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New opportunities to combat drug resistance in epilepsy

Rafał Skowronek, 6th year SUM student in Katowice

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New opportunities to combat drug resistance in epilepsy

PantherMedia

Brain

Drug resistance is a growing problem in modern medicine. It affects virtually every clinical discipline, although it is most often mentioned in the treatment of infections and anticancer therapy. In neurology, one of the current problems is drug-resistant epilepsy. Thanks to advances in basic science, new drugs to overcome the mechanism of multidrug resistance may soon enter the clinic.

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The metabolism of most drugs, or xenobiotics more broadly, consists of three phases: I - oxidation, reduction and hydrolysis, II - coupling and III - transport. Until recently, the main emphasis has been on phases I and II with a particular focus on the cytochrome P450 system. However, the importance of so-called 'xenobiotic transporters', which can prevent the passage of drugs into or even actively pump them out of a particular compartment of the body, is now increasingly recognised. Thus, even the best drug is of no use if, as a result of the activity of these proteins, it cannot act at its target site. Inhibition of drug transport at the cellular level is one reason for multidrug resistance (MDR).

The best known transporter of caesnobiotics is P-glycoprotein (P-gp). It is a protein belonging to the ATP binding cassette (ABC) family of proteins, so its other name is ABCB1. It is found in cell membranes, including those of placental tissues (where it participates in the fetoprotection mechanism), biliary and pancreatic ducts, renal tubules downstream and, importantly for neurologists, the endothelium of brain capillaries, astrocytes, microglia and neurons. P-glycoprotein activity is not always desirable (it provides an 'extra blood:brain barrier'). It may reduce or even eliminate the permeability of antiepileptic drugs to the epileptogenic focus and thus lead to drug resistance in epilepsy (in about 40% of patients).

Based on this knowledge, it was decided to introduce a new therapeutic strategy involving the inhibition of P-glycoprotein. A non-competitive inhibitor of P-glycoprotein has already been developed, called tariquidar (XR9576), which is currently undergoing clinical trials. This is an example of embodying the modern concept of translational medicine, i.e. medicine in which scientific discoveries go straight from the 'laboratory table' to the 'patient's bedside'.