Slight pH Adjustment May Turn Metabolic Inhibitor Drug Into Promising COVID-19 Treatment

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Professor of Mechanical Engineering and Materials Science David Needham has shown that a slight increase in the pH of the solution might be enough to transform a metabolic inhibitor drug, traditionally used to treat intestinal parasites, into a promising prophylactic / preventative nasal spray and an early throat treatment spray for COVID-19[FEMININE[FEMININE

The results appear online December 28 in the journal Pharmaceutical research.

Since 1958, niclosamide has been used to treat parasitic intestinal infections in humans, pets and farm animals. Supplied as oral tablets, the drug kills parasites on contact by inhibiting their crucial metabolic pathway and cutting off their energy supply.

In recent years, however, researchers have tested the potential of niclosamide to treat a much wider range of diseases, such as many types of cancer, metabolic diseases, rheumatoid arthritis, and systemic sclerosis. Recent laboratory studies in cells have also shown that the drug is a potent antiviral drug, inhibiting a virus’s ability to cause disease by targeting the host cell’s energy supply that the virus co-opts for self-replication. .

Niclosamide acts primarily on the host cell’s mitochondria, which are like energy-producing batteries in the cell. The drug stops the cell from making its main energy molecule, adenosine 5′-triphosphate, or ATP. Without the energy supply to the infected cell, the virus finds it difficult to replicate viable copies of itself to cause other infections. These effects are reversible and do not cause cell death.

“Niclosamide lowers a cell’s energy dimmer and essentially blocks the virus,” said Needham, the sole author of the new study. When used in conjunction with vaccines, masking and other mitigation measures recommended for COVID prevention, the new niclosamide solution has potential as a backup strategy, he said. “This development could enable safe and effective nasal and pharyngeal sprays that provide additional protection behind the mask. “

Pivot in times of pandemic

In an ongoing collaboration with Will Eward, a surgical oncologist at Duke, Needham had previously shown that niclosamide has activity in bone cancer in mice and dogs when turned into a nanoparticle which, as he puts it, , “makes the medicine look like cancer food.” In another collaboration with Christina Barkauskas, assistant professor of medicine in pulmonary medicine at Duke, they were starting preliminary studies on the potential use of the same formulation of niclosamide for pulmonary fibrosis when the pandemic struck.

Like many researchers around the world, Needham has switched to studies led by COVID. After a Korean article examining the effectiveness of existing drugs against COVID-19 identified niclosamide as a potential target, it spent the following year researching a range of solution formulations, nanoparticles and microparticles. Korean studies in animal cells have shown that a low concentration of niclosamide is sufficient before infection to completely stop the replication of the SARS-COV-2 virus.

The animal cells used, however, are extremely tough and durable. To find out how effective and tolerable niclosamide might be for human use to fight COVID-19, Needham and Barkauskas turned to cells that were more relevant for the initial nasal and bronchial infection; respiratory epithelial cells; and hired other clinical researchers from Duke.

With no live virus to test with, the researchers focused on measuring the amount of niclosamide reducing ATP levels in cells of the human airways. Based on the ATP inhibition measurements against the virus from the Korean study, Patty Lee, professor of medicine, cell biology and pathology at Duke, and his postdoctoral fellow Sojin Kim, found that a few micromolar concentrations of the drug can lower ATP levels enough to potentially shut down virus reproduction completely without damaging the cells themselves.

These studies, however, were performed on cells submerged in cell culture media, which slows the rate at which niclosamide is absorbed and can act in cells. In other bench-top cell studies with Barkauskas and Zach Kelleher, a lab technician in his lab, researchers focused on cells in the human airways treated with only niclosamide buffered solution. Funded by a grant from the American Lung Association, the study suggests that even lower doses are enough to positively affect cells in the airways.

But these three studies do not take mucus into account.

The need for reformulation

Traditional allergy medications such as Flonase and Nasonex contain about 6000 to 30,000 times more of their respective active ingredients in solution than it would take to affect cells in laboratory studies. This is because only a small amount of the active drug passes the protective layer of mucus that constantly covers the back of people’s noses and throats.

Niclosamide, however, does not dissolve easily in water-based liquids that can be sprayed into a person’s nose and mouth. The normal attainable solution concentration of the drug at a nasal pH of about 6 or 7 is near or even lower than what laboratory studies suggest is necessary to prevent the virus from replicating in cells without protective mucus.

Based on calculations of how molecules like niclosamide diffuse through a thin layer of mucus, Needham estimates that a solution concentration about 10 times greater than that which can usually be achieved is required to produce a prophylactic spray and treatment function, and that it can pass through the mucus layer in milliseconds.

The question for Needham, then, was how to achieve this concentration.

PH adjustment

In the new article, Needham demonstrates that it is enough to increase the alkalinity of the solution to cross the mucous barrier and enter the cells where a COVID-19 infection first sets in. He found that raising the pH of the solution to a slightly alkaline pH of 8.0; acceptable for a nasal spray; can dissolve enough niclosamide to meet the requirements of its calculations. And increasing the pH to 9.2, which is still tolerable for a throat spray, beats that benchmark 10 times more and could be used early in the infection.

While promising, Needham notes, these results have yet to be tested in cells actually infected with COVID-19, as well as such cells protected by a layer of mucus, which requires finding partner laboratories and agencies with the resources. biocontainment and live viruses required.

A protocol for making liter-sized batches that can be filled and sealed into sterile-capped 10ml vials has already been developed in Duke’s Prep Pharmacy by Vincent Gaver, Clinical Research Pharmacist, and Beth McLendon. -Arvik, director of Investigational Drug Services. And in its new patent application, Needham also described a method for extracting niclosamide from commercially available tablets into solution without using organic solvents.

Because it acts on cells rather than the virus, niclosamide may work as a respiratory viral prophylactic agent, not only against COVID-19 and all of its variants, but also against any new virus. Although the vaccines are clearly effective, a nasal preventative would add additional protection. And even if an infection has already set in, this formulation could be used as an early treatment spray for the throat that could stop the viral load from making its way to the lungs, causing the disease’s most devastating effects. “

David Needham, study author

Needham has already applied for a patent and is actively seeking partners from industry, government and infectious disease institutes to help continue clinical trials and commercialization.

Source:

Journal reference:

Needham, D., (2021) The pH dependence of niclosamide solubility, dissolution, and morphology: motivation for potentially universal mucin-penetrating nasal and pharyngeal sprays for COVID19, its variants, and other viral infections. Pharmaceutical research. doi.org/10.1007/s11095-021-03112-x.


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