Maximum a posteriori Bayesian estimation of oral cyclosporin pharmacokinetics in patients with stable renal transplants.

Objective: To develop a maximum a posteriori probability (MAP) Bayesian estimator for the pharmacokinetics of oral cyclosporin, based on only three timepoints, and evaluate its performance with respect to a full-profile nonlinear regression approach.

Patients: 20 adult patients with stable renal transplants given orally administered microemulsified cyclosporin and mycophenolate.

Methods: Cyclosporin was assayed by liquid chromatography-mass spectrometry.

Is LC-MS suitable for a comprehensive screening of drugs and poisons in clinical toxicology?

This paper reviews the different attempts made to develop efficient LC-MS techniques for systematic toxicologic analysis, or general unknown screening (GUS) of drugs and toxic compounds. Only particle beam interfaces are compatible with electron ionization, but they mainly cover the same range of compounds as GC-MS, i.e.

Nouvelles drogues de « rave-parties » : ketamine et prolintane.

"Rave parties", all-night dance parties based on "techno" music, represent an increasing phenomenon in France. "Rave drugs" refers to a wide variety of drugs used by the young participants owing to their hallucinogenic or stimulant effects. Uncertainties about the sources of these substances, the possible contaminants and the multiplicity of the associations make it difficult to evaluate the toxic consequences that might be expected in this particular context.

Fatal intoxications with chloral hydrate.

An alcoholic man, treated with chloral hydrate (CH) syrup to which he was dependent, was discovered comatose and in respiratory arrest. Death occurred on the ninth day of hospitalization following cerebral oedema. A woman, alcohol addicted, depressed, and epileptic was admitted in the Intensive Care Unit with heart and respiratory failure following CH absorption.

Determination of N-acetylation phenotype using caffeine as a metabolic probe and high-performance liquid chromatography with either ultraviolet detection or electrospray mass spectrometry.

A rapid, sensitive method using liquid chromatography-electrospray mass spectrometry (LC-ES-MS) was developed and evaluated for the simultaneous quantitative determination of caffeine metabolites 1U, 1X and AAMU in human urine. This method involved a simple dilution of urine samples. The chromatographic separation was achieved on a C18 reversed-phase column using a gradient of acetonitrile in 2 mM, pH 3.

Sensitive and specific multiresidue methods for the determination of pesticides of various classes in clinical and forensic toxicology.

Original and sensitive multiresidue methods are presented for the detection and quantitation, in human biological matrices, of 61 pesticides of toxicological significance in human. These methods involved rapid solid-phase extraction using new polymeric support (HLB and MCX) OASIS cartridges. Gas chromatography-mass spectrometry (GC-MS) was used for volatile (organophosphate, organochlorine, phtalimide, uracil) pesticides and liquid chromatography-ionspray-mass spectrometry (LC-MS) for thermolabile and polar pesticides (carbamates, benzimidazoles).

Multiresidue determination method for organophosphorus pesticides in serum and whole blood by gas chromatography-mass-selective detection.

This paper describes a rapid, specific and sensitive method for the determination of 29 organophosphorus pesticides in blood and serum, involving a rapid solid-phase extraction procedure using Oasis HLB cartridges and gas chromatography coupled to mass-selective detection. The ionization was performed by electron Impact and acquisition in the single ion monitoring mode followed three specific ions per analyte. Extraction recoveries were satisfactory and ranged between 40 and 108% in blood and serum.

[Functions of the 'Therapeutic Drug Monitoring (TDM)' Group of the French Society of Pharmacology].

Therapeutic Drug Monitoring consists of sampling organization, measurement and interpretation of the blood concentration or biological effect of a given xenobiotic, and sometimes using this result for pharmacokinetic computation, with the aim of individual dose adjustment. This branch of pharmacology is represented internationally by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) and has been organized, in France, as a working group of the French Society of Pharmacology (SFP). This group takes part in the main French organizations dealing with or using TDM, as well as the scientific activities of SFP and organizes multi-centre clinical trials studying exposure-effect relationships or based on 'concentration-controlled' protocols.

Application of a gamma model of absorption to oral cyclosporin.

Background: Some drugs, such as cyclosporin, exhibit flat and delayed absorption profiles, with a correlation between the delay and the peak width. Such profiles can be described by an absorption model in which the absorption rate is derived from a gamma distribution (of which the classical first-order absorption model is a special case).

Objective: To develop a model for the pharmacokinetics of extravascular administration of cyclosporin and apply it to a study of the pharmacokinetics of cyclosporin microemulsion in stable renal transplant recipients.

Sensitive determination of vinorelbine and its metabolites in human serum using liquid chromatography-electrospray mass spectrometry.

A liquid chromatography-electrospray mass spectrometry method was developed for the quantitation of vinorelbine (VNB) and two metabolites, vinorelbine N-oxide (VNO) and deacetyl vinorelbine (DAV) in human serum. The limits of quantitation (LOQ) reached 0.5 ng/ml for both VNB and VNO and 1 ng/ml for DAV.

High-performance liquid chromatographic determination of tianeptine in plasma applied to pharmacokinetic studies.

An improved analytical method for the quantitative measurement of tianeptine and its main metabolite MC5 in human plasma was designed. Extraction involved ion-paired liquid-liquid extraction of the compounds from 1.0 ml of human plasma adjusted to pH 7.

A quantitative analysis of L-glutamate-regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics.

The mode of Na+ entry and the dynamics of intracellular Na+ concentration ([Na+]i) changes consecutive to the application of the neurotransmitter glutamate were investigated in mouse cortical astrocytes in primary culture by video fluorescence microscopy. An elevation of [Na+]i was evoked by glutamate, whose amplitude and initial rate were concentration dependent. The glutamate-evoked Na+ increase was primarily due to Na+-glutamate cotransport, as inhibition of non-NMDA ionotropic receptors by 6-cyano-7-nitroquinoxiline-2,3-dione (CNQX) only weakly diminished the response and D-aspartate, a substrate of the glutamate transporter, produced [Na+]i elevations similar to those evoked by glutamate.

Extinction Thresholds and Metapopulation Persistence in Dynamic Landscapes.

Models of metapopulations have focused on the effects of extinction and colonization rate upon metapopulation persistence and dynamics, assuming static landscapes wherein patches are neither created nor go extinct. However, for species living in ephemeral (patchy) habitats, landscapes are highly dynamic rather than static. In this article, we develop a lattice metapopulation model, of the patch occupancy type, based on interacting particle systems that incorporate explicitly both metapopulation and patch dynamics.

A non-fatal case of intoxication with foxglove, documented by means of liquid chromatography-electrospray-mass spectrometry.

The non-fatal self-poisoning of a 36-year-old female patient, who ingested a concoction of foxglove (Digitalis Purpurea), is presented. On the admission, initial symptoms were nausea and vomiting, abdominal pain, and cardiovascular shock with sinus bradycardia. Blood and urine were assayed for 17 cardiotonic hetorosides, using a highly specific LC-MS procedure.

Ecology. Invariants, scaling laws, and ecological complexity.

There has been much debate about scaling laws in nature. It is believed that as body size increases the number of individuals in the population decreases. As Marquet explains in his Perspective, an elegant new study in two totally separate stream communities (Schmid et al.

Methods for the determination of seven selective serotonin reuptake inhibitors and three active metabolites in human serum using high-performance liquid chromatography and gas chromatography.

This paper describes a set of simple and sensitive multiresidue methods for the determination of the specific serotonin reuptake inhibitors (SSRIs) used as antidepressant drugs, and some of their respective active metabolites in human serum. It involves liquid-liquid extraction procedures followed by gas chromatography coupled to nitrogen phosphorus detection or isocratic reversed-phase high-performance liquid chromatography combined with fluorescence detection (HPLC-FL), depending on the analytes. Extraction recoveries were between 71 and 96% for the eight SSRIs and their metabolites analysed by GC and between 41 and 77% for the two of them analysed by HPLC.

Adaptive control methods for the dose individualisation of anticancer agents.

Numerous studies have found a clear relationship between systemic exposure and the toxicity or (more rarely) the efficacy of anticancer agents. Moreover, the clearance of most of these drugs differs widely between patients. These findings, combined with the narrow therapeutic index of anticancer drugs, suggest that patient outcome would be improved if doses were individualised to achieve a target systemic exposure.

Simultaneous determination of four anthracyclines and three metabolites in human serum by liquid chromatography-electrospray mass spectrometry.

A sensitive and very specific method, using liquid chromatography-electrospray mass spectrometry (LC-ES-MS), was developed for the determination of epirubicin, doxorubicin, daunorubicin, idarubicin and the respective active metabolites of the last three, namely doxorubicinol, daunorubicinol and idarubicinol in human serum, using aclarubicin as internal standard. Once thawed, 0.5-ml serum samples underwent an automated solid-phase extraction, using C18 Bond Elut cartridges (Varian) and a Zymark Rapid-Trace robot.

Sensitive determination of irinotecan (CPT-11) and its active metabolite SN-38 in human serum using liquid chromatography-electrospray mass spectrometry.

A couple of sensitive and accurate liquid chromatography-electrospray mass spectrometry (LC- S-MS) methods for the determination of the total forms of irinotecan and its active metabolite SN-38 in human serum, using the same chromatographic and detection conditions, is presented. Both used camptothecin as internal standard (I.S.

Sensitive and specific determination of midazolam and 1-hydroxymidazolam in human serum by liquid chromatography-electrospray mass spectrometry.

A liquid chromatographic-mass spectrometric technique was designed for the determination of the anaesthetic benzodiazepine midazolam (MID) and its active metabolite 1-hydroxymidazolam (1-OHM), with the aim of conducting pharmacokinetic/pharmacodynamic studies. MID and 1-OHM were extracted from alkalinised (pH 9.5) spiked and clinical serum samples using a single step, liquid-liquid extraction procedure with diethyl ether-2-propanol (98:2, v/v).

Liquid chromatography-mass spectrometry: potential in forensic and clinical toxicology.

A relatively limited number of papers concerning applications of liquid chromatography-mass spectrometry (LC-MS) to forensic or clinical toxicology, or analytical methods directly applicable to these topics have been published so far, but their number have greatly increased in the past two years, probably due to technical improvements and to a decrease in the price of such instruments. After a brief presentation and exemplary applications of the interfaces and/or sources proposed in the past for coupling HPLC to mass spectrometry (direct liquid inlet, moving belt, fast atom bombardment and thermospray interfaces), this paper describes electrospray-type and atmospheric pressure chemical ionisation interfaces and their most recent applications in forensic or clinical toxicology. In a third section, the different LC-MS solutions proposed for typical applications in human toxicology, such as the determination of morphine metabolites, LSD and its metabolites and corticosteroids in blood or urine, are reviewed in detail in order to highlight the strengths and weaknesses of each ionisation device and/or analytical method.

Dexamethasone in resting and exercising men. II. Effects on adrenocortical hormones.

This study presents the reactions of adrenocorticosteroids (cortisol and aldosterone) and sex steroids [testosterone, androstenedione, and dehydroepiandrosterone and its sulfate (DHAS)] 1) to a dexamethasone (Dex) treatment, which is expected to lower steroid levels via the ACTH blockade, and 2) to an exercise bout at maximal O(2) consumption, which is expected to increase steroid production via ACTH stimulation. Consistent with the decrease in ACTH, all steroids except testosterone reacted negatively to Dex, independently of the dose (0.5 and 1.