Ivermectin. A word that became all too well-known in the past few years when the world was in the grip of the Covid-19 pandemic. Suddenly WhatsApp groups were flooded with opinions on whether it's safe to use for humans and whether it has any benefits for those suffering from Covid-19.
“An alarming fact is that most people used ivermectin without supervision by a doctor and that they used a formulation prepared for use in farm animals (which may have different capacities to deal with breakdown of the drug)," says Professor Carine Smith, Head of the Zebrafish Research Unit within the Division of Clinical Pharmacology in the Department of Medicine.
Smith established the unit about 18 months ago and conducted a study on the risks of ivermectin use, given the increased incidence of ivermectin use during the Covid-19 pandemic. But how could zebrafish – a 5 cm long tropical fish native to Southeast Asia – help in a study to do with ivermectin and humans?
“They are 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," Smith says.
She explains ivermectin is a known anti-parasitic, but even when used at the low doses indicated for use against parasites, ivermectin use is linked to many adverse effects suggestive of neurological risk, including dizziness, headache, seizures, and loss of consciousness.
“We decided to probe different potential neurological risks. Firstly, we treated zebrafish larvae (that is the early life form of zebrafish just after they have hatched) with pure ivermectin and veterinary ivermectin – using a specific test to probe GABA function, 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 suggest a direct effect to inhibit GABA. GABA is an inhibitory neurotransmitter which protects the brain from excitotoxicity – an overstimulation of neurons which eventually lead to neuronal death."
They also exposed larvae to alternating bright light or darkness. “Normally, this 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."
Lastly, they probed the effect of ivermectin when the blood brain barrier is leaky, as this happens during viral infection such as Covid-19. 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, says 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."
Smith says the research is unique in that it specifically aligns with a real-life problem. “We are committed to science with a purpose, meaning our work should benefit the lay person."
She adds that zebrafish as research tool has only really been used for about 10 years globally and is much more recent in South Africa. “I believe that these little larvae (they are only about 3-4 mm long when we use them) can contribute significantly to medicine development and drug safety research."
Shortly after the study, SAPHRA – the medicines control body in South Africa – prohibited the use of ivermectin under any condition. “Ivermectin will always have a place to prevent or treat parasitic infections in animals, for example as a dip. It is important to note that the effect of a periodical acute application of ivermectin in animals is different from a long-term daily/weekly dose of ivermectin in people using it as preventative treatment in the context of viral infection. Thus, human use of ivermectin especially as prophylactic, should not be encouraged."
Caption: Prof Carine Smith in the zebrafish lab.
Photo credit: Damien Schumann