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No fleas on me

Sun, 5th Jul 2009

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A chemical made by a fungus might hold the key to a new anti-flea treatment for dogs and cats.

FleaWriting in the Journal of Medicinal Chemistry, Merck scientist Peter Meinke and his colleagues explain how they have developed an orally-active anti-flea and tick drug based on a chemical called nodulisporic acid, which is a metabolite produced by the nodulisporium fungus.  These fungi live on dead or dying plant matter and are generally not a threat to humans but the nodulisporic acid the make has been shown in the past to behave as a neurotoxin in insects and other invertebrates.  Amongst these vulnerable species the chemical blocks ion channels that are critical for the process of neurotransmission, leading to paralysis.

As vertebrates, including mammals like humans, dogs and cats, lack the ion channel targeted by nodulisporic acid the compound is harmless to us.  The problem is how to make sufficient quantities of the chemical.  It is a large molecule comprising a complex series of interlocking rings of carbon atoms and other active groups including oxygen and nitrogen, which means that it is very difficult to make in a test tube, at least in a cost-effective manner.  The team therefore set about modifying the chemical structure to arrive at a molecule that retained or even boosted the insect-killing capacity of the original chemical, but was simpler and cheaper to make.

They achieved this by retaining the core of the nodulisporic acid molecule, which has been shown to be critical to the agent's activity, and then tacking on a range of secondary chemical groups.  They were able to produce initially 335 candidate compounds, which were whittled down to a final fourteen by testing them for toxicity against fleas and for safety in mice.  These fourteen compounds were then tested in dogs and cats by administering a single dose of the agent, exposing the animals to fleas at various time points and then combing the fleas back out later to counting how many had died.

Remarkably, a single dose of one of the compounds, N-tert-butyl nodulisporamide, was effective at keeping animals flea-free for six to eight weeks, and it also worked against ticks too.

"No commercial product has the unique oral properties of nodulisporamide, and its systemic efficacy profile compares favourably to currently marketed topical agents," say the researchers.

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