The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Frédéric J. Baud - One of the best experts on this subject based on the ideXlab platform.
-
toxicodynetique au cours des intoxications par l alprazolam et le bromazepam
Revue Neurologique, 2021Co-Authors: Frédéric J. Baud, Mohamed Ali Saphia, Villa AntoineAbstract:Introduction La toxicodynetique etudie l’evolution temporelle des principales manifestations cliniques lors des intoxications aigues [1] . Objectifs L’objectif principal de l’etude etait de rapporter les parametres toxicodynetiques des intoxications aigues mono-medicamenteuses a l’alprazolam et au bromazepam. Patients et methodes Les donnees du centre antipoison de Paris recueillies de 1999 a 2015. Les cas de mono-intoxications a l’alprazolam et au bromazepam ont ete selectionnes en eliminant la prise d’alcool concomitante. Les parametres toxicodynetiques etaient l’Emax observe (effet clinique maximal) et l’index de toxicite (IT) (rapport entre la dose supposee ingeree et la dose quotidienne maximale recommandee). Resultats Au total, 554 et 2067 cas de mono-intoxications a l’alprazolam et au bromazepam ont ete inclus. L’Emax observe pour l’alprazolam et le bromazepam etait un coma survenant dans 5 et 25 cas, respectivement. L’IT median etait de 6,7 et 1,25, pour le bromazepam et l’alprazolam. Aucun patient comateux n’etait traite auparavant par les medicaments d’interet. La mediane d’apparition du coma etait de 75 min pour le bromazepam, non definie pour l’alprazolam. Mais le delai median des appels apres intoxication a l’alprazolam etait de 30 min. Discussion La comparaison de l’alprazolam et du bromazepam au Nordazepam et a l’oxazepam [2] montre que toutes les benzodiazepines n’induisent pas de coma. Le Nordazepam n’en induit pas, l’oxazepam uniquement a tres forte dose alors qu’alprazolam et bromazepam induisent des comas pour des IT proches des doses maximales recommandees. Dans tous les cas, le coma n’est survenu que chez des sujets naifs, non traites par ces medicaments. Conclusion Une molecule recoit une autorisation de mise sur le marche, l’etude toxicologique doit se faire par molecule et non par classe. L’approche toxicodynetique y contribue.
-
toxicodynetique au cours des intoxications par l alprazolam et le bromazepam
Toxicologie Analytique et Clinique, 2017Co-Authors: Mohamed S Ali, Antoine Villa, R Garnier, Frédéric J. BaudAbstract:Objectifs La toxicodynetique definit l’evolution temporelle des manifestations cliniques apres ingestion de medicaments (seuls ou en association). L’objectif principal de l’etude etait de rapporter les parametres toxicodynetiques des mono-intoxications a l’alprazolam et au bromazepam. Methodes Les donnees du centre antipoison (CAP) de Paris etaient recueillies de 1999 a 2015. Les cas de mono-intoxications a l’alprazolam et au bromazepam ont ete selectionnes en eliminant la prise d’alcool concomitante. Les parametres toxicodynetiques evalues etaient l’Emax observe (effet clinique maximal observe pour le signe ou le symptome d’interet) et l’index de toxicite (IT) (rapport entre la dose supposee ingeree et la dose quotidienne maximale recommandee). Resultats Au total, 554 et 2067 cas de mono-intoxications a l’alprazolam et au bromazepam ont ete inclus, respectivement. L’Emax observe pour l’alprazolam et le bromazepam etait un coma survenant dans 5 et 25 cas, respectivement. L’IT etait de 6,7 et 1,25, pour respectivement le bromazepam et l’alprazolam. Parmi les patients ayant presente un coma apres ingestion d’alprazolam ou de bromazepam, aucun n’etait traite par les medicaments d’interet. La mediane du delai d’apparition du coma etait de 75 min pour le bromazepam. Elle n’etait pas connue pour l’alprazolam. Cependant, le delai median des appels au CAP apres intoxication a l’alprazolam etait de 30 min. Le coma parait s’etre installe dans des delais tres courts, de l’ordre de la dizaine de minutes apres l’ingestion. Conclusion La methode toxicodynetique permet de determiner des parametres cliniques d’importance majeure durant l’evolution de surdosages par l’alprazolam et le bromazepam et leurs effets maximaux. En comparant les effets neurologiques de l’alprazolam et du bromazepam au Nordazepam et a l’oxazepam etudies precedemment [1] , nous pouvons conclure que tous les anxiolytiques n’entrainent pas de coma. L’oxazepam et de Nordazepam n’induisent pas de coma, meme pour un IT median de l’ordre de 20 pour le Nordazepam, alors que l’alprazolam et le bromazepam peuvent induire des comas. Mais dans les deux cas, il est notable que le coma n’est survenu que chez des sujets naifs, non traites par les medicaments d’interet. Une surveillance rapprochee est conseillee, plus particulierement pour les patients ayant pris de l’alprazolam, car ce dernier entraine des comas a des doses proches des doses therapeutiques.
-
toxicodynetics in mono intoxications with oxazepam and Nordazepam an approach to a better understanding of drug drug interaction and quality control of data collection
Toxicologie Analytique et Clinique, 2016Co-Authors: A Villa, Frédéric J. Baud, R Garnier, L SacreAbstract:Introduction We are currently developing a new discipline entitled “toxicodynetics” aiming at defining the time-course of major clinical events of toxicants either alone or in combination. Oxazepam and Nordazepam are frequently involved in drug overdose. The major aim of the present study was to report the toxicodynetic parameters in mono-intoxications with oxazepam or Nordazepam. The second objective was to retrospectively assess the ability of toxicodynetic parameters to assess the quality in collecting data at a PCC for a defined substance. Methods Data were collected at the Paris Poison Control Centre (PPCC) from 1999 to 2015. Cases of oxazepam or Nordazepam involved alone in poisonings were selected on the basis of self-report, with a particular attention paid to eliminate the concomitant alcohol ingestion [1] . The toxicodynetic parameters included – the supposed ingested dose, expressed as a therapeutic index (TI) defined by the ratio of the maximum recommended daily dose to the supposed ingested dose; – the time of ingestion (T0), the delay in onset (hours); – the rate of worsening; – the maximal observed effect (Emax); – the time of onset of the maximal effect (Tmax); – the shape of the duration of maximal effect; – the rate of recovery; – the duration of hospitalization in uncomplicated poisoning cases. Results Two hundred and fifty-seven and 74 cases of oxazepam and Nordazepam poisonings were studied. T0 was known in all cases (100%). The Emax for oxazepam and Nordazepam was sleepiness or obtundation occurring in 108 and 36 cases, respectively. Coma was never used to qualify alteration in consciousness. The median delay in onset was 1 h in both poisonings. In both poisonings, there was no reported delay in onset of the Emax, which was reported on a “on-off” mode. The median TI were 19.6- and 3.3-fold the maximum therapeutic recommended dose for Nordazepam and oxazepam, respectively. Long-term follow-up of the poisoned patients was performed in only 13 and 19% of the Nordazepam and oxazepam poisoning cases, respectively. Conclusion The results and others [1] showed that neither Nordazepam nor oxazepam are a cause of coma by themselves in the range of studied doses. The study supports the hypothesis of the underestimated role of drug–drug interactions in drug-induced coma. The toxicodynetic approach unveiled the ability of data routinely collected in PCC to describe the phases up to the Emax and the plateau phase. Long-term follow-up might be improved, at per request owing to the toxicity of the substance of interest, however, to prevent wasting time of the attending poison control staff.
-
effects of various combinations of benzodiazepines with buprenorphine on arterial blood gases in rats
Basic & Clinical Pharmacology & Toxicology, 2008Co-Authors: Stephane Pirnay, Patricia Risede, Bruno Megarbane, Claire Monier, Stephen W. Borron, Ivan Ricordel, Frédéric J. BaudAbstract:Abstract: Fatalities have been attributed to combinations of high-dose buprenorphine with benzodiazepines. In rats, high-dose buprenorphine combined with midazolam was shown to induce sustained respiratory acidosis, while buprenorphine alone did not. However, the effects of buprenorphine combined with pharmacological doses of benzodiazepines remain unknown. Our objective was to compare the acute effects of four selected benzodiazepines used intravenously at equi-efficacious doses in rats, alone and in combination with buprenorphine on sedation, respiratory rate and arterial blood gases. Buprenorphine (30 mg/kg) did not significantly modify sedation level or respiratory rate, but induced mild and transient effects on pH and PaCO2 (P < 0.05). Similarly, despite having no effects on respiratory rate, nordiazepam (10 mg/kg), bromazepam (1 mg/kg) and oxazepam (12 mg/kg) mildly and transiently altered pH and PaCO2 (P < 0.05), whereas clonazepam (5 mg/kg) did not. Buprenorphine combined with each benzodiazepine induced no significant effects on respiratory rate or blood gases, in comparison with buprenorphine alone. However, combinations of oxazepam or nordiazepam with buprenorphine significantly deepened sedation. While both combinations reduced respiratory rate, buprenorphine + 30 mg/kg clonazepam significantly increased PaCO2 and buprenorphine + 30 mg/kg nordiazepam decreased PaO2. In conclusion, not all benzodiazepines induce significant respiratory depression at therapeutic doses. We were unable to demonstrate significant effects on rat ventilatory parameters of buprenorphine combined with equi-efficacious pharmacological doses of benzodiazepines in comparison with buprenorphine alone. Our results may suggest that effects of these combinations are rather mild. Respiratory failure may, however, result from the association of buprenorphine with elevated doses of benzodiazepines.
J Masse - One of the best experts on this subject based on the ideXlab platform.
-
lyoavailability of Nordazepam solid dispersions in relation with phase diagrams
International Journal of Pharmaceutics, 1994Co-Authors: El A Moussaoui, A Chauvet, J Masse, D Gaudy, A PuechAbstract:Abstract We have prepared solid dispersions (melt, coprecipitate) of Nordazepam III (NDZ) with carriers polyoxyethylene glycol (PEG 6000), succinic acid, and with another drug, nicotinic acid, corresponding to the eutectic composition. From a study of the dissolution kinetics, we found that the highest value is obtained for the PEG 6000 melt. We have shown that there is a good correlation between PEG solid dispersion dissolution kinetics and mixing enthalpies.
-
etude des interactions a l etat solide du Nordazepam iii polyoxyethylene glycol 6000 et Nordazepam iii acide succinique
Journal of Thermal Analysis and Calorimetry, 1993Co-Authors: El A Moussaoui, A Chauvet, J MasseAbstract:We have determined the eutectic composition Nordazepam (NDZ) polyoxyethylene glycol 6000 (PEG): 4% NDZ, 96% PEG (Tf=59,0±0,5°C ΔHf=155,9±2,4 J·g−1; NDZ succinic acid: 0,32n (NDZ) and 0,68n (succinic acid) (Tf=163,8±0,4°C and ΔHf=119,34±2,1 J·g−1). No solid solution has been found. The negative and high absolute value of mixing enthalpy indicates that the eutectic composition is formed by interactions between OH, CO, NH groups of carrier and drug with hydrogene bonds formation, confirmed by X-ray diffraction.
-
etude de l interaction a l etat solide du binaire Nordazepam iii acide nicotinique
Journal of Thermal Analysis and Calorimetry, 1993Co-Authors: El A Moussaoui, A Chauvet, J MasseAbstract:The thermal behaviour of initial nicotinic acid shows a solid-solid transition T t =178,.8±0,6 o C ΔH t =0,78±0,01 kJ.mol -1 and melting T f =236,6±0,7 o C ΔH f =26,7±0,4 kJ.mol -1 ; after trituration (b) transitions temperatures and enthalpies are modified.
-
regular papersetude thermoanalytique et spectrale de benzodiazepines partie 2 Nordazepam
Thermochimica Acta, 1992Co-Authors: A Chauvet, El A Moussaoui, J MasseAbstract:Continuing our investigation of the thermal and spectral behaviour of benzodiazepines we have studied Nordazepam. After crystallization in various solvents at different temperatures the samples show thermal and spectral behaviour which allows us to characterize the polymorphism and pseudopolymorphism of Nordazepam. We have obtained form I after transition at 213.0 ± 0.5°C (Tf = 221.3±0.6°C; ΔH = 24.45 ± 0.75 kJ mol−1), form II (Tf = 216.7±0.4°C; ΔH = 34.00 ±0.49 kJ mol−1) form III (Tf = 216.0 ± 0.6°C; ΔH = 27.40 ± 0.58 kJ mol−1) form IV (Tf=214.2±0.3°C; ΔH= 33.62 ± 0.40 kJ mol−1) and a solvate (5-1) Nordazepam-dioxane.
Jean-michel Gaulier - One of the best experts on this subject based on the ideXlab platform.
-
unusual pattern in hair after prazepam exposure
Toxicologie Analytique et Clinique, 2014Co-Authors: Julie Maublanc, S Dulaurent, Laurent Imbert, Pascal Kintz, Jean-michel GaulierAbstract:Summary Prazepam is known to be totally and quickly metabolized in nordiazepam, oxazepam, and 3-hydroxyprazepam after oral intake, and consequently to be undetectable in blood or in urine. The authors reported a case of positive findings of prazepam in hair. After a drug-facilitated sexual assault (DFSA), a large screening for benzodiazepines, hypnotics and other psychotropic drugs was performed in the victim's hair sample, collected one month after the aggression. The positive analytical findings were firstly, zolpidem presence in the hair segment corresponding to the DFSA period (zolpidem was afterwards identified as the used weapon for the DFSA), and secondly, prazepam (together with nordiazepam) presence in all the analysed hair segments. This last result was in connection with the regular prazepam treatment of the victim (LYSANXIA, at a dose of 3 × 10 mg tablets per day). The presence in hair of a parent compound, which is not usually detected in blood or in urine is not incongruous, as attested by the presence of heroin in addicts’ hair. However, the possibility of prazepam presence in hair raises questions about the analytical methods that do not look for this benzodiazepine in hair, and worse still about those using prazepam as aninternal standard. Indeed, in case of the presence of prazepam in hair, theses analytical methods will not only be incapable of detecting prazepam, but, they will also underestimate the concentrations of other benzodiazepines sought at the same time.
-
mise en evidence de prazepam dans du sang post mortem apres intoxication par le paracetamol le dextropropoxyphene et le prazepam
Annales De Toxicologie Analytique, 2013Co-Authors: Francois Mathiaux, Bernard Magret, Gérard Lachâtre, Jean-michel GaulierAbstract:Objectif : Le prazepam est largement et rapidement metabolise apres ingestion. Sa detection dans le sang est de ce fait exceptionnelle. Nous rapportons le cas d’une polyintoxication par le prazepam, le dextropropoxyphene et le paracetamol pour laquelle une concentration significative de prazepam a ete relevee dans le sang post-mortem . Methode : Une expertise toxicologique a ete realisee par differentes techniques, incluant la chromatographie liquide avec detections par spectrophotometrie et spectrometrie de masse en tandem, et la chromatographie gazeuse avec spectrometrie de masse. Resultats : Il a ete detecte dans le sang les xenobiotiques suivants : dextropropoxyphene a une concentration de 6420 μ g/L, paracetamol a une concentration de 342 μ g/L, prazepam a une concentration de 178 μ g/L, Nordazepam et oxazepam aux concentrations respectives de 2517 μ g/L et 113 μ g/L. Conclusion : Deux hypotheses sont proposees pour expliquer la presence de prazepam : une interaction medicamenteuse et/ou une necrose hepatique induite par l’intoxication au paracetamol.
-
article original original article mise en evidence de prazepam dans du sang post mortem apres intoxication par le paracetamol le dextropropoxyphene et le prazepam prazepam detection in post mortem blood after acetaminophen dextropropoxyphene and praz
2013Co-Authors: Francois Mathiaux, Bernard Magret, Gérard Lachâtre, Jean-michel GaulierAbstract:Resume – Objectif : Le prazepam est largement et rapidement metabolise apres ingestion. Sa detection dans le sang est de ce fait exceptionnelle. Nous rapportons le cas d’une polyintoxication par le prazepam, le dextropropoxyphene et le paracetamol pour laquelle une concentration significative de prazepam a ete relevee dans le sang post-mortem. Methode : Une expertise toxicologique a ete realisee par differentes techniques, incluant la chromatographie liquide avec detections par spectrophotometrie et spectrometrie de masse en tandem, et la chromatographie gazeuse avec spectrometrie de masse.Resultats : Il a ete detecte dans le sang les xenobiotiques suivants : dextropropoxyphene a une concentration de 6420 µg/L, paracetamol a une concentration de 342 µg/L, prazepam a une concentration de 178 µg/L, Nordazepam et oxazepam aux concentrations respectives de 2517 µg/L et 113 µg/L. Conclusion : Deux hypotheses sont proposees pour expliquer la presence de prazepam : une interaction medicamenteuse et/ou une necrose hepatique induite par l’intoxication au paracetamol. Mots cles : Prazepam, dextropropoxyphene, paracetamol
Asbjorg S Christophersen - One of the best experts on this subject based on the ideXlab platform.
-
Inc. Comparison of drug concentrations in blood and oral fluid collected with the Intercept ® sampling device
2016Co-Authors: Hallvard Gjerde, Asbjorg S Christophersen, Jon Mordal, Jørgen G. BramnessAbstract:The aim of the study was to determine drug concentration ratios between oral fluid collected with the Intercept ® device and whole blood. Samples of blood and oral fluid were obtained from patients admitted to acute psychiatric treatment and drivers suspected of drugged driving, and were analysed for illegal drugs, benzodiazepines, opioids, carisoprodol and meprobamate. Drugs were detected in samples of both blood and oral fluid from 59 subjects; altogether 17 different drugs were found. Concentration ratios between oral fluid and blood were determined for all cases. The distributions of drug concentration ratios were wide for most drugs, and do not allow reliable estimations of drug concentrations in blood using concentrations in oral fluid. The median oral fluid/blood drug concentration ratios for the most prevalent drugs were: diazepam 0.036, nordiazepam 0.027, amphetamine 7.1, methamphetamine 2.9, codeine 5.4, morphine 1.9, and tetrahydrocannabinol 4.7. The correlation coefficients between drug concentrations in oral fluid and blood ranged from 0.15 to 0.96 for the six most prevalent drugs
-
drug screening of whole blood by ultra performance liquid chromatography tandem mass spectrometry
Journal of Analytical Toxicology, 2011Co-Authors: Elisabeth Leere Oiestad, Unni Johansen, Ase Marit Leere Oiestad, Asbjorg S ChristophersenAbstract:An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for screening of drugs in whole blood has been developed and validated. Samples were prepared by supported liquid-liquid extraction on ChemElute(®) columns with ethyl acetate/heptane (4:1). LC separation was achieved with an Acquity HSS T3-column (2.1 100 mm, 1.8-μm particle). Mass detection was performed by positive ion mode electrospray MS-MS and included the following drugs/metabolites: morphine, codeine, ethyl morphine, oxycodone, buprenorphine, methadone, cocaine, methylphenidate, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), Δ(9)-tetrahydrocannabinol (THC), fentanyl, alprazolam, bromazepam, clonazepam, diazepam, nordiazepam, 3-OH-diazepam, fenazepam, flunitrazepam, lorazepam, nitrazepam, oxazepam, zopiclone, zolpidem, carisoprodol, and meprobamate. The cycle time was 9 min, and within- and between-day relative coefficients of variation varied from 1% to 33% and 2% to 58%, respectively. Extraction recoveries from whole blood were > 50% except for morphine and THC. The limit of quantitation was 0.1 to 521 ng/mL, depending on the drug.
-
Comparison of drug concentrations in blood and oral fluid collected with the Intercept sampling device.
Journal of analytical toxicology, 2010Co-Authors: Hallvard Gjerde, Asbjorg S Christophersen, Jon Mordal, Jørgen G. Bramness, Jørg MørlandAbstract:The aim of the study was to determine drug concentration ratios between oral fluid collected with the Intercept device and whole blood. Samples of blood and oral fluid were obtained from patients admitted to acute psychiatric treatment and drivers suspected of drugged driving. Samples were analyzed for illegal drugs, benzodiazepines, opioids, carisoprodol, and meprobamate. Drugs were detected in samples of both blood and oral fluid from 59 subjects; altogether, 17 different drugs were found. Concentration ratios between oral fluid and blood were determined for all cases. The distributions of drug concentration ratios were wide for most drugs and do not allow reliable estimations of drug concentrations in blood using concentrations in oral fluid. The median oral fluid/blood drug concentration ratios for the most prevalent drugs were 0.036 diazepam, 0.027 nordiazepam, 7.1 amphetamine, 2.9 methamphetamine, 5.4 codeine, 1.9 morphine, and 4.7 tetrahydrocannabinol. The correlation coefficients between drug concentrations in oral fluid and blood ranged from 0.15 to 0.96 for the six most prevalent drugs.
Irene Panderi - One of the best experts on this subject based on the ideXlab platform.
-
development and validation of a liquid chromatographic electrospray ionization mass spectrometric method for the quantitation of prazepam and its main metabolites in human plasma
Journal of Mass Spectrometry, 2005Co-Authors: Paraskevi Valavani, Julia Attapolitou, Irene PanderiAbstract:A method was developed and fully validated for the quantitation of prazepam and its major metabolites, oxazepam and nordiazepam, in human plasma. Sample pretreatment was achieved by solid-phase extraction using Oasis HLB cartridges. The extracts were analysed by high-performance liquid chromatography (HPLC) coupled with single-quadrupole mass spectrometry (MS) with an electrospray ionization interface. The MS system was operated in the selected ion monitoring mode. HPLC was performed isocratically on a reversed-phase XTerra MS C18 analytical column (150 × 3.0 mm i.d., particle size 5 µm). Diazepam was used as the internal standard for quantitation. The assay was linear over a concentration range of 5.0–1000 ng ml −1 for all compounds analyzed. The limit of quantitation was 5n g ml −1 for all compounds. Quality control samples (5, 10, 300 and 1000 ng ml −1 ) in five replicates from three different runs of analysis demonstrated an intra-assay precision (CV) of ≤9.1%, an inter-assay precision of ≤6.0% and an overall accuracy (relative error) of <4.6%. The method can be used to quantify prazepam and its metabolites in human plasma covering a variety of pharmacokinetic or bioequivalence studies. Copyright 2005 John Wiley & Sons, Ltd.
-
kinetics and mechanism of acidic hydrolysis of Nordazepam studied by high performance liquid chromatography and fourth order derivative ultraviolet spectrophotometry
International Journal of Pharmaceutics, 1998Co-Authors: H A Archontaki, Irene Panderi, Evagelos Gikas, P M OvezikoglouAbstract:Abstract A reversed-phase HPLC method was developed to study the acid-catalysed hydrolysis of Nordazepam in hydrochloric acid solutions of 0.01, 0.1 and 1.0 M. One intermediate was observed, which was isolated and identified. The mechanism of hydrolysis appeared to be biphasic, showing a consecutive reaction with a reversible first step. Initial breakage of the azomethine bond, followed by a slow hydrolysis of the amide bond resulted to creation of the benzophenone product in strongly acidic solutions. A fourth-order derivative method for monitoring the parent compound itself was also proposed and evaluated, as well. Relative standard deviation was less than 2% for the HPLC and less than 5% for the derivative method. Detection limits for Nordazepam, intermediate and final degradation product were 1.8×10−9 M, 2.1×10−9 M and 2.0×10−9 M, respectively, in the former method and 7.0×10−7 M for Nordazepam in the latter. Estimation of k1, k−1 and k2 values was tried and results of HPLC and fourth-order derivative methods were compared.
