Could that once-monthly beef-flavored pill you give your dog to kill fleas and ticks save thousands of human lives in Zika virus- and malaria-infected areas of the world?
That’s the hypothesis examined in a 2018 publication “Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases”, published by Miglianico, et al., in PNAS.
Vector-Borne Diseases Under Siege
Mosquito-transmitted diseases, such as malaria and Zika virus, and sand fly-transmitted leishmaniasis are major causes of mortality in sub-tropical regions. Although with a lower mortality incidence, mosquito-borne West Nile virus has spread in temperate regions such as Europe and the United States.
Here in Wisconsin, USA, the Centers for Disease Control has allocated $10M for The Upper Midwestern Center of Excellence in Vector Borne Diseases. This center is led by insect experts from a 4-state area with the mission of staying ahead of the migration of vectors and their diseases northward into colder regions of the USA. The center’s goal, according to co-director Lyric Bartholomay, “is to boost surveillance, prevention and response against the backdrop of a trend toward the emergence of new diseases and old diseases – like Zika and West Nile – in regions far from their places of origin.” The center was profiled in this 2017 article on the U of WI-Madison’s website.
Disease carrying vectors are on the move.
The authors of this PNAS paper suggest that a treatment that is safe in humans, with a long half-life so that it required minimal dosing, would make compliance far easier, thus improving the success rate. Here is a closer look at the drug compounds they studied.
Are Isoxazoline Compounds Safe?
Since 2013 isoxazoline drugs (fluralaner and afoxolaner) have been licensed as veterinary drugs for use in companion animals to control fleas and ticks. These drugs have very long half-lives, providing protection for weeks to months (fluralaner, sold as Bravecto, has a once every 3 months dosing schedule in adult dogs). Moreover, these drugs are easy to use because they are administered in a dog-appealing chewy beef-flavored tablet.
In addition to their long half-lives, these drugs have a good safety profile. Although the drug targets are neuronal, the drugs show limited brain penetration and better selectivity for insect than for mammalian receptors. When incubated with dog or human hepatocytes, neither drug was metabolized to a measurable level.
Drug Testing on Human Samples
The researchers combined fluralaner (the active compound in Bravecto) or afoxolaner (active compound in Nexgard) with human blood samples, which were then tested on a variety of mosquito species by membrane feeding.
Twenty-four hours after feeding the IC50 for fluralaner was slightly higher than for afoxolaner but both drugs killed Anopheles, Aedes aegypti and Culex pipiens mosquitoes, important vectors for malaria, Zika/dengue and West Nile virus, respectively.
Additionally, both drugs were active against Anopheles gambiae Tiassale 13, a strain that carries a mutation making it resistant to certain insecticides. And afoxolaner and fluralaner were effective against pyrethroid- and carbamate-resistant mosquito strains, very exciting news for persons in areas where these mosquito populations thrive.
Membrane feeding of these compounds in human blood to sand flies, vectors of leishmaniasis was also performed, with good IC50 numbers against sand flies from India; sadly the drugs had far less activity against South American sand flies.
The authors note that actual human testing had not been performed at the time of their article, but they extrapolated from doses used in dogs to propose human blood levels, and using the blood-membrane test information, postulated that the needed IC50 values could be safe and effective for human subjects.
A Cure?
Oral medication against Zika- or malaria-carrying mosquitoes may not only improve human lives, but may also reduce mosquito populations in the long term. Once the mosquito numbers are reduced, so too would be the incidence of malaria and/or Zika infection. Ditto for leishmaniasis.
A Nobel Prize-Winning Precedent in Oral Anti-Parasitic Drugs
Onchocerchiasis or river blindness is a parasitic infection of humans that results in blindness, especially in sub-Saharan Africa, and Central and South America. The parasite is transmitted to humans by black flies, which bite and transmit microfilaria to the human, resulting in adult worms in human tissues.
In 1975, scientist Satoshi Ōmura was testing soil samples for antibacterial compounds and identified a compound avermectin that was purified to ivermectin. It was discovered that ivermectin killed the microfiliaria in humans, preventing river blindness caused by untreated parasites in humans.
The drug is taken orally once a year. Because the adult worms live and produce microfilaria for a long time, ivermectin is sometimes taken by infected persons for as long as 18 years.
Scientist Ōmura shared the 2015 Nobel Prize in Physiology or Medicine with William Campbell and Youyou Tu for their discovery and isolation of ivermectin.
Could History Repeat Itself?
Back in 1981, drug maker Merck donated ivermectin to everyone that needed treatment for river blindness.
That’s right. The ivermectin was donated.
Is it time to bring this to the attention of afoxolaner/flurolaner drug maker Merial/Boehringer-Ingelheim?
While it’s too early to pop a Nexgard if you’re headed to Africa or India, in this proposed use of isoxazoline drugs in humans, the benefits could be more far reaching than a treatment or cure. If these drugs come into human use, they could actually decrease vector numbers to the point of preventing infections. Fewer mosquitoes and sand flies means less malaria and leishmaniasis.
Here is the paper:
Miglianico, M. et al. (2018) Repurposing isoxazoline veterinary drugs for control of vector-borne human diseases. Proc. Natl. Acad. Sci. USA 115(29):E6920-E6926.
Kari Kenefick
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