Exploring the room for repurposed hydroxychloroquine to impede COVID-19: toxicities and multipronged combination approaches with pharmaceutical insights

ABSTRACT

Introduction: SARS-CoV-2 has fatally affected the whole world with millions of deaths. Amidst the dilemma of a breakthrough in vaccine development, hydroxychloroquine (HCQ) was looked upon as a prospective repurposed candidate. It has confronted numerous controversies in the past few months as a chemoprophylactic and treatment option for COVID-19. Recently, it has been withdrawn by the World Health Organization for its use in an ongoing pandemic. However, its benefit/risk ratio regarding its use in COVID-19 disease remains poorly justified. An extensive literature search was done using Scopus, PubMed, Google Scholar, www.cdc.gov, www.fda.gov, and who.int.

Areas covered: Toxicity vexations of HCQ; pharmaceutical perspectives on new advances in drug delivery approaches; computational modeling (PBPK and PD modeling) overtures; multipronged combination approaches for enhanced synergism with antiviral and anti-inflammatory agents; immuno-boosting effects.

Expert commentary: Harnessing the multipronged pharmaceutical perspectives will optimistically help the researchers, scientists, biotech, and pharmaceutical companies to bring new horizons in the safe and efficacious utilization of HCQ alone or in combination with remdesivir and immunomodulatory molecules like bovine lactoferrin in a fight against COVID-19. Combinational therapies with free forms or nanomedicine based targeted approaches can act synergistically to boost host immunity and stop SARS-CoV-2 replication and invasion to impede the infection.

KEYWORDS:

• SARS-CoV-2
• toxicity
• hydroxychloroquine
• pharmaceutical considerations
• drug delivery
• immunomodulation
• combinational therapy
• remdesivir
• angiotensin-converting enzyme-2

Article Highlights

• Safe and effective use of hydroxychloroquine (HCQ) in a battle with COVID-19 for chemoprophylaxis and treatment.

• Various HCQ associated toxicities with considerable benefit/risk ratio for vulnerable population.

• Pharmaceutical advances based on computational modelling (PBPK and PD modelling) with recent advances in drug delivery approaches.

• Retrospective learnings for dose adjustment for the vulnerable population.

• Multipronged combination approaches for enhanced synergism with antiviral and anti-inflammatory agents, and immuno-boosting effects.

Declaration of interest

A. Jain gratefully acknowledges financial support from the DBT-RA program (Govt. of India) in Biotechnology and Life Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Abbreviations

Abs Antibodies

ACE Angiotensin Convertase Enzyme

ACEIs ACE inhibitor

AKI Acute kidney injury

ARDS Acute respiratory distress syndrome

AZT Azithromycin

B.I.D. Two times a day

BDCQ Bisdesethylchloroquine

bLf Bovine lactoferrin

CADD Computer-aided drug design

CDC Centres for Disease Control and Prevention

cGAS GMP-AMP Synthase

COPD Chronic Obstructive Pulmonary Disease

CQ Chloroquine

DCGI Drug Controller General of India

DCQ Desethylchloroquine

DHCQ Desethylhydroxychloroquine

DMT1 Divalent metal transporter 1

EC₅₀Half maximal effective concentration

G6PD Glucose-6-Phosphate Dehydrogenas

GI Gastrointestinal

HCoVs Human coronaviruses

HCQ Hydroxychloroquine

HSPGs Heparan sulfate proteoglycanes

IC₅₀Half maximal inhibitory concentration

ICMR Indian Council of Medical Research)

IL Interleukin

MAP Mitogen-Activated Protein

MHC Major Histocompatibility Complex

Mpro Main protease

NAC N- acetyl-cysteine

NIMHANS National School of Mental Health and Neurosciences

NYR Not yet recruiting

PBPK Pharmacokinetic models

PBPK Physiologically based pharmacokinetic

PD Pharmacodynamic

PGA-co-PDL Poly(glycerol adipate-co-ω-pentadecalactone)

PICALM Phosphatidylinositol Binding Clathrin Assembly Protein

Q.D. Once in a day

QIVIVE Quantitative in vitro to in vivo extrapolation

RPE Retinal pigment epithelium

STING Stimulator of Interferon Genes

T.I.D. Three times a day

TB Tuberculosis