Ivermectin and Nitazoxanide Combination Therapy for COVID-19

Selected Drugs

Ivermectin has anti-parasitic effect along with anti-viral activity against a broad range of
viruses in vitro. Ivermectin was identified as an inhibitor of interaction between the human
immunodeficiency virus-1 (HIV-1) integrase protein (IN) and the importin (IMP) α/β1
heterodimer responsible for IN nuclear import. Ivermectin has since been confirmed to inhibit
HIV-1 replication. Importantly, Ivermectin has been demonstrated to limit infection by RNA
viruses such as West Nile Virus and influenza. This broad-spectrum activity is believed to be
due to the reliance by many different RNA viruses on IMPα/β1 during infection. Ivermectin has
similarly been shown to be effective against the DNA virus pseudorabies virus (PRV) both in
vitro and in vivo. Finally, Ivermectin was the focus of a phase III clinical trial in
Thailand against DENV infection, in which a single daily oral dose was observed to be safe
and resulted in a significant reduction in serum levels of viral NS1 protein, but no change
in viremia or clinical benefit was observed.

The causative agent of the current COVID-19 pandemic, SARS-CoV-2, is a single stranded
positive sense RNA virus that is closely related to severe acute respiratory syndrome
coronavirus (SARS-CoV). Studies on SARS-CoV proteins have revealed a potential role for
IMPα/β1 during infection in signal-dependent nucleocytoplasmic shutting of the SARS-CoV
nucleocapsid protein that may impact host cell division. In addition, the SARS-CoV accessory
protein ORF6 has been shown to antagonize the antiviral activity of the STAT1 transcription
factor by sequestering IMPα/β1 on the rough ER/Golgi membrane.

Taken together, these reports suggested that Ivermectin's nuclear transport inhibitory
activity may be effective against SARS-CoV-2. Interestingly, it has been postulated that the
FDA-approved drug Ivermectin inhibits the replication of SARS-CoV-2 in vitro whereas a single
treatment was able to provoke approximately 5000-fold reduction in viral load within 48h.
Ivermectin has an established safety profile for human use. Recent reviews and meta-analysis
indicate that high dose Ivermectin has comparable safety as the standard low-dose treatment,
although there is not enough evidence to make conclusion about the safety profile in
pregnancy. In clinical setting, Ivermectin was the focus of a phase III clinical trial on
patients with dengue viral infection in Thailand, in which a single daily dose (200 - 400
µg/kg once daily for 2 days in one arm and 200-400 µg/kg once daily for 3 days in the other
arm) was found to be safe but did not produce any clinical benefit. In previous clinical
study, one dose of Ivermectin 200 μg/kg or four doses of Ivermectin 200 μg/kg (given on days
1, 2, 15, and 16) for the treatment of non-disseminated strongyloidiasis were implicated. The
author proposed that, multiple doses of Ivermectin did not show higher efficacy and was
tolerated less than a single dose. A single dose should, therefore, be preferred for the
treatment of non-disseminated strongyloidiasis.

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 TNFα, 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 Ivermectin 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.

Common Side Effects of Ivermectin

- Itching and rash

- Swelling

- Headache

- Joint pain

- Pink eye, inflammation of the eyes or discomfort

- Dizziness and drop in blood pressure upon standing

- Racing heart beat

- Changes in liver function tests

- Serious Side Effects of Ivermectin (Generally with Ivermectin tablets)

- Severe skin reactions

- Seizures

- Asthma flare-up

- Changes in vision

- Sudden drop in blood pressure

- Dizziness upon standing

- Liver dysfunction

- Bleeding

Drug interactions of Ivermectin

1. Warfarin and Coumarin Ivermectin may decrease the anticoagulant activities of warfarin
and 4-hydroxycoumarin

2. Albendazole The metabolism of Albendazole can be increased when combined with Ivermectin

3. Doxycyline

Additive pharmacodynamic effect

- Contraindication of Ivermectin

- Abnormal liver function tests

- Allergies towards Ivermectin

- 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 should be used when administering Nitazoxanide to nursing women.

Interactions of Nitazoxanide

- 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 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 Ivermectin 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
COVID-19 patients 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).