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Biomedical subjects

P N Friel

Publications and source records attributed to P N Friel.

At least 19 recordsLinked to original sources
PubMed1999

Development of dosing guidelines for reaching selected target breath alcohol concentrations.

OBJECTIVE: This study evaluated gender-specific ethanol dosing protocols that were designed to result in one of two peak breath alcohol concentrations (BrACs)--0.07 or 0.10 g/2101. Inter- and intrasubject variability in BrAC were assessed and several possible methods for reducing variability in BrAC were evaluated. METHOD: Subjects (16 women, 16 men, ages 21-30 years) were studied after low (women 0.49 g/kg, men 0.53 g/kg consumed over 10 minutes) and high (women 0.81 g/kg, men 0.89 g/kg consumed over 20 minutes) ethanol doses, consumed following a 4-hour fast. All subjects were regular drinkers. RESULTS: Mean (+/-SD) peak BrACs actually achieved were 0.069+/-0.011 g/2101 after the low dose, and 0.105+/-0.014 g/2101 after the high dose. Mean values for peak BrAC, time to peak BrAC and area under the curve were not statistically significantly different between genders at either dose. BrACs varied by as much as twofold between subjects after equivalent gender and body weight adjusted doses. There was some reproducibility of ethanol pharmacokinetic parameters over dose and time in men, but not in women. CONCLUSIONS: The doses used resulted in equivalent mean ethanol exposures for women and men at each dose, with mean peak BrACs that closely approached the targets, but there was substantial inter- and intrasubject variability in ethanol pharmacokinetics.

Adult↗
PubMed1995

Variability of ethanol absorption and breath concentrations during a large-scale alcohol administration study.

Ethanol disposition was evaluated in 77 female and 97 male college seniors during an alcohol challenge study. All were regular drinkers who exceeded legal intoxication levels at least twice a month by history. A standard ethanol dose (females, 0.43 g/kg; males, 0.51 g/kg) was administered over 10 min, after a 4-hr fast, and breath alcohol concentrations (BrACs) were measured for 2 hr. Intersubject variability in BrACs was greatest early in the study, during ethanol absorption; the coefficient of variation decreased from 39% at 14 min to 14% at 125 min after the start of drinking. The time to peak BrAC varied from 10 to 91 min after the start of drinking (mean 39.6 min). Mean BrACs were significantly lower in females than males; mean peak BrACs were 0.054 g/210 liters in females and 0.058 g/210 liters in males (p = 0.031). The beta- and r-values for both genders were higher than those typically used in ethanol dose calculation formulas. Data are discussed to direct future research. The constants used in Widmark's formula need to be revised differentially for males and females in this population to reach specific target BrACs. Furthermore, substantial variability in absorption rates must be accounted for when assessing rising versus falling limb BrAC phenomena.

Adult↗
PubMed1995

An evaluation of the reliability of Widmark calculations based on breath alcohol measurements.

This study evaluated the reliability of Widmark calculations, based on breath ethanol reading (BrACs), for estimating the amount of alcohol consumed. A standard ethanol dose (males 0.51 g/kg; females 0.43 g/kg) was given to 115 college seniors, and BrACs were measured for two hours. Calculations of ethanol dose were performed using BrACs taken at 60, 75, 105, and 125 minutes after drinking. Mean calculated ethanol doses were lower than actual doses at each time point (P < 0.001). Mean underestimates were 13, 12, 15, and 14 mL of 100 proof vodka at 60, 70, 105, and 125 min after drinking. Calculated doses overestimated actual doses in 11, 10, 3, and 3 subjects at 60, 75, 105, and 125 min after drinking. The maximum overestimates were 13, 11, 6, and 8 mL of vodka at 60, 75, 105, and 125 min after drinking. At the 95% confidence level, the calculated dose at 105 and 125 min did not overestimate the true dose, but could underestimate it by as much as 30 mL vodka.

Adult↗
PubMed1992

Low and variable presence of valproic acid in human brain.

We studied the distribution of valproic acid (VPA) between brain (gray matter) and serum in 13 patients receiving chronic VPA therapy who underwent cortical resections for intractable seizures. Valproate concentration in cerebral cortex was remarkably low compared with either total or unbound valproate concentration in serum. The respective brain-to-serum partition ratios based on total and free drug in serum were 0.111 +/- 0.051 and 0.544 +/- 0.175. In comparison with other commonly used antiepileptic drugs, valproate has the distinction of exhibiting the lowest brain-to-blood partitioning. Moreover, the brain-to-serum concentration ratio varied over a four-fold range between patients. Some of this variability was related to variation in serum protein binding, as indicated by a modest correlation between the partition ratio and serum free fraction (r = +0.687). However, the brain-to-unbound concentration ratio still showed a three-fold variation. The variability in distribution of VPA between brain and blood is probably one of the underlying factors for the lack of a clearly definable therapeutic range of serum VPA concentration in epileptic patient populations.

Adolescent↗
PubMed1992

Antiepileptic drug disposition during pregnancy.

A significant proportion of women with epilepsy have an increase in their seizure frequency during pregnancy. Multiple factors may be involved in this phenomenon, but changes in antiepileptic drug (AED) concentration appear to be the most significant. AED concentration declines as pregnancy progresses, due primarily to dynamic changes in plasma protein binding. Total concentrations of all first-line AEDs (carbamazepine, phenytoin, phenobarbital, and valproic acid) fall significantly during pregnancy, compared to baseline. Free or unbound drug concentrations, however, fall significantly only for phenobarbital. Valproate free concentrations actually increase by 25% by delivery. Women taking carbamazepine, phenytoin, or valproate may be relatively protected by adequate free concentrations of these compounds. When managing pregnant women with epilepsy, measurement of free AED concentrations and appropriate dose adjustment to maintain therapeutic ranges will permit more effective clinical management than using total concentration values.

Adult↗
PubMed1990

Pharmacokinetics of anticonvulsants in pregnancy: alterations in plasma protein binding.

Anticonvulsant levels decline as pregnancy progresses, even in the face of constant and, in some cases, increased dosages of medications. It has been suggested that this decline is responsible for the increase in seizure frequency seen in approximately one-third of the women with epilepsy who become pregnant. Changes in plasma protein binding may explain the declines in anticonvulsant concentrations during pregnancy. A prospective cohort study was designed to test this hypothesis. Carbamazepine, phenytoin and phenobarbital were studied. The mean total concentrations of all 3 drugs declined as pregnancy progressed, rising in the postpartum period. Free concentrations also declined, but did so significantly only for phenobarbital. The free fraction for all anticonvulsants studied rose significantly throughout pregnancy. Protein binding is significantly altered during pregnancy for all 3 drugs studied and appears to account for much of the decline in anticonvulsant concentrations seen in this condition. It is suggested that free rather than total drug concentrations be monitored in pregnant women with epilepsy.

Adult↗
PubMed1990

Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4-ene-valproate, a hepatotoxic metabolite of valproic acid.

The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2-propyl-4-pentenoic acid (4-ene-VPA), formed by a cytochrome P450-mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4-ene-VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CLf) of 4-ene-VPA was increased twofold in the valproic acid-carbamazepine and valproic acid-phenytoin groups. In the valproic acid/stiripentol studies, the CLf of 4-ene-VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4-ene-VPA, in humans. The increased formation of 4-ene-VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid-related hepatotoxicity during polytherapy with P450 inducers.

Adult↗
PubMed1987

Use of unbound drug concentrations to determine neonatal anticonvulsant exposure.

Unbound and total concentrations of several anticonvulsant drugs were measured by liquid chromatography in maternal and neonatal cord serum collected at birth from 16 women being treated for epilepsy and their newborns. Maternal and neonatal unbound drug concentrations agreed closely for phenobarbital (n = 6), phenytoin (n = 7), carbamazepine (n = 8), and its epoxide metabolite. Mean maternal total drug concentrations were higher than neonatal concentrations in the cases of phenobarbital, carbamazepine, its epoxide and diol metabolites. The differences were due to greater protein binding in maternal serum. Measurement of total anticonvulsant concentrations in newborns may be misleading, because of altered protein binding in the neonate. For the medications tested, neonatal and maternal exposures to unbound drug appear to be equivalent.

Adult↗
PubMed1987

Serum prolactins in the diagnosis of epilepsy: sensitivity, specificity, and predictive value.

Serum prolactin levels rise after generalized tonic-clonic and partial complex seizures, but not after pseudoepileptic seizures. The criteria for a significant elevation in serum prolactin vary with individual investigators. The prevalence of pseudoseizures in the population studied determines the predictive value of serum prolactin determinations. In populations where most patients have epilepsy, a rise in serum prolactin is highly predictive for true epilepsy, but no increase in serum prolactin is not predictive for pseudoseizures.

Epilepsy↗
PubMed1986

Problem of spurious correlation in the evaluation of steady-state carbamazepine levels using metabolite data.

The statistical problem of spurious correlation occurs when ratio variables with the same denominator are correlated. The correlation between two variables is also altered when heterogeneous groups are pooled. The problem is illustrated in the assessment of steady-state plasma levels of carbamazepine (CBZ), CBZ-10,11-epoxide (CBZ-epoxide), and 10,11-dihydro-10, 11-trans-dihydroxy-CBZ (CBZ-diol) in 12 epileptic patients on CBZ monotherapy and 12 epileptic patients on CBZ polytherapy. Expressing outcomes as dose/level ratios and metabolite level/parent drug level ratios is shown to be inappropriate, leading to spurious correlation. The amount of spurious correlation induced can be assessed by use of available statistical methodology, as is illustrated in this paper. More appropriate, alternative approaches are illustrated, using the data on the 24 patients with epilepsy.

Adolescent↗
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

Carbamazepine protein binding and disposition in pregnancy.

The pregnancies of five women with epilepsy treated with carbamazepine monotherapy were studied prospectively. Free and total serum concentrations of carbamazepine and its epoxide and dihydrodiol metabolites were analyzed at monthly intervals from the first trimester through 8 weeks postpartum. Assays were by high performance liquid chromatography, and free compounds were separated by ultrafiltration. The mean intrinsic clearance of carbamazepine (clearance of free drug corrected for changes in maternal body weight) did not change appreciably during pregnancy and the postpartum period. The mean free fractions of carbamazepine and the epoxide were elevated during pregnancy (0.25 and 0.50) compared with postpartum (0.22 and 0.43). Mean total maternal carbamazepine and epoxide concentrations were 40 and 48% higher than neonatal levels at birth, but maternal and neonatal free concentrations agreed closely. The ratio of epoxide to parent drug increased during pregnancy, as reported by other authors. Evidence is presented that this may be a result of inhibition of further biotransformation of the epoxide rather than of increased production. Two patients missed at least one dose of carbamazepine during labor, resulting in markedly reduced serum concentrations at delivery.

Adult↗
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↗
PubMed1983

Cinromide in epilepsy: a pilot study.

Monotherapy with the experimental antiepileptic drug cinromide was evaluated in 11 adult outpatients with uncontrolled partial epilepsy. They were treated with phenytoin for 2 months, cinromide for 4 months, and carbamazepine for 4 months. Four patients withdrew from the study during or shortly after crossover to cinromide due to increased seizure frequency or severity. Of the remainder, three preferred carbamazepine, two cinromide, and two phenytoin, based on both seizure control and degree of toxicity. Overall seizure control was not significantly different with any of the three agents, but during cinromide administration secondarily generalized seizure control was uniformly worst and there was also a tendency toward decreased performance on neuropsychological tests. CNS toxicity and gastrointestinal toxicity were prominent during the first month of cinromide treatment, but subsided with time or dose reduction. No abnormalities requiring drug withdrawal were found with laboratory testing. The results suggested, at best, a very limited clinical usefulness for cinromide, and it has been withdrawn from testing by its manufacturer.

Adult↗
PubMed1983

Effect of doxepin on seizure frequency in depressed epileptic patients.

We performed a retrospective study of the effect of antidepressant treatment with doxepin on seizure frequency. From 47 patients treated with doxepin in 3 years, a confirmed seizure disorder and adequate follow-up (mean, 6.8 months) were available for 19 patients. Comparison of mean monthly seizure frequency during equal blocks of time before and during treatment with doxepin in doses of 5 to 400 mg/day demonstrated improved seizure control in 15, no change in 2, and increased seizures in 2 patients. The reduction in seizure frequency may have been a result of a direct antiepileptic effect of doxepin, an indirect effect because of improved affective state, drug interactions, or some combination of these mechanisms.

Adolescent↗
PubMed1982

Kinetics of phenobarbital in normal subjects and epileptic patients.

The kinetics of phenobarbital (PB) were evaluated in six normal subjects and six epileptic patients treated with phenytoin or carbamazepine. Each normal subject received three single doses of PB: PB-sodium 130 mg i.v. (IV), PB sodium 10 mg i.m. (IM), and PB acid 100 mg orally (PO), in random order at least one month apart. After IV PB distributive half-lives were 75 to 126 h, steady state volume of distribution (Vss) was 0.54 +/- 0.03 l/kg, and clearance (CL) was 3.8 +/- 0.77 ml/h/kg. Absolute bioavailability of IM PB was 101 +/- 11%. Peak serum PB concentrations were achieved from 2 to 8 h after IM administration, and from 0.5 to 4 h after PO administration. Epileptic patients exhibited similar PB kinetics: disposition half-lives were 77 to 128 h, Vss 0.61 +/- 0.05 l/kg, and Cl 3.9 +/- 0.76 ml/h/kg. Phenobarbital appears to represent an exception among antiepileptic drugs, in that pharmacokinetic data obtained in normal car reasonably be extrapolated to the epileptic population.

Administration, Oral↗
PubMed1981

Differential kinetics of cinromide and two of its metabolites in epileptic patients.

Cinromide is an experimental anticonvulsant currently in phase II testing. A single oral dose (900 mg) of cinromide was administered to 8 epileptic subjects on phenytoin therapy. Plasma samples drawn during the next 36 h were analyzed for cinromide and its amide and acid metabolites. The absorption rate of cinromide varied widely between subjects producing maximum cinromide concentrations between 0.5 and 2.5 h after the dose. The median elimination half lives of cinromide and the amide and acid metabolites were 0.73, 1.65, and 4.85 h respectively. The oral clearance of cinromide (median = 135 l/h) suggests that it is subject to first pass metabolism. In all subjects the area under the curve (AUC) of acid metabolite (632 to 1777 microM/l) was greater than the AUC of amide metabolite (77 to 185 microM/l) which was greater than the AUC of cinromide (5 to 89 microM/l). Steady-state concentration ratios of metabolite to parent drug predicted from the AUC data were 3.8 for the amide and 35.8 for the acid metabolite. The amide metabolite is known to have anticonvulsant properties and, until the relative contributions of metabolites and parent drug to the efficacy of cinromide are resolved, the monitoring of metabolites as well as parent drug is imperative.

Adult↗