Improved selectivity for high-performance liquid chromatographic determination of clonazepam in plasma of epileptic patients.

We report a high-performance liquid chromatography method for clonazepam determination in plasma. The use of a synthetic silica-based stationary phase markedly improved clonazepam resolution compared to standard reversed-phase columns. A liquid-liquid extraction was used, associated with reversed-phase chromatography, gradient elution and ultraviolet detection. Accuracy and precision were satisfactory at therapeutic concentrations. Selectivity was studied for benzodiazepines or other antiepileptic drugs, with particular attention to newly marketed drugs i.e., gabapentine and vigabatrin. No interfering substance was evidenced. Under the conditions described, it was possible to quantify clonazepam at nanogram level even when carbamazepine was present at therapeutic concentrations.

Nebulization and anti-Pseudomonas aeruginosa activity of colistin.

Colistin aerosols are frequently administered to patients with cystic fibrosis. However, questions arise concerning the effect of both jet and ultrasonic nebulizers on the properties of the drug. The aim of this study was to characterize the anti-Pseudomonas aeruginosa (PA) activity of colistin after jet (Pari LL) and ultrasonic (DP100) nebulization. A bench study was performed by capturing the aerosols, determining the drug mass, and assessing its anti-PA activity. Because the inhaled mass of colistin had to be entirely recovered for the bacteriological study, it was assessed by isotopic methods, mixing the drug with a 99mTc-labelled tracer and demonstrating that 99mTc activity accurately predicted the mass of colistin. Colistin was extracted from the filters and its antibiotic activity was determined using the method employed for the study of the bacteriostatic and bactericidal power of serum on the ATCC 27853 PA strain. The postnebulization minimum inhibitory concentrations (MIC) were 1.9 micrograms.mL-1 with DP100 and 0.5 microgram.mL-1 with Pari LL. These values were less than two dilutions different from the 1 microgram.mL-1 MIC of non-nebulized colistin. We conclude that neither jet nebulization nor ultrasonic nebulization alter the antibiotic properties of colistin and that both systems can be used to nebulize colistin.

Effect of tamoxifen on the pharmacokinetics of theophylline in rats.

The effect of tamoxifen on the pharmacokinetics of theophylline was investigated in male Sprague-Dawley rats. The oral administration of tamoxifen at a dose equal to 40 mg kg-1 48 h before the intravenous injection of theophylline 10 mg kg-1, significantly (P < 0.05) increased the clearance of theophylline by 39%, with no apparent effect on the volume of distribution. As a consequence, the elimination half-life of theophylline was significantly (P < 0.05) shortened in the tamoxifen-treated rats (3.56 +/- 0.39 h vs 5.25 +/- 0.48 h) as well as its mean residence time (5.04 +/- 0.60 h vs 7.50 +/- 0.75 h). Although these data cannot be directly extrapolated to the clinical situation, they provide experimental support to suggest that more attention should be paid to the potential risk of pharmacokinetic interactions in the presence of tamoxifen.

Stability of rifampin in plasma: consequences for therapeutic monitoring and pharmacokinetic studies.

Interest in determining plasma levels of rifampin for adjustment of dosage regimens has increased, but conflicting results exist concerning rifampin stability. The authors developed a high-performance liquid chromatography assay to monitor rifampin plasma concentrations that was used to study the possible degradation of rifampin in plasma samples. This report describes the stability of rifampin in plasma kept at an ambient temperature for 24 hours or stored at -20 degrees C for 2 weeks. The possible protective effect of adding ascorbic acid was also studied. The results indicate that rifampin degrades rapidly in plasma at an ambient temperature, and a 54% loss was observed within 8 hours. This degradation can be effectively prevented by adding ascorbic acid, thus prolonging stability for up to 12 hours. The same results were observed with samples obtained as part of routine drug monitoring. Degradation was found to be greater at low rifampin concentrations. The authors subsequently demonstrated that decomposition of rifampin occurs after storage for 1 week at -20 degrees C. However, in samples supplemented with ascorbic acid before freezing, no degradation was observed within 14 days at the two concentrations tested. Rifampin was more stable in specimens drawn from treated patients, suggesting possible in vivo stabilization of the molecule. Further studies are needed to determine stability of rifampin for longer storage periods. On the basis of these results, plasma samples obtained from patients receiving rifampin should be immediately supplemented with ascorbic acid and analyzed as soon as possible.

Deposition of amphotericin B aerosols in pulmonary aspergilloma.

The aim of the present study was to characterize amphotericin B aerosols nebulized by ultrasonic and jet nebulizers and to study their deposition and pharmacokinetics in patients with pulmonary mycetoma. The aerodynamic behaviour and pulmonary deposition of amphotericin B particles were measured using a direct isotopic method based on stable labelling of the drug with 99mTc. Each nebulizer was bench tested for inhaled mass and particle size distribution. Three patients suffering from pulmonary aspergilloma were enrolled for a 4 week clinical study. They received 5 mg of amphotericin B daily delivered by either Fisoneb or DP100 (ultrasonic) or Respirgard II (jet) nebulizers. Deposition of radiolabelled amphotericin B was measured once with each nebulizer using a gamma-camera. In two patients, amphotericin B serum concentration was monitored over a 330 min period after the nebulization had been completed. Inhaled masses of the three nebulizers, assessed as % of labelled drug caught in inspiratory filter in duplicate experiments, were: 5.8 and 3.6% for Respirgard II; 26.5 and 28.3% with Fisoneb; 5.9 and 6.3% for DP100. Mass median aerodynamic diameter (mean +/- SD) results were: 0.28 +/- 0.04 micron with Respirgard II; 4.82 +/- 0.78 microns with Fisoneb; and 2.27 +/- 1.14 microns with DP100. Because of larger particles and significantly greater inhaled mass, Fisoneb delivered more amphotericin B to the central airways, the lung periphery and in the mycetoma lung regions. Amphotericin B serum concentrations correlated with pulmonary deposition and remained below 25 ng.mL-1. No untoward effects were reported by the patients during the 4 week trial.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of paracetamol in the neonate and infant after administration of propacetamol chlorhydrate.

The pharmacokinetic parameters of paracetamol were studied after 15 min intravenous infusion of 15 mg/kg of propacetamol (Prodafalgan) in 5 neonates aged less than 10 days and 7 infants aged between 1 and 12 months. Blood was sampled at 0, 0.5, 2 and 6 h after the first intravenous infusion of propacetamol. The infants aged less than 10 days had higher plasma concentrations of paracetamol, a longer half-life (3.5 vs. 2.1 h) and a lower plasma clearance (0.149 vs. 0.365 l/h/kg) than the older children. Dose simulations were performed on the basis of individual data of each child in order to obtain steady-state plasma concentrations between 4 and 18 mg/l permitting the best antipyretic effect for each child. In infants aged less than 10 days a 15 mg/kg dose of propacetamol four times a day (i.e. 30 mg/kg/day paracetamol) is sufficient, corresponding to the dosage recommended by the French pharmacopoeia. On the other hand, double the dosage, nearer to the American dosage, is necessary for children aged over 10 days.

[Accidental chloral hydrate poisoning]. / Intoxication involontaire à l'hydrate de chloral.

A 42-year-old woman had an accidental overdose of chloral hydrate due to repeated absorption of a therapeutic dose of chloral syrup for insomnia. The total ingestion was estimated at 8 g. Overnight slight loss of consciousness associated with severe cardiac arrhythmia (bigeminia ventricular extra-systole) needed admission to the intensive care unit and intravenous lignocaine for two days. The evolution was satisfactory.

[Study of residual levels of delayed-action neuroleptics]. / Etude des taux résiduels de neuroleptiques à action prolongée.

Pharmacokinetics of the depot antipsychotics are unclear and mainly depend on releasing from the depot site (according to a "flip-flop" model). Few data are available on residual plasma concentrations of those drugs. We have practiced 38 blood determinations among 15 patients treated by long-acting neuroleptics (10 by fluphenazine decanoate, 4 by flupentixol decanoate and 1 by pipotiazine palmitate). Radio Receptor Assay method was used (based on competition for dopamine receptors binding), with results expressed as chlorpromazine equivalents. They showed; a wide interindividual variability; considering each subject, intraindividual variability is attenuated; blood measurements are mainly higher than therapeutic ranges (especially for patients on fluphenazine decanoate). Those results might involve that some patients are overdosed, but other studies are needed in this way.

Oxidative polymorphism of dextromethorphan in a Burundi population.

The wide availability, metabolism by the same cytochrome P450 as debrisoquine and, above all, the inocuity of dextromethorphan (DMP) favour the frequent choice of this drug as the test substance in determining oxidation phenotypes. 100 healthy Burundian volunteers (94 m and 6 f) in this study ingested 50 mg DMP bromhydrate, i.e. 38.5 mg of DMP base. Urine was collected for 8 h following the dose and TLC was used to analyse it. The method was particularly useful in view of its low cost, speed and the ease of applying it to a large study group. 5% of the Burundian subjects were poor metabolizers.

Effects of prenatal exposure to diazepam on exploration behavior and learning retention in mice.

Diazepam (2 mg/kg, DZP) or placebo were administered by oral gavage throughout gestation in 40 mice. The automatic hole board test for mice (Boissier and Simon) was used to measure the locomotor activity and the number of holes explored by the offspring (mean age 30.6 days). During the first test, this number represents curiosity. Its progressive decrease when the test is repeated (4 times at 1-day intervals) is a consequence of learning retention. In the first test, neither curiosity nor activity were linked with the mother's treatment or sex. During the next tests, there was no difference in locomotor activity between DZP and placebo groups. However, the DZP exposed pups explored fewer holes than controls. Although there was a tendency towards greater activity in the female group, the number of holes explored in the placebo group was significantly higher in females than in males. Paradoxically, this difference in learning memory function which exists between control males and females was not observed in the DZP group, corresponding to an impaired learning retention.

[Severe chloroquine poisoning. Favourable outcome with diazepam therapy. A toxicokinetic study]. / Intoxication sévère à la chloroquine. Evolution favorable sous diazépam. Etude toxicocinétique.

A severe chloroquine poisoning, featuring indicators of bad prognosis, has been treated by a diazepam-type therapy. The outcome was favourable in a dramatic way. A toxicokinetic study showed very high chloroquine plasmatic levels, consistent with the severity of the poisoning.

[Is the qualitative research of benzodiazepines by the EMIT method and diazocopulation in accidental poisoning in children relevant?]. / La recherche qualitative de benzodiazépines par la méthode EMITSt et la diazocopulation au cours des intoxications accidentelles de l'enfant est-elle pertinente?

A retrospective study was undertaken to evaluate the relevance of benzodiazepine detection in 42 children with accidental poisoning. Immunoenzymatic assay for benzodiazepine in serum and colorimetric method in urines were positive respectively in 3 and 4 patients only. Several reasons could explain these results: the high detection threshold, the different drug reactivity according to the molecular structure and the great delay between intoxication and toxicology analysis. An advised physician should not prescribe a toxicological analysis after a small quantity of benzodiazepine ingestion.

[Epidemiology of pediatric paracetamol poisoning (retrospective analysis of calls received by the Poison Control Center of Tours)]. / Epidémiologie des intoxications au paracétamol en pédiatrie (analyse rétrospective des appels reçus au Centre Anti-Poisons de Tours).

The authors analysed 101 phone calls received in 3 years and 8 months at the Poison Control Center of Tours for paracetamol poisoning in children under 15 years of age. 70% of children were between 1 and 5 years old, 15% under 1 year and 15% over 5 years old. The kind of poisoning differ according to age: iatrogenic in 93% of cases under 1 year old (medication given by parents; error in dosage); accidental in 85% of cases between 1 and 5 years old and "willful" poisoning (43%) or accidental (36%) over 5 years old. The average quantity of ingested paracetamol was low (58mg/kg). The delay before phone call from an individual or a doctor was usually quite short. The neurologic or digestive signs were present in 12% of the children. The outcome was uneventful in all cases indicating that this form of poisoning is being in childrens.

Accidental lidocaine overdosage in an infant.

A one month old child inadvertently received an intravenous bolus injection of 50 mg of lidocaine instead of contrast iodine. The clinical picture comprised collapse, respiratory arrest, convulsions and coma. The calculated maximum level of lidocaine was 5.39 mg/l. The recovery was complete. The toxicity of lidocaine is discussed.

[Are theophylline determinations useful to the clinician during treatment with a sustained-release form of theophylline?]. / Les dosages de théophylline sont-ils utiles au clinicien au cours des traitements par théophylline à libération continue?

The aims of the study were the correlation between dosage and plasmatic levels of slow release theophylline and the reason for dosage adjustment. 64 pharmacokinetic studies were performed in 58 asthmatic children between 17 months and 16 years. Plasmatic levels of theophylline were performed by fluoroimmunology technique at H0 (before the dose) 2 (H2), 4 (H4), 6 (H6) and 8 (H8) hours after the dose of slow release theophylline. The best correlation between dose and plasmatic levels were observed at H4 and H6 for Armophylline and Euphylline respectively. Dosage adjustment were based both upon clinical state and plasmatic levels in 55 cases. In 9 cases the modification of dose were decided only because of plasmatic levels out the therapeutic range. The authors proposed a schema of dosage modifications based upon clinical state; plasmatic levels must be used as a guide for dose adjustment in patients clinically uncontrolled.