Variety Of Antiepileptic Drugs Research Articles

Phenytoin is associated with increased risk of osteoporosis and fragility fractures in adult epileptic patients.

Osteoporotic fractures lead to significant decreases in the quality of life with increases in morbidity, mortality, and disability. Treatment with a variety of anti-epileptic drugs, such as phenytoin, has been understood to cause a decrease in bone mineral density. Cohort A was identified as patients that were 18-55years old that had epilepsy and recurrent seizures that were also prescribed phenytoin. Cohort B was identified as patients that were 18-55years old that had epilepsy and recurrent seizures but were not prescribed phenytoin or other anti-epileptic medications. Cohorts were matched for relevant confounding pathologies and demographic factors. Outcomes were evaluated from 1day to 5years after the indexed event. A total of 35,936 patients with epilepsy that were prescribed phenytoin were matched with 109,335 patients with epilepsy that were not prescribed phenytoin. Patients on phenytoin therapy were at significantly higher risk for osteoporosis without pathological fracture, fracture of metatarsal bone, fracture of shoulder and upper arm, fracture of distal radius, fracture of thoracic vertebra, fracture of cervical vertebra, fracture of lumbar vertebra, fracture of femoral head or neck, pertrochanteric fracture, femoral shaft fracture, and distal tibia fracture (all outcomes p < 0.001). Epileptic patients on phenytoin therapy that were 18-55years old exhibited higher associated risk of osteoporosis and osteoporotic-fragility fractures of various regions. Patients that undergo phenytoin therapy for epilepsy treatment should be educated on the increased risk of bone fractures and have appropriate lifestyle and diet modifications.

Therapeutic drug monitoring of anti-epileptic drugs - a clinical verification of volumetric absorptive micro sampling.

Background Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) can serve as a valuable tool in optimising and individualising epilepsy treatment, especially in vulnerable groups such as pregnant women, the elderly and children. Unfortunately, TDM is often performed suboptimally due to limitations in blood collection. Therefore, we investigated volumetric absorptive micro sampling (VAMS) - a new home-sampling technique. We aimed to evaluate VAMS to determine and quantify the different AEDs and concentrations of 16 different AEDs in whole blood collected by VAMS. Methods Patient blood samples (n = 138) were collected via venepunctures at the Academic Centre for Epileptology Kempenhaeghe. AED concentrations were determined, and these concentrations were used to compare the VAMS method (whole blood) with the conventional method (serum). In addition, the recovery was examined as well as the impact of haematocrit. Finally, AED-spiked blood was used to test the stability of the AEDs inside the micro-sampler devices over a period of time and whether temperature had an effect on the stability. Results VAMS allows for an accurate detection of 16 different AEDs within 2 days after sampling. Deviation in recovery was less than 10% and high correlations were found between VAMS and conventional sampling. Moreover, haematocrit does not have an effect with values between 0.3 and 0.5 (L/L). Finally, although storage temperature of VAMS does affect some AEDs, most are unaffected. Conclusions VAMS enables an accurate detection of a wide variety of AEDs within 2 days after sampling.

Quantitative EEG findings and response to treatment with antiepileptic medications in children with epilepsy

BackgroundEpilepsy is a common chronic disorder in pediatric neurology. Nowadays, a variety of antiepileptic drugs (AEDs) are available. A scientific method designed to evaluate the effectiveness of AEDs in the early stage of treatment has not been reported. PurposeIn this study, we try to use quantitative EEG (QEEG) analysis as a biomarker to evaluate therapeutic effectiveness. Methods20 epileptic children were enrolled in this study. Participants were classified as effective if they achieved a reduction in seizure frequency over 50%. Ineffective was defined as a reduction in seizure frequency less than 50%. Eleven participants were placed in the effective group, the remaining 9 participants were placed in the ineffective group. EEG segments before and after 1–3months of antiepileptic drugs start/change were analyzed and compared by QEEG analysis. The follow-up EEG segments after the 2nd examinations were used to test the accuracy of the analytic results. ResultsSix crucial EEG feature descriptors were selected for classifying the effective and ineffective groups. Significantly increased RelPowAlpha_avg_AVG, RelPowAlpha_snr_AVG, HjorthM_avg_AVG, and DecorrTime_snr_AVG values were found in the effective group as compared to the ineffective group. On the contrary, there were significantly decreases in DecorrTime_std_AVG, and Wavelet_db4_EnergyBand_5_avg_AVG values in the effective group as compared to the ineffective group. The analyses yielded a precision rate of 100%. When the follow-up EEG segments were used to test the analytic results, the accuracy was 83.3%. ConclusionThe developed method is a useful tool in analyzing the effectiveness of antiepileptic drugs. This method may assist pediatric neurologists in evaluating the efficacy of AEDs and making antiepileptic drug adjustments when managing epileptic patients in the early stage.

Anticonvulsant effects of iridoid glycosides fraction purified from Feretia apodanthera Del. (Rubiaceae) in experimental mice models of generalized tonic-clonic seizures.

BackgroundDespite the increasing number and variety of antiepileptic drugs, nearly 30 % of epileptic patients who receive appropriate medical attention have persisting seizures. Anticonvulsant activity has been demonstrated for different iridoid glycoside-rich plant extracts. This study was designed to investigate the anticonvulsant effects of iridoid glycosides purified from Feretia apodanthera and to explore the possible mechanisms involved in antiepileptic activity.MethodsThe anticonvulsant effects of iridoid glycosides extracts were investigated against 2.7 mg/kg bicuculline- and 70 mg/kg pentylenetetrazole-induced convulsions. The behavioural and electroencephalographic manifestations of 50 mg/kg pentylenetetrazole-induced seizures in mice as a model of generalized tonic-clonic seizures were also evaluated. Finally, the extracts were tested on the course of kindling development, kindled-seizures and oxidative stress markers in 30 mg/kg pentylenetetrazole-kindled mice. Their effects on brain GABA content were also determined.ResultsThe iridoid glycosides (30–90 mg/kg) protected mice against bicuculline-induced motor seizures in all pre-treated animals. Behavioural seizures- and mortality-induced by 70 mg/kg pentylenetetrazole were strongly antagonized by the extracts (60–90 mg/kg). The number of crisis (n/20 min), the cumulative duration of crisis (sec/20 min), and the mean duration of crisis (sec) recorded in 50 mg/kg pentylenetetrazole-treated mice were significantly decreased in all pre-treated mice with the extracts (60–90 mg/kg). Administration of the extracts (30–90 mg/kg) significantly increased the latency to myoclonic jerks, clonic seizures as well as generalized tonic-clonic seizures, improved the seizure mean stage and decreased the number of myoclonic jerks in 30 mg/kg pentylenetetrazole-kindled mice. Pentylenetetrazole kindling induced significant oxidative stress and brain GABA content alteration that was reversed by pretreatment with the extracts in a dose-dependent manner.ConclusionsThe results indicate that pretreatment with the iridoid glycosides extracts of Feretia apodenthera improves generalized tonic-clonic seizures-induced by chemo-convulsants, protects mice against kindling development and oxidative stress, and improves brain GABA content in pentylenetetrazole-kindled mice.

Surgical treatment of epilepsy in tuberous sclerosis complex

Tuberous sclerosis complex(TSC) is a rare autosomal dominant neurocutaneous disease.Epilepsy is the most common manifestation.Studies show that even with a variety of antiepileptic drugs, more than 50% of TSC related epilepsy are drug-resistant.Since cortical tubers are the main epileptogenic foci, resection surgery become an important treatment of intractable epilepsy in TSC.In recent years, with the development of electrophysiology and imaging technology, surgical treatment of epilepsy in TSC shows a great efficacy of controlling seizures and improving intelligence.Up to date, there are no standard procedures of surgical treatment for refractory epilepsy in TSC.This paper aimed to provide some instructions. Key words: Tuberous sclerosis complex; Refractory epilepsy; Cortical tubes; Surgical treatment

New antiepileptic drugs

Epilepsy is one of the most common chronic neurologic conditions. Pharmacologic therapy is by far the most common approach, with the other modalities typically limited to patients with pharmacoresistant epilepsies. A host of new antiepileptic drugs (AEDs) have been introduced over the last 20 years. The AEDs including the conventional ones are more or less equally effective in patients with partial epilepsy. Therefore, relative efficacy is not a useful factor in selecting a particular drug. A conventional AED, valproic acid is regarded as having superior efficacy than the other broad-spectrum AEDs including new ones in patients with generalized epilepsy. However, it can have considerable side effects, such as reproductive dysfunction and teratogenicity to young women with epilepsy. One of the clearest advantages of many new AEDs over the conventional ones has been their more favorable pharmacokinetic and drug-drug interaction profiles compared with the conventional ones involved in the cytochrome P450 enzymatic system, which may change the levels of other antiepileptic and nonantiepileptic drugs, and endogenous substances. Many new AEDs have unique mechanisms of action and slightly better tolerability than the conventional ones. Several new AEDs can allow young women with epilepsy, particularly those with idiopathic generalized epilepsy, to avoid valproic acid treatment. Furthermore, the new AEDs may provide a modest but positive effect in seizure control, particularly as an add-on treatment. The greater variety of AEDs allows better patient tailoring according to patient’s characteristics and contributes to improvement in quality of life.

Estimulación cerebral profunda para la epilepsia resistente: dianas extratalámicas

Epilepsy is a neurological disorder that affects 1-2% of the population. The majority of epileptic patients achieve a good seizure control with the current available treatments. However, there is a subgroup of patients that remain severely disable despite the variety of anti-epileptic drugs, the possibility of surgery for resection of the epileptogenic foci in selected patients, and vagal nerve stimulation; various lines of research are being carried out to look for new treatment alternatives. Deep brain stimulation (DBS) of the thalamus has emerged as a therapeutic alternative for patients who remain in-capacitated; the efficacy of this new therapy is subject of several studies, and its effectiveness and safety has not been established yet. There are other targets for deep brain stimulation that may be useful for drug-resistant epilepsy. Experiments with animal models and preliminary human studies have shown encouraging results with DBS on cerebellum, subthalamic nucleus, substantia nigra, hippocampus and cerebral cortex, among others. The purpose of this review is to revisit the studies that have been carried out on these brain nuclei, as targets for DBS for drug-resistant epilepsy. Studies have shown varying degrees of effectiveness, and there is a need for controlled trials to draw any definite conclusions.

CNS Adverse Events Associated with Antiepileptic Drugs

A variety of newer antiepileptic drugs (AEDs) are now available for treating patients with epilepsy in addition to the 'conventional' drugs that have been available throughout a large part of the last century. Since these drugs act to suppress the pathological neuronal hyperexcitability that constitutes the final substrate in many seizure disorders, it is not surprising that they are prone to causing adverse reactions that affect the CNS.Information on adverse effects of the older AEDs has been mainly observational. Equally, whilst the newer drugs have been more systematically studied, their long-term adverse effects are not clearly known. This is illustrated by the relatively late emergence of the knowledge of visual field constriction in the case of vigabatrin, which only became known after several hundred thousand patient-years of use. However, older drugs continue to be studied and there has been more recent comment on the possible effect of valproate (valproic acid) on cognition following exposure to this drug in utero.With most AEDs, there are mainly dose-related adverse effects that could be considered generic, such as sedation, drowsiness, incoordination, nausea and fatigue. Careful dose titration with small initial doses can reduce the likelihood of these adverse effects occurring. Adverse effects such as paraesthesiae are more commonly reported with drugs such as topiramate and zonisamide that have carbonic anhydrase activity. Weight loss and anorexia can also be peculiar to these drugs. Neuropsychiatric adverse effects are reported with a variety of AEDs and may not be dose related. Some drugs, such as carbamazepine when used to treat primary generalized epilepsy, can exacerbate certain seizure types. Rare adverse effects such as hyperammonaemia with valproate are drug specific. There are relatively very few head-to-head comparisons of AEDs and limited information is available in this regard.In this review, we discuss the available literature and provide a comprehensive summary of adverse drug reactions of AEDs affecting the CNS.

Availability and Costs of Antiepileptic Drugs and Quality of Phenobarbital in Vientiane Municipality, Lao PDR

Purpose: In developing countries, availability and quality of drugs are critical factors for effective management and control of epilepsy. This study investigated the availability and costs of antiepileptic drugs (AEDs), and the quality of phenobarbital in Vientiane Municipality, Lao PDR. Methods: In March 2004, we enrolled all pharmacies (categories I and II) of four central districts of Vientiane eligible to sell AEDs. Two hundred and eight pharmacies of category III (75.1% of all registered pharmacies) were excluded as the sale of AEDs was not authorized. All pharmacists were interviewed with a standard questionnaire. Whenever phenobarbital was available, a sample was purchased and assayed by liquid chromatography. Phenobarbital was defined as being of correct quality if the active substance average content corresponded to ±15% of the indicated amount. Results: 66 pharmacies were enrolled (13 and 45 of categories I and II, respectively, and 8 hospital pharmacies). Six generics of AEDs were found (phenobarbital, phenytoin, valproic acid, clonazepam, carbamazepine, diazepam) and all pharmacies sold at least 1 AED. The 2 most widely available drugs were diazepam (5 mg) and phenobarbital (100 mg), present in 87.9 and 53.0% of the pharmacies, respectively. All 34 phenobarbital samples examined showed a correct concentration of the active compound. However, the concentration of phenobarbital 100 mg tablets produced in Lao PDR (mean concentration 94.7 mg) was significantly lower (p = 0.005) than the imported equivalent (mean concentration 99.7 mg). The direct drug costs of a yearly treatment with phenobarbital were estimated to be at least 25.2 USD. Conclusions:A variety of AEDs are present. Their availability, particularly of phenobarbital, is restricted to higher-category pharmacies and within those it is rather limited. To meet the costs of AEDs in this setting is a major challenge for people with epilepsy. However, the quality of the available phenobarbital was rather satisfactory.

Limited P-glycoprotein mediated efflux for anti-epileptic drugs

A variety of anti-epileptic drugs (AEDs) were tested for their ability to be transported by P-glycoprotein (P-gp) through Caco-2 monolayers using bi-directional (apical (Ap) to basolateral (Bas), and Bas to Ap) studies. Transport rates were equivalent in both directions for vigabatrin, gabapentin, phenobarbitone, lamotrigine and carbamazepine, being 0.7 × 10− 6, 0.1 × 10− 6, 34 × 10− 6, 36 × 10− 6 and 55 × 10− 6 cm/s, respectively. Phenytoin displayed a 20% increase in Ap to Bas transport, while topiramate and ethosuximide each had greater transport in the uptake direction, with both drugs showing no efflux. None of the transport rates for these drugs were affected by P-gp inhibitors. However, the efflux rate for acetazolamide was 3-fold higher than its uptake and this was significantly reduced by P-gp inhibitors. Thus, only one anti-epileptic, acetazolamide, was shown to be weak P-gp substrate, suggesting that P-gp efflux may not be a factor in relation to the development of resistance of epilepsy therapy.

A potential role for astrocytes in mediating the antiepileptic actions of furosemide in vitro

Epileptic seizures are characterized by abnormal electrical discharge. In previous studies we established a powerful antiepileptic action for a commonly used diuretic (furosemide). However, it remains unclear precisely how furosemide terminates abnormal electrical discharges. To address this issue, we performed in vitro experiments to examine conditions where furosemide exerts antiepileptic activity and patch-clamp studies to analyze the effect of furosemide on neuronal membrane properties, synaptic function and inward potassium current. Furosemide was not found to alter synaptic field responses, excitatory postsynaptic currents or intrinsic membrane properties of principal hippocampal neurons. Our in vitro studies indicate that furosemide does not abolish spontaneous epileptiform bursting during co-application of Ba 2+ or Cs + ions (to block inwardly rectifying potassium channels). Our patch-clamp data indicate that furosemide enhances the function of astrocytic, but not neuronal, inward potassium channels and that this modulation may be required for its antiepileptic activity. Although a variety of antiepileptic drugs are already available, none of these compounds selectively target astrocytes while preserving synaptic/neuronal function. Thus, furosemide-mediated modulation of inward potassium current (on astrocytes) represents a new target for control of abnormal electrical discharge in the CNS.

Anesthetic implications of epilepsy, status epilepticus, and epilepsy surgery.

Epilepsy is a clinical paroxysmal disorder of recurring seizures, excluding alcohol or drug withdrawal seizures or such recurring exogenous events as repeated insulin-induced hypoglycemia. Epilepsy has a profound impact on each individual diagnosed with this disease. Seizures have been and are thought to arise as a result of abnormalities in (a) neural circuits, (b) excitation/inhibition balance, (c) potassium, and (d) genetic abnormalities. Therapy for epilepsy is either medical, entailing the use of a variety of antiepileptic drugs, or surgical. An urgent approach to seizure control is indicated when status epilepticus occurs. When all standard therapy fails, general anesthesia can be used to control status epilepticus. Surgery is an option in the treatment of epilepsy and requires extensive preoperative evaluation. The primary concerns for the neuroanesthesiologist anesthetizing the patient with epilepsy are the capacity of anesthetics to modulate or potentiate seizure activity and the interaction of anesthetic drugs with antiepileptic drugs. Proconvulsant and anticonvulsant properties have been reported for nearly every anesthetic. If seizure spikes are to be evoked during seizure surgery, then light anesthesia with a proconvulsant anesthetic is used. Conscious analgesia can be used for awake seizure surgery. However, if electrocorticography is not planned, then a general anticonvulsant anesthetic maintenance regimen is used. The latter technique also may be useful in patients whose anesthetic management is complicated by an incidental history of epilepsy.

A Comparison of the OPUS and TDx Analysers for Antiepileptic Drug Monitoring

Therapeutic drug monitoring of a variety of antiepileptic drugs is used routinely as a guide to individualising the drug treatment of patients with epilepsy. Thin dry film multilayer immunoassays (OPUS) for carbamazepine, phenytoin, phenobarbitone, and valproic acid were evaluated and compared with fluorescence polarisation immunoassay (TDx), using commercially available control material and patient sera. For the OPUS, the within-batch coefficient of variation (CV) for the different drugs in the control material varied between 3.9% (phenobarbitone) and 8.1% (valproic acid). The between-batch CVs varied between 5.3% (valproic acid) and 18.3% (carbamazepine). The comparative between-batch CVs for the TDx varied between 2.0% (phenytoin) and 7.0% (valproic acid). Analysis of 209 patient samples containing carbamazepine, phenytoin, phenobarbitone, or valproic acid demonstrated significant correlation between the two analytical methods, with correlation coefficients of 0.9336, 0.9560, 0.9448, and 0.9618, with slopes of the regression lines of 0.9042, 0.8663, 1.1368, and 1.1244, respectively. It is concluded that both the TDx and OPUS instruments exhibit comparable performance for the analysis of carbamazepine, phenobarbitone, phenytoin, and valproic acid in patient samples. Moreover, the OPUS instrument, with its facilities of random assay access and statim analysis, may be useful in an outpatient setting in which a major consideration would be a rapid turnaround of patient assay results.

Testing antiepileptic drugs in children.

Few drugs have been approved by the Food and Drug Administration specifically for the treatment of pediatric patients with epilepsy in the United States. There are many factors that make tests of drugs in this group different from studies among adults. This report reviews issues that must be considered in designing studies that will help bring to market antiepileptic drugs for children. Information on the wide variety of antiepileptic drugs rapidly being developed can only be obtained through well-controlled, well-designed clinical trials. Despite the obstacles and pitfalls, trials among the pediatric population are necessary to establish the unique efficacy and safety profile of each drug and to determine the target, population most likely to benefit from each drug.

Influence of CGS 15943 A (a nonxanthine adenosine antagonist) on the protection offered by a variety of antiepileptic drugs against maximal electroshock-induced seizures in mice

CGS 15943 A (a nonxanthine adenosine antagonist) was studied on the protective efficacy of carbamazepine (60 min prior to the convulsive test), diazepam (60 min), diphenylhydantoin (120 min), phenobarbital (120 min), and valproate (30 min) against maximal electroshock-induced convulsions in mice. Moreover, the influence of the adenosine antagonist on 2-chloroadenosine (1 mg/kg, 20 min prior to the test)- and valproate (250 mg/kg, 30 min)-induced inhibitions of locomotor activity was also studied. CGS 15943 A (1 mg/kg) was given 15 min before both tests and all the drugs were administered i.p.. The adenosine antagonist (1 mg/kg) remained without influence upon the protective activity of all studied antiepileptics, reflected by their respective ED50 values against maximal electroshock. However, both 2-chloroadenosine and valproate-induced inhibitions of locomotor activity were attenuated by CGS 15943 A, which alone did not affect this parameter. However, CGS 15943 A (5 mg/kg) diminished the protection offered by diphenylhydantoin, increasing its ED50 value from 13 to 16 mg/kg. It may be concluded that the protection provided by common antiepileptic drugs against electroconvulsions seems independent of adenosine-mediated inhibition. In the case of diphenylhydantoin, one may suggest the involvement of purinergic transmission in the final anticonvulsant effect.