Biomedical subjects

Karine Titier

Publications and source records attributed to Karine Titier.

15 recordsLinked to original sources

PubMed2006

Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia.

Using high-performance liquid chromatography-tandem mass spectrometry, we assessed trough imatinib plasma levels in 68 patients with chronic myeloid leukemia (CML) who responded or not to standard-dose imatinib, after at least 12 months' treatment. Mean trough imatinib plasma levels were significantly higher in the group with complete cytogenetic response (56 patients) than in the group without (12 patients; P = .03) and higher in the group with major molecular response (MMR) than in the group without (34 patients [1452 +/- 649 ng/mL] versus 34 patients [869 +/- 427 ng/mL]; P < .001). Regarding trough imatinib plasma levels and their discrimination potential for MMR, the area under receiver operating characteristic curve was 0.775, with best sensitivity (77%) and specificity (71%) at a plasma threshold of 1002 ng/mL. Therefore, monitoring of imatinib plasma levels could be very useful for the management of patients with CML or should at least be checked in the case of treatment failure or suboptimal response.

Adult↗

PubMed2006

Bioavailability and urinary excretion of isoflavones in humans: effects of soy-based supplements formulation and equol production.

Soy isoflavones (IF) are of particular interest for their possible estrogenic effects on the symptoms of menopause. The bioavailability of IF is clearly a factor influencing their biological activity. The first aim of this study was to elucidate the impact of the matrix process and especially the formulation of soy-based capsules on IF bioavailability. Twelve healthy volunteers were recruited for a randomized, double-blind, two-way crossover trial and received a single dose of the two soy-based formulations, one containing a pure soy standardized extract of IF, and the other containing soy flour in addition to the standardized extract of IF. Using a new and validated ELISA method, we measured the plasma and urinary concentrations of genistein, daidzein and its metabolite equol. Based on European Medicine Evaluation Agency recommendations, the main pharmacokinetic parameters allowed us to demonstrate the bioequivalence of the two formulations, indicating that the presence or absence of soy flour did not alter either the absorption or the elimination of daidzein and genistein. As bioequivalence was demonstrated, we pooled data collected during the two study-periods to address another original issue: Did the ability to produce equol affect the bioavailability of daidzein? We demonstrated that daidzein excretion was significantly lower in equol producers compared with equol non producers over the entire elimination period of the soy IF. This difference disappeared when equol excretion was added to daidzein excretion in equol producers. Our results indicated that the production of equol could partly explain the difference in daidzein bioavailability after IF ingestion.

Adult↗

PubMed2006

Myocardium distribution of sertindole and its metabolite dehydrosertindole in guinea-pigs.

Sertindole, like other atypical antipsychotics, has been shown to increase the action potential duration and QT interval in a concentration dependent manner, in in vitro electrophysiological studies. However, this does not always translate into increased duration of the QT interval, increased risk of torsade de pointes or sudden death in clinical practice. The reasons for these apparent discrepancies are unclear and many studies have underscored the importance of the interpretation of in vitro electrophysiological data in the context of other pharmacodynamic (e.g. cardiac ion channels target, receptor affinity) and pharmacokinetic parameters (total plasma drug concentration and drug distribution). To address the possible relevance of the concentrations used in experimental studies, the myocardium distribution of sertindole and its metabolite was determined after single and repeated intraperitoneal administration to guinea-pigs. The data suggest that the plasma concentration appears to predict the concentration in the myocardium and that the myocardium concentrations of sertindole are 3.1 times higher than plasma concentrations. Using these data, the relevance of in vitro electrophysiological studies to clinical plasma concentrations has been appraised.

Animals↗

PubMed2006

Postmortem redistribution of two antipsychotic drugs, haloperidol and thioridazine, in the rat.

Antipsychotic drugs may be associated with arrhythmia, ventricular fibrillation, or torsades de pointes, which can result in sudden death. These drugs could therefore be found in postmortem toxicological analyses of autopsy specimens following unexplained sudden death. The drug concentrations in tissues and body fluids change between the death and postmortem specimens collection because of postmortem redistribution. For this reason, it is often difficult to interpret the postmortem analysis. The aim of this study was to investigate postmortem redistribution of the two cardiotoxic antipsychotic drugs, haloperidol and thioridazine, in order to interpret the postmortem analysis. We have chosen the rat as an animal model. The rats received 1 mg/kg of haloperidol and 5 mg/kg of thioridazine by intraperitoneal injection. They were sacrificed and left at room temperature for 2, 6, 12, 24, or 48 h, at which times blood and tissue samples were taken. The drug analyses in tissues and blood were done using a liquid chromatography- tandem mass spectrometry method. Our results show that there is a redistribution of the two drugs from the lung to the cardiac blood. The concentration of the antipsychotic drugs in the lung decreased rapidly, whereas in the cardiac blood, this concentration increased within the first 2 h postmortem. By 48 h after death, the concentrations of the antipsychotic drugs were about twice as high as the initial concentrations in the cardiac blood. For the lungs, a decrease of 50% was observed between 0 and 48 h. Only myocardium and muscle concentrations did not change with the postmortem delay.

Animals↗

PubMed2006

Fully automated analytical method for mycophenolic acid quantification in human plasma using on-line solid phase extraction and high performance liquid chromatography with diode array detection.

We have developed a new fully automated method for mycophenolic (MPA) acid quantification in plasma to optimize therapeutic drug monitoring of tranplant patients. This method involved solid-phase extraction on disposable extraction cartridges and reversed-phase high-performance liquid chromatography with diode array detection. Solid-phase extraction was performed automatically by an automated sample with extraction catridges system. After washing, MPA was eluted from the cartridge onto a Chromolith RP-18e column. MPA and the internal standard were detected at 306 nm. The retention time of MPA was 6.3 minutes. The developed method was linear from 0.2 to 20 microg/mL. The limit of quantification was 0.2 microg/mL. The method showed a good precision with intraday and interday variation coefficient less than 6%. The intraday accuracy ranged from 97.6% to 100.4% and the interday accuracy varied from 97.1% to 100.8%. The extraction efficiency was greater than 90%. This method is simple and shows a good specificity with respect to commonly co-prescripted drugs.

Antibiotics, Antineoplastic↗

PubMed2005

Simplified ultraviolet liquid chromatographic method for determination of sertindole, dehydrosertindole and norsertindole, in human plasma.

An ultra-violet high-performance liquid chromatographic method was developed for the determination of sertindole, an atypical antipsychotic drug and its main metabolites dehydrosertindole and norsertindole, in human plasma. With a small sample volume, after a single-step liquid-liquid extraction, the compounds were separated on a reversed-phase XTerra RP(18) column, eluted with 45% of acetonitrile and 55% of ammonium acetate buffer (0.05 M, adjusted pH 8) and detected at 256 nm within 11 min. This method shows a good linearity for plasma concentration between 5-100 ng/ml and 100-1000 ng/ml, a good precision (inter and intra day CV < 11%) and a good inter-assay accuracy (bias < 11%). The limit of quantification concentration was 5 ng/ml. The absolute recovery of sertindole was higher than 99%. This rapid and sensitive method could be used for therapeutic drug monitoring as well as for overdose management.

Antipsychotic Agents↗

PubMed2005

Clonal analysis of HIV-1 variants in proviral DNA during treatment interruption in patients with multiple therapy failures.

BACKGROUND: Treatment interruption (TI) in antiretroviral-treated patients on virological failure (VF) often results in a shift from resistant to wild-type HIV-1 in plasma. A clonal analysis was set out to determine the importance of archiving of resistant HIV-1 variants during TI and its relationship with the occurrence of a VF after treatment resumption. METHODS: A fragment of the pol gene was cloned and sequenced from peripheral blood mononuclear cells DNA sampled at the end of TI. Clonal sequences were compared to bulk plasma sequences determined before TI, after TI and at VF. RESULTS: Four patients were enrolled; all had a complete reversion to wild-type HIV-1 at the end of TI. In two patients with subsequent VF, archiving of minority resistant variants was detected in proviral DNA. Archived resistant variants were found to be phylogenetically linked to sequences detected before TI and at VF, suggesting the re-expansion of resistant HIV-1 from archived quasi-species. CONCLUSION: In patients having a TI in the context of VF, archiving of resistant HIV-1 variants in proviral DNA can be involved into the mechanisms of further VF after treatment resumption.

Anti-HIV Agents↗

PubMed2005

Quantification of imatinib in human plasma by high-performance liquid chromatography-tandem mass spectrometry.

Imatinib, also known as Gleevec or Glivec, is a selective tyrosine kinase inhibitor currently used for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and for other malignant pathologies. We have developed a LC-MS-MS [corrected] method that could be used for imatinib therapeutic drug monitoring in plasma. After a liquid-liquid extraction, the imatinib and its deuterated internal standard were eluted on an XTerra RP18 column with a gradient of acetonitrile-ammonium formiate buffer 4 mmol/L, pH 3.2. Imatinib was detected by electrospray ionization mass spectrometry with multiple reaction-monitoring mode. The calibration curves were linear over the range 10-5000 ng/mL. The limit of quantification was set at 10 ng/mL. The bias was lower than 8%. Intra-day and inter-day precisions were lower than 8%. The extraction recovery was higher than 90%. This method is simple, adapted to routine application, and allows accurate therapeutic monitoring of imatinib. It can be used to evaluate patient adherence to daily oral therapy, drug-drug interactions, or pharmacokinetic/pharmacodynamic relationships.

Antineoplastic Agents↗

PubMed2005

Atypical antipsychotics: from potassium channels to torsade de pointes and sudden death.

Syncope and sudden death are features of schizophrenia that can be attributed to ischaemic heart disease, the use of antipsychotics (because of proarrhythmia or other reasons such as pharyngeal dyskinesia) or the psychiatric disease itself. Cases have been described with most antipsychotics and have led to the withdrawal, temporary suspension from the market or restricted use of antipsychotics, such as sultopride, droperidol, sertindole or thioridazine. Reviewing the available data shows that all antipsychotics tested affect the cardiac potassium channel, with the concentration that produces 50% inhibition (IC50) ranging from 1 nmol/L (haloperidol) to 6 micromol/L (olanzapine). Experimental in vitro or in vivo electrophysiological studies have shown a dose-dependent increase in the duration of the action potential with various degrees of indicators of serious arrhythmogenicity. However, this does not always translate clinically into an increased duration of the QT interval or increased risk of torsade de pointes or sudden death in clinical trials or pharmacoepidemiological studies. In turn, QT prolongation in clinical trials does not always translate to an increased risk of torsade de pointes or sudden death. The reasons for these apparent discrepancies are unclear and could be related to insufficiently powered field studies, low plasma and tissue drug concentrations with reference to in vitro data or drug effects on other receptors or ion channels that have a protective effect. Alternatively, risks that were not apparent from preclinical or clinical data could be related to the use of the drug in high-risk patients, metabolic interactions or other factors that would only be encountered in large postmarketing populations. The assessment of cardiovascular safety, both preclinical and during premarketing clinical trials, needs to be supported by appropriately powered pharmacoepidemiology studies.

Animals↗

PubMed2004

Determination of myocardium to plasma concentration ratios of five antipsychotic drugs: comparison with their ability to induce arrhythmia and sudden death in clinical practice.

Reviewing available data shows that most of antipsychotic drugs are associated with arrhythmia and sudden death. Experimental studies have shown a HERG channel blockade, a dose-dependent increase in duration of action potential or of QT interval, with various degrees of indicators of serious arrhythmogenicity. However, it seems difficult to relate these in vitro and in vivo preclinical models to clinical findings, in part, because the relationship between concentrations used and in vivo tissue concentrations during treatment in man is not known. Consequently, we established the myocardium to plasma concentration ratios for a series of antipsychotic drugs by intraperitoneal administration of different level doses to the guinea pig. Then, we compared these values to their ability to induce arrhythmia or torsade de pointes in clinical practice. The myocardium to plasma concentration ratios were 2.2 for clozapine, 2.7 for olanzapine, 3.1 for sertindole, 4.5 for risperidone, and 6.4 for haloperidol. These data suggest that when the ratio is higher than 4, arrhythmia and sudden death may be expected. On the contrary, when the ratio is less than 3, little effect may be predicted. These results underscore the importance of interpreting HERG channel data and electrophysiological data in the context of other pharmacokinetic parameters such as myocardium to plasma distribution.

Animals↗

PubMed2003

High-performance liquid chromatographic method with diode array detection for identification and quantification of the eight new antidepressants and five of their active metabolites in plasma after overdose.

A high-performance liquid chromatographic method is described for the determination of selective serotonin reuptake inhibitors (fluvoxamine, paroxetine, sertraline, fluoxetine, citalopram, mirtazapine), serotonin norepinephrine reuptake inhibitors (milnacipram, venlafaxine), a noradrenergic and specific serotoninergic antidepressant (mirtazapine), and five pharmacologically active metabolites (desmethylcitalopram, didesmethylcitalopram, norfluoxetine, O-desmethylvenlafaxine, desmethylmirtazapine). After a double-step liquid-liquid extraction, compounds are separated on a Symmetry C8 column eluted with a gradient of acetonitrile-phosphate buffer 10 mM pH 3.8 and detected at 230 nm and 290 nm. Calibration curves were linear in the range 25 to 500 ng/mL (100-2000 ng/mL for venlafaxine and its metabolite). The limit of quantification was 25 ng/mL (100 ng/mL for venlafaxine and its metabolite). For all quality controls good accuracy was achieved (93% to 99.5%) with intraday and interday variation coefficients less than 12%. This method allows simple and rapid (run time 18 min) identification and quantification of the eight new antidepressants and five of their active metabolites. This method can be used for toxicologic purpose.

Antidepressive Agents↗

PubMed2002

In vivo and in vitro myocardial binding of risperidone and 9-hydroxyrisperidone.

Antipsychotic drugs have been found to prolong the QT interval, a phenomenon that, when severe, may facilitate the occurrence of complex ventricular arrhythmia such as torsade de pointes. Concentration-dependent QT prolongation has been demonstrated in vitro with such recent drugs as risperidone on Purkinje fibers and in isolated feline hearts. In vivo, there appears to be a relationship between plasma levels and QTc prolongation. This study was designed to estimate cardiac levels in vivo during treatment. For that purpose, we examined both in vivo and in vitro the ratio between plasma and cardiac tissue concentrations of risperidone and its active metabolite 9-hydroxyrisperidone. Binding parameters for different concentrations were determined in vitro by equilibrium dialysis. In vivo, they were determined by intraperitoneal administration of three doses in the guinea pig. Drug concentrations were determined by a high-performance liquid chromatography method with UV detection developed for that purpose. For risperidone, plasma protein binding varied from 67 to 43% and cardiac homogenate binding varied from 90 to 78%. 9-Hydroxyrisperidone values were lower. Tissue levels were 4.5-fold higher than plasma levels. Binding parameters were similar both in vivo and in vitro. From this model, the relevance of in vitro electrophysiological studies to clinical plasma concentrations can be approached.

Animals↗

PubMed2002

High-performance liquid chromatographic method for the simultaneous determination of the six HIV-protease inhibitors and two non-nucleoside reverse transcriptase inhibitors in human plasma.

A selective and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the determination of the six human immunodeficiency virus (HIV)-protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir) and the non-nucleoside reverse transcriptase inhibitors (efavirenz and nevirapine) in a single run. After a liquid-liquid extraction with diethyl ether, the six protease inhibitors and the two non-nucleoside reverse transcriptase inhibitors are separated on a Stability RP18 column eluted with a gradient of acetonitrile and phosphate buffer 50 mmol/L pH 5.65. A sequential ultraviolet detection (5-minute sequence set at 240 nm for nevirapine acquisition, 22-minute sequence set at 215 nm for other antiretroviral drugs acquisition followed by a sequence set at 260 nm for internal standard acquisition) allowed for simultaneous quantitation of the six protease inhibitors, nevirapine, and efavirenz. Calibration curves were linear in the range 100 ng/mL to 10,000 ng/mL. The limit of quantitation was 50 ng/mL for all drugs except nevirapine (100 ng/mL). Average accuracy at four concentrations ranged from 88.2% to 110.9%. Both interday and intraday coefficients of variation were less than 11% for all drugs. The extraction recoveries were greater than 62%. This method is simple and shows a good specificity with respect to commonly co-prescribed drugs. This method allows accurate therapeutic monitoring of amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, efavirenz, and nevirapine.

Alkynes↗

PubMed2002

Pharmacokinetic interaction between high-dose methotrexate and oxacillin.

An 18-year-old man received two high-dose methotrexate cycles for the treatment of an osteosarcoma. Fifteen grams of methotrexate were infused over 6 hours. During the second cycle, co-administration of oxacillin (1g/8h) resulted in prolonged and marked elevation of methotrexate plasma concentrations. The patient experienced acute toxicity with renal failure, myelosuppression, mucitis, fever, and dermatologic abnormalities. After an initial improvement with folinic acid rescue and hemodialysis, the patient died. Oxacillin may thus inhibit the elimination of methotrexate.

Adolescent↗

PubMedDate not supplied

Identification and quantitation by high-performance liquid chromatography of mancozeb following derivatization by 1,2-benzenedithiol.

Ethylenebisdithiocarbamate (EBDC) fungicides are the most important class of organic fungicides and exhibit a high degree of carcinogenicity, mutagenicity, and neurotoxicity. For that reason, the safe application of these fungicides in practice requires a convenient method for their determination, applicable to biological fluids. We describe a high-performance liquid chromatography (HPLC) assay. After elimination of the metal which defines the product (maneb, mancozeb, zineb.) with EDTA, the resulting EBDC is derivatized with 1,2-benzenedithiol to yield a cyclocondensation product, 1,3-benzodithiole-2-thione, which can then be quantitated by reversed-phase HPLC at 365 nm using a microBondapak C18 column. The mobile phase was methanol/H2O (70:30, v/v). The assay was linear from 0.25 to 100 microg/mL. Within- and between-day precision and accuracy for this assay were better than 9% and 6%, respectively. The lower limits of detection and quantitation were estimated to be 0.1 and 0.25 microg/mL, respectively. This simple new method has been applied to determine mancozeb concentration in rat urine samples from urinary excretion studies.

Animals↗