Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide-reviewed in the order in which these agents received approval by the US Food and Drug Administration) in the treatment of children and adults with newly diagnosed partial and generalized epilepsies. METHODS: A 23-member committee, including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy, evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until September 2002, with selected manual searches up until 2003. RESULTS: There is evidence either from comparative or dose-controlled trials that gabapentin, lamotrigine, topiramate, and oxcarbazepine have efficacy as monotherapy in newly diagnosed adolescents and adults with either partial or mixed seizure disorders. There is also evidence that lamotrigine is effective for newly diagnosed absence seizures in children. Evidence for effectiveness of the new AEDs in newly diagnosed patients with other generalized epilepsy syndromes is lacking. CONCLUSIONS: The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with newly diagnosed epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society.

OBJECTIVE: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. METHODS: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. RESULTS: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. CONCLUSIONS: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.

Childhood migraine.

Migraines are a common and often undiagnosed and undertreated problem in children of all ages. Migraine symptoms can vary dramatically in terms of character and severity, from brief self-limited headaches to prolonged events with complex neurologic and systemic symptoms. Identification of migraines requires an index of suspicion in any child with acute recurrent headaches or neurologic symptoms. Diagnosis remains predominately based on the patient's history of symptoms and supported by a positive family history. Neurodiagnostic tests are often unnecessary and of value predominately to exclude nonmigraine disorders that may present with similar symptoms. A number of recent advances in our understanding of the pathophysiology and genetics of migraines have occurred, and continued progress in these exciting areas of investigation is anticipated. Identification of genetic markers in individuals with FHM is potentially the first step in discovery of genetic markers that may be useful in other migraine syndromes and may lead to the development of new therapeutic interventions. The movement from a vascular to integrated neurovascular pathogenesis for migraine headaches is already being translated into the study of new pharmacologic treatments, such as nitric oxide inhibitors and continued development of 5-HT1 agonist (triptans) medications. Although not currently approved for use in children, triptans are being widely evaluated in clinical trials. As additional triptans and new dosage formulations are developed and approved, it is anticipated that the treatment of migraine headaches in children may change significantly in the next several years.

The impact of childhood epilepsy on neurocognitive and behavioral performance: a prospective longitudinal study.

PURPOSE: To assess neurocognitive and behavioral performance in children with idiopathic epilepsy (CWE, n = 74), their siblings without epilepsy (control, n = 23), and children with migraine (CWM, n = 13), and to identify medical factors related to learning or behavioral problems in CWE. METHODS: Subjects, ages 8-13 years with IQs of >/=80, completed a neurocognitive test battery annually for

Increased muscular beta-hydroxyacyl CoA dehydrogenase with McArdle's disease.

Enzymes of energy production were measured in muscle homogenates and in individual muscle fibers from 5 patients with McArdle's disease. Individual fibers were investigated to determine whether fibers of all types were completely devoid of glycogen phosphorylase activity and whether the involved fibers might be biochemically altered in a fiber type dependent manner to enhance the energy-generating capabilities of the cells through other metabolic pathways. Using highly sensitive biochemical assays, a complete absence of glycogen phosphorylase, a and b, activity was found in fibers of all types in the McArdle's patients. Levels of enzymes representing glycolysis, the Krebs cycle, and high energy phosphate metabolism were essentially normal in each fiber type, indicating an apparent lack in metabolic adaptation of these energy pathways to the absence of glycogen utilization. However, a key enzyme in the beta-oxidation of fatty acids (beta-hydroxyacyl CoA dehydrogenase, beta OAC) was elevated in all patients, and substantially in 4 of the 5. This suggested that lipid substrates can provide support for oxidative endurance capacity in some patients. Individual fiber analyses indicated that the compensation involved fibers of all types.

Induction of intestinal microsomal enzymes by polycyclic aromatic hydrocarbons.

1. The efficacy of induction of intestinal microsomal aryl hydrocarbon hydroxylase (AHH), 7-ethoxyresorufin o-deethylase and cytochrome P-450 by various polycyclic aromatic hydrocarbons were studied. 2. The greatest induction of the specific MFO activities tested was produced by 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) with 3-methyl-cholanthrene (MC) a close second. 3. Rank order of efficacy of induction of spectrally determined cytochrome P-450 was 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD), Arochlor 1254 (ARO), 3-methylcholanthrene (MC) and benz(a)anthracene(BA). 4. No unique protein peaks were found when the sodium dodecyl sulfate-polyacrylamide gel electrophoresis of MC treated intestinal microsomes were prepared.

Liquid chromatographic determination of glibenclamide in human plasma.

The oral hypoglycemic agent glibenclamide was determined in human plasma by liquid chromatography (LC). Samples, with internal standard added, are extracted with dichloromethane. The organic phase is evaporated, and the residue is reconstituted in mobile phase for injection onto the LC column. Intra- and inter-day variability of the method was assessed at high and low levels of the drug. Although coefficients of variation were similar for both intra- and inter-day studies at both levels, CVs were smaller at the higher concentration level. Recovery of the drug was good at both high and low levels. The minimum level of detection was 5 ng/mL.

Dietary iron and 2,3,7,8-tetrachlorodibenzo-p-dioxin induced alterations in hepatic lipid peroxidation, glutathione content and body weight.

The effects of various levels of dietary iron on hepatic lipid peroxidation (malondialdehyde [MDA] content), reduced glutathione (GSH) and GSH peroxidase (GSH-PX) activity as well as liver and body weights of female rats following TCDD administration were examined. Rats were fed diets containing deficient (6 ppm), normal (35 ppm) and supplemented (120 ppm) iron for 17, 24 and 31 days. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, 40 micrograms/kg/day P.O.) in corn oil or the vehicle was given on days 9, 8 and 7 prior to sacrifice. TCDD treatment produced a 3-fold increase in hepatic MDA content in animals on normal iron diet. TCDD administration failed to increased MDA content in iron deficient animals. In the iron supplemented groups, TCDD resulted in 2.5 fold increases in lipid peroxidation. Dietary iron had no effect on hepatic GSH-PX activity. Animals on the iron deficient diet had 12-21% decreases in hepatic GSH content. TCDD administration resulted in 15-22% decreases in GSH content in animals on the control and iron supplemented diets. TCDD treatment resulted in significant decreases in body weights of animals on all 3 diets. TCDD induced lipid peroxidation appears to be iron dependent. However, the loss in body weight due to TCDD toxicity may not be dependent on lipid peroxidation.

Intersubject variability in plasma theophylline levels after oral and intravenous administration in Jordanian patients with chronic obstructive pulmonary disease.

Plasma theophylline concentrations were determined in 151 Jordanian patients with chronic obstructive pulmonary disease. Mean plasma levels after oral administration were below the therapeutic range and significantly lower than after intravenous administration. Plasma levels in patients with congestive heart failure (CHF) were higher than in patients with no CHF. Trough plasma theophylline concentrations after intravenous administration in patients less than 18 years of age were significantly lower than in those aged 18-60 years. The overall results are in agreement with observations made in other ethnic groups.

Influence of protein and RNA synthesis inhibitors on methylcholanthrene-mediated induction of aryl hydrocarbon hydroxylase activity in intestinal mucosa.

The sensitivity of the 3-methylcholanthrene (MC)-mediated induction of aryl hydrocarbon hydroxylase (AHH) activity to pretreatment with inhibitors of protein and RNA synthesis was studied. Cordycepin significantly inhibited the induction at 12 h but not at 3 h post-treatment with MC. Both cycloheximide and actinomycin D significantly inhibited the MC-mediated induction at 3 and 12 h after MC treatment. An MC-mediated stimulation of 3H-leucine incorporation into microsomal protein in vivo was observed at 12 h following MC treatment. A cell-free protein synthesis system employing intestinal ribosomes was developed. The rate of protein synthesis (3H-leucine incorporation/mg rRNA/3 min) and the number of active ribosomes (3H-peptidyl-puromycin formed/mg rRNA) were determined. No effect of in vivo MC treatment was observed in subsequently isolated intestinal ribosomes at either 3, 9 or 18 h post-treatment. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis was performed on intestinal microsomes prepared from control, corn-oil- and MC-treated rats 18 h after treatment. The microsomal proteins depicted only slight quantitative changes in microsomal proteins following MC treatment, and no unique protein peaks. These results may explain the lack of detectable stimulation of the activity of isolated ribosomes. In addition, the methods used may lack sufficient sensitivity to detect the small net change in protein necessary to account for the increase in AHH activity seen after MC induction.

Effect of cimetidine on the pharmacokinetics of theophylline.

1. The effect of the therapeutic doses of cimetidine (400 mg/twice daily) on theophylline metabolism in Jordanian volunteers was studied. 2. The administration of the above therapeutic cimetidine dose did not alter theophylline clearance and elimination half-life. 3. Cimetidine administration also failed to alter the elimination of theophylline metabolites in urine.

Effect of ofloxacin on the pharmacokinetics of a single intravenous theophylline dose.

The effect of ofloxacin taken for 8 days (200 mg twice daily) on the pharmacokinetics of a single intravenous dose of theophylline (4.3 mg/kg over 15 min) was studied in a crossover procedure among seven healthy male volunteers. Theophylline concentrations were measured serially for 10 h by the immunofluorescence polarization technique. No significant effect of ofloxacin was found on theophylline clearance, half-life, or volume of distribution. It is therefore concluded that ofloxacin and theophylline can be safely administered together.

Spectrophotometric study of the photodecomposition kinetics of nifedipine.

Nifedipine is a photosensitive compound. Irradiation for 4 h under a fluorescent lamp placed 30 cm from a solution of nifedipine in 95% ethanol leads to complete photo-oxidation as determined spectrophotometrically. The disappearance of the reduced form and appearance of the oxidized form is best described by zero-order kinetics at concentrations higher than 4 x 10(-4) M. At lower concentrations pseudo-first order kinetics are followed. Monochromatic irradiation of nifedipine at wavelengths 400 to 700 nm in 25 nm increments showed no change in the absorbance at 280 nm, and, except for a hyperchromic effect at 237 nm, no other spectral changes were observed. Its photo-oxidation was dependent on the intensity of light and increased exponentially as solutions were irradiated progressively closer to a fluorescent light source. The pH studies showed that aqueous solutions of nifedipine photo-oxidized fastest at pH 2.

Comparative determination of phenytoin in plasma by fluorescence polarization immunoassay and high performance liquid chromatography.

The need for careful monitoring of plasma concentrations of phenytoin during use of the drug in the treatment of epilepsy is well recognized; there can be great intersubject variation in the absorption rate and clearance rate of the drug, and its therapeutic ratio is narrow. In this study, two methods for determining plasma phenytoin concentrations were compared. One, based on fluorescence polarisation immunoassay (FPIA), is utilised in a commercially-available kit. The other, our own modification of a published procedure, was based on high performance liquid chromatography (HPLC). The accuracy and precision of both methods were evaluated, and the coefficients of variation (C.V.) were calculated. The C.V.'s ranged from 0.71 to 1.86% for the FPIA method, and from 2.81 to 8.69% for the HPLC method. Corresponding bias values were 1.20 to 1.60%, and 2.81 to 8.69%, respectively. A good correlation coefficient (0.977) was obtained, but estimated phenytoin concentrations were significantly higher (95% confidence level) using the HPLC method. We conclude that both methods perform adequately for clinical purposes. The HPLC method is, however, less expensive than the FPIA method.

Effects of glucagon on cAMP accumulation and ketogenesis in hepatocytes from euthyroid and hypothyroid rats.

The resistance to the effects of glucagon was studied in isolated hepatocytes prepared from male rats treated with 6N-propyl-2-thiouracil (PTU). Incorporation of [14C]oleate into ketone bodies in response to various concentrations of glucagon (10(-5) to 10(-10) M) was reduced in hepatocytes from hypothyroid rats compared with the euthyroid group. The reduced sensitivity to the effects of glucagon on ketogenesis after treatment with PTU was associated with a reduced ability of those hepatocytes to maintain cyclic adenosine-3',5'-monophosphate (cAMP) at levels required to stimulate ketogenesis. The concentration of cAMP in response to glucagon (10(-5) to 10(-10) M) was diminished in hepatocytes from hypothyroid rats, compared with those from euthyroid animals.

Effects of food and gender on the pharmacokinetics of methotrexate in children.

The effects of food and gender on the oral absorption of methotrexate (MTX) in 16 Jordanian children were investigated. Plasma levels of MTX were measured by a fluorescence polarization immunoassay. The extent of absorption and the rate of elimination of the drug were determined in both males and females, before and after meals and data were statistically analyzed using two-way analysis of variance. The results showed great variability in individual MTX Cmax, t1/2, Kel. and AUC. Although no statistically significant differences were found in the pharmacokinetic parameters of the drug among the groups, apparent differences were observed in the mean values of these parameters.

Glutathione, glutathione S-transferase and glutathione reductase in human erythrocytes and lymphocytes as a function of sex.

We review the role of glutathione (GSH) and its metabolizing enzymes, glutathione S-transferase (GST) and glutathione reductase (GSR) in drug metabolism and in the elimination of foreign compounds. Levels of GSH and the activity of these enzymes may be greatly influenced by drugs and other substances in the body. We therefore determined GSH levels and the activities of GST and GSR in human erythrocytes and lymphocytes in males and females in three age groups. There was no significant difference between males and females in the three age groups in respect of GSH levels and GST and GSR activities. GSH levels in erythrocytes were higher than those in lymphocytes when expressed per mg protein, but lower than those in lymphocytes when expressed per 10(6) cells. The activities of both GST and GSR were found to be higher in lymphocytes than in erythrocytes.

Changes in glutathione, glutathione reductase and glutathione-S-transferase as a function of cell concentration and age.

The activities of glutathione-S-transferase (GST) and glutathione reductase (GSR) in mouse lymphocytes as a function of cell concentration and age were determined. Lymphocytes from 2-, 9- and 24-month-old mice were isolated and the activity of GST was determined spectrophotometrically using 1-chloro-2,4-dinitrobenzene as the substrate. Lymphocyte concentrations of 0.44, 0.75 and 0.55 X 10(6) cells/ml were found to be optimal for assaying GST in 2-, 9- and 24-month-old mice, respectively. Determination of GSR activity was based on NADPH reduction of oxidized glutathione and cell concentrations of 0.29, 0.30 and 0.22 X 10(6) cells/ml were chosen for assaying the enzyme activity for the three age groups, respectively. Glutathione levels and GSR activity of mice lymphocytes were higher in 2- and 24-month-old mice as compared to 9-month-old animals. However, GST activity of mouse lymphocytes was low in 2- and 9-month-old mice and increased significantly in 24-month-old animals.