[Plasma levels of metapramine and its 3 major metabolites in patients with depression. Results and preliminary interpretations]. / Concentrations plasmatiques de la métapramine et de ses trois principaux métabolites chez des patients déprimés. Résultats et interprétations préliminaires.

Metapramine (Timaxel) and his three major metabolites (19148 RP, 23669 RP, 19749 RP) have been determined in the plasma of 18 depressed inpatients treated by the antidepressant drug (12 women and 6 men; 7 are smokers and 11 non-smokers). In a steady state, interindividual variability is very important, especially for 23669 RP. No significant correlation exists between normalized doses (mg.kg-1) and normalized plasma concentrations (ng.ml-1/dose mg.kg-1) of metapramine or anyone of its metabolites. The plasma metabolic ratios reveal also important intraindividual and interindividual variability. Two populations of patients seem to exist: extensive metabolizers and relatively poor metabolizers, without apparent clinical consequence because 23669 RP shows an antidepressant activity. Women seem, with equal normalized doses, to exhibit higher plasma levels of unchanged metapramine than men, due to a lower protein-binding rather than to a more active metabolism. In patients who received a poly-medication smoking seems not to induce desmethylation of metapramine. The plasma metabolic ratios, compared by the analysis of variance and the Wilcoxon distribution-free test, are significatively influenced by sex and not by tobacco-smoking.

Comparative study of the pharmacokinetics of zuclopenthixol decanoate and fluphenazine decanoate.

Seventeen outpatients were treated with depot neuroleptics, zuclopenthixol decanoate in Viscoleo or fluphenazine decanoate in sesame oil, with dosage intervals of 3 weeks. During the 4th, 6th, and 8th dosage interval blood samples were drawn in oxalated tubes. Plasma concentrations of the active neuroleptic drugs, zuclopenthixol and fluphenazine, were determined by high performance liquid chromatography. The concentrations indicated some interindividual as well as intraindividual variations. For zuclopenthixol the maximum concentration was most often seen at day 7 after injection, whereas the kinetics of the fluphenazine concentrations was more variable. There was an indication of more fluctuation in the 4th dosage interval than in the 8th dosage interval, possibly due to the fact that steady state has not yet been achieved at the 4th dosage interval.

Respiratory symptoms and air pollution changes in children: the Gardanne Coal-Basin Study.

The influence of daily changes in sulfur dioxide (SO2) levels on the induction of respiratory symptoms was studied during the 1983-1984 winter in 450 children, aged 9 to 11 yr, living in the Gardanne coal-basin, France. In this area, SO2 originates mainly from a coal-fueled power plant. The mean SO2 level during the winter was 22 micrograms/m3 in low-pollution areas and 93 micrograms/m3 in polluted areas, with daily SO2 levels up to 356 micrograms/m3. Children completed a daily diary about respiratory symptoms. In the polluted communities only we demonstrated a significant association between daily SO2 levels (after controlling for temperature and respirable particle variations) and prevalence of upper and lower respiratory symptoms. However, in each polluted town, and for each respiratory symptom, there was no evidence for either a latency period or a delay in the effects of pollutants. Mean daily temperature was also closely correlated with upper and lower respiratory symptoms in most of the polluted and some low-pollution communities. In a second step, the prevalence of respiratory symptoms in each town was compared, during two 2-wk periods, with air pollution levels; higher prevalences were found during the pollution period. In conclusion, moderate daily changes in SO2 levels induce a significant but transient increase in the prevalence of respiratory symptoms in children.

Citalopram--a highly selective 5-HT uptake inhibitor--in the treatment of depressed patients.

In an open, clinical trial comprising a total of 21 depressed in-patients (6 men and 15 women) citalopram was administered in doses of 20-60 mg once daily for a period of at least 3 weeks. Fourteen of the patients were treated for 4 weeks, and 6 of these patients were treated for another 2 weeks. The CPRS subscale for depression (MADRS) and a global evaluation were used for assessment of the therapeutic effect. Twelve patients showed complete or partial response to treatment, and generally onset of therapeutic effect was seen within the first 2 weeks of treatment. Side-effects were generally few and mild, anxiety being the most frequent one. No pathological laboratory values were recorded, and apart from one case of slight and transient bradycardia no changes were observed in the cardiovascular parameters. Determination of plasma levels in 16 of the patients under presumed steady-state conditions showed an inter-individual variation between 28 and 616 nM/l for citalopram and between 32 and 338 nM/l for its monodemethylated metabolite for daily citalopram doses of 30-60 mg. The average ratio citalopram-desmethyl citalopram was 1.70. No correlation was found between clinical response and the plasma levels.

Time-dependence of clobazam and N-demethylclobazam kinetics in healthy volunteers.

The pharmacokinetic behavior of clobazam and its main metabolite, norclobazam, was investigated in healthy subjects after single dose administration, repeated dose administration (28 days) and discontinuation of the treatment (15-day follow-up). The aim of the study was to confirm the time-invariance of the clobazam and/or norclobazam kinetics, in order to evaluate the predictive value of the single dose parameters for chronic administration of this drug. The comparisons of parameters after single dose and for 15 days following cessation of chronic administration, experimental and simulated plasma level-time courses, experimental and calculated steady-state minimum plasma concentrations, and half-life values at apparent and deep elimination phase, indicate a time-invariant behavior of clobazam, whereas the norclobazam pharmacokinetics appeared to be clearly time-dependent. The clinical importance of this difference cannot be adequately assessed until more is known about the contribution of norclobazam to the overall effect of the parent drug.

Determination of metapramine, imipramine, trimipramine and their major metabolites in plasma by reversed-phase column liquid chromatography.

The determination of metapramine, imipramine, trimipramine and their desmethyl metabolites after alkaline diethyl ether extraction from plasma is achieved by column liquid chromatography using two internal standards and mu Bondapak C18 column. Elution is carried out isocratically at 1 or 0.6 ml min-1 with two mixtures of acetonitrile-potassium dihydrogen phosphate-distilled water (45:55:10 for metapramine and its metabolites; 45:50:5 for imipramine, trimipramine and their metabolites). Detection is monitored by absorption at 254 nm. The detection limit is less than 5 ng ml-1 for each compound. The coefficients of variation (within-day and day-to-day) for the eight compounds are less than 11.3%. Interference from several possible co-medications is discussed. The technique can be used for routine therapeutic monitoring of the antidepressants as well as analytical toxicology. However, the three antidepressants cannot be analysed simultaneously by this method because metapramine requires a different elution system and imipramine interferes with monodesmethyltrimipramine (retention times 8.90 and 8.60 min, respectively).

[Air pollution by cadmium in Marseille (author's transl)]. / Le Cadmium dans l'atmosphère de l'agglomération marseillaise.

The control of the air pollution by cadmium in Marseille was realized between July 1st 1977 and June 30 1979 by determining the metal in the air dust by atomic absorption spectrophotometry without flame. The samples were taken on eight different stations located in the urban-center and in the suburbs. The atmospheric levels of cadmium in Marseille are low but a note-worthy increase was noticed from september 1978. A principal components analysis of the data compared with these obtained with other atmospheric pollutants, revealed the particular characteristic of cadmium in Marseille, which seems to be bound neither with the pollutants issued from motor vehicles, nor with zinc of which it is yet an impurity. However vigilance is indispensable against the environmental contamination by cadmium in consideration of its potential risks for the health.

[Direct determination of clonazepam (Rivotril) and 7-amino clonazepam in plasma by gas-chromatography (author's transl)]. / Au sujet de la détermination directe dans le plasma du clonazépam (Rivotril) et de l'amino-7 clonazépam par chromatographie en phase gazeuse.

A method is developed for direct gas-chromatographic determination of clonazepam (Rivotril) and its main metabolite, 7-amino clonazepam, in plasma, using desmethylflunitrazepam as internal standard. Following selective extraction, the benzodiazepines are analyzed by gas-chromatography, with a glass column filled with 3% OV17 on Gas Chrom Q and 63Ni electron capture detector. The procedure, which requires neither hydrolysis nor derivatisation, has a good selectivity. The sensitivity is 5 ng/ml of plasma for a valid quantitative determination. We have to improve this limit for fine pharmacokinetic studies, but the method is already available for therapeutic and pharmacovigilance controls. It is also suitable for diagnostic of eventual overdosing or poisoning, based on plasma or urine analysis.