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Mathieu Molimard

Publications and source records attributed to Mathieu Molimard.

At least 19 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

Increased secretion of leukemia inhibitory factor by immature airway smooth muscle cells enhances intracellular signaling and airway contractility.

Airway smooth muscle cells (ASMC) play a major role in airway inflammation, hyperresponsiveness, and obstruction in asthma. However, very little is known regarding the relation between inflammatory mediators and cytokines and immature ASMC. The aim of this study was to evaluate 1) the secretion of leukemia inhibitory factor (LIF) (an IL-6 family neurotrophic cytokine) by ASMC; 2) intracellular calcium concentration ([Ca(2+)](i)) signaling; and 3) the effect of LIF on mast cell chemotaxis and rat airway contractility. Immature and adult human ASMC were cultured. ELISA and real-time PCR were performed to assess LIF protein secretion and mRNA production, [methyl-(3)H]thymidine incorporation to quantify ASMC DNA synthesis, a Boyden chamber to evaluate the effect of LIF on mast cell chemotaxis, microspectroflurimetry using indo-1 (at baseline and after stimulation bradykinin, U-46619, histamine, and acetylcholine, in the presence or absence of LIF or TNF-alpha) for [Ca(2+)](i) signaling, and isolated rat pup tracheae to determine the effect of LIF on airway contractility to ACh. TNF-alpha-stimulated immature ASMC produce more LIF mRNA and protein than adult ASMC, although this cytokine induces a moderate increase in DNA synthesis (+20%) in adult ASMC only. Human recombinant LIF exerts no chemotactic effect on human mast cells. In immature ASMC, ACh-induced [Ca(2+)](i) response was enhanced twofold after incubation with LIF, whereas TNF-alpha increased the [Ca(2+)](i) to U-46619 threefold. In TNF-alpha-exposed adult ASMC, [Ca(2+)](i) responses to ACh were of greater magnitude (sixfold increase) than in immature ASMC. Human recombinant LIF increased contractility to ACh by 50% in immature, isolated rat tracheae. Stimulated immature human ASMC greatly secrete LIF, thus potentially contributing to neuroimmune airway inflammation and subsequent remodeling. Increased LIF secretion enhances airway reactivity and [Ca(2+)](i) signaling.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
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

A new method for assessing drug causation provided agreement with experts' judgment.

BACKGROUND AND OBJECTIVE: The many methods proposed for causality assessment of adverse drug reaction (ADR) generally rely on algorithms. They have no clear relationship to probabilities, however, a situation we attempted to improve. STUDY DESIGN AND SETTING: Thirty ADR cases corresponding to 32 suspect drugs were randomly selected from the French pharmacovigilance database. The statistical weighting was performed by using a multilinear regression with logit(p) as the dependent variable and seven judgment criteria as independent variables. The best model (i.e., giving the best correlation with the gold standard) was retained for the new causality assessment method. RESULTS: The weights [logit(p)] for the 21 choices, on average three for each of the seven criteria, ranged from -3.95 to 0.86, secondarily rounded to multiples of 0.5. The correlation between the probability obtained from the final method and the gold standard was quite good (R(2) = .92). CONCLUSION: This method based on the rational weighting of seven causality criteria is straightforward to use and provides very good agreement with experts' judgment. Moreover, unlike most classical algorithms, it respects one basic rule of probabilities-namely, a symmetrical probability distribution for drug causation around the .5 neutral position (maximum uncertainty).

Adverse Drug Reaction Reporting Systems↗
PubMed2006

Underdiagnosis of nocturnal symptoms in asthma in general practice.

OBJECTIVE: To evaluate the prevalence of nocturnal symptoms in a large sample of asthmatic patients, and to assess the agreement between patients' complaints and general practitioners' (GPs') reports in primary care. DESIGN: Cross-sectional survey involved 3,526 GPs and 751 specialists (pulmonologists and allergists) and included 13,493 patients with persistent asthma. Symptoms, treatment, and social and medical data were collected in real time by the patients and their GPs. SETTING: France. RESULTS: Prevalence of nocturnal symptoms was 60%. A total of 7,989 patients with nocturnal symptoms had complete data for both patients and GPs; 3,849 (48.1%) had perfect agreement between GP and their complaints for nocturnal symptoms (agreement group; [kappa = 1]); 3,376(42.2%) declared having no symptoms during the night, but these were detected by the GP during the visit (underestimated by patients and detected by GPs); 773(9.6%) declared having nocturnal symptoms, but these were not detected by GPs. Patients with a good agreement with their GP's opinion were significantly more frequently followed-up by a specialist than other patients (p = 0.002). CONCLUSIONS: Nocturnal symptoms appear to be underdeclared by patients. GPs should therefore systematically ask their patients about nocturnal symptoms to increase control of asthma and to adequately manage its treatment.

Asthma↗
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

Psychiatric disorders and their comorbidity in subjects with parasuicide by intentional drug overdose: prevalence and gender differences.

The aims of the present study were to assess the prevalence and comorbidity of psychiatric disorders in subjects with intentional drug overdose and to explore whether there were gender differences in prevalence and comorbidity. A standardized psychiatric evaluation was performed in 100 randomly selected subjects, 18 years old and older, with intentional drug overdose referred to an emergency department. The prevalences of psychiatric morbidity and comorbidity were very high in both genders: 88% presented with at least one psychiatric diagnosis, and three-quarters presented with comorbid psychiatric disorders. Affective and anxiety disorders were the most prevalent diagnoses. One patient out of three presented with alcohol or substance misuse. Compared to females, males suffered five times more often from substance misuse and three times more often from psychotic syndrome and were three times less likely to present with anxiety disorder. When subjects are referred to hospital for intentional drug overdose, medical management should systematically involve a psychiatric assessment in order to identify not only affective and anxiety disorders, but also alcohol and substance misuse, due to the high prevalence of these disorders, especially in male subjects.

Adolescent↗
PubMed2005

Agreement of expert judgment in causality assessment of adverse drug reactions.

BACKGROUND: Global introspection is, with operational algorithms and Bayes' theorem, one of the three main approaches used to assess the causal relationship between a drug treatment and the occurrence of an adverse event. OBJECTIVE: To analyze and compare the judgments of five senior experts using global introspection about drug causation on a random set of putative adverse drug reactions. METHODS: A random sample of 150 drug-effect pairs was constituted. For each pair, five senior experts had to independently assess the probability of drug causation from 0 to 1 by using a 100 mm visual analog scale (VAS). For analysis, those probabilities were secondarily split into seven levels of causality: excluded (0-0.05); unlikely (0.06-0.25); doubtful (0.26-0.45); unassessable/unclassifiable (0.46-0.55); plausible (0.56-0.75); likely (0.75-0.95); and certain (0.95-1). Agreement among the five experts was assessed using kappa coefficients (kappa). RESULTS: The overall agreement between experts was poor (kappa=0.20), although significantly different from chance, and varied according to the level of causality. It was lower for the unlikely, doubtful, unassessable/unclassifiable, and plausible categories (kappa=0.03, 0.03, -0.01, and 0.13, respectively) than for VAS extremes: excluded, likely, and certain (kappa=0.40, 0.32, and 0.30, respectively). CONCLUSION: This study confirms that experts express marked disagreements when assessing drug causality independently. The agreement rate was lower for intermediate levels of causality, especially when strong evidence was lacking for confirming or ruling out drug causality. Therefore, in a decision-making context, a step-by-step consensual approach such as the Delphi method seems necessary to make the assessment of such cases more reliable.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Total reversibility testing as indicator of the clinical efficacy of formoterol in COPD.

RATIONALE: The Global Initiative for Chronic Obstructive Lung Disease guidelines recommend bronchodilator reversibility testing to guide treatment decisions. This study evaluated the relationship between the change in forced expiratory volume in 1 s (FEV1) with salbutamol or formoterol and the clinical effects of a 4-week formoterol (Foradil) treatment. METHODS: At Visit 1, patients (n = 448) with stable chronic obstructive pulmonary disease took an FEV1 reversibility test using 200 microg salbutamol via a metered dose inhaler. At Visit 2 (Day 0), an FEV1 reversibility test was performed using formoterol via a dry-powder inhaler (Aerolizer). Patients then received formoterol 12 microg twice daily until Visit 3 (Day 21-30), when a further formoterol FEV1 reversibility test was performed. Clinical parameters included FEV1, symptom questionnaires and rescue medication use. RESULTS: There was no significant relationship between the immediate change in FEV1 with salbutamol and the absolute change from baseline in FEV1, symptom scores or rescue medication use after a 4-week formoterol treatment. Relative immediate change in FEV1 with formoterol was correlated with change in rescue medication use (P = 0.02) and FEV1 at Visit 3 (P < 0.001). Total reversibility in FEV1 with formoterol (post-dose Visit 3-pre-dose Visit 2) was correlated with all treatment efficacy variables (P<0.01). CONCLUSIONS: Immediate salbutamol reversibility testing, as performed under these study conditions, failed to predict the clinical efficacy of formoterol. Total reversibility after 4 weeks of formoterol treatment may be a better predictor of clinical benefits of long-term bronchodilator therapy.

Administration, Inhalation↗
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

Improvement of asthma control with beclomethasone extrafine aerosol compared to fluticasone and budesonide.

Qvar Autohaler efficacy on asthma control, assessed with E. Juniper asthma control questionnaire (ACQ), was compared with fluticasone and budesonide. An open randomized study, stratified (2:1) on the intake of long-acting beta2-mimetics (LAbeta2), was performed in patients with moderate to severe poorly controlled asthma (defined by at least one nocturnal discomfort in the last 5 days or a mean of 2 puffs of short-acting beta2-mimetics in the last 7 days or exercise dyspnea) despite treatment with beclomethasone < or = 1000 microg/day (or equivalent). 460 patients received Qvar Autohaler 800 microg/day (n = 149), fluticasone Diskus 1000 microg/day (n = 149) or budesonide Turbuhaler 1600 microg/day (n = 162) during 12 weeks. Asthma control improved in all groups, with no difference between groups. For patients treated with LAbeta2 (n = 286) a significantly greater improvement of the ACQ score was obtained with Qvar Autohaler versus fluticasone (1.0 +/- 1.0 vs. 0.6 +/- 0.9; P = 0.019), but not versus budesonide (0.9 +/- 0.9). Pulmonary function test improvements were similar in the 3 groups. The significant improvement in asthma control in patients receiving LAbeta2 suggests potential advantages for extrafine aerosols as part of anti-inflammatory treatment optimization.

Administration, Inhalation↗
PubMed2005

Pharmacological approach to evaluate aerosol pulmonary deposition.

Drug delivery to the lung in vivo may be assessed using pharmacokinetic or pharmacodynamic techniques. The choice of method depends on drug class specificities. Pharmacokinetic determination of deposition to the lung for drugs without hepatic first-pass effect, such as short acting beta2-agonists, has to be done shortly after inhalation to minimize the effect of gastrointestinal absorption. For medication undergoing important hepatic first-pass metabolisation, such as inhaled corticosteroid, plasma concentration indirectly reflects bronchial deposition. The pharmacodynamic profile should be assessed through clinical effects and adverse events induced by inhaled drugs. Dose ranking of lung deposition for bronchodilators requires patient selection with sufficient bronchial obstruction to maintain room for improvement after the first dose. To assess dose effect relationship between inhaled corticosteroid, the Finney parallel line bioassay is the reference method with a study period of at least 6 weeks. Analysis of side effects with high doses of beta2-agonists or inhaled corticosteroids may also be used to compare lung deposition. Finally, pharmacological evaluation of lung deposition provides complementary information to scintigraphic studies, based on their clinical relevance.

Administration, Inhalation↗
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

Drugs with anticholinergic properties and cognitive performance in the elderly: results from the PAQUID Study.

OBJECTIVES: To measure the association between the use of drugs with anticholinergic properties and cognitive performance in an elderly population, the PAQUID cohort. METHODS: The sample studied was composed of 1780 subjects aged 70 and older, living at home in South western France. Data on socio-demographic characteristics, medical history and drug use were collected using a standardized questionnaire. Cognitive performance was assessed using the following neuropsychological tests: the Mini-Mental State Examination (MMSE) which evaluates global cognitive functioning, the Benton Visual Retention Test (BVRT) which assesses immediate visual memory, and the Isaacs' Set Test (IST) which assesses verbal fluency. For each test, scores were dichotomized between low performance and normal to high performance using the score at the 10th percentile of the study sample as the cut-off point, according to age, gender and educational level. The association between the use of drugs with anticholinergic properties and cognitive performance was examined using logistic regression models, adjusting for several potential confounding factors. RESULTS: About 13.7% of the subjects used at least one drug with anticholinergic properties. In multivariate analyses, the use of these drugs was significantly associated with low performance in the BVRT [odds ratio (OR) = 1.6; 95% confidence interval (CI) 1.1, 2.3] and in the IST (OR = 1.9; 95% CI 1.3, 2.8). The association found with low performance in the MMSE (OR = 1.4; 95% CI 1.0, 2.1) was barely statistically significant. CONCLUSION: These findings suggest that the use of drugs with anticholinergic properties is associated with low cognitive performance among community-dwelling elderly people.

Aged↗
PubMed2005

How to achieve good compliance and adherence with inhalation therapy.

The correct use of inhaler devices is an inclusion criterion for all studies comparing inhaled treatments. However, in real life patients make many errors when inhaling their medication which may negate the benefits observed in clinical trials. A recently published observational study evaluated inhaler handling in 3811 patients for at least 1 month using the Aerolizer, Autohaler, Diskus, pressurised metered dose inhaler (pMDI) or Turbuhaler devices. Inhalation errors were considered critical if they could have substantially affected drug delivery to the lung. The two most common errors made by patients were device-independent errors and included not breathing out before actuation of the device (28.9%) and failure to breath-hold for a few seconds after inhalation (28.3%). These errors were observed in 40%-47% of patients. The number of patients making at least one error with breath-actuated inhalers was high; with less than 50% of patients inhaling correctly. Seventy-six per cent of patients made at least one error with pMDI compared to 49%-55% with breath-actuated inhalers. With respect to device-dependent errors, the pMDI fared worst with 69% of patients exhibiting at least one error, closely followed by the Turbuhaler (32%) and Autohaler (41%). Critical errors were made by only 11%-12% of patients treated with Aerolizer, Autohaler or Diskus compared to 28% and 32% of patients treated with pMDI and Turbuhaler, respectively. Over-estimation of good inhalation by GPs was maximal for Turbuhaler (24%) and lowest for Autohaler and pMDI (6%). Ninety per cent of GPs felt that participation in the study would improve error detection. Compliance may be improved by educating patients and physicians in the correct use of inhaler devices. Inhalers should be easy to use correctly, and have multiple feedback and control mechanisms which would reduce physician over-estimation of a correct inhalation, allow compliance to be monitored, facilitate patient self-education and give reassurance to patients in the real life setting.

Administration, Inhalation↗
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↗