatment duration or in the event of symptoms suggestive of dysrhythmia. The dose-limiting adverse effect of HCQ is the retinopathy risk, which affects 8% of treated patients, mostly at high doses (> 5 mg/kg) or prolonged treatment (> 5 years) (Jorge et al., 2018).
HCQ is metabolized by cytochrome P450 (CYP) isoforms, especially 3A4/5, 2D6, and 2C8, there is an elevated risk of adverse effects with drugs that inhibit these CYPs. If it is COVID-19, interest should be taken with other anti-virals, such as the lopinavir/ritonavir (LPV/R), which inhibits CYP3A. In France, several cases of serious adverse cardiac effects have been linked to the treatment with HCQ in COVID-19 patients.
Remdesivir showed inhibition against SARS-CoV and MERS-CoV in human airway epithelial cells, at early stages of replication by inhibiting viral RNA synthesis (Yethindra, 2020). The LPV/R, a strategy that prescribed for many years to treat HIV patients; LPV/R in the presence of interferon-β, an immunomodulatory and anti-viral drug, and HCQ. In this study, treatment with one of these drugs in the 29 days preceding randomization was a criterion for non-inclusion. The inability to quickly conclude the effectiveness of these different treatments would be extremely detrimental to public health. In the context of a pandemic, it is dif icult to conduct randomized controlled trials until such pandemics are brought under control.

USE OF HCQ IN COVID-19
At the present COVID-19 pandemic, in vitro data showed that HCQ has some anti-viral activity against SARS-CoV-2 compared to other drugs, with a lower half-maximal effective concentration for HCQ (0.72 µM vs 5.47 µM), showing that it is more potent (Yao et al., 2020). HCQ should not be used, except in severe cases where patients have been hospitalized, and based on decisions made by doctors and under strict medical supervision. HCQ should not be prescribed to healthy people or for non-life-threatening cases of COVID-19.
HCQ is prescribed in treating autoimmune diseases (Mok, 2017). Within the framework of the management of COVID-19, high variability in concentrations is expected in the light of the people likely to be treated (i.e., old or dialysis patients) (Guilhaumou et al., 2019). Additionally, given the short duration of the proposed treatment, steady-state concentrations may not be reached, thereby increasing pharmacokinetic variability. Based on our indings, we estimated that the low threshold was 0.1 µg/mL and 0.3 µg/mL for plasma and total blood assay. These values may change depending on future data.

CONCLUSION
HCQ showed in vitro activity against SARS-CoV-2, and high-quality research studies are conducted at present. It is important that we can recruite COVID-19 patients in these research studies to generate appropriate data regarding drugs that show promising ef icacy against COVID-19. The absence of conirming bene its related to existing averse effects of HCQ. Although it is relatively well tolerated at therapeutic doses and for a short time, it is a drug with a narrow therapeutic window and one that requires cardiac and pharmacological monitoring to limit the severe adverse effects already reported in COVID-19 patients. This is particularly true considering polypharmacy, especially with azithromycin. Therefore, HCQ treatment must be limited to use in clinical environments and under appropriate supervision.