James C. Cloyd

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

Although no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose‐dependent pharmacokinetics, particularly phenytoin.

Benzodiazepines in epilepsy : pharmacology and pharmacokinetics

Benzodiazepines (BZDs) remain important agents in the management of epilepsy. They are drugs of first choice for status epilepticus and seizures associated with post‐anoxic insult and are also frequently used in the treatment of febrile, acute repetitive and alcohol withdrawal seizures. Clinical advantages of these drugs include rapid onset of action, high efficacy rates and minimal toxicity. Benzodiazepines are used in a variety of clinical situations because they have a broad spectrum of clinical activity and can be administered via several routes. Potential shortcomings of BZDs include tolerance, withdrawal symptoms, adverse events, such as cognitive impairment and sedation, and drug interactions. Benzodiazepines differ in their pharmacologic effects and pharmacokinetic profiles, which dictate how the drugs are used. Among the approximately 35 BZDs available, a select few are used for the management of seizures and epilepsy: clobazam, clonazepam, clorazepate, diazepam, lorazepam and midazolam. Among these BZDs, clorazepate has a unique profile that includes a long half‐life of its active metabolite and slow onset of tolerance. Additionally, the pharmacokinetic characteristics of clorazepate (particularly the sustained‐release formulation) could theoretically help minimize adverse events. However, larger, controlled studies of clorazepate are needed to further examine its role in the treatment of patients with epilepsy.

A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures

BACKGROUND Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. METHODS We conducted a randomized, double-blind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at a dosage varying from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses -- one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. RESULTS Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P<0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P<0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P<0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P<0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P<0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. CONCLUSIONS Rectal diazepam gel, administered at home by trained care givers, is an effective and well-tolerated treatment for acute repetitive seizures.

Epidemiological and medical aspects of epilepsy in the elderly

Both the incidence and prevalence of epilepsy are high among the elderly. Cerebrovascular disease is the most common underlying cause, although as many as 25-40% of new epilepsy cases in the elderly have no obvious underlying etiology. Status epilepticus appears to occur more frequently in individuals greater than 60 years, and the morbidity and mortality of status epilepticus are significantly greater in this age group. Elderly patients with seizures, particularly complex partial seizures, present differently than younger adults, which can lead to misdiagnosis. Post-ictal confusion may last as long as 1-2 weeks in an elderly patient, as opposed to minutes in younger individuals. Adverse events are similar in symptomatology, but are more common in elderly patients and occur at lower doses and plasma drug concentrations. Neuropsychiatric disorders, such as depression and anxiety, are common in elderly patients with epilepsy, although often under-diagnosed and inadequately treated. The risk of osteoporosis is high among elderly women taking antiepileptic drugs, which underscores the importance of assessing bone health and treatment in this group. Management of the older patient with epilepsy requires an understanding of the etiologies and the medical and psychological aspects unique to this age group.

Rufinamide : Clinical pharmacokinetics and concentration-response relationships in patients with epilepsy

Rufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox‐Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose‐proportional plasma concentrations up to 1,600 mg/day, but less than dose‐proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half‐life of 6–10 h. The apparent volume of distribution (Vd/F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age‐related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme‐inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight‐to‐moderate decrease in plasma rufinamide concentrations, ranging from a minimum of −13.7% in female children comedicated with vigabatrin to a maximum of −46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from placebo‐controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady‐state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration‐related.

Home use of rectal diazepam for cluster and prolonged seizures: efficacy, adverse reactions, quality of life, and cost analysis

From 1982 through 1987, 128 families, who were instructed in the use of rectally administered diazepam (R-DZP) for the treatment of severe epileptic seizures, were surveyed. Sixty-seven families returned questionnaires and met inclusion/exclusion criteria; the results were used to analyze the medical, psychosocial, and economic impact of this program during the first year following instruction. Twenty-six families did not use R-DZP, primarily because of patient improvement. Among families using R-DZP, a total of 428 doses were administered to 41 children. R-DZP was effective in controlling seizures in 85% of patients. Adverse reactions usually were mild, consisting of drowsiness and/or behavioral changes. Compared to the year prior to instruction, emergency room visits decreased in both R-DZP-treated and -nontreated children; however, cost-savings were greater for the R-DZP group (

Antiepileptic drug use in nursing home residents: effect of age, gender, and comedication on patterns of use.

1,039.00 vs

Pharmacological and clinical aspects of antiepileptic drug use in the elderly

420.00 per patient per year). Improvements in quality of life associated with the availability of R-DZP were observed by 58% of users and 27% of nonusers which included improved management of their childrens seizures, increased flexibility in family activities, and greater peace of mind. R-DZP appears to be a practical method in the effective treatment of severe seizures at home.

N-acetylcysteine boosts brain and blood glutathione in gaucher and Parkinson diseases

Summary: Purpose: Examine antiepileptic drug (AED) use in nursing homes by age, gender, and use of comedication that can interact with AEDs.

The established status epilepticus trial 2013.

In this article, epidemiological and clinical aspects related to the use of antiepileptic drugs (AEDs) in the elderly are highlighted. Studies have shown that people with epilepsy receiving AED treatment show important deficits in physical and social functioning compared with age-matched people without epilepsy. To what extent these deficits can be ascribed to epilepsy per se or to the consequences of AED treatment remains to be clarified. The importance of characterizing the effects of AEDs in an elderly population is highlighted by epidemiological surveys indicating that the prevalence of AED use is increased in elderly people, particularly in those living in nursing homes. Both the pharmacokinetics and the pharmacodynamics of AEDs may be altered in old age, which may contribute to the observation that AEDs are among the drug classes most commonly implicated as causing adverse drug reactions in an aged population. Age alone is one of several contributors to alterations in AED response in the elderly; other factors include physical frailty, co-morbidities, dietary influences, and drug interactions. Individualization of dosage, avoidance of unnecessary polypharmacy, and careful observation of clinical response are essential for an effective and safe utilization of AEDs in an elderly population.