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Biomedical subjects

Ilo E Leppik

Publications and source records attributed to Ilo E Leppik.

At least 19 recordsLinked to original sources
PubMed2006

Felbamate: consensus of current clinical experience.

An expert panel convened to evaluate data and review current clinical practices regarding the novel antiepileptic drug (AED) felbamate. Felbamate has demonstrated efficacy against a variety of refractory seizures types, including seizures associated with Lennox-Gastaut syndrome, but postmarketing experience revealed serious idiosyncratic adverse effects that were not observed during clinical trials. Although felbamate is not indicated as first-line antiepileptic therapy, its utility in treating seizures that are refractory to other AEDs is undisputed, as shown by the number of patients who continue to use it. New exposures to felbamate number approximately 3200-4200 patients annually, and it is estimated that over the past 10 years, approximately 35,000 new starts have occurred. Recommendations by the American Academy of Neurology and a review of felbamate literature were evaluated in conjunction with the clinical experience of the expert panel to determine current medical opinion and practice regarding felbamate. The past 10 years of clinical experience have demonstrated that when used in accordance with existing recommendations and close clinical monitoring, felbamate is an effective treatment for some patients with seizures refractory to other AEDs. This review of clinical data and discussion of the current understanding of the risk:benefit of felbamate therapy supports its use as an important therapeutic option for some patients with refractory epilepsy.

Anticonvulsants↗
PubMed2006

Paradoxical urinary phenytoin metabolite (S)/(R) ratios in CYP2C19*1/*2 patients.

Phenytoin (PHT) is primarily metabolized to 5-(4'-hydroxyphenyl)-5-phenylhydantoin (p-HPPH), accounting for 67-88% of an administered dose in humans. p-HPPH is formed by the cytochrome (CYP) 450 enzymes CYP2C9 and CYP2C19, then glucuronidated and excreted into the urine. CYP2C9 catalyses the prochiral formation of (R) and (S)-p-HPPH, and is approximately 40 times more stereoselective towards the formation of the (S) isomer whereas CYP2C19 is not stereoselective. Because of differential stereoselectivity, polymorphisms in the genes can alter the (S)/(R)-p-HPPH ratios. Genotyping for CYP2C9 and CYP2C19 was accomplished by a Taqman based assay. Twelve and twenty-four hour urine samples were collected from 45 epilepsy patients taking PHT under steady-state conditions and (S)/(R) ratios of p-HPPH were determined by chiral HPLC separation. The mean urinary (S)/(R) ratio in the 12-24h urine collection in subjects homozygous for CYP2C9*1/*1, CYP2C19*1/*1 was 24.2+/-3.1(n=21), whereas ratios in CYP2C9*1/*2 and CYP2C9*1/*3 subjects, were 11.1+/-3.3(n=7) and 2.7+/-0.6(n=2), respectively. One CYP2C9*2/*3 patient had a ratio of 2.1. Unexpectedly, CYP2C9*1/*1, CYP2C19*1/*2 subjects had a mean (S)/(R) ratio as low as 12.9+/-1.7(n=12). Our results are generally consistent with single dose PHT studies. However, the (S)/(R)-p-HPPH ratios for the CYP2C9*1/*1, CYP2C19*1/*2 subjects, expected to be in the range of 30-40, were only 12.9, suggesting some undetected linkage disequilibrium between CYP2C9 and CYP2C19 genes that could affect PHT elimination. Furthermore, our study suggests that measurement of urine ratios cannot be used as a marker for genotype determination.

Anticonvulsants↗
PubMed2006

Outcomes research: clinical trials in the elderly.

Very few clinical trials have been done in the elderly. This report reviews results of two completed studies and describes one in progress. The largest published study was a United States Veterans Affairs Administration study in newly diagnosed patients with epilepsy. It compared carbamazepine to gabapentin and lamotrigine, and found that, although equivalent in efficacy, the newer antiepileptic drugs (AEDs) were better tolerated. This study also highlighted many of the difficulties in recruiting and retaining elderly patients in studies, the large number of comorbidities, and the problems of distinguishing seizures in the elderly from other symptoms. Another study of new-onset epilepsy suggested that a large percentage of elderly patients respond to initial AED therapy, but side effect profiles differ. More studies are needed to better define the risk/benefit relationships in elderly patients.

Aged↗
PubMed2006

Practical prescribing and long-term efficacy and safety of zonisamide.

Long-term efficacy, tolerability and safety of antiepileptic drug (AED) therapy is essential given the chronic nature of epilepsy. Zonisamide (Zonegran), a novel AED with a broad range of mechanisms of action contributing to its antiseizure efficacy, has been evaluated extensively for the long-term management of epilepsy. Open-label extension studies in the United States and Europe suggest continued efficacy of zonisamide in long-term treatment without development of adverse events further to those seen in registration studies. Baseline seizure frequency is reduced by approximately 40-70% during long-term treatment for up to 2 years, and 30-50% of patients attain >or=50% reduction in seizure frequency across all categories of seizure and durations of treatment. Preliminary data indicate a progressive decline in seizure frequency with continued zonisamide treatment. Zonisamide is well tolerated in long-term use, with a trend towards decreasing incidence of generally mild adverse events over time and a low rate of withdrawal during chronic use. Nephrolithiasis and other serious adverse events are infrequent, and can be minimised by appropriate management and patient education. This profile of maintained efficacy, tolerability and safety during sustained administration in combination with other AEDs supports zonisamide as a valuable adjunctive agent in the long-term management of refractory partial epilepsy.

Adolescent↗
PubMed2006

Ginkgo biloba use in nursing home elderly with epilepsy or seizure disorder.

PURPOSE: Ginkgo biloba, among the most widely used herbs, possesses the capacity both to induce and to inhibit seizures. The purpose of this study was to describe the prevalence of ginkgo and other common herb prescribing in a sample of nursing home (NH) elderly diagnosed with epilepsy/seizure (Epi/Sz) disorder and to determine demographic, clinical, and functional factors associated with ginkgo use. METHODS: This was a 1-year prevalence study of 68,403 NH residents living in 557 nursing facilities throughout the United States. RESULTS: Overall, herb use in the NHs was very low (0.41%). Ginkgo was prescribed 162 times, more than any other herb. St. John's wort was prescribed 40 times; garlic, 29 times; and all others, <20 times, for a total of 307 herb orders. Among all residents with an herb order, ginkgo was prescribed for 61.9% of residents with an Epi/Sz diagnosis and 58.0% (p = 0.820) of residents without an Epi/Sz diagnosis. Dementia, educational level, and the interaction of age group with cognitive impairment were all significantly associated with herb use among Epi/Sz residents. Cognitive impairment and the interaction of Epi/Sz disorder with dementia were associated specifically with ginkgo use. CONCLUSIONS: Ginkgo is the most frequently prescribed herb in this population in which >50% of all herb orders were written for ginkgo. The concern with ginkgo use among elderly with Epi/Sz is the lack of standardization that characterizes ginkgo products. In the absence of standardization, the likelihood is increased that ginkgo products may be adulterated with the Ginkgo biloba plant parts most commonly associated with seizure provocation.

Age Distribution↗
PubMed2006

Epilepsy in the elderly.

The elderly are the most rapidly growing segment of the population and the incidence of epilepsy is higher in the elderly than in any other age group. They have been subdivided into the "young old," 65-74 years, "middle old" 75-84 years, and the "old old," 85 years or older. But further subdivisions are needed: persons with only epilepsy, those with epilepsy and multiple medical problems, and the frail elderly. Thus, when considering therapy, one must tailor the interventions to nine categories: young old healthy, young old with medical problems, frail young old, old healthy, old with medical problems, frail old, old old healthy, old old with medical problems, and frail old old. The prevalence of antiepileptic drug (AED) use in community dwelling elderly is 1.5%; in the nursing home population it is 10%. Surprisingly, 3% have an AED newly prescribed after admission. Overall, 6.2% were using phenytoin, 1.8% carbamazepine, 0.9% valproic acid, 1.7% phenobarbital, and others combined, 1.2%. AEDs rank fifth among all drug categories as a cause of adverse reactions. There are very few data regarding the clinical use of AEDs in the elderly. The paucity of information makes it very difficult to recommend specific AEDs with any confidence that the outcomes will be optimal. An appropriate for elderly healthy may not be appropriate for elderly with multiple medical problems, and in frail elderly variable absorption may be a major problem. One of the major advantages of some newer AEDs is lack of drug interactions. Cost is an advantage of the older AEDs. Regardless of the AED chosen, one must use doses appropriate to the clearance of the drug, and AED levels, especially unbound (free) levels, must be monitored. The elderly nursing home resident may be more frail, be taking many medications, and have several concomitant illnesses, making them difficult to treat. The most commonly used AED, phenytoin, may not be the easiest or safest AED to prescribe in the elderly with multiple medical problems or the frail elderly.

Adult↗
PubMed2005

Basic research in epilepsy and aging.

A PubMed search of the years 1965 to 2003 found only 30 articles that were directly related to modeling seizures or epilepsy in aged animals. This lack of research is disturbing but explainable because of the high cost of aged animals and their increasing infirmity. Many changes occur in the older brain: cell loss in the hippocampal formation, changes in long-term potentiation maintenance, alteration in kindling, increased susceptibility to status epilepticus, and neuronal damage from stroke. The effect of aging on voltage-gated sodium and calcium channels has not been studied sufficiently. With increasing numbers of elderly persons with epilepsy needing appropriate treatment, the need to better understand the basic mechanisms of epilepsy is crucial.

Aged↗
PubMed2005

Hyponatremia from oxcarbazepine and carbamazepine.

The authors examined sodium concentrations from 97 oxcarbazepine-treated (OXC) and 451 carbamazepine-treated (CBZ) patients with epilepsy using cross-section and follow-up studies. The frequency of hyponatremia (Na+ < or = 134 mEq/L) was 29.9% among OXC-treated patients and 13.5% among CBZ-treated patients (p < 0.0001). Hyponatremia (Na+ < or = 128 mEq/L) was severe: 12.4% of OXC-treated patients and 2.8% of CBZ-treated patients (p < 0.001). Advanced age was a risk factor for hyponatremia. Hyponatremia, once present, persisted in both groups.

Adult↗
PubMed2005

Prevalence of appropriate and problematic antiepileptic combination therapy in older people in the nursing home.

OBJECTIVES: To determine the prevalence of mono- and poly-antiepileptic drug (AED) therapy in a cohort of nursing home (NH) residents and to describe specific AED combinations used, as well as demographic, clinical, and functional factors associated with poly-AED therapy and the most common AED combination. DESIGN: Retrospective, point prevalence study. SETTING: All NHs owned/managed by Beverly Enterprises. PARTICIPANTS: All residents aged 65 and older residing in one of the study NHs on July 1, 1999, and receiving an AED (N=3,881). MEASUREMENTS: Data were gathered using two secondary source data sets: physicians' orders (AED use) and the Minimum Data Set (health status indicators). RESULTS: Of residents taking AEDs, 370 (9.5%) were taking two or more; 268 of those (72%) were taking problematic AED combinations (those with the potential of undesirable pharmacokinetic or pharmacodynamic interactions). Phenytoin (PHT) with phenobarbital (PB) was the most common combination (27.0%). Logistic regression indicated that poly-AED subjects were more likely to have a diagnosis of epilepsy/seizure (epi/sz) and less likely to have a diagnosis of cerebrovascular accident (CVA). Residents taking the PHT/PB combination were more likely to have an epi/sz diagnosis and longer NH stay. The association between CVA and PHT/PB polytherapy differed by presence or absence of aphasia. CONCLUSION: The overall prevalence of poly-AED therapy is less than 10% in NH residents, but 72% of those residents were receiving problematic polytherapy combinations, thereby exposing them to potential risk of adverse reactions and toxicity.

Age Distribution↗
PubMed2005

Choosing an antiepileptic. Selecting drugs for older patients with epilepsy.

After age 65, the incidence of epilepsy increases rapidly. Approximately 1.5% of Medicare recipients and 10% of nursing home residents are being treated with antiepileptic drugs (AEDs). The most commonly used AED is phenytoin, a first generation agent. Appropriate drug selection in this population is complicated by the fact that multiple comorbidity is commonplace. Most older patients receive a number of drugs in addition to AEDs. The average nursing home patient receives six additional medications. Age-related issues affecting the choice of an AED include changes in protein binding, decreases in hepatic and renal clearance, and alterations in gastrointestinal absorption. AEDs that do not have drug-drug interactions, are not metabolized by the liver, and are readily absorbed may be better suited for the elderly. This paper reviews the present knowledge base and attempts to develop a more rational approach to AED selection for the elderly.

Age Factors↗
PubMed2004

Valproic acid doses, concentrations, and clearances in elderly nursing home residents.

VPA daily dose and total VPA concentrations for 146 elderly (> or =65 years) nursing home residents collected from June 1998 to December 2000 in homes located throughout the United States are presented. Average age was 78.5+/-8.0 years old. The mean VPA daily dose was 16.2+/-11.2mg/kg and mean total VPA concentration was 48.5+/-24.8 mg/L. The majority (56.2%) of the VPA residents are being maintained at total VPA levels <50mg/L. Mean daily dose (19.4+/-11.4, 16.3+/-12.1, and 11.3+/-7.6 mg/kg/day; p=0.003) and total VPA concentration (56.4+/-25.8, 47.7+/-22.6, and 38.7+/-23.1mg/kg/day; p=0.003) decreased by age groups (65-74, 75-84, and > or =85 years). Daily dose and total VPA concentration were not different in residents receiving inhibitory or inducing co-medications, between men and women, or by albumin level. Total VPA clearance was similar between men and women, among age groups, or according to inducing or inhibiting co-medications.

Age Factors↗
PubMed2004

Zonisamide: chemistry, mechanism of action, and pharmacokinetics.

Zonisamide is a synthetic 1,2-benzisoxazole-3-methanesulfonamide with anticonvulsant properties. The sulfamoyl group on zonisamide was expected to suppress seizures in a manner similar to another sulfonamide analogue, acetazolamide, through inhibition of carbonic anhydrase. However, this does not appear to be the primary mechanism of action since zonisamide requires much higher doses than acetazolamide to achieve equivalent titration in vivo. Studies with cultured neurons indicate that zonisamide blocks repetitive firing of voltage-sensitive sodium channels and reduces voltage-sensitive T-type calcium currents without affecting L-type calcium currents. Its dual mechanism of action may explain its efficacy in patients resistant to other antiepileptic drugs (AEDs). Zonisamide has a pharmacokinetic profile favorable for clinical use. It is rapidly and completely absorbed and has a long half-life (63-69h in healthy volunteers) which allows twice-daily, or even once-daily, dosing. Zonisamide is not highly bound to plasma proteins. Consequently, it does not affect protein binding of other highly protein-bound AEDs. Furthermore, zonisamide does not induce its own metabolism and does not induce liver enzymes. However, since zonisamide is metabolized by cytochrome P450, liver enzyme-inducing AEDs will increase zonisamide clearance, and dosage adjustments may be necessary when it is used in combination with certain AEDs.

Animals↗
PubMed2004

Advances in antiepileptic drug treatments. A rational basis for selecting drugs for older patients with epilepsy.

Incidence of epilepsy increases rapidly after age 65; recent studies indicate that approximately 10% of nursing home residents are being treated with antiepileptic drugs (AEDs). Almost all are being treated with first generation AEDs. The average nursing home patient receives six medications, has age-related changes in protein binding, decreases in hepatic and renal clearance, and may have alterations in gastrointestinal absorption. AEDs that do not have drug-drug interactions, are not metabolized by the liver, and are readily absorbed may offer benefits in this population. New studies are demonstrating that the first generation AEDs have a number of shortcomings for treating older patients, whereas some of the newer AEDs may overcome these limitations. This paper reviews the present knowledge base and compares properties of the first generation AEDs with newer agents to develop a more rational approach for drug selection in older adults.

Aged↗
PubMed2004

Epilepsy in the elderly.

The elderly population (Z age 65) continues to grow; this increase extends even to the oldest of the old (Z age 85). This aging population is accompanied by an increase in the cases of epilepsy, which can be especially difficult to diagnose and treat. Age-related difficulties in optimum treatment arise from increased drug sensitivity, altered drug metabolism, comorbid conditions, concomitant multiple medications, inability to self-report symptoms, and drug cost. Although the older antiepileptic drugs (AEDs) are still appropriate treatment for some of the elderly, the newer AEDs should be considered because of their different efficacy and safety profiles.

Aged↗
PubMed2003

Antiepileptic drug use in nursing home admissions.

Although 1 of 10 nursing home residents is taking an antiepileptic drug (AED), no study to our knowledge has determined whether most residents are already receiving AED treatment when they are admitted or are given these drugs afterward. That differentiation was the focus of this study. The study group consisted of 10,318 residents, 65 years and older, admitted to 510 nursing homes located throughout the United States during the first quarter of 1999. AED prevalence at admission was 7.7%; three fifths had an epilepsy/seizure indication. In a multivariate analysis, factors associated with AED use at admission included epilepsy/seizure, bipolar depression, age group, and cognitive performance. In the follow-up cohort (N = 9,516), postadmission initiation of AEDs was 2.7%; one fifth had an epilepsy/seizure indication. In the multivariate analysis, factors associated with postadmission AED initiation included epilepsy/seizure indication, bipolar depression, age group, peripheral vascular disease, and cognitive performance. This rate of AED postadmission initiation within the first 3 months of admission was much higher than expected, suggesting that new symptoms may develop after admission. Results also show that the rate of AED use in nursing homes is not static.

Aged↗
PubMed2003

Tolerability of levetiracetam in elderly patients with CNS disorders.

The purpose of this analysis was to compare treatment-emergent adverse events (TEAE) related to use of levetiracetam (LEV) reported by young and elderly patients with anxiety and cognitive disorders, and young epilepsy patients. The LEV database includes reports of TEAE from trials of patients with diagnoses of a cognitive disorder (N=719), an anxiety disorder (N=1510), or localization-related epilepsy (N=1023) who participated in clinical trials lasting up to 16 weeks. Patients were grouped as young (<65 years) or elderly (> or = 65 years). The most common TEAE occurring most frequently in the LEV-treated groups were abdominal pain, asthenia, headache, anorexia, weight loss, dizziness, insomnia, somnolence, and tremor. The only significant differences in TEAE were seen between young and elderly groups with anxiety disorders (>3% higher for LEV than for placebo-treated patients) in headache (5.2% elderly, -0.9% young, P=0.041), and tremor (5.2 and -0.5%, respectively, P=0.022) and between young anxiety patients and young epilepsy patients for somnolence (-0.7 and 5.4%, respectively, P=0.036). For the other TEAEs there was no evidence for consistent differences between young and elderly patients and between patients with different CNS disorders. Overall, LEV was well tolerated by all patient groups. The favorable adverse event profile suggests that LEV might be suitable for use by elderly patients.

Adolescent↗
PubMed2003

Rapid infusion of sodium valproate in acutely ill children.

The purpose of this study was to investigate the clinical safety of sodium valproate and total and unbound valproic acid plasma concentrations after rapid infusion in hospitalized, acutely ill children. Four children (5-15 years) completed the study. Sodium valproate doses (8.3-15.4 mg/kg) were administered in <or=15 minutes. No clinically significant changes in vital signs were observed nor were there any significant adverse events. Both total and unbound valproic acid concentrations were higher at 0.5 hour than at pre-infusion or 6 hours after infusion. Rapid administration of valproate to acutely ill patients can be done safely. Unbound valproic acid concentrations in acutely ill as compared with relatively healthy epilepsy patients were higher and could not be predicted based on their total pre-infusion valproic acid concentrations.

Acute Disease↗