Serum phenytoin concentrations in uremia.
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Chromatography, Gas↗
Biomedical subjects
P N Friel
Publications and source records attributed to P N Friel.
High-performance liquid chromatographic and gas-liquid chromatographic determination of diazepam and nordiazepam in plasma.
A one-step method for extraction of diazepam, nordiazepam, and internal standard into toluene is followed by chromatographic separation and detection with either dual-wave-length high-performance liquid chromatography or electron-capture gas-liquid chromatography. Agreement between the two methods was excellent for diazepam (r = 0.99, n = 38) and good for nordiazepam (r = 0.96, n = 79) over a concentration range that included subtherapeutic, therapeutic, and toxic plasma levels.
Adult↗
Single-dose pharmacokinetics and anticonvulsant efficacy of primidone in mice.
The pharmacokinetics and efficacy of the anticonvulsant primidone (PRM) and its active metabolites, phenobarbital (PB) and phenylethylmalonamide (PEMA), were studied after single-dose administration in mice. The half-life of PB is twice that of PRM and PEMA. The plasma/brain ratios provide evidence of poor penetration of PRM into brain. The results support our findings of negligible or absent PRM concentrations in the brains of patients on primidone therapy who were undergoing surgery for intractable epilepsy. The anticonvulsant properties of PRM, PB, and PEMA against maximal electroshock in mice were also studied with the use of the metabolic inhibitor SKF 525A. The half-life, potency, peak anticonvulsant effect, and effective dose curves of these compounds indicate that the anticonvulsant effect of short-term oral PRM administration in mice is from derived PB.
Animals↗
Valproic acid-phenytoin interaction.
The interaction between valproic acid (VPA) and phenytoin (DPH) was examined during therapeutic monitoring in an epileptic outpatient population. Gas-liquid chromatographic methods were used to measure DPH and VPA concentrations. (1) In 12 patients on stable DPH regimens, the mean DPH level declined from 19.7 to 15.3 microgram/ml when VPA was added (p less than 0.001). (2) In 20 patients receiving DPH and VPA, the median free fraction was 15.8%, compared to 9.1% free DPH in 40 patients receiving DPH only or DPH and phenobarbital (p less than 0.001). (3) Addition of VPA to a stable DPH regimen may result in a transient increased risk of DPH toxicity, followed by restabilization at the original free DPH level.
Adult↗
A methods comparison: clonazepam by gas chromatography-electron capture and gas chromatography-mass spectroscopy.
Clonazepam is an antiepileptic drug for which a number of analytical procedures have been presented, none of which have been subjected to comparison studies. We present two gas chromatographic (GC) methods involving distinct forms of detection for determining plasma or serum drug levels. Both methods involve simple extractions, common GC conditions, and routine data reduction. Both employ nitrazepam as an internal standard, require 1 ml of sample, and have a detection limit of 1 ng/ml. The two methods, GC-electron capture and GC-mass spectroscopy, are precise and accurate. Correlation of the two methods paired sample analysis gave a regression equation of y = 0.988x - 0.14 (n = 30, r = 0.971, p less than 0.001). We suggest that either method is a reasonable alternative for the clinical laboratory with the proper instrumentation.
Benzodiazepinones↗
Human epileptic brain Na, K ATPase activity and phenytoin concentrations.
An abnormal flux of monovalent cations may be related to the epileptogenic process in man. One possible mechanism for deranged electrolyte metabolism in epileptic brain is an abnormality in sodium, potassium-dependent adenosine triphosphatase (Na, K ATPase). We found the activity of Na, K ATPase to be significantly less in epileptic human corfex than in nonepileptic cortex. Histological changes have been simultaneously evaluated in epileptic brain. A second membrane-bound enzyme, acetylcholinesterase (AChE), was also assayed as a marker for neuronal membranes and found not to correlate with the epileptogenicity of human brain. In addition, the concentrations of the anticonvulsant compound phenytoin have been determined in the serum and cerebral cortex of epileptic and nonepileptic patients. The ratio of phenytoin in cortex to serum concentration is significantly lower in epileptic patients than in nonepileptic controls.
Acetylcholinesterase↗
Human brain phenytoin: correlation with unbound and total serum concentrations.
Simultaneous brain (gray matter) and serum specimens from 18 patients treated with oral phenytoin, who underwent cortical resections for intractable seizures, were analyzed by HPLC. The correlation between brain phenytoin concentration and unbound (free) phenytoin (r = 0.98-0.99) was significantly better than the correlation between brain phenytoin and total serum phenytoin (r = 0.90-0.93). Phenytoin concentrations in tissue from epileptic foci were slightly lower than brain phenytoin concentrations in non-epileptic regions in the same patient (means 15.0 vs. 15.5 micrograms/g, P less than 0.05). The results support the value of monitoring unbound phenytoin in clinical situations where phenytoin binding is highly variable.
Adolescent↗
Three fatal drug overdoses involving bupropion.
Bupropion is a "second generation" antidepressant agent structurally related to the phenethylamines. Postmortem toxicology data are presented from three suicidal drug overdoses in which bupropion was detected. In two cases in which bupropion was the major toxicology finding, peripheral blood levels of the parent drug were 4.0 and 4.2 mg/L and total metabolite levels were 15 and 16.6 mg/L. Lethal doses in both cases were estimated by history to be less than 10 g.
Adolescent↗
Analysis of sertraline (Zoloft) and its major metabolite in postmortem specimens by gas and liquid chromatography.
We report methods for the analysis of sertraline and desmethylsertraline in postmortem biological fluids. The extraction method is based on a widely used procedure employing n-butyl chloride, and instrumental analysis is performed using GC/MS and HPLC with photodiode array detection. We report retention index, mass spectral, and UV-vis properties of the drug and its metabolite. Samples from three sertraline-related deaths were analyzed and revealed concentrations up to 10 times greater than the normal therapeutic levels, although two of the deaths were obviously the result of other causes. We also noted in one case that the drug concentrations in central and peripheral blood were very similar, suggesting that postmortem distribution may be uniform.
1-Naphthylamine↗
Analysis of ketorolac in postmortem blood.
This paper describes analytical methods using high-performance liquid chromatography and gas chromatography-mass spectrometry (GC-MS) for the isolation of the nonsteroidal anti-inflammatory drug, ketorolac. The drug is isolated from postmortem blood using a batched solid-phase extraction method on Amberlite XAD-2 resin. Derivatization of ketorolac using diazopropane was necessary prior to GC-MS analysis. The methods were applied in the investigation of a death occurring shortly after the administration of an intramuscular injection of ketorolac tromethamine. Death was attributed to an adverse reaction to the drug, resulting in anaphylaxis and cardiac arrest.
Adult↗
Zonisamide in epilepsy: a pilot study.
We compared zonisamide monotherapy (12 weeks) to carbamazepine monotherapy (12 weeks) after phenytoin baseline monotherapy (8 weeks) in an open crossover pilot study of eight adults with uncontrolled partial seizures. Zonisamide had definite antiepileptic activity in five subjects. In two of these, response to zonisamide was superior to that to either phenytoin or carbamazepine. A third subject became seizure free on zonisamide, but had to be withdrawn after 18 days because of mild Stevens-Johnson syndrome. The other three subjects were withdrawn from the study because of drug toxicity, manifested mainly by impaired higher mental function and increased seizures. The best response to zonisamide was at doses approximating 6 mg/kg/day, with plasma levels of 20-30 mg/L. Plasma levels of greater than 30 mg/L usually were associated with toxicity. The pharmacokinetics of zonisamide are complex and nonlinear, with steady-state plasma levels being approximately three times higher than those predicted from a single-dose study.
Adolescent↗
Pharmacokinetics of W-554 (ADD 03055) in epileptic patients.
W-554 (ADD 03055, 2-phenyl-1,3-propanediol dicarbamate) has broad-spectrum antiepileptic activity in animal models of epilepsy. We evaluated its pharmacokinetics and toxicity as an adjunctive medication in eight adult male patients with uncontrolled seizures, treated with phenytoin (n = 4) or carbamazepine (n = 4). After a single 200-mg dose, peak W-554 serum levels of 2.65-4.10 mg/L were achieved in 1-4 h. Half-lives were 11.2-16.1 h and clearance varied from 34.2-64.6 ml/h X kg. The apparent volume of distribution was 0.726-1.046 L/kg. Chronic dosing at 400, 800, 1,200, and 1,600 mg/day resulted in median steady-state trough levels of 5.1, 10.2, 14.6, and 20.3 mg/L. A second kinetic study at the end of chronic dosing indicated no change in volume of distribution, decreased clearance, and increased half-life, compared with single dose data. Urinary excretion of unchanged drug was 13.8-28.6% of the dose. Only one subject had toxicity (mild blurred vision and tremor) possibly attributable to W-554. Seizure control was improved in six of eight subjects, and seizures were less severe in three, while on W-554. Addition of W-554 resulted in increases in serum phenytoin levels, and small decreases in serum carbamazepine levels.
Adult↗
Pharmacokinetics of primidone in mice after acute and chronic administration.
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Animals↗