Biomedical subjects
Publications and source records attributed to B J Wilder.
A retrospective review of the safety, tolerability, and efficacy of vagus nerve stimulation (VNS) in 48 patients with intractable partial epilepsy was performed. Side effects were few and mild to moderate. Mean seizure frequency decreased by 26% after 1 year, 30% after 5 years, and 52% after 12 years with VNS treatment.
Advances in our understanding, diagnosis, and treatment of seizure disorders have transformed the management of epilepsy. As the number of antiepileptic drugs and their formulations increase, so do the expectations of therapy. Once limited to attaining complete control of seizures, epilepsy management now strives to enable patients to lead lifestyles consistent with their own capabilities. Extended-release antiepileptic drug formulations can help achieve the primary treatment goals for many patients with epilepsy: preventing occurrence of seizures and preventing or reducing side effects. The dosing flexibility and consistency of serum levels (without marked peak-to-trough fluctuations) conferred by extended-release formulations help achieve these goals. These same attributes of extended-release formulations may also improve compliance, quality of life, and patient satisfaction with treatment.
PURPOSE: Acute pancreatitis has been associated with a number of medications, including valproate (VPA). Valproate-coincident pancreatitis is uncommon and is usually associated with other risk factors; however, the United States Food and Drug Administration has issued a box warning for risk of acute pancreatitis with VPA products. We reviewed cases of pancreatitis in VPA-treated patients from the clinical database of VPA/divalproex trials and compared the incidence of elevated amylase levels between VPA- and placebo-treated patients. METHODS: Report rates of acute pancreatitis coincident with VPA use in 34 clinical trials were calculated. Incidence rates of amylase elevations above the normal range in three clinical placebo-controlled migraine trials were compared between VPA- and placebo-treated patients. RESULTS: Among 3,007 VPA-treated patients in 34 clinical trials, two reports of pancreatitis were considered by investigators to be probably related to VPA. Both patients recovered. Similar rates of amylase elevations were observed in VPA- (5.9%) and placebo-treated (6.1%) patients in the three migraine headache trials. CONCLUSIONS: VPA-coincident acute pancreatitis is uncommon and idiosyncratic. Checking amylase levels in the absence of other clinical signs and symptoms provides little value for predicting pancreatitis. Physicians should be guided by clinical symptoms of pancreatitis to identify cases.
BACKGROUND: Because of phenytoin's narrow therapeutic index and nonlinear pharmacokinetics, food-induced alterations in absorption may markedly influence drug concentrations and, in turn, safety and effectiveness. Potential food-associated differences between 100-mg Mylan (Mylan Pharmaceuticals) extended-release phenytoin sodium capsules and Parke-Davis 100-mg Dilantin Kapseals were examined. METHODS: A single-dose, two-way crossover study was conducted in 24 healthy subjects to determine the effect of a high-fat meal on the pharmacokinetics of both formulations. Pharmacokinetic parameters were estimated by noncompartmental methods. The impact of switching products on steady-state phenytoin concentrations was investigated through simulation using pharmacokinetic data previously obtained from 30 epileptic patients. RESULTS: Based on AUC(0-infinity), bioavailability of the Mylan product administered with food was 13% lower than that observed with Dilantin Kapseals. Simulations of substituting the Mylan product for Dilantin suggested that the 13% decrease in bioavailability would result in a median 37% decrease (range 19 to 58%) in plasma phenytoin concentrations when the drug is given with food; in 46% of patients, phenytoin concentrations would likely fall below the therapeutic range of 10 to 20 mg/L. Simulations of substituting Dilantin for the Mylan product suggested that the 15% increase in bioavailability would result in a median 102% increase (range 24 to >150%) in plasma phenytoin concentrations, with 84% of patients having phenytoin concentrations above the therapeutic range. CONCLUSIONS: Results suggest that when taking phenytoin sodium with food, product switches may result in either side effects or loss of seizure control.
The authors examined the effect of food on the bioavailability of Dilantin Kapseals in a nonblinded, single 100-mg dose, randomized, crossover trial. Drug was administered after an 8-hour fast and after a high-fat meal. Differences in mean dietary state values were +6% for maximum concentrations (C(max)) and -2% for area under the curve. Associated 90% CI were within US Food and Drug Administration criteria, confirming the absence of a food effect. Thus, patients may take 100-mg Dilantin Kapseals without regard to meals.
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Fosphenytoin (Cerebyx), is a water soluble prodrug that is rapidly and completely converted to phenytoin. This study reports the injection-site tolerance and safety of intramuscular fosphenytoin (> 10 mg/kg doses) in 60 patients requiring a phenytoin loading dose. Patients received injections at single or multiple sites with volumes ranging from 4 to 30 ml per injection site. The majority of patients had no irritation (erythema, swelling, tenderness, bruising) or complaints of discomfort related to fosphenytoin injection either after injection (95%) or at follow-up (88%). Irritation, when reported, was mild in all cases. Forty of 60 patients (67%) reported transient side effects, primarily involving the central nervous system, such as nystagmus, dizziness or ataxia, which are commonly associated with phenytoin therapy. All patients received prescribed doses; no patient had an injection(s) stopped due to intolerance or side effects. No serious adverse events occurred with intramuscular fosphenytoin. In this study, intramuscular fosphenytoin was demonstrated to be a safe and well tolerated, and in many instances, a preferable alternative to other means of phenytoin loading.
BACKGROUND: Safety, tolerability, and pharmacokinetics of fosphenytoin sodium, a water-soluble phenytoin prodrug, were investigated after a temporary substitution of intramuscular fosphenytoin for oral phenytoin sodium in 240 epileptic or neurosurgical patients taking oral phenytoin sodium (100-500 mg/d). METHODS: Patients were randomly assigned to 1 of 2 parallel groups. During screening and follow-up, patients were maintained on a regimen of oral phenytoin at an individualized dose. During treatment, the phenytoin-treated patients received intramuscular placebo and their prescribed dose of oral phenytoin; the fosphenytoin-treated patients received oral placebo and intramuscular fosphenytoin equimolar to their phenytoin dose. RESULTS: Both groups had similar types and frequencies of mild to moderate adverse events. Fosphenytoin was as well tolerated as intramuscular placebo at the injection site. Intramuscular fosphenytoin equimolar to a patient's oral phenytoin dose produced equal or greater plasma phenytoin concentrations. CONCLUSIONS: Dosing adjustments are not required when intramuscular fosphenytoin is temporarily substituted or oral phenytoin therapy is resumed. Intramuscular fosphenytoin is a safe and well-tolerated alternative to oral phenytoin when oral administration is not feasible.
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In the last few years a number of new antiepileptic drugs have been introduced for the treatment of epilepsy. In addition to the standard antiepileptic drugs, clobazam, vigabatrin, gabapentin, and lamotrigine have been introduced. The choice of the best antiepileptic drug for an individual patient has become more complex. In this review the clinical benefits of the standard and the new antiepileptic drugs are presented.
We report a patient with Friedreich's disease (FD) who exhibited abnormalities of antioxidant metabolism, including decreased levels of glutathione peroxidase, glutathione reductase, and selenium, and an increased lipid peroxide index. These abnormalities became normal after treatment with N-acetylcysteine, selenium, and low-dose vitamin E therapy. Treatment was associated with a decreased rate of clinical decline. FD is a neurodegenerative disorder that may be related to disturbed antioxidant metabolism; the disorder may be treatable with antioxidant compounds.
We conducted a randomized double-blind comparison of three doses of the novel antiepileptic drug (AED) topiramate (200, 400, and 600 mg/day) and placebo as adjunctive therapy in patients with refractory partial onset epilepsy receiving one or two other AEDs at therapeutic concentrations. A total of 181 patients completed the 12-week baseline phase and were randomized to double-blind therapy. Median percent reductions from baseline in average monthly seizure rate, the principal efficacy evaluation, were 13% for placebo, 30% for topiramate 200 mg/day, 48% for topiramate 400 mg/day, and 45% for topiramate 600 mg/day. For the seizure rate comparison of active drug to placebo p values were: topiramate 200 mg/day, p = 0.051; topiramate 400 mg/day, p = 0.007; topiramate 600 mg/day, p < 0.001. Percent responders ( > or = 50% reduction in seizure rates) were 18% for placebo, 27% for topiramate 200 mg/day, 47% for topiramate 400 mg/day (p = 0.013), and 46% for topiramate 600 mg/day (p = 0.027). A significant (p = 0.003) reduction in secondarily generalized seizures compared with placebo treatment was also documented with topiramate. Topiramate plasma concentrations were closely related to dosage, and there were no significant interactions between topiramate and other AEDs. The minimal effective dose of topiramate in this study population was approximately 200 mg/day. Mild or moderate CNS symptoms were the primary treatment-emergent adverse events, but treatment-limiting adverse events occurred in only 9% of patients given topiramate compared with 7% given placebo. Results of this initial well-controlled study in patients indicate that topiramate is a very promising new AED.
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Phenobarbital, diazepam, lorazepam, and phenytoin are all currently used for the treatment of acute seizures, including status epilepticus. None of these drugs is considered ideal. Fosphenytoin is a new phenytoin prodrug that fulfills many of the properties of an ideal anticonvulsant drug. The safety, tolerance, and pharmacokinetics of intramuscularly administered fosphenytoin have been evaluated in three clinical trials involving patients requiring loading or maintenance doses of phenytoin. These investigations demonstrated that fosphenytoin is rapidly and completely absorbed after injection into muscle and is quickly converted to produce therapeutic phenytoin plasma concentrations within 30 min of administration. Plasma concentrations of phenytoin achieved with i.m. fosphenytoin exceeded those associated with an equimolar dose of oral phenytoin. i.m. fosphenytoin was well tolerated both locally and systemically. Only mild and transient reactions occurred at the injection site. The most common systemic adverse events reported--somnolence, nystagmus, dizziness, and ataxia--are side effects commonly seen with phenytoin and tended to be mild. Preexisting seizure disorders remained stable. Combination treatment with i.v. diazepam or lorazepam to attain rapid seizure control and i.m. fosphenytoin to maintain the anticonvulsant effect theoretically offers many advantages for control of acute seizures and should be studied.
The finding of increased activity of the enzyme extracellular superoxide dismutase in four siblings with progressive myoclonus epilepsy of the Unverricht-Lundborg type (PME-UL) prompted the addition of antioxidants to these patients' treatment regimen. After 6 months treatment with vitamin E, selenium, riboflavin, and zinc, there was some improvement in patient awareness and speech. N-acetylcysteine (NAC) is a sulfhydryl antioxidant that increases cellular glutathione and the activity levels of several antioxidant enzymes and has additional actions that contribute to its demonstrated efficacy in preventing or decreasing damage in models of neuronal toxicity. We treated the affected siblings with 4 to 6 grams a day of NAC in addition to the other antioxidants and magnesium. There has been a marked decrease in myoclonus and some normalization of somatosensory evoked potentials with NAC treatment. The patients were treated with NAC for up to 30 months with continued beneficial effects. NAC may prevent further deterioration in the clinical course of patients with PME-UL and may be indicated in other neurodegenerative conditions where excess free radical activity may contribute to disease progression.
Rational polypharmacy is in its earliest stages of development and will require substantial additional development to realize its full potential. Indeed, despite the powerful appeal of the concept, clinical proof is not yet available that RP is superior to monotherapy. Important questions need to be addressed: 1. Will RP control seizures more effectively than monotherapy? 2. What data are needed to develop RP for a specific patient? 3. Will RP be cost effective? 4. Can RP be developed which will treat or prevent epilepsy while controlling seizures? Possible approaches to these questions could include: 1. The development of a data base for prospective use to monitor patients being treated at Epilepsy Centers using RP principles. 2. Use the data obtained from the above to construct more specific studies to compare identified combination therapies with monotherapy. 3. Prospectively compare in a placebo controlled, blinded study, the effect of the combination of an anti-ictal medication and a laboratory proven antiepileptic drug for prevention of the development of epilepsy in an at risk population such as head trauma or stroke.
The efficacy and safety of felbamate monotherapy were evaluated in 52 patients with refractory partial seizures with or without secondary generalization in a double-blind, randomized, placebo-controlled trial. Each patient completed a routine evaluation for epilepsy surgery and was randomized to receive either felbamate, titrated to a maximum daily dose of 3600 mg over 2 days, or placebo during the 10-day, inpatient, treatment phase. An intent-to-treat analysis was performed on the data of all 52 patients who received study medication, while a separate efficacy analysis also was performed on the data of 43 evaluable patients, which excluded protocol violators. The endpoint of the trial was completing 10 days of treatment or the occurrence of a fourth seizure. The primary efficacy variable was the average daily seizure frequency during the treatment phase for each patient. For the intent-to-treat analysis based on all 52 patients who received study medications, the mean rank of the daily seizure frequency for patients treated with felbamate was 21.6 compared to 29.6 for patients treated with placebo (P = 0.065). In the analysis based on the 43 evaluable patients, the mean rank of the daily seizure frequency for felbamate-treated patients was 17.0 compared to 25.4 for placebo-treated patients. This difference was statistically significant (P = 0.032) in favor of felbamate. Seizure frequency was decreased by 89.5% compared to baseline in nine patients who completed 10 days of felbamate therapy. This study permitted the rapid determination of the anticonvulsant activity of felbamate and demonstrated that felbamate is effective as monotherapy for the treatment of partial seizures.
About 30% of patients with epilepsy remain refractory to medical management despite optimal use of conventional antiepileptic drugs. Seizure control for many patients is often achieved at the expense of adverse drug effects. The need for new drugs is obvious. After 15 years, three new antiepileptic drugs are now clinically available: felbamate, gabapentin, and lamotrigine. These drugs have undergone double-blind, controlled clinical trials for efficacy and safety in patients with predominantly simple, complex partial, and generalized tonic-clonic seizures. All of these new drugs will be used initially in a polypharmacy regimen.