Access To Antiepileptic Drugs Research Articles

Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel.

Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the "hinged lid"-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water-protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors.

Pharmacoresistant epilepsy and nanotechnology.

Epilepsy is one of the most common chronic neurological disorders. Furthermore, it is associated to diminished health-related quality of life and is thus considered a major public health problem. In spite of the large number of available and ongoing development of several new antiepileptic drugs (AEDs), a high percentage of patients with epilepsy (35-40%) are resistant to pharmacotherapy. A hypothesis to explain pharmacoresistance in epilepsy suggests that overexpression of multidrug resistance proteins, such as P-glycoprotein, on the endothelium of the blood brain barrier represents a challenge for effective AED delivery and concentration levels in the brain. Proven therapeutic strategies to control pharmacoresistant epilepsy include epilepsy surgery and neuromodulation. Unfortunately, not all patients are candidates for these therapies. Nanotechnology represents an attractive strategy to overcome the limited brain access of AEDs in patients with pharmacoresistant epilepsy. This manuscript presents a review of evidences supporting this idea.

The intrinsic severity hypothesis of pharmacoresistance to antiepileptic drugs

Pharmacoresistance to antiepileptic drugs (AEDs) is a barrier to seizure freedom for many persons with epilepsy. For nearly two decades, pharmacoresistance has been framed in terms of factors affecting the access of AEDs to their molecular targets in the brain or the actions of the drugs on these targets. Shortcomings in this prevailing view led to the formulation of the intrinsic severity hypothesis of pharmacoresistance to AEDs, which is based on the recognition that there are neurobiologic factors that confer phenotypic variation among individuals with etiologically similar forms of epilepsy and postulates that more severe epilepsy is more difficult to treat with AEDs. In recent years, progress has been made identifying potential genetic mechanisms of variation in epilepsy severity, including subclinical mutations in ion channels that increase or reduce epilepsy severity in mice. Efforts are underway to identify clinically important genetic modifiers. If it can be demonstrated that such severity factors play a role in pharmacoresistance, treatments could be devised to reverse severity mechanisms. By overcoming pharmacoresistance, this new approach to epilepsy therapy may allow drug refractory patients to achieve seizure freedom without side effects.

Impact of seizure activity on free extracellular phenytoin concentrations in amygdala-kindled rats

Access of antiepileptic drugs (AEDs) to the epileptic focus region is considered to be influenced by seizure-associated changes in blood–brain barrier (BBB) function and blood flow. Enhanced leakiness of the BBB has been reported as a consequence of seizure activity, and this is controversially discussed to either favor accumulation of AEDs in epileptic tissue or to limit free extracellular concentrations of AEDs due to enhanced protein extravasation. On the other hand, multidrug transporter overexpression has been described following seizure activity, which can limit brain penetration of AEDs in brain regions involved in seizure generation and spread. Aim of the present study was to determine, how these complex alterations at the BBB influence penetration of a standard AED to the site of seizure initiation. Microdialysis experiments were performed in amygdala-kindled rats and in electrode-implanted, non-kindled rats with the microdialysis probe located directly adjacent to the stimulation-recording depth electrode. Penetration of the AED phenytoin to the extracellular fluid in the focus region was investigated at different time points in relation to seizure activity elicited in kindled rats. Integrity of the BBB was determined by Evans blue. Access of phenytoin to the amygdala proved to be comparable in non-kindled, electrode-implanted control rats and in kindled rats 2 h or fourteen days following a single generalized seizure. When a single generalized seizure was elicited 10 min following phenytoin administration, average phenytoin brain dialysate levels were significantly lower (up to 45%) than those of control animals. During a self-sustained status epilepticus, phenytoin access to the site of seizure initiation tended to be lower in the early phase following drug administration, but reached control level 2 h later. The data clearly demonstrate that seizure-induced alterations in BBB integrity and function do not increase extracellular brain levels of phenytoin in affected brain regions, but rather tend to decrease the free concentration of phenytoin in the extracellular compartment.

Potential role of multidrug resistant proteins in refractory epilepsy and antiepileptic drugs interactions

Epilepsy is a common neurological disorder. About one-third of epilepsy patients have a multidrug resistance (MDR) phenotype and develop refractory epilepsy (RE). Changes in the properties of the antiepileptic drugs (AEDs) targets resulting in reduced drug sensitivity, can't explain the MDR phenotype. This particular refractoriness is now attributed to overexpression of multidrug transporters in brain, leading to impaired access of AEDs to CNS targets, and it was documented in both human as well as in experimental models of RE. Single nucleotide polymorphism (SNP) identified in the MDR1-ABCB1 gene (C3435T/CC-genotype) is associated with increased intestinal expression of P-glycoprotein (P-gp) that affects levels of AEDs in plasma. The functional studies of P-gp using P-gp inhibitors could show the still unclear clinical impact of ABCB1 polymorphisms on AEDs resistance. Some drug-drug interactions previously believed to be cytochrome P450 (CYP) mediated are now also considered to be due to the modulation of multidrug-transporters. Because in certain cases pharmacoresistance can be overcome by add-on therapy, co-administered P-gp inhibitors could contribute to the effectiveness of AEDs treatment in RE. And in this regard, perhaps we can postulate to P-gp as a new clinical therapeutic target in multidrug-refractory epilepsy.

The current availability of antiepileptic drugs in Zambia: implications for the ILAE/WHO "out of the shadows" campaign.

Recent concerns regarding antiepileptic drug (AED) availability in Zambia led us to conduct a study in the Lusaka and Southern Provinces to quantify the availability and cost of AEDs and assess determinants. Among 111 pharmacies, almost one-half did not carry AEDs (N = 54; 49.1%). Available AEDs were phenobarbitone (21; 18.9%), carbamazepine (27; 24.3%), valproic acid (4; 3.6%), and phenytoin (3; 2.7%). Adult out-of-pocket monthly costs ranged from US $7 to $30. Pediatric syrups were universally unavailable. Interviews revealed several barriers to AED provision, including that handling phenobarbitone (historically the most affordable AED) has become increasingly difficult because of newly enforced regulatory requirements. Personal communications with epilepsy-care providers in other low income countries suggest that this problem may be widespread. Improved enforcement of existing drug regulations may be contributing to the AED shortage. Social programs aimed at encouraging people with epilepsy to come "out of the shadows" must be preceded by improved AED access.

Brain access and anticonvulsant efficacy of carbamazepine, lamotrigine, and felbamate in ABCC2/MRP2-deficient TR- rats.

Different adenosine triphosphate (ATP)-driven multidrug transporters have been described to be expressed in the luminal membrane of blood-brain barrier (BBB) endothelial cells. At this site, multidrug transporters have been suggested to restrict penetration of drugs into the brain. Increasing evidence suggests that overexpression of different multidrug transporters occurs in the region of the epileptic focus of pharmacoresistant epilepsy patients. Based on the assumption that antiepileptic drugs (AEDs) are substrates of these transporters, this overexpression may limit access of AEDs to epileptic neurons and may contribute to drug-refractoriness. In a recent study, overexpression of multidrug resistance protein 2 (ABCC2; MRP2) was reported in BBB endothelial cells of epileptic focal tissue from pharmacoresistant patients. With brain microdialysis, we recently demonstrated that the AED phenytoin is subject to transport by ABCC2 at the BBB, whereas phenobarbital does not seem to be a substrate of ABCC2. We investigated whether ABCC2 is functionally involved in transport of the AEDs carbamazepine (CBZ), lamotrigine (LTG), and felbamate (FBM) across the BBB. The distribution of these AEDs into the brain of ABCC2-deficient TR- rats was determined. AED concentrations in plasma and brain extracellular space of these mutant rats did not differ significantly from those of rats of the corresponding background strain. In the amygdala-kindling model of epilepsy, the anticonvulsant efficacy of LTG and FBM was comparable in both groups of rats. In contrast, CBZ exhibited a higher anticonvulsant activity in kindled ABCC2-deficient rats as compared with nonmutant rats. In this present study, the microdialysis results gave no evidence that ABCC2 function modulates entry of CBZ, LTG, and FBM into the CNS of naïve rats. However, ABCC2 deficiency was associated with an increased anticonvulsant response of CBZ in the kindling model. Future investigations are planned to identify the underlying mechanism for this difference, clarifying whether a pharmacokinetic difference is detectable only when brain access of CBZ is compared in kindled ABCC2-deficient rats and kindled nonmutant rats, which may have an increased expression of ABCC2 in response to seizures. The data substantiate that ABCC2-deficient TR- rats are a useful tool for defining the role of ABCC2 for transport of AEDs, and give evidence that the use of kindled TR- rats may provide important supplementary information.

Antiepileptic therapies in the Mifi Province in Cameroon.

To evaluate the availability and accessibility of antiepileptic drugs (AEDs) in two health districts in Cameroon. The study included 33 patients with epilepsy, 26 physicians, 13 private pharmacists, eight hospital pharmacists, three distributors, and eight traditional healers. Structured questionnaires were used to assess the knowledge of the disease, treatment accessibility, the methods of prescriptions, and the availability and the frequency of delivery of drugs. Only one of 33 patients did not take modern treatment; 91% of the patients were followed up by a traditional healer, and 78%, by an hospital physician. Phenobarbitone (PB) was the most frequently prescribed drug by 69% of the doctors; 54% of the physicians considered the traditional therapies to be incompatible with modern drug treatment. By pharmacists, PB was delivered regularly. Other drugs went out of stock frequently. The number of packages in stock varied significantly directly with the frequency of delivery. The mean price per package and the mean number of packages in stock were higher in the public hospital pharmacies than in the private pharmacies. A majority of healers explained epilepsy as the presence of excess foam in the abdomen. The remedies proposed were to stop foam secretion. Availability of AEDs was quite high, but with no strict correspondence between the rate of prescriptions and the supply of the drugs.