It can look like a child is simply in a daze, awake but daydreaming. Yet inside their brain, a flurry of high-frequency signals is firing from neurons resulting in a so-called absence seizure.A Canadian-led research team has developed a new drug that completely suppresses absence seizures in rats, and could have groundbreaking effects on the treatment of epilepsy in children. The findings were published Wednesday in the peer-reviewed science journal Science Translational Medicine.
The team began testing the drug on humans in December and expects to finish the first phase of clinical trials later this year, said neuroscientist Terry Snutch, the senior author of the study. Snutch, a professor and Canada Research Chair in the Michael Smith Laboratories at the University of British Columbia, said his team is cautiously optimistic the drug will have the same effect on humans. “It’s far enough along that we would know in relatively short order,” he said. “We are quite confident that it will interact with the human channel in the same way that it does in the rats to alleviate the epilepsy.” Although the drugs have only been completely tested on rats so far, earlier tests on cloned human cells had the same effect, said Snutch. Absence seizures are a symptom of epilepsy that most commonly affects children. During an absence seizure, the person will appear conscious but in a daze. The seizures can disrupt a child’s ability to learn in school, and can also be dangerous, especially if they occur while a person is swimming or driving. “The kids and teenagers that have these absence seizures can have hundreds of them in a day,” said Snutch. “They just come and go very, very rapidly.” The new drugs, called Z941 and Z944, work by blocking the flow of calcium ions into what are called T-type calcium channels in the brain. Scientists believe absence seizures are caused by a mutation in the T-type calcium channels that causes them to fire at a high frequency, allowing too much calcium to enter, said Snutch. “This T-type calcium channel (mutation) causes the frequency and the patterning of that firing to go haywire up to hundreds of times a day,” he explained.
The mutation was first discovered in 2009 by Terry O’Brien, one of the co-authors of Wednesday’s study and a professor of medicine at the University of Melbourne in Australia. The new drugs, which can be taken in pill-form and are easily absorbed in rats, completely block the flow of the calcium ions into the calcium channels. In rats with absence epilepsy, the drugs suppressed their seizures by 85 to 90 per cent. However, as calcium channels are responsible for a number of important bodily functions like heartbeat, the researchers said they needed to ensure the drug only targeted those that fire at a high frequency causing the seizures. “The drugs that we’ve developed act in a very specific way so they block the T-type channels but not all of them,” said Snutch. As a result, it is expected the drugs should have minimal negative side effects for the patients, he said. Other medications currently used to treat epilepsy don’t completely control absence seizures, and often cause severe side effects, including sleepiness, blurred vision and diminished motor control.
Aside from epilepsy, Snutch said the new drugs could also be used to treat chronic pain. T-type calcium channels are also found in the neurons outside the brain and are responsible for sending pain signals to the brain, said Snutch. In rats, Snutch said the drugs have been effective in blocking the T-type channels that affect pain signalling. “The hope is that the drugs will be useful for multiple indications,” he said.
The study was a collaborative effort between researchers at the University of British Columbia, Zalicus Pharmaceuticals Ltd. in Vancouver, and the University of Melbourne in Australia.