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Biomedical subjects

G Lachâtre

Publications and source records attributed to G Lachâtre.

At least 19 recordsLinked to original sources
PubMed2006

Simultaneous determination of six dialkylphosphates in urine by liquid chromatography tandem mass spectrometry.

Dialkylphosphates (DAP) are urinary markers of the exposure to organophosphates pesticides. The aim of this study was to develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantitative determination of the following DAP: dimethylphosphate (DMP), dimethythiophosphate (DMTP), dimethyldithiophosphate (DMDTP), diethylphosphate (DEP), diethylthiophosphate (DETP) and diethyldithiophosphate (DEDTP). Dibutylphosphate (DBP) was used as internal standard. This method was based on a liquid-liquid extraction procedure, a chromatographic separation using an Inertsil ODS3 C18 column and mass spectrometric detection in the negative ion, multiple reaction monitoring (MRM) mode, following two ion transitions per compound. It yielded a limit of quantification of 2 microg/L for the six compounds and intra-assay coefficients of variation (CV%) lower than 20%. This method was applied to the analysis of urines samples from a small cohort of non-exposed volunteers. At least one of the six DAP was detected in each sample. This result confirmed the feasibility of a LC-MS/MS procedure for monitoring the general population exposure to some frequently employed organophosphate pesticides.

Adult↗
PubMed2006

[Inductively coupled plasma mass spectrometry. Perspectives in analysis and in biology].

ICP-MS is an instrumental method of multi-elementary qualitative and quantitative analysis. It associates with a mass spectrometer (MS) an ion source composed of a plasma torch fed with inductive coupling with a high frequency electromagnetic generator (ICP), similar to that used as a light source in highly-successful Atomics Emission Spectrometry (AES). ICP-MS can be applied to simultaneous analysis of numerous metallic and metalloid elements (80 or so). Its sensitiveness is all in all far better than that available with previous spectrometric techniques, which nevertheless remain more advantageous for processing certain low atomic mass elements. Thanks to its broad dynamic range, ICP-MS allows quantification of an array of elementary concentrations within a single sample. ICP-MS offers particularly interesting perspectives in geochemistry and metal processing, as well as in biochemistry and food or toxicology and environmental analysis. Implementation is rapid and the technique is suitable for series or continuous analyses, or for analysis of any evolving medium such as effluents from gas or liquid chromatography or from capillary electrophoresis, making it a valuable tool for speciation analyses. Finally it enables non-radioactive isotopic labeling, essential for nutritional studies of trace elements, and sufficiently accurate isotopic dilutions, even with more accessible machines.

Animals↗
PubMed2006

A fully automated turbulent-flow liquid chromatography-tandem mass spectrometry technique for monitoring antidepressants in human serum.

Antidepressants belong to a variety of chemical and pharmacologic classes. Most require therapeutic drug monitoring, at least in certain circumstances, such as unexplained inefficacy or suspected toxicity. Several types of chromatographic methods have generally been used. This paper presents a fully automated, sensitive, and specific method for the therapeutic drug monitoring of 13 antidepressants of all classes (amoxapine, amitriptyline, citalopram, clomipramine, dothiepin, doxepin, fluoxetine, imipramine, maprotiline, mianserin, paroxetine, sertraline, trimipramine) and some of their respective active metabolites (nortriptyline, monodesmethylcitalopram, desmethylclomipramine, desipramine, norfluoxetine, desmethylmianserin, N-desmethylsertraline), based on the innovative turbulent-flow liquid chromatography (TFC) technology, coupled to tandem-mass spectrometry (MS/MS). The antidepressants were divided in two groups depending on their chromatographic properties, so that two injections would be necessary to screen all compounds (which is infrequent for therapeutic drug monitoring). Calibration curves ranged from 10 to 500 ng/mL. No significant memory effect was observed after the injection of a blank serum sample spiked at 500 ng/mL. The intra-assay and inter-assay precision CVs ranged from 0.4% to 12% and from 1% to 16%, respectively. The method was further validated by blindly analyzing Heathcontrol-Therapeutic Drugs Scheme samples (Cardiff Bioanalytical Services Ltd.) containing several antidepressants.

Antidepressive Agents↗
PubMed2006

[Treatment of pesticides determination requests in biological samples: some problems frequently encountered ].

Currently, the determination of pesticides in human fluids is complex. Our scientific knowledge on pesticide intoxication is fragmentary. This leads to numerous difficulties regarding the diagnosis, the analysis request, the choice of the analytical technique, the interpretation of the results. Consequently the waiting time to provide a result is not compatible with the initiation of a treatment in the intoxicated patients. Very few information about Human intoxication with pesticides is available from the literature. In this context, we tried to acquire our own experience. We chose to deal with all pesticides intoxication suspicions received, in collaboration with clinicians. We are presenting the main problems we encounter.

Hair↗
PubMed2005

Determination of chromium in whole blood by DRC-ICP-MS: spectral and non-spectral interferences.

Quantification of chromium in whole blood has been performed by ICP-quadrupole MS. The spectrometer was equipped with a dynamic reaction cell (DRC) with ammonia as reaction gas. The rejection parameter q (RPq) of the DRC and the flow rate of ammonia (NH3) were optimized and set at 0.7 and 0.6 mL min(-1), respectively. Blood was diluted 1:51 (v/v) with an aqueous solution containing 0.1 mg L(-1) NH4OH, 0.1 g L(-1) EDTA, 5 mg L(-1) n-butanol, and 0.1 per thousand Triton X100. Non-spectral matrix effects observed when using the DRC were confirmed by use of vanadium. External calibration with blank and standard solutions prepared in purified water led to biased results for quality control samples. Standard addition calibration was therefore used and its validity verified. By comparing the slopes and calculating residues, it was proved that the plot obtained with standard additions and the plot obtained from blood samples of different concentrations were aligned down to 0.05 microg L(-1) after dilution.

1-Butanol↗
PubMed2002

[New drugs at "rave parties": ketamine and 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. This report presents toxicological cases documented by analytical findings in which two pharmacological agents abused in "rave parties" in South-West of France were found. The day following a party, a 17 year-old girl showed a confused state with drowsiness and hallucinations. She confessed having consumed a white powder sold as "ecstasy", that sample analysis identified as pure ketamine. Ketamine is an anaesthetic agent primarily used in veterinary medicine and paediatrics. This drug seems to be abused, mainly by the intranasal route, owing to its hallucinogen effects. Its used in "rave-party" appears to be marked by unsuspected consumption. All long another party, a large quantity of orange tablets were sold and abused by several participants. Analysis performed on some fragments of these tablets revealed the presence of prolintane and ascorbic acid. Prolintane, an amphetamine-related substance, is a central nervous system stimulant. This compound is "freely" available in Spain in combination with several vitamins, under the form of tablets with orange coating named "Katovit" and sold at low price: 1.93 [symbol: see text]/20 tablets (200 mg of prolintane).

Adolescent↗
PubMed2001

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). Acquisition was performed in the selected ion monitoring (SIM) mode. Extraction recovery varied owing to the nature of pesticides, but was satisfactory for all. Limits of detection (LODs) and limits of quantitation (LOQs) ranged, respectively, from 2.5 to 20 and from 5 to 50ng/ml. An excellent linearity was observed from LOQs up to 1000ng/ml for all the pesticides studied. The proposed procedures yielded reproducible results with good inter-assay accuracy and precision. A few cases of intoxication are presented to demonstrate the diagnostic interest of these methods: in two cases were determined lethal concentrations of endosulfan and carbofuran; in four other cases, the procedures helped diagnose intoxication with, respectively, parathion-ethyl, the association of bromacil and strychnine, bifenthrin and aldicarb.

Adult↗
PubMed2001

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. Limits of detection ranged from 5 to 25 ng/ml and limits of quantitation (LOQs) ranged from 10 to 50 ng/ml, in blood and serum. An excellent linearity was observed from these LOQs up to 1000 ng/ml. Intra- and inter-assay precision and accuracy were satisfactory for most of the pesticides analyzed.

Gas Chromatography-Mass Spectrometry↗
PubMed2001

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. PATIENTS AND PARTICIPANTS: 21 renal transplant patients receiving oral cyclosporin microemulsion 75 to 175 mg twice daily. METHODS: The equation of the plasma concentration-time curve after oral administration was expressed as a convolution product between the absorption rate and a multi-exponential impulse response. The convolution integral was computed analytically and expressed in terms of the incomplete gamma function. Cyclosporin was assayed by liquid chromatography/mass spectrophotometry. The model was fitted by nonlinear regression, using a specially developed program. RESULTS: The gamma model yielded a good fit in all of the 21 patients studied. Attempts to fit the same data by a classical exponential with lag-time model failed in most patients. CONCLUSIONS: This model could simplify the Bayesian monitoring of cyclosporin therapy.

Area Under Curve↗
PubMed2001

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. She died three days later after a deep coma. In these two cases, CH intoxication was confirmed by toxicological analysis: CH and its major metabolite, trichloroethanol (TCE), were identified and determined in serum and urine using headspace-capillary gas chromatography-mass spectrometry. The concentrations measured were compared with those found in previously published fatalities. The analytical method used can be proposed for both clinical and forensic cases.

Adult↗
PubMed2000

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. Limits of detection (LODs) and limits of quantitation (LOQs) ranged, respectively, from 2.5 to 5 microg/l and from 10 to 20 microg/l. Intra-assay and inter-assay precision was studied at three and four concentration levels, respectively, and was less than 19% for all compounds. Accuracy was also satisfactory for all. An excellent linearity was observed from the LOQs up to 1000 microg/l for milnacipram and paroxetine and from each LOQ up to 400 mg/l for the other compounds. The performance of the methods described thus allows the therapeutic drug monitoring of the currently commercialised SSRIs.

Antidepressive Agents, Second-Generation↗
PubMed2000

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. Bayesian maximum a posteriori probability (MAP) forecasting is an efficient and robust method for the optimisation of drug therapy, but its use for anticancer drugs is not yet extensive. The aim of this paper is to review the application of population pharmacokinetics and MAP to anticancer drugs and to evaluate whether and when MAP Bayesian estimation improves the clinical benefit of anticancer chemotherapy. For each drug, the relationships between pharmacokinetic variables [e.g. plasma concentration or the area under the concentration-time curve] and pharmacodynamic effects are described. Secondly, the methodologies employed are considered and, finally, the results are analysed in terms of predictive performance as well as, where possible, the impact on clinical end-points. Some studies were retrospective and intended only to evaluate individual pharmacokinetic parameter values using very few blood samples. Among the prospective trials, a few studied the pharmacokinetic/pharmacodynamic relationships which provided the basis for routine pharmacokinetic monitoring. Others were performed in clinical context where MAP Bayesian estimation was used to determine maximum tolerated systemic exposure (e.g. for carboplatin, topotecan, teniposide) or for pharmacokinetic monitoring (e.g. for methotrexate or platinum compounds). Indeed, its flexibility in blood sampling times makes this technique much more applicable than other limited sampling strategies. These examples demonstrate that individual dose adjustment helps manage toxicity. The performance of pharmacokinetic monitoring is linked to the methodology used at each step of its design and application. Moreover, a limitation to the use of pharmacokinetic monitoring for certain anticancer drugs has been the difficulty in obtaining pharmacokinetic or pharmacodynamic data. Recent progress in analytical methods, as well as the development of noninvasive methods (such as positron emission tomography) for evaluating the effects of chemotherapy, will help to define pharmacokinetic-pharmacodynamic relationships. Bayesian estimation is the strategy of choice for performing pharmacokinetic studies, as well as ensuring that a given patient benefits from the desired systemic exposure. Together, these methods could contribute to improving cancer chemotherapy in terms of patient outcome and survival.

Animals↗
PubMed2000

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. Serum and urine specimens were collected over five days and analyzed by liquid chromatography-electrospray-mass spectrometry (LC-ES-MS). This accurate procedure allowed the determination of the digitalis glycosides and their metabolites in serum and urine. The serum concentrations of digitalis glycosides were maximum on the first day (gitoxin 13.1 ng/mL, digitoxin 112.6 ng/mL, digitoxigenin 3.3 ng/mL, and digitoxigenin mono-digitoxoside 8.9 ng/mL) and decreased over five days. We observed a peak gitaloxin level (112.6 ng/mL) on the fifth day only. After administration of atropine as well as dimeticone, alginic acid, and metoclopramide, health status improved. The peak urine concentrations were reached at hour 30 and were respectively 91.3 and 69.9 ng/mL for gitaloxin and digitoxin, while those of digitoxigenin, digitoxigenin mono-digoxoside and gitoxin were lower (respectively 0.7, 1, and 5.6 ng/mL). The patient was discharged on the fifth day when there were no residual symptoms.

Adult↗
PubMed1999

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.). The sample pretreatment for irinotecan involved a simple protein precipitation with acetonitrile, whereas a liquid-liquid extraction was necessary for SN-38. A Symmetry C18, 3.5 microm (150 x 1 mm I.D.) reversed-phase column was used for the chromatographic separation, together with a gradient elution of acetonitrile in 5 mM ammonium formate buffer (pH 3) as mobile phase. After ionisation in the pneumatically-assisted electrospray source and in-source collision induced dissociation, acquisition was performed in the selected ion monitoring mode. Recoveries were 69 and 47% on average, detection limits 2.5 and 0.25 ng/ml and quantitation limits 10 and 0.5 ng/ml for irinotecan and SN-38, respectively. Reproducibility was good and the method was linear from limits of quantitation up to 10,000 ng/ml for irinotecan, and up to 100 ng/ml for SN-38. This sensitive and highly specific method is suitable both for pharmacokinetic studies and routine therapeutic drug monitoring.

Acetonitriles↗
PubMed1999

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). The chromatographic separation was performed on a Nucleosil C18, 5 microm (150x1 mm I.D.) column, using a gradient of acetonitrile in 5 mM ammonium formate, pH 3.0 as the mobile phase, delivered at a flow-rate of 50 microl/min. The compounds were ionised in the ionspray source of an atmospheric pressure mass spectrometer, fragmented by in-source collisions and the pseudomolecular and fragment ions detected in the selected ion monitoring mode. The recovery was between 79 and 87% for MID, between 83 and 87% for 1-OHM and 81.5% for methylclonazepam. The limit of detection was 0.2 microg/l for MID and 0.5 microg/l for 1-OHM, the limit of quantitation (LOQ) was 0.5 microg/l for both. Linearity was verified from these LOQs up to 2000 microg/l and the method was found accurate and precise over this range. It was successfully applied to a preliminary study to establish the concentration versus time curve of MID and 1-OHM in a patient administered midazolam by continuous infusion.

Anesthetics, Intravenous↗
PubMed1999

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. The last section envisages the new analytical fields opened up by LC-MS in toxicology, regarding mainly peptides, proteins and large molecules, as well as the possible use of LC-MS as a complement to GC-MS for "general unknown" screenings; it also deals with the perspectives concerning technical improvements in ionisation interfaces/sources or mass spectrometers, as well as in sample preparation and liquid chromatography techniques applied to this type of coupling. Though LC-MS is still a relatively new technique in toxicology, on taking into consideration its success so far and owing to the simplification of instruments and concept handling thanks to user-friendly software, it is the authors' opinion that it will become a major success in analytical toxicology in the next few years.

Atmospheric Pressure↗
PubMed1999

In vitro and in vivo study of the antithyroid side effects of trimeprazine.

Trimeprazine (TMP), a phenothiazine used as antipsychotic drug, was previously shown to induce a decrease in thyroid hormone serum levels in rats. Different mechanisms might be involved, mainly (i) a central mechanism, involving a reduction of thyroid-stimulating hormone (TSH) secretion; (ii) a peripheral mechanism, acting upon the synthesis of thyroid hormones, by inhibition of thyroperoxidase (TPO) or trapping of molecular iodine present in the thyroid gland. These different hypotheses were investigated in the present study, using in vitro and in vivo experiments. In vitro studies concerned TMP and its three main metabolites: trimeprazine sulphoxide (TSO), N-desmethyl trimeprazine (NDT), and 3-hydroxy-trimeprazine (3-OHT). TMP and TSO expressed a high affinity for iodine in vitro, contrary to NDT, which did not complex iodine. Only 3-OHT inhibited TPO in vitro. Administration of 5 mg/kg TMP ip twice daily for 11 days to Wistar rats induced a decrease of free triiodothyronine and free thyroxine (fT(3) and fT(4)) and a trend toward an increase of TSH serum levels. Thyroid concentrations of TMP, NDT, and TSO were significantly higher than serum levels, while 3-OHT was never detected. An iodine-supplemented diet administered to a group of rats treated with TMP significantly increased the thyroid concentration of TMP and TSO, but not that of NDT, while it did not affect the concentrations observed in serum and other organs. The increase in plasma TSH is not consistent with the central mechanism hypothesis, and the absence of TPO inhibition by TMP, TSO, and NDT contradicts the TPO inhibition hypothesis. On the contrary, three findings support the hypothesis of iodine trapping through formation of a complex with TMP and TSO: these molecules complex iodine in vitro, they accumulate in the thyroid, and their thyroid concentration is increased when the rats are fed an iodine-supplemented diet.

Animals↗