Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 57

There are many possible causes of pharmacoresistant epilepsy. The mechanisms of drug resistance are likely to be variable and multi-factorial (Regesta and Tanganelli, 1999; Kwan et al., 2011). Genetic factors, such as the aforementioned polymorphisms, may be relevant and help to explain why two dogs of the same breed and with the same epilepsy characteristics differ in their response to AED therapy. Disease-related factors are also of importance, and these include the aetiology and pathophysiology underlying the seizure disorder, the clinical course of the disease, changes in drug targets or binding sites, drug uptake into the brain and changes of the epilepsy circuit. Finally, drug-related factors such as ineffective pharmacodynamics or -kinetic properties and/or development of tolerance can all play a role in the formation of pharmacoresistance.

Most pharmacoresistant patients will often not respond to multiple AEDs despite the individual differences in their mechanisms of action (Regesta and Tanganelli, 1999; Löscher and Potschka, 2002). Patients that do not respond to the first standard AED will only have a 3% chance to respond to the subsequent chosen AEDs, which needs especially to be considered during AED trials (Kwan and Brodie, 2000). This argues against epilepsy-induced changes in specific drug targets as a major cause of drug-resistant epilepsy, and makes it more likely that nonspecific mechanisms are responsible.

There are three proposed major theories for AED resistance:

1. The drug-target hypothesis: reduced drug-target sensitivity in epileptogenic brain tissue.

2. The multidrug transporter hypothesis: clearance of anti-epileptic drugs from the epileptogenic tissue through over-expression of multidrug transporters.

3. Change in the neuronal network properties.