PubMed Health⌕ Search

Biomedical subjects

R H Levy

Publications and source records attributed to R H Levy.

At least 73 records · Page 4Linked to original sources
PubMed1989

Inhibition of human liver microsomal epoxide hydrolase by valproate and valpromide: in vitro/in vivo correlation.

On the basis of drug interactions with carbamazepine epoxide, it has been hypothesized that valproic acid and valpromide are inhibitors of epoxide hydrolase, but the role of epoxide hydrolase in these interactions has not been clearly established. In this study, therapeutic concentrations of valproic acid (less than 1 mmol/L) and valpromide (less than 10 mumol/L) inhibited hydrolysis of carbamazepine epoxide and styrene oxide in human liver microsomes and in preparations of purified human liver microsomal epoxide hydrolase. Valpromide (KI = 5 mumol/L) was 100 times more potent than valproic acid (KI = 550 mumol/L) as an inhibitor of carbamazepine epoxide hydrolysis in microsomes. After administration of carbamazepine epoxide to volunteers, the transdihydrodiol formation clearance was decreased 20% by valproic acid (blood concentration approximately 113 mumol/L) and 67% by valpromide (blood concentration less than 10 mumol/L). For both valproic acid and valpromide, a striking similarity exists between in vitro and in vivo inhibitory potencies. Valproic acid and valpromide are the first drugs known to inhibit microsomal epoxide hydrolase, an important detoxification enzyme, at therapeutic concentrations.

Anticonvulsants↗
PubMed1989

Pharmacokinetics of old, new, and yet-to-be-discovered antiepileptic drugs.

The pharmacokinetics of antiepileptic drugs have been investigated extensively during the last two decades. It has become evident that the therapeutic management of epileptic patients would be significantly improved with the elimination of the drawbacks associated with existing antiepileptic drugs. Based on the information accumulated to date, the following set of principles is proposed: (1) The requirement of central nervous system (CNS) penetration automatically creates vulnerability to CNS toxicity. (2) The narrower the therapeutic range of a given drug, the more limiting its pharmacokinetic properties become. (3) The requirements of chronic administration and compliance place narrow limits on the optimum half-life (24 h). (4) The practice of polytherapy and the potential for pharmacodynamic and pharmacokinetic interactions make it necessary to simplify metabolic schemes (i.e., use of metabolically directed design approaches). (5) New antiepileptic drugs have shown that widely different structures are associated with anticonvulsant properties--it becomes important to minimize toxicity and optimize pharmacokinetic characteristics early in the development of future antiepileptic drugs. (6) Yet-to-be-discovered antiepileptic drugs will probably include biotechnology-based pharmaceuticals. Such biologic agents as neuropeptides present a new set of pharmacokinetic requirements because they are generally receptor targeted, they do not cross absorption barriers easily, and they are labile and subject to degradation.

Anticonvulsants↗
PubMed1988

Clinical pharmacokinetics of carbamazepine.

The relationship between daily dose and plasma levels of carbamazepine is poor. The slope of that relationship varies with the patient population. Children require twice as much of the drug as adults do to achieve a given level. Also, dosage requirements increase in the presence of other drugs that are enzyme inducers. Recent reports suggest that the 10,11-epoxide metabolite of carbamazepine can contribute to the neurotoxicity attributed to carbamazepine. Carbamazepine is a broad-spectrum enzyme inducer. Three reports in the past 2 years show that haloperidol levels are reduced by approximately 50% when carbamazepine is introduced. Those interactions may complicate the interpretation of clinical trials of carbamazepine.

Adolescent↗
PubMed1988

[Neurophysiological and therapeutic evaluation of stiripentol in epilepsy. Preliminary results].

The main objective of this study was to determine whether stripentol (STP) alleviates side-effects commonly observed in treated epileptic patients, since preliminary data suggested a positive psychotropic effect. A secondary objective was an evaluation of drug efficacy. Eleven patients with either a drug-resistant epilepsy or toxic effects of AEDs completed the study. Ten had symptomatic partial epilepsies and one an idiopathic generalized epilepsy. STP was added to the baseline therapy (1 or 2 AEDs) and the dose of the baseline AEDs was reduced to maintain plasma levels unchanged (mean reduction: PB 26%, PHT: 49%, CBZ: 38%). Several motor, perceptual and attention tasks and the Washington Psychosocial Seizure Inventory were performed before and after STP administration. Seizure frequency and clinical side-effects were evaluated during a baseline period and after two months of constant therapy. Effects of repeated administration of the neuropsychological battery were assessed by administration of the battery on two occasions at 12-week interval to a randomized subgroup of patients. No practice effect was observed. A trend of improvement (p less than 0.05) in the performance of two tasks requiring sustained attention was noted. Previous side-effects (mainly drowsiness) decreased or disappeared in 7 of 9 patients who became more alert. Six of the nine uncontrolled patients experienced a decrease in seizure frequency equal to or larger than 50 per cent.

Adult↗
PubMed1986

Comparative pharmacokinetics of zonisamide (CI-912) in epileptic patients on carbamazepine or phenytoin monotherapy.

Zonisamide (CI-912) is an experimental antiepileptic drug. Since this drug is to be evaluated initially as an add-on medication, an investigation was conducted to study its kinetics in the presence of two standard antiepileptic drugs. Patients in two groups, one on maintenance phenytoin (PHT) monotherapy and the other on maintenance carbamazepine (CBZ) monotherapy, each received a single dose of four 100-mg capsules of zonisamide; and blood samples were obtained at periodic intervals. Plasma and red blood cell (RBC) concentrations of zonisamide were measured by high performance liquid chromatography. Plasma and RBC areas under the curve produced by single doses of zonisamide in patients receiving CBZ were significantly higher than those receiving PHT (p less than 0.05). Clearance values, although not statistically significantly different, were lower for the CBZ group; and consistent with this, plasma and RBC concentrations decreased more rapidly in the PHT group. The approximate values for t1/2 were 36.4 h in plasma and 54.2 h in RBC for patients treated with CBZ, and 27.1 h in plasma and 35.8 h in RBC for patients treated with PHT. The RBC/plasma ratio varied eightfold within a given curve. These findings suggest that the dosage of zonisamide in epileptic patients might need to be varied depending on the comedication.

Adolescent↗
PubMed1985

Diurnal oscillations of CSF valproate in monkey.

Valproate (VPA) was administered to four rhesus monkeys by constant-rate intravenous infusion for two weeks under controlled conditions. Plasma and CSF samples were collected for a period of 27 hours at 3-hour intervals during steady-state and post-infusion periods. The mean correlation coefficient between total plasma and CSF VPA concentrations was found to be 0.78 +/- 0.09. The CSF VPA levels reflected the changes in free VPA in plasma but the two were not equivalent. Diurnal fluctuations in CSF VPA concentration were similar to those found in plasma but the inter-animal variation was greater in CSF than in plasma.

Animals↗
PubMed1985

Inhibition of epoxidation of carbamazepine by valproic acid in the isolated perfused rat liver.

The effect of valproic acid on carbamazepine epoxidation in the perfused liver was investigated in two separate studies. In study I, significant decreases were observed both in the intrinsic clearance of carbamazepine and the intrinsic formation clearance of carbamazepine-epoxide in the presence of therapeutic concentrations of valproate. The same inhibitory effect of valproate was also observed in liver preparations from a group of animals pretreated with carbamazepine. Study II focused on the effect of valproate and carbamazepine on the apparent Michaelis-Menten parameters (Vmax,m, Km,m) associated with the intrinsic formation clearance of carbamazepine-epoxide in the perfused liver. Valproate had no statistically significant effect on either the Vmax,m or the Km,m of epoxidation, although the Km,m value was 43% higher in the presence of valproate. However, the ratio of Vmax,m and Km,m (intrinsic formation clearance) was significantly reduced by valproate. The Vmax,m and Km,m values obtained in study II predicted a significant decrease in the intrinsic formation clearance of carbamazepine-epoxide, consistent with the results of study I. Carbamazepine pretreatment was associated with significant increases in apparent Vmax,m and Km,m of epoxide formation.

Animals↗
PubMed1985

Fractions metabolized in a triangular metabolic system: cinromide and two metabolites in the rhesus monkey.

A previous study of the metabolic fate of cinromide (3-bromo-N-ethylcinnamamide) in rhesus monkey established that half of a dose is metabolized by N-deethylation to an active metabolite, 3-bromocinnamamide. Both cinromide and its proximal metabolite can be metabolized by amide hydrolysis to a second metabolite, 3-bromocinnamic acid, resulting in a triangular metabolic problem. This investigation was undertaken to distinguish between these two nonexclusive possibilites. A preliminary study was carried out to characterize the pharmacokinetics of 3-bromocinnamic acid. In the main study, six monkeys received an intravenous dose of cinromide, 3-bromocinnamamide, and 3-bromocinnamic acid in a randomized order. The time courses of compound administered and corresponding metabolites were followed. The following fractions of dose metabolized (mean +/- SD) were obtained: cinromide to 3-bromocinnamide: 0.53 +/- 0.24; 3-bromocinnamamide to 3-bromocinnamic acid: 0.53 +/- 0.21; cinromide to 3-bromocinnamic acid directly: 0.48 +/- 0.32. Thus, it was found that 3-bromocinnamic acid is formed directly from cinromide and from 3-bromocinnamamide. Also, as primary metabolites, 3-bromocinnamic acid and 3-bromocinamamide account for all of a cinromide dose with a mean value of 1.00 +/- 0.34. The observed variability in these fractions metabolized was explained by the fact that in the solution of the triangular metabolic problem, three clearances are assumed to remain constant over three studies.

Animals↗
PubMed1985

Valproic acid clearance: unbound fraction and diurnal variation in young and elderly adults.

Six young (22 to 25 years old) and six elderly (60 to 88 years old) healthy adults took valproic acid, 250 mg by mouth, at 8 am and 8 pm for 5 days. On the fifth day, blood samples were drawn over each dosage interval. Both young and elderly subjects exhibited diurnal variability. Total and unbound clearances in the young and elderly subjects were about 10% and 15% higher during the evening. These changes led to lower total and unbound steady-state and peak concentrations during the nighttime dosage interval. There were no differences in total steady-state concentrations and kinetics computed from total concentrations between the young and elderly, but there were differences in unbound steady-state concentrations and kinetics. Unbound clearances were 65% lower, which resulted in unbound steady-state concentrations 67% higher in the elderly. The average unbound fractions in the elderly and young were 10.7% and 6.4%. To minimize the influence of diurnal variability, drug concentrations should be determined at the same time each day. Total valproic acid concentration data may be less useful in elderly patients; unbound concentrations may be more reliable in this population.

Adult↗
PubMed1985

Effects of pregnancy on antiepileptic drug utilization.

Pregnancy is associated with characteristic changes in the disposition of antiepileptic drugs; recent findings on this aspect of drug utilization are presented. In one study involving 48 pregnancies, the mean level-dose ratio of phenytoin decreased by 34%. In another study of 111 patients, phenytoin clearance increased gradually over the first 32 weeks of pregnancy and reached twice the preconception value. In two studies with phenobarbital, levels tended to decrease, although this effect was less pronounced than for phenytoin. Similarly for primidone, pregnancy had little effect on steady-state levels; however, levels of phenobarbital formed from primidone exhibited large decreases during pregnancy followed by increases after delivery. This effect was quite consistent. Carbamazepine clearance tended to increase to a relatively small extent. Limited data indicate that valproate levels decrease by 30 to 40% during pregnancy. The mechanisms responsible for these effects have not been elucidated and possibly include decreased bioavailability or compliance, increased metabolic clearance, or decreased plasma protein binding. Since the patient at risk of an increase in seizure frequency cannot be identified prior to conception, therapeutic monitoring is imperative during and after pregnancy.

Anticonvulsants↗
PubMed1984

Stiripentol kinetics in epilepsy: nonlinearity and interactions.

Stiripentol kinetics during oral therapy were assessed in six patients with epilepsy who were receiving other antiepileptic drugs. Steady-state levels at 600, 1200, and 2400 mg/day increased in a nonlinear fashion, indicating Michaelis-Menten kinetics. Oral clearance of stiripentol at 600 mg/day was 41.5 +/- 23.4 l/day/kg (mean +/- SD), greater than that at 1200 mg/day (20.3 +/- 8.8 l/day/kg; P less than 0.05) or 2400 mg/day (8.5 +/- 3.8 l/day/kg; P less than 0.01). The apparent in vivo Michaelis-Menten parameters were determined from three mean steady-state concentrations. The average velocity of conversion of stiripentol to its metabolites (Vm), Michaelis constant (Km), and the ratio Vm/Km were 49.3 +/- 13.1 mg/day/kg, 1.35 +/- 1.08 mg/l, and 50.2 +/- 27.5 l/day/kg. Stiripentol reduced the elimination clearances of concomitant antiepileptic drugs. Phenytoin clearance was reduced in all five subjects who received this drug, from a mean control of 29.5 +/- 13.4 l/day to 18.5 +/- 4.6 l/day at a stiripentol dose of 1200 mg/day (P = 0.05) and to 6.48 +/- 2.59 l/day at 2400 mg/day (P less than 0.01). Stiripentol reduced the clearance of carbamazepine in one subject from a control value of 209 l/day to 128 l/day (1200 mg/day) and 61 l/day (2400 mg/day). Stiripentol reduced phenobarbital clearance in two subjects from 3.8 and 5.1 l/day to 2.3 and 3.4 l/day (2400 mg/day). The Michaelis-Menten kinetics of stiripentol, as well as its interactions with other antiepileptic drugs, have important implications in the designing of controlled clinical trials.

Administration, Oral↗
PubMed1984

Diurnal variation in valproic acid clearance.

Diurnal variation in total and unbound valproic acid concentrations was measured at steady state in seven healthy men and three healthy women after 250-mg oral doses every 12 hr. Total average steady-state concentration (Css) during the morning dosage interval was 50.4 mg/l. During the evening dosage interval, total Css was 45.7 mg/l. Unbound Css was also less during the evening (2.9 and 3.4 mg/l). These changes were due to higher total and unbound clearance rates during the evening dosage interval. Total peak concentrations were lower (56.8 and 64.3 mg/l) and time of peak concentrations slightly longer (2.2 and 1.8 hr) during the evening. There was marked interindividual variability in all these changes. For best reproducibility of steady-state valproic acid concentrations, our results suggest that total and unbound levels be drawn at the same time of day.

Administration, Oral↗
PubMed1984

Filtration for free drug level monitoring: carbamazepine and valproic acid.

Free carbamazepine and valproic acid monitoring using the EMIT FreeLevel filtration system was evaluated and compared with reference equilibrium dialysis and gas chromatographic (GC) techniques. For carbamazepine, free levels after filtration or dialysis were essentially identical (mean 1.74 vs. 1.77 mg/L, r = 0.940, n = 28, EMIT assay). Free levels were 16% higher by EMIT than by GC, possibly due to cross-reaction with carbamazepine-10,11-epoxide. Free fractions were not significantly different using any combination of filtration or dialysis with EMIT or GC (means 0.24-0.26). There was a significant correlation between epoxide and parent-drug free fractions (r = 0.642). Free fraction varied from 0.20 to 0.41 among 61 patient samples and was independent of total drug concentration. For valproic acid, there was a strong correlation between filtration and dialysis results for free level (r = 0.974) and free fraction (r = 0.892), but filtration values were 6-7% higher. Free fraction was concentration dependent (r = 0.597), and lower free fractions by dialysis were attributed to dilution of total drug concentration. Free fraction varied from 0.01 to 0.14 among 50 patient samples. For carbamazepine and valproic acid the EMIT FreeLevel filtration system compared favorably with equilibrium dialysis, and had the advantage of being rapid.

Blood Proteins↗
PubMed1984

Michaelis-Menten kinetics of stiripentol in normal humans.

Michaelis-Menten kinetic parameters for stiripentol, and anticonvulsant, were assessed in six normal volunteers. Stiripentol was administered orally three times a day in dosage increments of 600, 1,200, and 1,800 mg/day for consecutive periods of 3, 4, and 7 days, respectively. Stiripentol steady-state levels at the three dosing rates increased more than proportionally with dose. The mean +/- SD oral clearance of stiripentol at 600 mg/day (1,090 +/- 624 L/day) was significantly greater (p less than 0.01) than at 1,200 (506 +/- 219 L/day) or 1,800 (405 +/- 151 L/day) mg/day. Average steady-state concentrations predicted from individually determined Vm and Km parameters were in good agreement with experimentally observed levels, indicating that the kinetics of stiripentol are of the Michaelis-Menten type. The mean Vm, Km, and Vm/Km ratio were 2,299 +/- 490 mg/day, 2.20 +/- 1.28 mg/L, and 1,241 +/- 837 L/day, respectively. Neuropsychological tests carried out before and after 14 days of stiripentol treatment showed a significant decline in verbal learning ability (p = 0.038) and a significant improvement in a test of memory and attention (p less than 0.01).

Adult↗