Both the scientific community and the general public now know that hydroxychloroquine is ineffective against SARS-CoV-2, the virus that causes COVID-19. The FDA revoked its Emergency Use Authorization (EUA) for the drug in June 2020, after it failed in clinical trials. Now there is another drug, a close chemical relative of hydroxychloroquine’s called amodiaquine, that has shown promise against SARS-CoV-2.
The Amodiaquine Origin Story
Amodiaquine was discovered in the 1940s when scientists were researching ways to synthesize quinine, an antimalarial compound made from the bark of the cinchona tree. Amodiaquine’s molecular structure is very close to both chloroquine and hydroxychloroquine. Benjamin tenOever from the Icahn School of Medicine at Mount Sinai describes it as being “dirtier” than its chemical cousins, meaning that its effects on cells are more spread out and hit a greater variety of molecular targets.
It was first tested in owl monkeys and humans in the 1970s and found to be effective against chloroquine-resistant strains of malaria. Amodiaquine has been tested against Ebola, Zika and dengue fever, with mixed results. Amodiaquine has shown positive results against SARS and MERS in experiments using Vero cells sourced from African green monkey kidneys, which are not a good translational model for the human lung.
Amodiaquine and Hamster Studies
In August 2020, a group of researchers led by Benjamin tenOever released “Human organ chip-enabled pipeline to rapidly repurpose therapeutics during viral pandemics” on preprint server BioRxiv. (A preprint paper has not been peer-reviewed for errors, including flawed research methods or conclusions.) In repeated trials, tenOever and his colleagues found that amodiaquine can help protect against SARS-CoV-2.
The team dosed dozens of hamsters with amodiaquine and then exposed them to aerosolized SARS-CoV-2. After exposure, hamsters received the drug for three more days. Compared to a control group of hamsters that were also exposed, the hamsters treated with amodiaquine had 70 percent less viral genetic material in their lungs.
In a second study, healthy hamsters started amodiaquine one day before being exposed to hamsters infected with SARS-CoV-2. The hamsters dosed with amodiaquine had 90 percent less viral genetic material in their lungs than hamsters that weren’t treated with the drug.
Additional Amodiaquine Tests
tenOever and colleagues were surprised to see that it gave considerable protection against SARS-CoV-2 in repeated trials. They stress that it is a far leap from hamsters to humans, but given amodiaquine’s close chemical proximity to hydroxychloroquine, it deserves further research and close scrutiny. The researchers also showed that in human lung cells, amodiaquine can reduce the levels of a harmless virus that carries the same spike protein as SARS-CoV-2. According to many skeptics, though, this surrogate virus is not the same as the novel coronavirus. Vincent Racaniello, a microbiologist from Columbia University, argues that current evidence in favor of amodiaquine’s efficacy is insufficient to warrant clinical trials.
Previous hamster trials and human lung cell trials with hydroxychloroquine returned negative results. So tenOever and his team ran a head-to-head comparison with chloroquine and hydroxychloroquine versus amodiaquine in hamsters, with a control group. Amodiaquine reduced the amount of viral material as before, but neither chloroquine nor hydroxychloroquine showed any reduction in viral material in hamster lungs.
The hamsters were all given each drug one day prior to viral exposure, so it remains unknown what might happen when the drug is administered to an animal that is already sick. Thus, amodiaquine shows potential for preventative measures but not necessarily for treatment.
Risks and Limitations of Amodiaquine
The outstanding question is whether we have learned to be cautious in the desperate search for a cure. If the world repeats the same pattern of hysteria and stockpiling that it did in the wake of misguided claims about hydroxychloroquine, the consequences could be disastrous. Amodiaquine is used as a prophylactic for malaria, a disease that kills more than 500,000 people a year — the majority of whom are African children under the age of five. The drug is given to healthy children — 20 million children in 2019 — in countries such as Chad and Niger during the rainy season.
And there is another complication: amodiaquine is not currently available in the U.S. — its use was discontinued after researchers in the 1980s documented liver damage in long-term amodiaquine users. There are also signs that it can cause heart abnormalities when it accumulates in high concentrations in the body.
Global health experts warn about creating hype around amodiaquine’s possible effects on SARS-CoV-2. “This is all speculation. All bets should be off,” says George Jagoe, of the Medicines for Malaria Venture. The glimmer of hope that tenOever’s research provides will be a test to see whether the scientific community will exercise restraint and caution in the search for an end to the global pandemic.
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