Identification and quantitation of neutral and basic drugs in blood by gas chromatography and mass spectrometry.

There is an increasing need for the quantitation of drugs that act on the central nervous system in blood of patients suspected of poisoning. A simple method for quantitative determination of neutral and basic drugs is described. The method involves a basic extraction without derivatization. The plasma extracts are injected on a Hewlett-Packard chromatograph using two nitrogen-specific detectors. In most cases, the comparison of relative retention times on the two columns is sufficient for identification of the ingested drugs. But when the method falls, the use of a gas chromatograph/mass spectrometer equipped with a chemical ionization source is necessary.

[Level of urinary phenol and hippuric acid in control subjects and subjects exposed to benzene and toluene]. / Dosage du phénol et de l'acide hippurique urinaires chez des témoins et des sujets exposés au benzène et au toluène.

Two high-performance liquid chromatographic methods are described, one for assay of phenol in urine, the other for assay of hippuric acid. Steam distillation was used to hydrolyse the sample and separate the phenol from the matrix. A dilution was the only pretreatment of urine for assay of hippuric acid. The upper reference limits obtained from 42 non-exposed subjects were 7.09 mmol/mol creatinine for urinary phenol and 1,174 mmol/mol creatinine for hippuric acid. The mean concentration of urinary phenol was higher in 190 exposed workers (7.21 +/- 5.05 mmol/mol creatinine; mean +/- SD) than in control subjects (3.97 +/- 1.56 mmol/mol creatinine).

[Plasma noradrenaline in hyperthyroidism and hypothyroidism]. / Noradrénaline plasmatique dans l'hyperthyroïdie et l'hypothyroïdie.

Plasma noradrenaline concentrations (NA) were measured in 11 hypothyroid patients, 24 hypothyroid patients and 30 normal subjects after 30 minutes of supine rest and after 5 minutes of standing. Observed noradrenaline levels, after rest as well as after standing, were significantly higher in hypothyroid patients (NA rest = 0.66 +/- 0.35 microgram/l, NA standing = 1.26 +/- 0.70 micrograms/l) and significantly lower in hyperthyroid patients (NA rest = 0.22 +/- 0.13 micrograms/l, NA standing = 0.37 +/- 0.20 microgram/l) than in normal subjects (NA rest = 0.32 +/- 0.13 microgram/l, NA standing = 0.55 +/- 0.20 microgram/l). The increase in noradrenaline with standing, when expressed in percent, was similar for the three groups studied (about 100%). These results suggest that a sympathetic nervous system adaptation occurs in hyperthyroidism and hypothyroidism as a compensatory phenomenon to the direct effect of thyroid hormones on the heart.

[Pharmacokinetics of thiopental in women and newborn infants]. / Pharmacocinétique du thiopental chez la femme et le nouveau-né.

Plasma thiopentone concentrations after a single intravenous dose were determined by high pressure liquid chromatography in female surgical patients (n = 13), in pregnant women at term (n = 13) and in neonates (n = 13). In pregnant women, the apparent volume of distribution (Vd = 10.02 +/- 3.26 l X kg-1), plasma clearance (Cl = 22.03 +/- 7.55 l X h-1) and elimination half-life (t 1/2 (3) = 21.71 +/- 11.12 h) were significantly greater than in the surgical patients (Vd = 4.22 +/- 1.16 l X kg-1; Cl = 12.49 +/- 3.50 l X h-1; t 1/2 (3) = 13.79 +/- 3.09 h). Elimination half-life in neonates (t 1/2(e) = 17.9 +/- 9.7 h) was not different from half-life in mothers or in the surgical group. At delivery, the simultaneous concentrations were 5.3 +/- 1.3 mg X l-1 in venous blood and 3.8 +/- 1.6 mg X l-1 in cord venous blood. Apgar score was 10 in eleven neonates. For two babies, an Apgar score at 6 was explained by a uterine incision-to-delivery time interval greater than 2 min.

[Plasma concentration of noradrenaline in essential arterial hypertension]. / Concentration plasmatique de noradrénaline dans l'hypertension artérielle essentielle.

Plasma norepinephrine concentrations after supine rest and after standing were measured by high-pressure liquid chromatography with electrochemical detection in 49 normotensive controls and in 79 patients with essential hypertension. Twenty-nine hypertensive patients were not treated for hypertension. In normotensive subjects--but not in hypertensive patients--supine plasma norepinephrine levels increased significantly with age. No significant difference in supine plasma norepinephrine levels was found between hypertensive patients (NE = 0.28 +/- 0.16 microgram/l, n = 79 and NE = 0.28 +/- 0.14 microgram/l, n = 29) and normotensive subjects (NE = 0.30 +/- 0.13 microgram/l). When expressed as percentage, the rise in norepinephrine levels when standing was greater in hypertensive patients (127.4 +/- 77.4%, n = 79 and 122.6 +/- 65.6%, n = 29) than in normotensive subjects (93.2 +/- 60.3%). When patients and controls aged less than 40 years were compared, similar results were obtained. Supine plasma norepinephrine levels do not support the theory that sympathetic system activity is enhanced in essential hypertension.

[Influence of metals and non-steroid anti-inflammatory drugs on the activity of human red cell ALA dehydratase "in vitro" (author's transl)]. / Influence de quelques métaux et de quelques anti-inflammatoires non stéroïdiens sur l'activité de l'ALA déhydratase érythrocytaire humaine in vitro.

The effect of metals and drugs on the activity of human erythrocyte ALA dehydratase has been studied in vitro. The most inhibitory metals are with decreasing effect silver, copper, gold and selenium. Zinc, cadmium, mercury are inhibitory at high concentrations and activator at low concentrations. Arsenic, calcium, magnesium, manganese, potassium, cobalt have no effect. Within the drugs studied the non steroidal anti-inflammatory drugs (aspirin, keptoprofen, indometacin, phenylbutazone, sodium salicylate and niflumic acid) are the only group which inhibits the enzyme ALA dehydratase. This inhibition is suppressed by zinc. The non steroidal anti-inflammatory drugs can inhibit the activity of enzymes which need zinc for optimal activity.

Screening for neutral and basic drugs in blood by dual fused-silica column chromatography with nitrogen-phosphorus detection.

We describe a capillary gas-chromatographic method for detection and quantification of basic and neutral drugs in the plasma of patients thought to be poisoned after dangerous overdose. Without further derivatization, the drugs are extracted from 1 mL of plasma, at basic pH, into diethyl ether. The extracts are injected onto two fused-silica capillary columns of different polarity (Ultra 1 and CP Sil 19 CB) coupled to nitrogen-phosphorus detectors. Under these conditions, drug-free plasmas give blank chromatograms, with a peak only for the internal standard (RN 927, an antihistamine not being marketed). Plasma samples from patients who have taken drugs show additional peaks, the relative retention times (RRTs) of which are used to identify the drugs. Here we list the RRTs of about 200 drugs on the two columns. Analyses are routinely performed with an automatic injector; overall analysis time is about 1 h per sample. During the last six years, more than 1000 plasma samples per year have been analyzed. We find this method a powerful tool for toxicological analysis, especially in cases of multi-drug intoxications.

Normal reference intervals for free catecholamines and their acid metabolites in 24-h urines from children, as determined by liquid chromatography with amperometric detection.

We used two methods of reversed-phase liquid chromatography with amperometric detection, one for assay of unconjugated norepinephrine, epinephrine, and dopamine in urine, the other for determination of unconjugated vanillylmandelic acid and homovanillic acid. The catecholamines were extracted from urine by passage through a weak-cation exchange resin, then through alumina. Vanillylmandelic acid and homovanillic acid were isolated from urine by a two-step solvent-extraction procedure. The between-day CV was 5% for norepinephrine, 3% for epinephrine, 3% for dopamine, 4.5% for vanillylmandelic acid, and 6.4% for homovanillic acid. Reference ranges for these analytes in 76 children, ages 3-16 years, are reported.

Automated fluoroimmunoassay of theophylline and valproic acid by flow-injection analysis with use of HPLC instruments.

For automated determination of theophylline and valproic acid by use of Ames' fluoroimmunoassays we used a high-pressure liquid-chromatographic system consisting of a pump, a robotic unit (Gilson 231/401, to prepare and inject the samples into the flowing carrier), and a fluorometer with a 10-microL flow cell. Results correlated well with those of conventional liquid- and gas-chromatography (r less than 0.96). The between-run CV is about 5%. In comparison with the manual method, the volume of reagents (and thus the cost per analysis) was decreased by eightfold.

Toxicological screening of drugs by microbore high-performance liquid chromatography with photodiode-array detection and ultraviolet spectral library searches.

We use ultraviolet data, acquired with a photodiode-array detector coupled to a reversed-phase liquid-chromatographic system, to identify unknown drugs in plasma samples of acutely poisoned patients. Both retention time and spectra of the peaks obtained with a microbore Hypersil ODS column under gradient elution are compared with a library of approximately 350 compounds. We present our three-year experience with this system, which identifies drugs in less than 1 h, with a high degree of confidence.

Pharmacokinetics of 2-(p-methylallylaminophenyl) propionic acid, alminoprofene, in man after single and multiple oral doses.

2-(p-methylallylaminophenyl) propionic acid, alminoprofene (INN), a new antalgic drug, was administered orally to men as a single (300 mg) and multiple doses (300 mg three times daily). Plasma and urine concentrations of alminoprofene were determined by gas-liquid chromatography. After the single oral dose, the peak plasma level (36.2 to 41.5 mg/l) was reached within 0.5 -1.5 h. the biological half-life ranged from 2.5 to 3.2 h. During chronic administration of alminoprofene, steady-state equilibrium was established within 24 h. The urinary excretion of alminoprofene as unchanged product and as glucuronide was very important.

[Determination of plasma noradrenaline by automatic high pressure liquid chromatography with electrochemical detection]. / Détermination de la noradrénaline plasmatique par chromatographie liquide haute pression en mode automatique avec détection électrochimique.

A method for the plasma noradrenaline (NA) analysis by reversed-phase liquid chromatography with electrochemical detection is described. The plasma sample preparation includes two-steps: ion-exchange and alumina adsorption. The use of a data system and an automatic sampler enables the injection of samples in series. Using this technique, determination of plasma NA concentration in 34 healthy subjects (27.4 +/- 7.2 years) gave the following results: 0.28 +/- 0.10 micrograms/l after 30 min of resting in the supine position and 0.52 +/- 0.17 micrograms/l after 5 min of upright position.