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Pharmacoresistant Epilepsy: A Current Update on Non-Conventional Pharmacological and Non-Pharmacological Interventions.

Sharma AK, Rani E, Waheed A, Rajput SK - J Epilepsy Res (2015)

Bottom Line: Indeed, the presence of several anti-epileptic drug including carbamazepine, phenytoin, valproate, gabapentin etc.But no promising therapeutic remedies available to manage pharmacoresistance in the present clinical scenario.Strategies include add on therapy with adenosine, verapamil etc or ketogenic diet, vagus nerve stimulation, focal cooling or standard drugs in combinations have shown some promising results.

View Article: PubMed Central - PubMed

Affiliation: Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh-201313, India ;

ABSTRACT
Uncontrolled seizure or epilepsy is intricately related with an increase risk of pharmacoresistant epilepsy. The failure to achieve seizure control with the first or second drug trial of an anticonvulsant medication given at the appropriate daily dosage is termed as pharmacoresistance, despite the fact that these drugs possess different modes of action. It is one of the devastating neurological disorders act as major culprit of mortality in developed as well as developing countries with towering prevalence. Indeed, the presence of several anti-epileptic drug including carbamazepine, phenytoin, valproate, gabapentin etc. But no promising therapeutic remedies available to manage pharmacoresistance in the present clinical scenario. Hence, utility of alternative strategies in management of resistance epilepsy is increased which further possible by continuing developing of promising therapeutic interventions to manage this insidious condition adequately. Strategies include add on therapy with adenosine, verapamil etc or ketogenic diet, vagus nerve stimulation, focal cooling or standard drugs in combinations have shown some promising results. In this review we will shed light on the current pharmacological and non pharmacological mediator with their potential pleiotropic action on pharmacoresistant epilepsy.

No MeSH data available.


Related in: MedlinePlus

Representation of different mechanisms associated with resistance development in epilepsy (A) shows the normal activity of transporter protein (P-gp transporter) and sufficient concentration at target site; (B) shows the over-expression of transport protein leading reduced concentration of AEDs at target site; (C) represents the normal target protein orientation and hence good efficacy of AEDs (D) represents the modified orientation of target protein leading inefficacy of AEDs; (E) represents overall mechanisms for the development of pharmacoresistance in epilepsy.
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f1-er-5-1-1: Representation of different mechanisms associated with resistance development in epilepsy (A) shows the normal activity of transporter protein (P-gp transporter) and sufficient concentration at target site; (B) shows the over-expression of transport protein leading reduced concentration of AEDs at target site; (C) represents the normal target protein orientation and hence good efficacy of AEDs (D) represents the modified orientation of target protein leading inefficacy of AEDs; (E) represents overall mechanisms for the development of pharmacoresistance in epilepsy.

Mentions: Several mechanisms have been proposed to explain pharmacoresistance like disease related mechanisms, drug related mechanisms and genetics. The transporter hypothesis relates to pharmacokinetic aspects, which suggests that over expressed efflux transporters at the BBB limits brain penetration of AED’s.10,11 One of the glycoprotein active efflux systems i.e. P-glycoprotein (P-gp) consists group of closely related intrinsic membrane proteins which are involved in multidrug resistance and encoded by a small family of multidrug resistance are encoded by MDR1 and mdr1a genes in human and rodent respectively.12 Preclinical study reveals that the absence of its substituent (mdr1a or mdr1b genes) shows a significant increase in-uptake of various lipophilic drugs in brain.13Fig. 1A illustrate ATP dependent multi drug transporters such as P-gp or MRP2 located at the apical cell membrane of the endothelial cells acts as an active efflux pump by transferring part of drug back into the blood, thus limiting penetration of many lipophilic drugs into brain parenchyma. By lowering the concentration of drug in endothelial cells, multidrug transporter proteins also promotes flux from brain extracellular space into endothelial cells. Moreover, as Fig. 1B shows these transporters are over expressed and may contribute to barrier function. Hence, AED concentrations would be insufficient to cause antiepileptic potential.14–21


Pharmacoresistant Epilepsy: A Current Update on Non-Conventional Pharmacological and Non-Pharmacological Interventions.

Sharma AK, Rani E, Waheed A, Rajput SK - J Epilepsy Res (2015)

Representation of different mechanisms associated with resistance development in epilepsy (A) shows the normal activity of transporter protein (P-gp transporter) and sufficient concentration at target site; (B) shows the over-expression of transport protein leading reduced concentration of AEDs at target site; (C) represents the normal target protein orientation and hence good efficacy of AEDs (D) represents the modified orientation of target protein leading inefficacy of AEDs; (E) represents overall mechanisms for the development of pharmacoresistance in epilepsy.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494988&req=5

f1-er-5-1-1: Representation of different mechanisms associated with resistance development in epilepsy (A) shows the normal activity of transporter protein (P-gp transporter) and sufficient concentration at target site; (B) shows the over-expression of transport protein leading reduced concentration of AEDs at target site; (C) represents the normal target protein orientation and hence good efficacy of AEDs (D) represents the modified orientation of target protein leading inefficacy of AEDs; (E) represents overall mechanisms for the development of pharmacoresistance in epilepsy.
Mentions: Several mechanisms have been proposed to explain pharmacoresistance like disease related mechanisms, drug related mechanisms and genetics. The transporter hypothesis relates to pharmacokinetic aspects, which suggests that over expressed efflux transporters at the BBB limits brain penetration of AED’s.10,11 One of the glycoprotein active efflux systems i.e. P-glycoprotein (P-gp) consists group of closely related intrinsic membrane proteins which are involved in multidrug resistance and encoded by a small family of multidrug resistance are encoded by MDR1 and mdr1a genes in human and rodent respectively.12 Preclinical study reveals that the absence of its substituent (mdr1a or mdr1b genes) shows a significant increase in-uptake of various lipophilic drugs in brain.13Fig. 1A illustrate ATP dependent multi drug transporters such as P-gp or MRP2 located at the apical cell membrane of the endothelial cells acts as an active efflux pump by transferring part of drug back into the blood, thus limiting penetration of many lipophilic drugs into brain parenchyma. By lowering the concentration of drug in endothelial cells, multidrug transporter proteins also promotes flux from brain extracellular space into endothelial cells. Moreover, as Fig. 1B shows these transporters are over expressed and may contribute to barrier function. Hence, AED concentrations would be insufficient to cause antiepileptic potential.14–21

Bottom Line: Indeed, the presence of several anti-epileptic drug including carbamazepine, phenytoin, valproate, gabapentin etc.But no promising therapeutic remedies available to manage pharmacoresistance in the present clinical scenario.Strategies include add on therapy with adenosine, verapamil etc or ketogenic diet, vagus nerve stimulation, focal cooling or standard drugs in combinations have shown some promising results.

View Article: PubMed Central - PubMed

Affiliation: Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh-201313, India ;

ABSTRACT
Uncontrolled seizure or epilepsy is intricately related with an increase risk of pharmacoresistant epilepsy. The failure to achieve seizure control with the first or second drug trial of an anticonvulsant medication given at the appropriate daily dosage is termed as pharmacoresistance, despite the fact that these drugs possess different modes of action. It is one of the devastating neurological disorders act as major culprit of mortality in developed as well as developing countries with towering prevalence. Indeed, the presence of several anti-epileptic drug including carbamazepine, phenytoin, valproate, gabapentin etc. But no promising therapeutic remedies available to manage pharmacoresistance in the present clinical scenario. Hence, utility of alternative strategies in management of resistance epilepsy is increased which further possible by continuing developing of promising therapeutic interventions to manage this insidious condition adequately. Strategies include add on therapy with adenosine, verapamil etc or ketogenic diet, vagus nerve stimulation, focal cooling or standard drugs in combinations have shown some promising results. In this review we will shed light on the current pharmacological and non pharmacological mediator with their potential pleiotropic action on pharmacoresistant epilepsy.

No MeSH data available.


Related in: MedlinePlus