Flushing away cocaine: New drug could be an anti-overdose first

(28 August 2008: VIDYYA MEDICAL NEWS SERVICE) -- A slight change to a naturally occurring enzyme means that chemists have created a molecule that could flush a cocaine overdose out of the body before it can cause irreparable damage to the central nervous system.

Though the enzyme has not been tested in humans, if it works, it would be the first therapy to remove the drug from a user's body. Right now, a doctor can only reduce or relieve the anatomical fall out from a cocaine overdose, by lowering the patient's temperature and reducing their heart rate.

"When patients go to the emergency room, the doctors really can't help a lot," says Chang-Guo Zhan at the University of Kentucky in Lexington. "The cocaine is still in their system."

Enzymes in the body combine cocaine with water and then, over a sequence of reaction steps, break it down into two harmless products. But this process is very slow - it takes up to 90 minutes to dispose of even a tiny dose, and much longer for a large overdose.

Now Zhan and his colleagues say they have a way to speed up the natural process. By modifying one of the enzymes, they have created a molecule that can break down cocaine much faster.

The team started by calculating the energy required to perform each reaction step, enabling them to identify the most energetic step, known as the energy barrier. Only if molecules have energy greater than this can they successfully react, so the energy barrier determines the rate of cocaine breakdown.

Using computer simulations that systematically tweak the structure of the enzyme and predict the effect of these tweaks on the energy barrier, Zhan's team arrived at a candidate molecule that promised to speed up the reaction by 2000 times (Journal of the American Chemical Society, DOI: 10.1021/ja803646t).

The team synthesised the molecule and tested whether it might work in the body. Sure enough, when they gave 18 mice a highly toxic dose of cocaine, the 12 that they also injected with the modified enzyme all survived, with only two suffering seizures. The six controls, which did not receive the enzyme, died.

Because only five of the 574 amino acids that make up the naturally occurring enzyme are changed in the modified enzyme, the team suggests that their overdose therapy should have few side effects in humans.

Pharmacologist Stewart Paterson of King's College London describes the therapy as "promising", but points out that its effectiveness would depend on how quickly it was taken after the overdose. He says the team also need to be sure that it does not also break down beneficial compounds in the patient's body.

http://www.newscientist.com

NEW SCIENTIST MAGAZINE ISSUE: 30 AUG 2008.

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