Biomedical subjects
Publications and source records attributed to C Riche.
The authors describe a method of dosage of valproic acid by gas chromatography. The derivation consists of the synthesis of esters of the valproic acid using heavy alcohols. This method of derivation can be applied to other carboxylic acids.
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The measurement of cardiac output by electrical impedance plethysmography (non-invasive technique) may be disturbed by a certain number of factors, including respiration. The authors sought to demonstrate that this factor could be eliminated during measurement calculations. By this method, in 18 adult subjects with coronary artery disease, 50 measurements during respiration and 50 measurements in apnoea (paired measurements) of stroke volume and of cardiac output were performed. Stroke volume was calculated using Kubicek's formula: SV = P(L2/Zo2) (dz/dt min)t Results were as follows: highly significant correlation between values for stroke volume obtained during respiration and in apnoea (r ;.9767; n=50; P < 0.001); highly significant correlation between values for cardiac output obtained under the same conditions (r = 0.9744; n=50; P < 0.001). The authors conclude that with the limits of certain technical conditions of measurement, respiration does not disturb measurements of stroke volume and of cardiac output by electrical impedance plethysmography.
The authors describe a micromethod for the determination of blood concentration of theophylline in premature newborn infants. The method includes the specificity of separation in gas phase chromatography on a glass capillary column, and the sensitivity of thermo-ionic detection. After addition of isobutyl-3-methyl-1-xanthine, which constitutes an internal standard, extraction is performed in acid pH, with the mixture dichloromethane-isopropanol. The derivation consists of an N-pentyl reaction. Analysis was carried out on a glass capillary column SE-30 measuring 75 m x 0.5 mm. The technic used is simple and rapid. Its application in pediatrics has been particularly studied; the limit of quantitative detection was 0.1 mg/l. The plasma sample may be 0.05 ml. The reproducibility is about 2% in usual therapeutic doses. The specificity of the method has been widely debated, in particular the stages of extraction, derivation, separation and detection. The authors are convinced that the analyses requiring systems of specific detection, more and more widely used, require a chromatographic apparatus with a high power of resolution; this is illustrated by an example.
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The optically active lignan (-)-steganol was prepared from natural (-)-steganacin by selective deacetylation and was transformed, via a three-step sequence, into the corresponding 4', 6'-O-ethylidene- and thenylidene-beta-D-glucopyranosides, 3b and 3c, respectively, which are the analogues, in the steganol series, of the podophyllotoxin derived, and clinically useful, anticancer drugs, VP16-213 and VM26. Formation of the dimeric compound distegyl ether as a minor by-product was established. Complete elucidation of all the asymmetric centres was performed with the help of high resolution 1H-nmr studies at 400 MHz, COSY experiment at 500 MHz and X-ray analysis. Contrary to the podophyllotoxin series, the glycosylation of (-)-steganol occurred with retention of configuration, and all the synthesized compounds, including distegyl ether, exhibited the starting natural R configuration at C-5.
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Caffeine biotransformation and four monooxygenase activities involving cytochrome P-450IA2, namely ethoxy- and methoxyresorufin O-dealkylases, phenacetin O-deethylase, and acetanilide 4-hydroxylation were studied in 25 human liver microsomes. All these activities were highly significantly intercorrelated (r greater than 0.72, p less than 0.001) and correlated with the level of immunoreactive P-450IA2 content (r greater than 0.65; p less than 0.001). P-450IA content was measured by immunoblotting with anti-rat P-450 beta-naphthoflavone-B, an antibody that detects only a single band corresponding to P-450IA2. The formation rate of two caffeine metabolites, namely paraxathine and theobromine, was correlated with the four monooxygenase activities measured and P-450IA2-specific content (r greater than 0.75). However, inhibition studies of caffeine metabolism by phenacetin, a specific substrate of P-450IA2, clearly indicated that only the N-3 demethylation of caffeine was supported by this enzyme. These in vitro data demonstrate that P-450IA2 is predominantly responsible for the major metabolic pathway of caffeine and that the formation of other demethylated metabolites is mediated, at least partly, by other P-450 enzymes.
Genetic-controlled drug oxidation and acetylation were studied using dextromethorphan and caffeine as test compounds respectively in white Briton subjects (41 Britons and 27 Bigoudens considered as an ethnic group). Phenotyping was performed using the metabolic ratio (MR) calculated as the urinary output dextromethorphan/dextrorphan ratio and the urinary output of 5-acetylamino-6-formylamino-3-methyluracil (AFMU)/1-methylxanthine (1-MX) ratio in subjects given 40 mg of dextromethorphan and 150 mg caffeine respectively. Frequence distribution of hydroxylator and acetylator status in Briton and Bigouden groups showed no significant difference relatively to the French population. However the frequence distribution of the intermediate acetylator group in the Bigouden population was significantly different from that observed in the Briton population (7.4% vs 31.7%). The signification of this latter result was discussed on the basis of genetic transmission.
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Blood levels of Maprotiline were analysed and their relationship to the clinical response was examined in 89 depressed inpatients, according DSM III criteria for Major Depressive Episode, given the drug treatment for 3 weeks. Maprotiline produced marked decreases in mean MADRS and COVI scale scores by the end of treatment. On day 21, no correlation between blood levels of Maprotiline and MADRS or COVI scores were found when all patients were considered. Nevertheless, significant correlations were observed on day 14 (r = .22; p less than .05 for MADRS and r = .23; p less than .05 for COVI scale). In addition, a significant correlation between MADRS or COVI scale scores and Maprotiline blood levels were observed on days 14 and 21 in subgroups of young patients, severe depression (high scores to clinical global investigations), during of at least 3 months, treated without other drug than Maprotiline and good responders.
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Theophylline has been administered to 76 premature infants with apnea in two therapeutic indications: curative and preventive treatment. Plasmatic theophylline and caffeine concentrations have been performed by gas chromatography for ten days for the determination of the therapeutic range. The maximum effective concentration has been defined from the data observed in 33 subjects presenting with symptoms considered as signs of toxicity. The minimum effective concentration has been determined from the data observed during the failure of treatment (n = 4) and at the reappearance of apnea at the end of treatment (n = 10). The therapeutic concentrations of theophylline has be found on average to be 3 to 8 mg/l and for the theophylline and caffeine together from 5 to 10 mg/l. The sum theophylline and caffeine data is better for therapeutic monitoring than the determination of theophylline alone.
The case of a female patient with longstanding epilepsy is reported. Many problems in achieving a satisfactory therapeutic regimen were encountered. They originated in storage of phenobarbital, which had been prescribed since childhood, interference between phenobarbital, dipropylacetic acid, and phenylhydantoins. Some pharmacokinetic principles are reviewed in the light of this clinical experience.
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