Chloroquine [CQ] is used to prevent and treat malaria and
is efficacious as an anti-inflammatory agent for the treatment of rheumatoid
arthritis and lupus erythematosus. Chloroquine (C18H26ClN3), a
4-amino-quinoline, has been demonstrated to have broad-spectrum antiviral
activities by increasing endosomal pH required for virus/cell fusion, as well
as interfering with the glycosylation of cellular receptors of SARS-CoV in cell
culture and in animal studies [1,2]. Interest in anti-corona virus treatments
was generated after the SARS coronavirus epidemic of 2003 , and has now been
greatly reignited with the Covid-19 epidemic ravaging the world. A recent open-label
non-randomized clinical trial from France in humans infected with Covid 19
receiving the related compound hydro-chloroquine sulfate [HCQS] showed a rapid
decline in viral cell counts and rapid progression to cure .
both antiviral and anti-inflammatory actions. Initial in-vitro evaluation
indicates the anti-viral action of chloroquine is mediated by inhibition of the
entry of the virus into the cells. On tissue culture therefore its efficacy is
therefore noted to be maximal in the early phase of the tissue culture being
infected, and its efficacy is noted to be limited in the late phase of the
infection [1, 2]
Both CQ and HCQ are weak
bases that are known to elevate the pH of acidic intracellular organelles, such
as endosomes/lysosomes, essential for membrane fusion . In addition, CQ
could inhibit SARS-CoV entry through changing the glycosylation of ACE2
receptor and spike protein . Time-of-addition experiment confirmed that HCQ
effectively inhibited the entry step, as well as the post-entry stages of
SARS-CoV-2, which was also found upon CQ treatment. Endosome maturation might
be blocked by CQ at intermediate stages of endocytosis, resulting in failure of
further transport of virions to the ultimate releasing site .
A number of recent publications have favoured the use
of chloroquine and its related compound HCQS against the novel corona virus 2019-nCoV;
SARS-CoV-2 [6-12]. Recently, the US Food and Drug Administration and the ICMR
has recommended weekly HCQS for health care workers exposed to Covid-19 [13,
14]. However there is no data on usage of topical CQ against COVID-19 pandemic.
Topical 0.03% Chloroquine Eye Drops are used in the
treatment of Dry Eye Disease (DED). A recently published prospective
comparative pilot study in 150 patients with mild to moderate DED, from our
institute, demonstrated its efficacy (and so its bio-availability) &
superiority to artificial tear drops alone (Carboxy methyl cellulose). Further,
there were also no adverse effects such as conjunctival hyperemia, increase in
ocular irritation or pain, blurring of vision or decreased field of vision was
reported in any case, indicating the safety of topical chloroquine drops .
proposal: [Dosage, safety, efficacy]
proposes to repurpose Chloroquine eye drops for nasal use in Covid-19 patients.
There is no scientific evidence so far that eye drops is not safe for nasal
mucosa. In fact, all eye drops administered to the eye, in any case rapidly
transit to the nose via the naso-lacrimal duct. The demonstrated efficacy and
safety of the available 0.03% Chloroquine eye drops (Uv Lubi Unims 0.03% Drops,
Manufactured by FDC Ltd)., as also regulatory approval of the same indicates of
its safety for such use . The very
low total dose per aliquot (0.3mg/ 1ml aliquot) again indicates to no concerns
with regard to the total dose exceeding the oral systemic dose.
studies report that the 50% effective concentration (EC50) of chloroquine for
the inhibition of SARS-CoV to be 8.8 microMolar (282 ug/100ml), and for
HCoV-OC43 to be 0.4 microMolar (12.8 ug/ml) [1, 2]. For novel SARS CoV -2, chloroquine at EC50 =
1.13 μM potently blocked virus infection and showed high safety index . The
concentration of chloroquine in the drops planned for treatment (0.03% i.e. 30
mg/ 100ml) is significantly above this EC50 and so inspires confidence with
regard to efficacy.
Nasal & Oropharyngeal Swabs on Day
0, Day 3, Day 7, Day 10 if necessary.
(Day of admission taken as Day 0)
Swabs shall be tested for a) Covid 19 Ag
b) Ct ( cycles to Test +ve- surrogate marker of viral
Ct values on Day 0, 3, 7, 10 shall be plotted on a graph for all patients.
rate of decline for each patient shall be calculated.
The time to cure (Covid 19 RT PCR -ve.)
shall be determined
two groups shall be compared for
of decline of Ct values
of Cure or alternate outcome
1. Keyaerts E,
Vijgen L, Maes P, Neyts J, Van Ranst M.
In vitro inhibition of severe acute respiratory syndrome coronavirus by
chloroquine.Biochem. Biophys. Res. Commun. 2004; 323:264–268.
2. Keyaerts E, Li
S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M, Maes P. Antiviral Activity of Chloroquine against
Human Coronavirus OC43 Infection in Newborn Mice. Antimicrobial Agents and
Chemotherapy, 2009, 58: 3416–3421
3. Gautret P,
Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J,
Giordanengo V, Vieira VE, Dupont HT, Honoré S, Colson P, Chabrière E, La Scola
B, Rolain JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a
treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Mar 20:105949.
4. Mauthe, M. et
al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome
fusion. Autophagy 14, 1435–1455 (2018).
5. Savarino, A. et
al. New insights into the antiviral effects of chloroquine. Lancet Infect. Dis.
6, 67–69 (2006)
6. Liu J, Cao R,
Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative
of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell
Discov. [Internet]. 2020;6:16. Available from: https://doi.org/10.1038/s41421-020-0156-0.
7. Wang M, Cao R,
Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively
inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res
8. Chen Z, Hu J,
Zhang Z, et al. Efficacy of hydroxychloroquine in patients with COVID-19:
results of a randomized clinical trial. Version 2. medRxiv 2020.03.22.20040758.
9. Yao X, Ye F,
Zhang M, Cui C, Huang B, Niu P, et al. 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). Clin Infect
Dis. 2020 Mar 9. pii: ciaa237. doi: 10.1093/cid/ciaa237. [Epub ahead of print]
10. Gao J, Tian Z,
Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in
treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends
2020 Feb 19. doi: 10.5582/bst.2020.01047. [Epub ahead of print]
11. 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 [Epub
ahead of print]
12. Colson P,
Rolain JM, Raoult D. Chloroquine for the 2019 novel coronavirus SARS-CoV- 2.
Int J Antimicrob Agents. 2020 Feb 15:105923. doi:
10.1016/j.ijantimicag.2020.105923. [Epub ahead of print]
13. Lenzer J.
Covid-19: US gives emergency approval to hydroxychloroquine despite lack of
evidence. BMJ 2020;369:m1335. 10.1136/bmj.m1335 32238355
14. Indian Council
for Medical Research. Recommendation for empiric use of hydroxychloroquine for
prophylaxis of SARS-CoV-2 infection. https://icmr.nic.in/sites/
3 April 2020
15. Titiyal JS,
Kaur M, Falera R, Bharghava A, Sah R, Sen S. Efficacy and Safety of Topical
Chloroquine in Mild to Moderate Dry Eye Disease. Curr Eye Res. 2019
Dec;44(12):1306-1312. doi: 10.1080/02713683.2019.1641824.