Gilles Caillé

Pharmacokinetics of Lidocaine after Prolonged Intravenous Infusions in Uncomplicated Myocardial Infarction

The kinetics of the elimination of lidocaine upon discontinuation of lidocaine infusions lasting more than 24 h were studied in 12 patients with uncomplicated myocardial infarctions. In this group of patients the mean half-life of the elimination phase was found to be 3.22 h. This is significantly different from the half-life of 100 min that has been reported after bolus injections or infusions lasting less than 12 h. This longer half-life should be taken into consideration in estimating the duration of toxicity and the rate of administration of the drug during and after intravenous infusions lasting 24 h or more.

Pre- and postsynaptic effects of zimelidine and norzimelidine on the serotoninergic system: single cell studies in the rat.

The pre‐ and postsynaptic effects of zimelidine and norzimelidine were studied in adult male Sprague‐Dawley rats. The potency of the presynaptic effect was estimated from their ability to depress the rate of firing of serotonin (5‐HT)‐containing raphe neurons. Chronic administration of tricyclic antidepressant drugs has been shown to sensitize forebrain postsynaptic 5‐HT receptors. The effect of zimelidine on these receptors was compared to that of saline and chlorimipramine by assessing the responsiveness of hippocampal pyramidal cells to microiontophoretic applications of 5‐HT, norepinephrine (NE) and γ‐aminobutyric acid (GABA).

Stereospecific high-performance liquid chromatographic assay of ibuprofen: improved sensitivity and sample processing efficiency

A high-performance liquid chromatographic (HPLC) assay suitable for the analysis of the enantiomers of the non-steroidal anti-inflammatory drug ibuprofen (IB) in plasma was developed. Following the addition of racemic fenoprofen as internal standard (I.S.), samples are acidified and extracted with a mixture of isooctane-isopropanol (95:5, v/v). After evaporation of the organic layer, the drug and I.S. are derivatized with S-(-)-1(1-naphthyl)ethylamine (S-NEA) after addition of ethyl chloroformate as the coupling reagent. Ethanolamine is added 3 min after the addition of S-NEA to react with the excessive ethyl chloroformate. The resultant diastereomers corresponding to IB and I.S. were chromatographed at ambient temperature on a 100 mm x 4.6 mm I.D. C18 reversed-phase column using acetonitrile-water-acetic acid-triethylamine (60:40:0.1:0.02) as the mobile phase pumped at a flow-rate of 1.2 ml/min. Detection of the fluorescent chromophore was at 280 and 320 nm for excitation and emission, respectively. The suitability of the assay for clinical pharmacokinetic studies of IB was determined by the analysis of plasma samples obtained from a healthy volunteer, following administration of a single 400-mg oral dose of racemic IB.

Influence of Drug Formulation on Drug Concentration-Effect Relationships

SummarySlow release formulations (SRFs) are developed on the basis that the response elicited by a drug is closely related to changes in its plasma concentrations. As a consequence, the drug in the SRF is considered bioequivalent to the same drug administered in a conventional or immediate release formulation (IRF). The available literature suggest that for drugs eliciting a simple response, i.e. theophylline, the response is not affected by the rate of input of drug into the systemic circulation. Therefore, the pharmacodynamics are closely related to the pharmacokinetics of the drug, which are independent of formulation. In this case, SRFs and IRFs are truly bioequivalent.The pharmacological effect of some drugs, e.g. nifedipine, prazosin, furosemide (frusemide), etc., triggers compensatory homeostatic mechanisms. Therefore, the measured effect may not directly relate to the plasma drug concentration. Furthermore, the characteristics of the response will be modulated by the rate of input of the drug, i.e. drugs in SRF will elicit a greater response because a slow input triggers fewer homeostatic reactions. As a consequence, for drugs that trigger homeostatic reactions, a drug released from an SRF may not be bioequivalent to the same drug released from an IRF.Finally, when tolerance to an effect develops, a drug administered as an SRF will elicit a smaller effect than when administered as an IRF. Therefore, even if the different formulations of a drug were bioequivalent on the basis of pharmacokinetic parameters, they would not be equivalent on the basis of pharmacodynamic factors. A better understanding of the influence of the rate of input of a drug on its pharmacodynamic profile will lead to optimisation of drug therapy.

Isopropanol and acetone potentiation of carbon tetrachloride‐induced hepatotoxic1ty: Single versus repetitive pretreatments in rats

Acute oral pretreatment of rats with isopropanol or acetone results in a dose-related potentiation of CCl4 hepatotoxicity. Minimally effective doses (MED) and noneffective doses (NED) of both agents were estimated to be 0.25 and 0.10 ml/kg, respectively. Six MED given twice a day over 3 d caused a greater potentiation than a single MED, but not as much as that produced by the total dose given singly. Six NED given over 3 d did not potentiate CCl4, whereas the total dose did when given singly. A threshold for isopropanol and acetone appears to exist in the rat. A total dose of 1.5 ml/kg acetone was administered by four different treatment regimens (bolus, divided doses, infusion) over 3 d. Potentiation of CCl4 hepatotoxicity was then correlated with blood pharmacokinetic parameters: area under the concentration-time curve and peak blood concentration. An excellent correlation was found between the degree of potentiation observed and the peak blood concentration attained, but no correlation was found with area under the curve. Results of iv acetone infusions (over 3 d) with higher doses support the hypothesis that a threshold concentration of acetone is critical in the potentiation of CCl4 hepatotoxicity in the rat.

Acute and Chronic Role of 5-HT3 Neuronal System on Behavioral and Neuroendocrine Changes Induced by Intravenous Cholecystokinin Tetrapeptide Administration in Humans

The influence of single and multiple oral doses of ondansetron, a selective 5-HT3 receptor antagonist, was evaluated against placebo on cholecystokinin tetrapeptide (CCK-4)-induced behavioral and neuroendocrine changes in humans. As compared to placebo, subjects receiving acute ondansetron treatment showed a significant decrease in the sum intensity of CCK-4-induced-panic symptoms (iPSS). Pre-CCK-4 neuropeptide Y (NPY) plasma levels were significantly higher and maximal changes in cortisol, growth hormone, and prolactin secretion from baseline (Δmax) were significantly lower in the ondansetron group. After ondansetron and placebo chronic administration, there were no statistical differences in the iPSS between groups. Pre-CCK-4 NPY plasma levels were significantly higher; whereas, Δmax for NPY significantly lower in the ondansetron group as compared to placebo. These results suggest a role for the 5-HT3 receptor in the neurobiology of panic disorder through a possible interaction with CCK and NPY systems. Ondansetron chronic effect on CCK-4-induced behavioral changes needs further exploration.

High-resolution liquid chromatographic method using ultraviolet detection for determination of ondansetron in human plasma

This paper describes a simple technique for extraction and a sensitive high-performance liquid chromatographic method for separation and quantitation of ondansetron in human plasma. The procedure involved liquid-liquid extraction of ondansetron from plasma, reversed-phase HPLC separation and ultraviolet detection at 305 nm. The internal standard method was applied for quantitation. The recovery of ondansetron was >85%. Linearity was good throughout the concentration range anticipated in human plasma from investigations in panic disorder (0.5-15 ng/ml, r2 ranging from 0.9953 to 0.9988). This method was applied to the determination of plasma concentrations of ondansetron in humans.

Stereospecific high-performance liquid chromatographic assay of ketoprofen in human plasma and urine

A high-performance liquid chromatographic (HPLC) assay suitable for the analysis of the enantiomers of ketoprofen (KT), a 2-arylpropionic acid (2-APA) non-steroidal antiinflammatory drug (NSAID), in plasma and urine was developed. Following the addition of racemic fenoprofen as internal standard (I.S.), plasma containing the KT enantiomers and I.S. was extracted by liquid-liquid extraction at an acidic pH. After evaporation of the organic layer, the drug and I.S. were reconstituted in mobile phase and injected into the HPLC system. The enantiomers were separated at ambient temperature on a commercially available 250 x 4.6 mm amylose carbamate-packed chiral column (Chiralpak AD) column with hexane-isopropyl alcohol-trifluoroacetic acid (80:19.9:0.1, v/v/v) as the mobile phase pumped at 1.0 ml/min. The enantiomers of KT were quantified by ultraviolet detection with the wavelength set at 254 nm. The assay described allows for the direct quantitation of KT enantiomers without pre-column derivatization, and is suitable for clinical studies of KT enantiomers in human plasma and urine after administration of therapeutic doses.

Enhancement of nadolol elimination by activated charcoal and antibiotics

This study was carried out to assess whether nadolol undergoes enterohepatic circulation. Eight healthy subjects received 80 mg nadolol orally on three occasions at least 2 wk apart. The first experiment was a control. The second consisted of nadolol followed in 3 hr by 3 gm activated charcoal given over a 9‐hr period. In the third, the subjects received 0.5 gm erythromycin base and 0.5 gm neomycin four times a day orally for 2 days before nadolol. After the activated charcoal, the nadolol AUC fell from 2455 ± 155 to 1355 ± 123 ng · hr/ml (mean ± SE), as did the percentage nadolol recovered in urine (15.4 ± 1.4 to 10.2 ± 0.7%) and the nadolol t½ (17.3 ± 1.7 to 11.8 ± 1.6 hr). These data suggest that nonrenal elimination increased. After the antibiotics, nadolol AUC was constant, percentage of nadolol recovered in urine fell to 12.7 ± 1.7%, nadolol t½ fell to 11.6 ± 1.3 hr, and mean peak nadolol concentration rose from 146 ± 15 to 397 ± 52 nglml. These results suggest that there is an enterohepatic circulation for nadolol, that activated charcoal may decrease nadolol bioavailability, and that antibiotics may increase the nadolol effect.

Quantification of ketoprofen enantiomers in human plasma based on solid-phase extraction and enantioselective column chromatography

An HPLC method for the quantification of ketoprofen enantiomers in human plasma is described. Following extraction with a disposable C18 solid-phase extraction column, separation of ketoprofen enantiomers and I.S. (3,4-dimethoxy benzoic acid) was achieved using a chiral column [Chirex 3005; (R)-1-naphthylglycine 3,5-dinitrobenzoic acid] with the mobile phase, 0.02 M ammonium acetate in methanol, set at a flow-rate of 1.2 ml/min. Baseline separation of ketoprofen enantiomers and I.S., free from interferences, was achieved in less than 20 min. The calibration curves (n = 14) were linear over the concentration range of 0.16 to 5.00 micrograms/ml per enantiomer [mean r2 of 0.999 for both enantiomers, root mean square error were 0.015 for R(-) and 0.013 for S(+)]. The inter-day coefficient of variation for duplicate analysis of spiked samples was less than 7% and the accuracy was more than 93% over the over the concentration range of 0.2 to 4.0 micrograms/ml for individual enantiomer using 1 ml of plasma sample. This method has been applied to a pharmacokinetic study from healthy human volunteers following the administration of a ketoprofen extended release product (200 mg). This method is simple, fast and should find wide application in monitoring pharmacokinetic studies of ketoprofen.