Intraventricular and Intracerebral Delivery of Anti-epileptic Drugs in the Kindling Model

Abstract

Summary:A means to avoid the pharmacokinetic problems affecting the anti-epileptic drugs may be their direct intracerebroventricular (ICV) or intracerebral delivery. This approach may achieve a greater drug concentration at the epileptogenic area while minimizing it in other brain or systemic areas, and thus it could be an interesting therapeutic alternative in drug-resistant epilepsies. The objective of this article is to review a series of experiments, ranging from actute ICV injection to continuous intracerebral infusion of anti-epileptic drugs or grafting of neurotransmitter producing cells, in experimental models, especially in the kindling model of epilepsy in the rat.Acute ICV injection of phenytoin, phenobarbital or carbamacepine is able to diminish the intensity of kindling seizures, but it is also associated with a high neurologic toxicity, especially phenobarbital. Continuous ICV infusion of anti-epileptic drugs can effectively control seizures, but neurologic toxicity is not improved compared with systemic delivery. However, systemic toxicity may be improved, as in the case of valproic acid, whose continuous ICV infusion results in very low plasmatic or hepatic drug concentrations. Continuous intracerebral infusion at the epileptogenic area was studied as an alternative to minimize neurologic toxicity. Thus, intra-amygdalar infusion of gamma-aminobutyric acid (GABA) controls seizures with minimal neurotoxicity in amygdala-kindled rats. Similarly, continuous infusion of GABA into the dorsomedian nucleus of the thalamus improves seizure spread, while not affecting the local epileptogenic activity at the amygdala. Grafting of GABA releasing cells may reduce kindling parameter severity without behavioral side effects.We may conclude that ICV or intracerebral delivery of antiepileptic drugs or neurotransmitters may be a useful technique to modulate epilepsy.

Risperidone and Divalproex Differentially Engage the Fronto-Striato-Temporal Circuitry in Pediatric Mania: A Pharmacological Functional Magnetic Resonance Imaging Study

“…Additionally, after treatment and consistent with the increase over the course of treatment, the divalproex group showed greater activation relative to the risperidone group in VLPFC and middle temporal gyrus. Furthermore, during the angry face condition, each patient group showed increased activation over time relative to HC in the VLPFC, ACC, 11, 46, 47, 48 ventral striatum 49, 50 and middle temporal lobe 51, 52 all of which may be critical for mood stabilization in patients, irrespective of the type of medication. Across all comparisons, the happy face condition did not elicit notable findings to the same extent as the angry face condition, probably by the virtue of it being a less effective emotional probe to elicit BOLD signal responses.…”

Convection-Enhanced Delivery in the Treatment of Epilepsy

“…Targeted delivery overcomes this limitation. Traditional CNS delivery methods, such as intrathecal or intraventricular administration, do not provide targeted delivery 3. Conventionally, focal intraparenchymal injection (bolus deposition) is used for targeted delivery in the brain 4.…”

Adenosine-associated delivery systems

“…This approach may be limited by complications including the need for cyclic refilling or replacement during the lifetime of an epilepsy patient, mechanical failure, obstruction, and infection (Wang et al, 2002, Barcia and Gallego, 2009). A future option for clinical use of pump systems may be the steady local release of low concentrations of adenosine (Elger and Lehnertz, 1998, Boison et al, 2002a).…”