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P-glycoprotein Responsible For Innefectiveness of AED's During Status Epilepticus

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TJW

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Status epilepticus (SE) is a medical emergency, characterised by continuous or intermittent seizures without full recovery of consciousness in between. Approximately one third of people who experience SE do not respond to anti-epileptic drugs (AEDs).

One possible reason for this is that, in these people, the receptors in the brain needed for the AEDs to work simply aren't available. However an alternative explanation is that there is something lowering the level of AED actually in the brain.

A protein called P-glycoprotein (Pgp) is involved in the transport of drugs out of the brain, and it increases in quantity as a result of SE. In theory this increase could render SE unresponsive to AEDs, by reducing the amount of the AEDs present in the brain. However this can only be the case if the increase in Pgp happens quickly enough after the onset of SE.

Scientists in Germany have been trying to determine whether this is the case. They induced SE in rat models, using either chemical or electrical means, and administered four drugs commonly used to treat SE - phenytoin, fosphenytoin, diazepam and phenobarbital - at different intervals. In some cases they also added an inhibitor of Pgp to the treatments, to see if lowering the amount of active Pgp would make the drugs more effective at stopping SE.

The results showed that chemically induced SE was unresponsive to all of the drugs individually, but that a combination of diazepam and phentobarbital treated it successfully. Electrically induced SE responded to either diazepam or phenobarbital, but not phenytoin or fosphenytoin. Interestingly, the addition of a Pgp inhibitor to the drug treatments had no effect on the responsiveness of SE. Also, when the brains were studied more closely, it was found that the increase in Pgp didn't happen until 48 hours after SE. This time frame is too long for Pgp activity to be responsible for the resistance to drugs witnessed in these SE models.

The study is not conclusive, but it goes some way to disprove Pgp as a cause for unresponsive SE. It is often the case with research that the results eliminate potential factors rather than prove them, which is why it takes such a lot of time and work for breakthroughs to occur. These findings are potentially useful as a means of guiding future research.

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