EPILEPSY in the 21st CENTURY:
New Medications and How They will be Administered

Neurologist Dr. Jack Schneiderman reviewed an array of exciting new epilepsy medications on the horizon, some much closer to release than others.

Diastat, a new rectal formulation of valium which targets cluster seizures, will soon be released in Canada. Diastat seems quite effective. It also has the advantages of working quickly and being useful to patients who cannot take oral medication.

Trileptal is on the horizon for the treatment of partial onset seizures, and seems similar to Tegretol but with fewer drug interactions. Another new drug, Tiagabine, seems to be quite effective as an add-on therapy for partial seizures. Tiagabine increases the brain's levels of GABA (the brain's natural anti-convulsant drug), but because it may actually worsen some kinds of seizures, it must be used very carefully.

The drugs of the next generation are in various stages of development. The research is focusing on a host of new mechanisms of action and ways of delivering drugs to the brain. These drugs include ADCI and AWD 131-138 (both in early stages of development), Ganaxsolone (related to sex hormones), Levetiracetam (mainly for partial onset seizures), Losigamone (also an anti­depressant), Pregabalin (similar to Gabapentin but more potent), Remacimide (currently being tested in Canada), Reticabine (increases the production of GABA), Rufinamide, Soretolide, local anaesthetics, TV 1901 (a derivative of GABA) and DP Valproic Acid.

Dr. Schneiderman pointed out that today, our anticonvulsants are limited in their effectiveness more by side effects than by their ability to control seizures. The most important side effects are drowsiness and cognitive problems. However, some of the next generation of epilepsy drugs may actually enhance cognitive function and mood.

Taking anti-epileptic drugs orally means you have to remember to take your medication. And your body has to get the drug to the right place - the brain. Today's drugs are absorbed from the stomach or gut into the bloodstream, where they bind to proteins before passing through the liver and being broken down.

"The drug is distributed to all of the tissues, and we don't want it in all the tissues- in the kidney, liver, skin- we want it in the brain," said Dr. Schneiderman.

But the brain doesn't want the drug: in fact, the blood brain barrier (BBB) is designed to keep things out. (Even the body's own natural anti­convulsant, GABA, can't get into the brain, but has to be manufactured there). A very small percentage of medication actually gets to where it's needed. And if you have focal seizures, the drug is not needed by the whole brain, but only by one part of the brain: the seizure focus.

"If you can get drugs to limited locations in the brain in small amounts, you can virtually guarantee that the side effects are going to be very, very much less, especially the side-effects on the central nervous system."

DP Valproic Acid is an example of the next generation of drugs that uses a different mechanism of action to get around some of these problems. It wraps the anticonvulsant valproic acid in a lipid membrane to create a "bag" of the drug. The drug stays "bagged" and inactive until it meets an enzyme which opens up the vesicles and releases the valproic acid. The idea is that this enzyme is only released when the person's seizure focus becomes activated. The more activity, more valproic acid is released. Eventually, enough is released to block seizures, with the other side of the brain not getting any drug. After the seizure stops, the brain "mops up" the drug.

"It's a clever way to get drug to the right place at the right time," commented Dr. Schneiderman.

Speculating on the future, we can envision a catheter that will inject a drug (perhaps a drug that would not otherwise be able to cross the blood brain barrier) directly into the lobe of the brain having seizures. If the person's seizures do not have a single focus, the drug could be injected into the fluid-filled spaces in the centre of the brain (the ventricles). Getting the drug directly to one small area would lower the body's total drug exposure, reducing organ toxicity and drug side effects. However, this would require surgery, a reloading of the pump, and the risks of possible infection and even brain damage from the catheter

"Seizures are brief and intermittent, and we don't need the drug all the time. Only some of the time." A timed drug delivery system, where a patient who has an aura can push a button to release a drug and stop the progression of the seizure would be advanta­geous. Speculating even further down the road, Dr. Schneiderman envisioned a system similar to Dr. Wennberg's, where a sensor implanted into the brain can automatically detect a seizure, perhaps even before it starts, and inject a drug. The sensor would need to be connected to a computerized controller and a pump. It would be miniaturized so it can be implanted like a pacemaker under the skin.

"I am fully confident that it will be possible one day."