Ivermectin triggered an intense debate within the medical profession during the Covid-19 pandemic with some touting it as an effective remedy for the virus while others were intensely opposed to its use. But the country’s medical authority, the South African Healthcare Products Regulatory Authority, warned against its use insisting the drug is not registered for human use.
Manufactured for animals
Professor Carine Smith, who heads the Zebrafish Research Unit within Stellenbosch University’s division of clinical pharmacology in the department of medicine, recently led a study to further explore this vexed matter. She said it was alarming that most people use ivermectin without strict supervision of a medical doctor. Furthermore, what makes this even more distressing is that people continue using it even though it is originally formulated to treat parasites in animal.
Significance of zebrafish
Professor Smith set up the unit about 18 months ago following the spike in the use of ivermectin during the coronavirus pandemic. She wanted to look into the health risks poses by the drug and to obtain scientific evidence she turned to zebrafish – a 5 cm long tropical fish native to Southeast Asia.
Asked why they relied on zebrafish for the research, Professor Smith said: “[Zebrafish] is globally becoming immensely popular in drug discovery research, as well as research into drug safety. What makes zebrafish such an amazing research tool is that they are genetically more like humans than rodents – and can be used to match behavioural data to physiology. In other words, we can probe specific physiological mechanisms and correlate it with the behavioural outcome it will facilitate,” Professor Smith says.
According to Professor Smith, the use of zebrafish as a research tool has only really been used for about 10 years globally and is much more recent in South Africa. She says even when used at the low doses for use against parasites, ivermectin’s use is linked to many adverse effects suggestive of neurological risk, including dizziness, headache, seizures, and loss of consciousness. To probe different and possible neurological risks, explains Professor Smith, they had to carry out a few experiments.
Series of experiments
Firstly, says Professor Smith, they treated zebrafish larvae with pure ivermectin and veterinary ivermectin – using a specific test to probe GABA function. GABA is an inhibitory neurotransmitter which protects the brain from excitotoxicity – an overstimulation of neurons which eventually lead to neuronal death, she explains. “We saw that both formulations resulted in seizures in zebrafish at the higher doses which are suggested to be anti-viral. This outcome is in line with the adverse effects reported by humans after ivermectin use and suggests a direct effect to inhibit GABA,” adds Professor Smith.
Secondly, the team exposed larvae to alternating bright light or darkness, which she says under normal circumstances, will induce anxiety-like behaviour in the zebrafish. “They show a startled response to bright light and freeze, and then when the light is removed, they show increased hyperlocomotion, which is interpreted as anxiety and escape behaviour. We found that ivermectin treated larvae showed a dulled response to this protocol, suggesting limited cognitive function,” Professor Smith further observes.
Lastly, Professor Smith’s team probed the effect of ivermectin when the blood brain barrier is leaky, as this happens during viral infection such as Covid-19. Available literature has shown ivermectin to interact with SARS viruses to make the blood brain barrier – a layer that keeps unwanted substances from the bloodstream out of the brain – even more penetrable, she adds.
Says Professor Smith: “Our data indicated that even a short-duration exposure to ivermectin in these conditions, resulted in long-lasting neurocognitive limitations. Thus, our research shows that ivermectin – and specifically the veterinary formulation – should not be used at the high doses thought to be effective against viruses. Even at the doses indicated as anti-parasitic, should be investigated a bit more thoroughly, given the symptoms reported, which are in line with the neurological risk we have demonstrated.” In the final analysis Professor Smith’s conclusion is that ivermectin’s use should be limited to treating parasitic infections in animals. However, its use as prophylactic for humans should be discouraged. She is upbeat about the future of medicine in the country, saying the use of little larvae can contribute significantly to medicine development and drug safety research.”