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Biomedical subjects

Barry E Gidal

Publications and source records attributed to Barry E Gidal.

18 recordsLinked to original sources
PubMed2006

Pathological fractures in epilepsy.

Fracture rates in epilepsy are two to three times that for the general population, although the influence of gender and age is not well defined. We examined, over a 7-year period at a single health care center, 750 patients with epilepsy who sustained the fractures. Among these patients, 293 (39%) had pathological fractures and 457 (61%) had traumatic/seizure-related fractures. Pathological fractures accounted for 71% of the 146 patients >60 years, a group traditionally at risk for pathological fractures (P<0.02). Fractures in epilepsy are distributed with bimodal peaks in the fifth and eighth decades of life, although pathological fractures are a significant contributor across the life span, accounting for 20 to 40% of patients traditionally thought not to be at risk for involutional osteoporotic fractures. Together these findings suggest that epilepsy, and/or its treatment, is a dominant influence in the pathogenesis of fractures and may exacerbate the effects of aging-related involutional osteoporosis.

Adolescent↗
PubMed2006

Drug absorption in the elderly: biopharmaceutical considerations for the antiepileptic drugs.

The management of antiepileptic drug (AED) pharmacokinetics remains a challenge in the treatment of patients with epilepsy. Drug characteristics, such as protein binding, mechanisms of drug elimination, and the potential for pharmacokinetic/pharmacodynamic interactions, are important considerations for drug selection and may help determine overall effectiveness. In elderly patients with epilepsy, the likelihood of polytherapy, along with physiological changes associated with aging, can make pharmacokinetic issues even more significant. One aspect of pharmacokinetics that has received less attention is the process of oral drug absorption. Aging can have variable effects on the gastrointestinal system. Some of these physiological changes have the potential to impact absorption patterns of some medications, including AEDs. Altered oral protective reflexes, xerostomia, and delayed esophageal emptying in elderly patients may complicate oral administration of some medications. Altered gastric pH could modify drug absorption, and modified gastric emptying rates can influence the bioavailability of some AEDs. Finally, intestinal transit times may be slower in elderly patients compared to younger patients, possibly altering the absorption of some AEDs. These age-related physiological changes that may affect AED pharmacokinetics should be considered when treating elderly patients with epilepsy.

Absorption↗
PubMed2006

Protracted ictal confusion in elderly patients.

BACKGROUND: Ictal confusion, particularly if protracted, often presents a diagnostic challenge. OBJECTIVES: To define protracted ictal confusion in elderly patients and to characterize its features and outcome. DESIGN: Case series. SETTING: Neurology outpatient and emergency departments at 2 tertiary care centers. PATIENTS: Consecutive series of 22 ambulatory patients with acute ictal confusion. MAIN OUTCOME MEASURES: Duration of ictal confusion was correlated with age and lesions noted on cerebral images and videoelectroencephalographic studies. RESULTS: The ictal basis underlying confusion was not recognized for up to 5 days in 22 patients (mean +/- SD age, 70 +/- 8.5 years). Twenty patients had partial complex status epilepticus, and 2 patients had newly diagnosed primary generalized status epilepticus. Motor movements were not present in either group, although reduced mood states and ictal neglect were noted in some patients. Fifteen patients had previous episodes (2-10) of protracted ictal confusion. Once identified, treatment reversed confusion, and eventually patients were discharged to home, although a few patients sustained persistent reduction in baseline cognition. CONCLUSIONS: Protracted ictal confusion is often not considered in the ambulatory elderly patient, with resulting delay in diagnosis. Electroencephalographic and videoelectroencephalographic studies performed while the patient is experiencing symptoms are crucial to early diagnosis and timely management.

Age Factors↗
PubMed2006

Optimizing epilepsy management in teenagers.

Optimal epilepsy management in teenage patients represents a particular challenge. These patients are often likely to respond more positively to a regimen that least disrupts their activities. In addition, as a patient group, they are more sensitive to peer perception. Current perceptions of older antiepilepsy drugs do not take into account frequent undesirable side effects or potential adverse interactions with other drugs. Furthermore, they often do not completely control seizures. Recent data suggest that not only do the newer antiepileptic drugs appear to be as efficacious as the older drugs, they also often have more favorable cognitive, cosmetic, and teratogenic side-effect profiles. In addition, newer antiepileptic drugs are being used more often in monotherapy. Successful management of epilepsy in teenagers requires that physicians not only understand the advantages that the newer antiepileptic drugs appear to provide but also consider the social impact of treatment on their patients.

Adolescent↗
PubMed2006

New and emerging treatment options for neuropathic pain.

A large number of neuroanatomical, neurophysiologic, and neurochemical mechanisms are thought to contribute to the development and maintenance of neuropathic pain (NP). As a result, a corresponding wide range of treatments have been employed to treat patients with NP, including antiepileptic drugs, opioid analgesics, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, N-methyl-D-aspartate receptor antagonists, cholecystokinin receptor antagonists, adenosine, lipoic acid, cannabinoids, isosorbide dinitrate, dronabinol, capsaicin, protein kinase C inhibitors, aldose reductase inhibitors, and VR-1 receptor modulators. Many of these compounds are limited by marginal efficacy and clinically significant adverse events; few have been evaluated in well-controlled, large-scale clinical trials. At present, the only agents approved for the treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia are lidocaine patches 5%, duloxetine, gabapentin, and pregabalin. Of these, only pregabalin is indicated for both conditions.

Diabetic Neuropathies↗
PubMed2005

Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: a pooled analysis of data from randomized clinical trials.

The purpose of this study was to determine the influence of levetiracetam on the steady-state serum concentrations of other commonly used antiepileptic drugs (AEDs). Serum AED concentrations were measured at baseline and after adjunctive therapy with levetiracetam (1000-4000 mg/day) or placebo in four phase III trials in patients with refractory partial epilepsy receiving stable AED dosages. The data were pooled, and repeated measures covariance analysis was used to calculate the ratio (and 90% confidence intervals) of the geometric mean serum drug concentrations during adjunctive levetiracetam therapy relative to baseline. Levetiracetam did not increase or decrease mean steady-state serum concentrations of carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. For each of these AEDs, the 90% confidence interval of the geometric mean drug concentrations ratio was included within the 80-125% bioequivalence range. Serum concentrations of these AEDs did not change over time after adjunctive levetiracetam therapy, irrespective of the dosage of levetiracetam used. For vigabatrin, there was no evidence for a significant change in serum drug concentration after the addition of levetiracetam, but the number of observations was too small for the limits of the confidence interval to fall within the 80-125% range. Thus, adjunctive therapy with levetiracetam does not influence the steady-state serum concentrations of concomitantly administered carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital, or primidone. Consequently, no need for adjusting the dosages of these AEDs is anticipated when levetiracetam is added on or removed from a patient's therapeutic regimen.

Adolescent↗
PubMed2005

Oral absorption kinetics of levetiracetam: the effect of mixing with food or enteral nutrition formulas.

BACKGROUND: Levetiracetam (LEV) is an antiepileptic drug with a favorable pharmacokinetic profile, including negligible protein binding and linear elimination kinetics. Because LEV is likely to be used in populations that include children and the elderly, alternative techniques of administration, such as crushing the tablet and mixing its contents with semisolid food or enteral nutrition formulas (ENFs), may be required in some clinical settings. Although previous studies have suggested that administration with food does not affect the overall absorption of LEV, there is a lack of data regarding concomitant administration with ENFs. OBJECTIVE: The objective of this study was to evaluate the oral absorption of LEV after concomitant administration with food or ENFs. METHODS: This was an unblinded, 3-way crossover study. After an overnight fast, subjects received a single dose of LEV 500 mg administered either as an intact tablet with 120 mL water (control, treatment A) or crushed and mixed with 4 oz applesauce (treatment B) or 120 mL of a common ENF (treatment C). All subjects received each treatment in a randomized sequence; there was a 7-day washout period between treatments. Serial blood samples were obtained over 24 hours for determination of the LEV serum concentration-time profile using gas chromatography with nitrogen phosphorus detection. AUC(0-24), C(max), and T(max) were calculated using noncompartmental methods and analyzed using analysis of variance. RESULTS: Ten healthy adult volunteers (6 men, 4 women) participated in the study (mean [SD] age, 28.9 [6.5] years; mean body weight, 78.6 [12.9] kg). No significant differences were noted between control and any other study treatment. Mean AUC values were 191.9 (50.2), 165.7 (43.4), and 168.3 (43.9) microg/mL . h for treatments A, B, and C, respectively. Mean T(max) values were 1.08 (0.65), 1.32 (0.75), and 1.62 (0.73) hours, respectively. Mean C(max) values were 14.8 (5.6), 12.1 (2.8), and 10.8 (2.0) microg/mL for the respective treatments. Mean LEV serum concentrations at 12 hours after dosing were similar for all study treatments (3.9, 4.1, and 4.0 microg/mL). The long-term stability of LEV in the various combinations was not assessed. CONCLUSIONS: In these healthy volunteers, the overall rate and extent of absorption of oral LEV were not significantly impaired after crushing and mixing of the tablet with either a food vehicle or a typical ENF product. The data suggest that peak serum concentrations of LEV may be slightly reduced after mixing with ENFs, although the difference was not significant compared with control values.

Administration, Oral↗
PubMed2005

Blood homocysteine, folate and vitamin B-12 concentrations in patients with epilepsy receiving lamotrigine or sodium valproate for initial monotherapy.

To evaluate whether the administration of lamotrigine (LTG) or valproate (VPA) changes concentrations of plasma total homocysteine (tHcy), plasma and red-cell folate and plasma Vitamin B-12, we measured these indices in a total of 20 patients with epilepsy before and after a 32-week period of monotherapy of LTG or VPA. We found that the 32-week administration of a mean daily dose of 250mg LTG had no significant effect on any of the blood indices. On the other hand, the administration of a mean daily dose of 2070mg of VPA resulted in a 57% increase in plasma Vitamin B-12 concentrations over the baseline value and a 27% decline in plasma tHcy concentrations, although the mechanisms of such changes are unknown. Our data indicate that hyperhomocysteinemia may not be a serious clinical problem among patients with epilepsy, who receive either LTG or VPA.

Adult↗
PubMed2005

Sleep architecture in children with idiopathic generalized epilepsy.

PURPOSE: Children with epilepsy experience sleep disturbances, behavioral and attentional problems at higher rates than their peers. However, the relation between sleep disturbances and the observed behavioral and attentional abnormalities is poorly defined. METHODS: Children with primary generalized epilepsy who were seizure free and between the ages of 5 and 18 years were matched with age- and gender-matched healthy controls and underwent two consecutive nights of nocturnal polysomnography with extended electroencephalography. Connor's Continuous Performance Test (CPT) was administered to assess daytime attentional function. Parents completed the Child Behavior Checklist (CBCL) to assess their emotional-behavioral status. Two sample t tests were used to examine group differences. Spearman correlations were used to examine the relation between sleep variables and behavior and attention variables. Multiple regression analysis was used to identify independent predictors of abnormal behavior and attention among patients. RESULTS: Eleven children with primary generalized epilepsy and eight age- and sex-matched controls participated in the study. Children with epilepsy had longer stage 1 sleep percentage (7.19 +/- 3.2 vs. 4.8 +/- 3.5; p = 0.05) and latency to rapid-eye-movement (REM) sleep (123.5 +/- 40.1 vs. 101.75 +/- 24.3; p = 0.018) compared with controls. Children with epilepsy had worse attention (CPT index, 10.94 +/- 6.55 vs. 3.42 +/- 4.04; p = 0.004) and exhibited significantly higher CBCL Total Behavior and Internalizing Behavior Problem scales. Whereas regression analysis showed no independent predictors of abnormal behavior and attention, a tendency toward association between CBCL total behavior scale and REM percentage (r= 0.55; p = 0.07), and between CPT overall index and stage 1 sleep percentage (r= 0.40; p = 0.10) was noted. CONCLUSIONS: Sleep architecture is abnormal in children with primary generalized epilepsy. Further studies are needed to determine whether abnormalities in sleep architecture contribute to poor daytime behavior and attention.

Adolescent↗
PubMed2004

Fractures, epilepsy, and antiepileptic drugs.

The risk for skeletal fractures in patients with epilepsy is two to six times greater than in the general population. Fractures may be caused by seizures themselves or by falls, with or without seizures. Side effects of antiepileptic drugs (AEDs), such as ataxia, and coexisting neurological deficits contribute to the risk for falls. The effects of older AEDs on bone mineral density probably increase the risk for fractures associated with seizures and falls. Preventive measures include optimal control of seizures and supplementation with calcium and vitamin D. Whether newer AEDs prove to be without adverse effects on bone mineral metabolism remains to be determined.

Anticonvulsants↗
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↗
PubMed2003

Levetiracetam does not alter body weight: analysis of randomized, controlled clinical trials.

INTRODUCTION: Increases in body weight gain are important, and clinically significant adverse effects of several antiepileptic drugs (AED) including valproate and gabapentin. Weight gain may contribute to medication non-compliance, discontinuation, and importantly, may have secondary medical implications as well. Levetiracetam (LEV) is indicated for adjunctive treatment of partial seizures. The objective of the present evaluation was to examine the effects of LEV treatment on body weight in adult patients. METHODS: We analyzed data derived from four prospective, placebo-controlled randomized, clinical trials conducted in both in the US and Europe. Patients included in the present analysis were both men and women, greater than 16 years old, and who had LEV exposure for at least 1 month. Body weight was measured at baseline and at the final LEV study visit. Data are analyzed for all patients, by gender, body mass index (BMI), duration of LEV exposure and by concomitant AED treatment. Wilcoxan Signed Rank, or Rank Sum test used where appropriate, with significance assigned at P<0.05. Data are presented as mean values+/-1 S.D. RESULTS: Nine-hundred and seventy patients (age=37.5 years, 54% men/46% women) were evaluated. There were no significant differences in baseline demographics between LEV (n=631) or placebo (n=339) treated patient groups. Mean LEV dose and duration of treatment were 2053 mg/day (maximum dose of 4000 mg/day) and 125 days (maximum=181 days), respectively. Concomitant AED therapy included CBZ, PHT, VPA, PB, GBP, LTG, and VGB. For LEV-treated patients, no significant changes in body weight were noted. Mean body weight at baseline versus final study visit for LEV was 74.3+/-16.6 kg and 74.3+/-16.6 kg, respectively. For placebo-treated patients, baseline versus end of treatment weight was 72.4+/-15.4 kg and 72.7+/-15.9 kg, respectively, representing a slight, yet clinically trivial increase. Clinically significant weight change as defined as >7% change from baseline weight, occurred in 9% of LEV-treated patients (4.5% had increase in weight/4.5% decrease) versus 9.4% (5.9% had increase/3.5% decrease) in placebo-treated patients. Weight changes were not significantly different between groups. Neither baseline BMI, gender, or background AEDs, appeared to predispose to significant weight change for LEV-treated patients. CONCLUSIONS: We conclude that treatment with LEV at clinically relevant dosages is not associated with significant weight change. LEV would, therefore, appear to be a weight neutral AED.

Adult↗
PubMed2003

Evaluation of VPA dose and concentration effects on lamotrigine pharmacokinetics: implications for conversion to lamotrigine monotherapy.

OBJECTIVE: Lamotrigine (LTG) is approved for monotherapy following withdrawal from enzyme-inducing antiepileptic drugs. LTG is also frequently used in combination with sodium valproate (VPA), and withdrawal to monotherapy in this setting is also frequently desirable. Given the known pharmacokinetic interaction between these two drugs, clinically relevant questions that should be answered include (1) at what dose and/or concentration of VPA does this interaction begin, and (2) at what dose of VPA does maximal inhibition occur. METHODS: LTG pharmacokinetics was evaluated using single-dose LTG (25 mg) given before and following low-dose VPA co-medication (125, 250, 375, 500 mg per day VPA) in healthy subjects. Serial blood samples were obtained over 120 h post-dose in order to calculate LTG kinetic parameters including area under the concentration-time curve, apparent oral clearance, elimination half-life and percent inhibition of LTG clearance at each dosage level of VPA. Pharmacodynamic modeling was used to calculate EC(50) values for this interaction. RESULTS: LTG pharmacokinetic parameters were evaluated in adult healthy female & male volunteers. Mean trough VPA concentrations at doses of 125, 250, 375 and 500 mg per day were 6.5, 13.9, 16.1 and 31.9 microg/ml, respectively. Maximal theoretical inhibition of LTG oral clearance by VPA is approximately 65%, with an EC50 concentration value of approximately 5.6 microg/ml of VPA. Mean inhibition of LTG oral clearance during concomitant treatment with VPA 125, 250, 375 and 500 mg per day was 30.8, 51.5, 52.8 and 50.3%, respectively. CONCLUSIONS: These data suggest that VPA inhibition of LTG clearance begins at very low VPA doses and concentrations. Importantly, maximal inhibition can be expected at VPA doses of approximately 500 mg per day, with the magnitude of inhibition diminishing at doses below this. These data provide useful information to develop a dosing algorithm to facilitate conversion to LTG monotherapy.

Adult↗
PubMed2003

Gabapentin dosing in the treatment of epilepsy.

BACKGROUND: Gabapentin is considered a safe and well-tolerated antipileptic drug (AED) with a favorable pharmacokinetic profile and a broad therapeutic index. However, recent studies have used higher doses and faster titration schedules than those used in the pivotal trials that established the efficacy of gabapentin in the treatment of partial seizures. OBJECTIVE: The purposes of this review were to assess the gabapentin titration and dosing regimens that have been published in peer-reviewed journals, to develop dosing recommendations to maximize antiseizure efficacy without compromising tolerability, and to formulate guidelines for an adequate therapeutic assessment of gabapentin dosage efficacy. METHODS: In the absence of sufficient placebo-controlled, double-blind studies, a formal evidence-based assessment could not be performed. However, a MEDLINE search using the search terms gabapentin and epilepsy, spanning back to the year 1986, produced numerous published reports from randomized, placebo-controlled and open-label trials, as well as case reports. These were reviewed to assess the range of dosing and titration schedules reported. Reports that employed gabapentin doses and titration schedules were selected for review. RESULTS: Our review of this literature suggests improved seizure control at higher gabapentin maintenance dosages (< or =3600 mg/d) than are used today in clinical practice (1800 mg/d) without an increase in the incidence of adverse reactions. Most of the patients who received high dosages (eg, 3600 mg/d) or experienced fast titration rates tolerated gabapentin well. Side effects occurred around the onset of dosing and were reported in some studies to be transient. CONCLUSIONS: Based in the literature here, in most adult patients, gabapentin may be initiated at a dosage of 900 mg/d and titrated to maintenance dosages > or = 3600 mg/d. Children may be treated with gabapentin 23 to 78 mg/kg per day. Based on controlled and open trials, the majority of patients will tolerate gabapentin well enough for an adequate therapeutic assessment. Titration to effect can be accomplished rapidly, if necessary; however, as with other AEDs, optimal seizure control may take months to achieve.

Acetates↗
PubMed2002

Time course of lamotrigine de-induction: impact of step-wise withdrawal of carbamazepine or phenytoin.

OBJECTIVE: The objective of the present analysis is to examine lamotrigine (LTG) pharmacokinetics both during polytherapy with enzyme inducing antiepileptic drugs and to evaluate the time course of de-induction following the step-wise withdrawal of enzyme inducers. BACKGROUND: LTG pharmacokinetics can be significantly influenced by concomitant AEDs, and the addition of enzyme inducers can markedly increase LTG clearance, thereby reducing serum concentrations. A clinically relevant question is how will LTG clearance and resulting plasma concentrations be altered during concomitant enzyme inducer withdrawal/conversion process. DESIGN/METHOD: As part of a previously published, active-control, LTG monotherapy trial, dose and plasma concentration data for LTG, carbamazepine (CBZ) or phenytoin (PHT) were obtained. Following the attainment of a LTG target dose of 500 mg/day, CZB or PHT were withdrawn in weekly 20% decrements. Following inducer withdrawal, LTG was then continued as monotherapy for an additional 12 weeks. Plasma concentrations and daily doses of LTG, CBZ, or PHT were obtained at regularly scheduled study visits during inducer withdrawal and during LTG monotherapy. Pharmacokinetic analysis of the plasma concentration data was done to determine the time-course and effect of inducer plasma concentration on LTG oral clearance (Cl(o)), where LTG Cl(o) was estimated as the dose/concentration ratio. RESULTS: Of the 156 patients enrolled in this trial, 76 were assigned to LTG arm, 43 completed the withdrawal to monotherapy phase with 28 successfully completing the study. In a subset analysis of completers, LTG Cl(o) determined prior to withdrawal of the inducers was significantly greater in patients (n=28) on LTG+PHT (160% increase) than in those (n=48) receiving LTG+CBZ (62% increase): 1.77+/-0.77 vs. 1.06+/-0.41 ml/min/kg, respectively, p=0.017. The significant reduction in LTG Cl(o) occurred only when CBZ plasma concentrations reached approximately 2 microg/ml or PHT plasma concentrations reached zero. CONCLUSIONS: Mean LTG plasma concentrations will approximately double following the withdrawal PHT; however increases of only 60% may occur following the withdrawal of CBZ. Importantly, these data suggest that LTG concentrations would not be expected to increase until the concomitant inducer is almost completely removed.

Adolescent↗
PubMed2002

Levetiracetam: a different approach to the pharmacotherapy of epilepsy.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of levetiracetam in the treatment of epilepsy. DATA SOURCES: A MEDLINE search restricted to English-language publications was conducted (January 1993-October 2000). Unpublished data provided by the manufacturer and information found in proceedings of professional meetings were also included. DATA EXTRACTION/STUDY SELECTION: Information regarding basic pharmacology was collected from studies in animals. Pharmacokinetic data were collected from human trials. Only randomized, placebo-controlled clinical trials were included to describe the efficacy and safety of levetiracetam. DATA SYNTHESIS: Levetiracetam is a new antiepileptic drug (AED) that appears to work by a unique mechanism. Animal studies have shown that levetiracetam may prevent epileptogenesis. Levetiracetam is rapidly and completely absorbed, minimally bound to plasma proteins, eliminated through the kidneys, and has a half-life of 6-8 hours. Doses must be adjusted for varying degrees of renal function. In clinical trials, levetiracetam significantly decreased seizure frequency compared with placebo when added to existing AED regimens. One clinical trial indicated that levetiracetam may be effective as monotherapy. Few major adverse effects were reported in the clinical trials; however, several patients reported psychological and psychotic reactions. CONCLUSIONS: Levetiracetam is a safe and effective new AED. Its apparent unique mechanism of action makes levetiracetam an important addition to therapy with older medications. Caution should be exercised when administering levetiracetam to individuals who may be prone to psychotic or psychiatric reactions.

Animals↗