Mechanical engineering and materials science professor David Needham has shown that a slight increase in the pH of the solution could be enough to turn a metabolism-inhibiting drug traditionally used to treat intestinal parasites into a promising prophylactic / preventive nasal spray and throat spray for early treatment transform COVID-19.
The results will appear online in Pharmaceutical Research on December 28th.
Niclosamide has been used to treat intestinal parasite infections in humans, pets and farm animals since 1958. Administered as oral tablets, the drug kills the parasites on contact by inhibiting their crucial metabolic pathway and interrupting their energy supply.
In recent years, however, researchers have tested niclosamide’s potential to treat a much wider range of diseases, including many cancers, metabolic disorders, rheumatoid arthritis, and systemic sclerosis. Recent laboratory studies on cells have also shown that the drug is a potent antiviral drug that inhibits a virus’ ability to cause disease by targeting the host cell’s energy supply, which the virus uses for its self-replication.
Niclosamide acts primarily on the host cell’s mitochondria, which act like the cell’s energy-producing batteries. The drug prevents the cell from producing its main energy molecule, adenosine 5′-triphosphate, or ATP. Without the infected cell’s energy supply, the virus has difficulty replicating viable copies of itself to cause further infection. These effects are reversible and do not lead to cell death.
“Niclosamide turns the dimmer on a cell’s energy and essentially locks the virus in,” said Needham, the sole author of the new study. When coupled with vaccines, masking, and other recommended mitigation measures for COVID prevention, the new niclosamide solution has potential as an add-on strategy, he said. “This development could enable safe and effective nasal and throat sprays that provide additional protection behind the mask.”
Panning during a pandemic
In an ongoing collaboration with Will Eward, a surgical oncologist at Duke, Needham had previously shown that niclosamide was effective in bone cancer in mice and dogs when made into a nanoparticle, which he says essentially “like the drug.” makes the food of cancer look like “. . “In another collaboration with Christina Barkauskas, Assistant Professor of Medicine in Pulmonary Medicine at Duke, they began preliminary studies on the possible use of the same niclosamide formulation for pulmonary fibrosis when the pandemic broke out.
Like many researchers around the world, Needham has switched to COVID-directed studies. After a Korean paper testing existing drugs for effectiveness against COVID-19 identified niclosamide as a potential target, it spent the next year researching a range of solution, nanoparticle and microparticle formulations. The Korean studies on animal cells showed that only a low concentration of niclosamide was required prior to infection to completely stop the replication of the SARS-COV-2 virus.
However, the animal cells used are extremely robust and durable. To find out how effective and well-tolerated niclosamide could be in humans for fighting COVID-19, Needham and Barkauskas turned to cells more relevant to the initial nasal and bronchial infection – respiratory epithelial cells – and hired other clinical researchers at Duke.
Without testing live viruses, the researchers focused on measuring how much niclosamide reduced the levels of ATP in human airway cells. Based on the ATP-to-virus inhibition measurements of the Korean study, Patty Lee, professor of medicine, cell biology and pathology at Duke, and her postdoc Sojin Kim found that only a few micromolar concentrations of the drug can lower the ATP level sufficiently, in order to possibly completely interrupt virus replication without damaging the cells themselves.
However, these studies were performed on cells immersed in cell culture media, which slows the rate at which niclosamide is absorbed and can act in the cells. In further benchtop cell studies with Barkauskas and Zach Kelleher, a laboratory assistant in their laboratory, the researchers focused on human airway cells that were only treated with the buffered niclosamide solution. The study, funded by the American Lung Association, suggests that even lower doses are enough to have a positive effect on airway cells.
But all three of these studies don’t consider mucus.
The need to reformulate
Conventional allergy medication such as Flonase and Nasonex contain around 6,000 to 30,000 times more of their respective active ingredients in solution than would be needed in benchtop studies to influence the cells. This is because only a small amount of the active ingredient actually passes through the protective layer of mucus that constantly covers the back of the nose and throat.
However, niclosamide does not dissolve easily in water-based liquids that can be sprayed into a person’s nose and mouth. The normally achievable solution concentration of the drug at a nasal pH of around 6 or 7 is close to or even below what the benchtop studies suggest, in order to stop the replication of the virus 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 ten times higher than that normally achievable is needed to make a working prophylaxis and treatment spray, and that it passes through the layer of mucus within Milliseconds.
So the question for Needham was how to get that focus.
Adjust the pH value
In the new release, Needham shows that simply increasing the alkalinity of the solution could be enough to get across the mucosal barrier and into the cells where COVID-19 infection first occurs. He found that increasing 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 his calculations. And raising the pH to 9.2, which is still tolerable for a throat spray, exceeds this benchmark by 10 times and could be used in the event of an early infection.
While promising, Needham notes, these results have yet to be tested in cells that are actually infected with COVID-19, as well as those cells that are protected by a layer of mucus, which requires, partner laboratories and agencies with the necessary biosecurity resources and resources to find live viruses.
A protocol for producing liter-sized batches that can be filled and sealed in sterile-capped 10 ml vials was previously developed in Duke’s compounding pharmacy by Vincent Gaver, Clinical Research Pharmacist, and Beth McLendon-Arvik, Director of Investigational Drug Services, developed. And Needham also described in his new patent application a process to extract niclosamide from commercially available tablets into the solution without using organic solvents.
Because it acts on the cells and not the virus, niclosamide could act as a respiratory virus prophylactic agent, not only against COVID-19 and all of its variants, but against any new virus as well. While vaccines are clearly effective, a nasal preventive would increase protection. And even if an infection has already spread, this formulation could be used as an early treatment throat spray that could stop the viral load on the lungs that is causing the disease’s most devastating effects. “
David Needham, study author
Needham has already filed a patent application and is actively seeking partners from industry, government and infectious disease institutes to support clinical trials and commercialization.
Needham, D., (2021) The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, Its Variants, and Other Viral Infections. Pharmaceutical research. doi.org/10.1007/s11095-021-03112-x.