Hydroxychloroquine and Nitazoxanide Combination Therapy for COVID-19

Selected Drugs

Hydroxychloroquine (an analog of chloroquine) has been demonstrated to have an anti-SARS-CoV
activity in vitro. Hydroxychloroquine clinical safety profile is better than that of
chloroquine (during long-term use) and allows higher daily dose and has fewer concerns about
drug-drug interactions. Hydroxychloroquine has long-term safety (600 mg/day for 12 to 18
months was safe). Hydroxychloroquine effectively inhibited both the entry, transport and the
post-entry stages of SARS-CoV-2, similar to the chloroquine, and one study found
Hydroxychloroquine to be a more potent agent than chloroquine in inhibiting SARS-CoV-2 in
vitro. Hydroxychloroquine acts as a weak base that can change the pH of acidic intracellular
organelles including endosomes/lysosomes, essential for the membrane fusion. Besides, the
significant decrease in the production of pro-inflammatory markers and cytokines with
Hydroxychloroquine has made this agent a successful disease modifying anti-inflammatory agent
in the treatment of various autoimmune diseases. An additional issue to be considered in
severely sick patients is cytokine storm associated with disease severity of SARS-CoV-2.

There are no currently available data from randomized clinical trials (RCTs) to inform
clinical guidance on the use, dosing, or duration of Hydroxychloroquine for prophylaxis or
treatment of SARS-CoV-2 infection. Although optimal dosing and duration of Hydroxychloroquine
for treatment of COVID-19 are unknown, some U.S. clinicians have reported anecdotally
different Hydroxychloroquine dosing such as 400 mg twice daily on day one, then daily for 5
days; 400 mg twice daily on day one, then 200 mg twice daily for 4 days; 600 mg twice daily
on day one, then 400 mg daily on days 2-5. In a recent clinical trial, Hydroxychloroquine
sulfate 200 mg, three times per day during ten days was used in patients with COVID-19.

Nitazoxanide is originally developed as an antiprotozoal agent and has a broad-spectrum
antiviral activity undergoing development for the treatment of influenza and other viral
respiratory infections. In addition to its antiviral activity, Nitazoxanide inhibits the
production of pro-inflammatory cytokines TNF-α, IL-2, IL-4, IL-5, IL-6, IL-8 and IL-10 in
peripheral blood mononuclear cells. Nitazoxanide could improve outcomes in patients infected
with MERS-CoV by suppressing overproduction of pro-inflammatory cytokines, including IL-6.
Nitazoxanide has been tested in clinical setting for the treatment of acute uncomplicated
influenza, where the subjects received either 600 or 300 mg of Nitazoxanide or placebo orally
twice daily for five days and were followed for 28 days. Subjects who received Nitazoxanide
600 mg twice daily experienced shorter times to alleviation of symptoms compared with
subjects who received 300 mg Nitazoxanide twice daily, which in turn, was shorter than
placebo.

According to the National Health Commission of the People's Republic of China, there is lack
of effective antiviral therapy against COVID-19. Nearly all patients who suffered from
COVID-19-associated pneumonia accepted oxygen therapy and WHO recommended extracorporeal
membrane oxygenation (ECMO) to patients with refractory hypoxemia. Rescue treatment with
convalescent plasma and immunoglobulin G are delivered to some critical cases according to
their condition.

The rationale of the use of Hydoxychloroquine and Nitazoxanide combination for treatment of
COVID-19 infected patients is based on the antiviral and anti-inflammatory activity of the
selected drugs. Since the two drugs exhibit different modes of action, it would be of value
in containing the viral infection through targeting different sites in the pathophysiology of
the disease.

Diagnostic criteria

The viral research institution in China has conducted preliminary identification of the
SARS-CoV-2 through the classical Koch's postulates and observing its morphology through
electron microscopy. So far, the golden clinical diagnosis method of COVID-19 is nucleic acid
detection in the nasal and throat swab sampling or other respiratory tract samplings by
real-time PCR and further confirmation by next-generation sequencing.

Side effects of Hydroxychloroquine

- The most common adverse effects are mild nausea and occasional stomach cramps with mild
diarrhea, reduced appetite and vomiting

- The most serious adverse effects are retinopathy and heart problems

- Long term use may cause liver toxicity Contraindications of Hydroxychloroquine

- Heart conditions, diabetes or psoriasis.

- The drug transfers into breast milk so should be used with care by pregnant or nursing
women

Interactions of Hydroxychloroquine

- Antacids may decrease the absorption of Hydroxychloroquine.

- Both neostigmine and pyridostigmine antagonize the action of Hydroxychloroquine.

- There may be a link between Hydroxychloroquine and hemolytic anemia in those with
glucose-6-phosphate dehydrogenase deficiency.

- Digoxin; concomitant administration with Hydroxychloroquine may result in increased
serum digoxin levels.

- Insulin or antidiabetic drugs; concomitant administration with Hydroxychloroquine may
enhance the effects of the hypoglycemic treatment.

- Hydroxychloroquine prolongs the QT interval and may increase the risk of inducing
ventricular arrhythmias if used concurrently with other arrhythmogenic drugs.

- Mefloquine and other drugs that lower the convulsive threshold, when co-administered
with Hydroxychloroquine, there may be an increased risk of convulsions.

- Concurrent use of Hydroxychloroquine with antiepileptics may impair the antiepileptic
activity.

- Cyclosporin when used concomitantly with Hydroxychloroquine, an increased plasma
cyclosporin level was reported.

Side effects of Nitazoxanide

The most common adverse effects are GIT as nausea and occasional stomach cramps with mild
diarrhea, reduced appetite and vomiting. Nervous system side effects as headache, dizziness,
somnolence, insomnia, tremor, and hypesthesia have been reported in less than 1% of the
patients.

Contraindications of Nitazoxanide

There are no data on the excretion of Nitazoxanide into human milk. The manufacturer
recommends that caution be used when administering Nitazoxanide to nursing women.

Tizoxanide (the active metabolite of Nitazoxanide) is highly bound to plasma protein (>
99.9%). Therefore, it is necessary to monitor for adverse reactions when administering
Nitazoxanide concurrently with other highly plasma protein-bound drugs with narrow
therapeutic indices, as competition for binding sites may occur (e.g., warfarin).

Warning

Nitazoxanide should be used with caution in patients with significant renal and hepatic
impairment.

Research Objectives

The pandemic disease COVID-19 is particularly of major importance in Egypt where a heavy
population lives. There is an acute need for comprehensive, continuous, and cost-effective
health care delivery for infected people. Early detection and strategies for prevention of
progression of COVID-19 would make a major difference for these patients and would also be
economically beneficial for a resource-constrained country.

This research proposal was employed as a practical strategy for providing a suitable drug
combination for possible treatment of COVID-19 infected patients. This drug combination may
help to prevent the progression of respiratory complications. This can be achieved through
different goals as follows:

1. Screening of different drugs related to different pharmacological classes depending on
its possible activity against COVID-19 virus.

2. Providing cost-effective and easy-to-implement treatment strategy for infected patients
and/or patients with high risk of developing respiratory failure.

3. Finally, this clinical strategy remains an important goal in improving the Egyptian
health state which can save people life and save a lot of money.

Scope of Work

The scope of work will be conducted through:

1. Use of new drug combination of Hydroxychloroquine and Nitazoxanide for treatment of
COVID-19 infected people. Since the two drugs exhibit different modes of action, it
would be of value in containing the viral infection through targeting different sites in
the pathophysiology of the disease.

2. Evaluation of the effect of new drug combination on the symptomatic treatment of newly
diagnosed COVID-19 patients through a clinical trial designed according to WHO (clinical
management of severe acute respiratory infection (SARI) when COVID-19 disease is
suspected) interim guidance published at 13 March 2020.

3. Investigating the impact of new drug combination on the prevention of severe
compilations such as acute respiratory distress syndrome (ARDS).