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Chadi Abbara - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic analysis of pralidoxime after its intramuscular injection alone or in combination with atropine-Avizafone in healthy volunteers
British journal of pharmacology, 2010Co-Authors: Chadi Abbara, J.-m. Rousseau, Alain Turcant, Guy Lallement, Isabelle Bardot, Bénédicte Lelièvre, Séverine Férec, Bertrand DiquetAbstract:BACKGROUND AND PURPOSE Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with Avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACH The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), Avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTS The injection of pralidoxime combination with atropine and Avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When Avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONS The two approaches, non-compartmental and compartmental, showed that the administration of Avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.
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Modélisation appliquée à la pharmacocinétique de molécules médicamenteuses indiquées en prévention ou en traitement d'atteintes neurologiques chez l'homme
2009Co-Authors: Chadi AbbaraAbstract:L'aspect expérimental de la pharmacocinétique nécessite le développement de techniques analytiques dans les milieux biologiques pour la quantification des médicaments dans les échantillons prélevés à des temps choisis. L'interprétation des données pharmacocinétiques implique ensuite le développement de modèles et de méthodes statistiques permettant l'évaluation des paramètres pharmacocinétiques caractéristiques des molécules considérées. Dans la première partie de ce travail, une méthode LC/MS/MS sensible et spécifique, a été développée et validée pour le dosage simultané de pralidoxime, diazépam et atropine dans le plasma. Une étude pharmacocinétique de chacun des trois composés chez le sujet sain recevant par voie intramusculaire l'association Avizafone-atropine-pralidoxime, traitement recommandé pour l'intoxication par les agents organophosphorés, a ensuite été conduite. Les données issues du dosage plasmatique ont été analysées afin de caractériser la cinétique d'hydrolyse de l'Avizafone et la pharmacocinétique de la pralidoxime. La modélisation individuelle, sujet par sujet, a permis de déterminer le meilleur modèle pharmacocinétique de la transformation d'Avizafone en diazépam après injection intramusculaire d'Avizafone seule ou en association avec atropine et pralidoxime. Une approche de pharmacocinétique de population a enfin été appliquée pour caractériser la pharmacocinétique de la pralidoxime après injection intramusculaire seule ou en association avec atropine et Avizafone. Dans la deuxième partie de cette thèse, l'approche non compartimentale et la modélisation individuelle ont été appliquées à des données obtenues au cours d'une étude de pharmacocinétique évaluant l'administration orale de 50 mg de riluzole chez des enfants atteints d'amyotrophie spinale. Par simulations, il a été possible de montrer que l'administration de riluzole, à la dose de 50 mg deux fois par jour se traduirait par des concentrations résiduelles et maximales comparables à celles obtenues chez l'adulte après une dose de 100 mg deux fois par jour. La dose de 50 mg une fois par jour a donc été retenue pour l'étude clinique évaluant l'efficacité du riluzole chez les patients atteints d'amyotrophie spinale infantile. Mots-clés : Pharmacocinétique, Organophosphorés, Amyotrophie spinale infantile, Riluzole.
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Bioavailability of diazepam after intramuscular injection of its water-soluble prodrug alone or with atropine–pralidoxime in healthy volunteers
British journal of pharmacology, 2009Co-Authors: Chadi Abbara, J.-m. Rousseau, Alain Turcant, Guy Lallement, Emmanualle Comets, Isabelle Bardot, Pascal Clair, Bertrand DiquetAbstract:Background and purpose: The aim of this study was to assess the relative bioavailability of diazepam after administration of diazepam itself or as a water-soluble prodrug, Avizafone, in humans. Experimental approach: The study was conducted in an open, randomized, single-dose, three-way, cross-over design. Each subject received intramuscular injections of Avizafone (20 mg), diazepam (11.3 mg) or Avizafone (20 mg) combined with atropine (2 mg) and pralidoxime (350 mg) using a bi-compartmental auto-injector (AIBC). Plasma concentrations of diazepam were quantified using a validated LC/MS‐MS assay, and were analysed by both a non-compartmental approach and by compartmental modelling. Key results: The maximum concentration (Cmax) of diazepam after Avizafone injection was higher than that obtained after injection of diazepam itself (231 vs. 148 ng·mL -1 ), while area under the curve (AUC) values were equal. Diazepam concentrations reached their maximal value faster after injection of Avizafone. Injection of Avizafone with atropine‐pralidoxime (AIBC) had no effect on diazepam Cmax and AUC, but the time to Cmax was increased, relative to Avizafone injected alone. According to the Akaike criterion, the pharmacokinetics of diazepam after injection as a prodrug was best described as a twocompartment with zero-order absorption model. When atropine and pralidoxime were injected with Avizafone, the best pharmacokinetic model was a two-compartment with a first-order absorption model. Conclusion and implications: Diazepam had a faster entry to the general circulation and achieved higher Cmax after injection of prodrug than after the parent drug. Administration of Avizafone in combination with atropine and pralidoxime by AIBC had no significant effect on diazepam AUC and Cmax. British Journal of Pharmacology (2009) 157, 1390‐1397; doi:10.1111/j.1476-5381.2009.00330.x
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High-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of diazepam, atropine and pralidoxime in human plasma.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2008Co-Authors: Chadi Abbara, Alain Turcant, Guy Lallement, Isabelle Bardot, Pascal Clair, A. Cailleux, Anne Le Bouil, Bertrand DiquetAbstract:A high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) procedure for the simultaneous determination of diazepam from Avizafone, atropine and pralidoxime in human plasma is described. Sample pretreatment consisted of protein precipitation from 100microl of plasma using acetonitrile containing the internal standard (diazepam D5). Chromatographic separation was performed on a X-Terra MS C8 column (100mmx2.1mm, i.d. 3.5microm), with a quick stepwise gradient using a formate buffer (pH 3, 2mM) and acetonitrile at a flow rate of 0.2ml/min. The triple quadrupole mass spectrometer was operated in positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges of 1-500ng/ml for diazepam, 0.25-50ng/ml for atropine and 5-1000ng/ml for pralidoxime. The coefficients of variation were always
Bertrand Diquet - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic analysis of pralidoxime after its intramuscular injection alone or in combination with atropine-Avizafone in healthy volunteers
British journal of pharmacology, 2010Co-Authors: Chadi Abbara, J.-m. Rousseau, Alain Turcant, Guy Lallement, Isabelle Bardot, Bénédicte Lelièvre, Séverine Férec, Bertrand DiquetAbstract:BACKGROUND AND PURPOSE Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with Avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACH The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), Avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTS The injection of pralidoxime combination with atropine and Avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When Avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONS The two approaches, non-compartmental and compartmental, showed that the administration of Avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.
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Bioavailability of diazepam after intramuscular injection of its water-soluble prodrug alone or with atropine–pralidoxime in healthy volunteers
British journal of pharmacology, 2009Co-Authors: Chadi Abbara, J.-m. Rousseau, Alain Turcant, Guy Lallement, Emmanualle Comets, Isabelle Bardot, Pascal Clair, Bertrand DiquetAbstract:Background and purpose: The aim of this study was to assess the relative bioavailability of diazepam after administration of diazepam itself or as a water-soluble prodrug, Avizafone, in humans. Experimental approach: The study was conducted in an open, randomized, single-dose, three-way, cross-over design. Each subject received intramuscular injections of Avizafone (20 mg), diazepam (11.3 mg) or Avizafone (20 mg) combined with atropine (2 mg) and pralidoxime (350 mg) using a bi-compartmental auto-injector (AIBC). Plasma concentrations of diazepam were quantified using a validated LC/MS‐MS assay, and were analysed by both a non-compartmental approach and by compartmental modelling. Key results: The maximum concentration (Cmax) of diazepam after Avizafone injection was higher than that obtained after injection of diazepam itself (231 vs. 148 ng·mL -1 ), while area under the curve (AUC) values were equal. Diazepam concentrations reached their maximal value faster after injection of Avizafone. Injection of Avizafone with atropine‐pralidoxime (AIBC) had no effect on diazepam Cmax and AUC, but the time to Cmax was increased, relative to Avizafone injected alone. According to the Akaike criterion, the pharmacokinetics of diazepam after injection as a prodrug was best described as a twocompartment with zero-order absorption model. When atropine and pralidoxime were injected with Avizafone, the best pharmacokinetic model was a two-compartment with a first-order absorption model. Conclusion and implications: Diazepam had a faster entry to the general circulation and achieved higher Cmax after injection of prodrug than after the parent drug. Administration of Avizafone in combination with atropine and pralidoxime by AIBC had no significant effect on diazepam AUC and Cmax. British Journal of Pharmacology (2009) 157, 1390‐1397; doi:10.1111/j.1476-5381.2009.00330.x
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High-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of diazepam, atropine and pralidoxime in human plasma.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2008Co-Authors: Chadi Abbara, Alain Turcant, Guy Lallement, Isabelle Bardot, Pascal Clair, A. Cailleux, Anne Le Bouil, Bertrand DiquetAbstract:A high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) procedure for the simultaneous determination of diazepam from Avizafone, atropine and pralidoxime in human plasma is described. Sample pretreatment consisted of protein precipitation from 100microl of plasma using acetonitrile containing the internal standard (diazepam D5). Chromatographic separation was performed on a X-Terra MS C8 column (100mmx2.1mm, i.d. 3.5microm), with a quick stepwise gradient using a formate buffer (pH 3, 2mM) and acetonitrile at a flow rate of 0.2ml/min. The triple quadrupole mass spectrometer was operated in positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges of 1-500ng/ml for diazepam, 0.25-50ng/ml for atropine and 5-1000ng/ml for pralidoxime. The coefficients of variation were always
Ronald A. Siegel - One of the best experts on this subject based on the ideXlab platform.
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Diazepam Prodrug Stabilizes Human Aminopeptidase B during Lyophilization
Molecular pharmaceutics, 2019Co-Authors: Davin Rautiola, Kathryn M. Nelson, Joel L. Updyke, Ronald A. SiegelAbstract:Human aminopeptidase B (APB) is a labile enzyme that is being investigated as a biocatalyst for intranasal delivery of prodrug/enzyme combinations. Therefore, the stability of APB is a major concern to ensure a viable drug product. Lyophilization is one technique commonly used to extend shelf life of enzymes. However, the lyophilization process itself can cause conformational changes and aggregation, leading to inactivation of enzymes. In this study, we demonstrate the use of the substrate Avizafone (AVF), a prodrug for diazepam, as a stabilizer to minimize inactivation of APB during lyophilization. Permutations of APB samples combined with AVF, trehalose, and/or mannitol were snap-frozen and lyophilized, and subsequently reconstituted to measure the activity of APB. Of the formulation permutations, an APB + AVF + trehalose combination resulted in minimum degradation with 71% retention of activity. This was followed by APB + AVF and APB + trehalose with 60 and 56% retention of activity, respectively. In comparison, APB + mannitol and APB alone retained only 16 and 6.4% activity, respectively. Lyophilizates of the APB + AVF + trehalose formulation were subjected to a 6 month accelerated stability study, at the end of which negligible reduction in activity was observed. These results suggest that colyophilization of an enzyme with its substrate can impart stability on par with the commonly used lyoprotectant, trehalose, but the combination of substrate and trehalose provides a greater stabilizing effect than either additive alone.
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Conversion of a soluble diazepam prodrug to supersaturated diazepam for rapid intranasal delivery: Kinetics and stability
Journal of controlled release : official journal of the Controlled Release Society, 2018Co-Authors: Davin Rautiola, James C. Cloyd, Ronald A. SiegelAbstract:Abstract The low aqueous solubility of diazepam (DZP) presents a challenge in formulating nasal sprays without the use of organic solvents. One approach to overcome this challenge involves co-administration of a soluble prodrug, Avizafone (AVF), with a converting enzyme to produce supersaturated DZP at the site of administration. In addition to overcoming solubility issues, the supersaturated state of DZP provides an increased driving force for enhanced permeation across nasal mucosa. However, supersaturated solutions are metastable, and there is a limit to the degree of supersaturation (S) that can be reached without causing spontaneous phase separation of the solute. The aim of this article was to determine how formulation parameters affect the rate of DZP supersaturation, maximum degree of supersaturation, and phase separation kinetics. A model enzyme, Aspergillus oryzae protease (AOP), was used to convert AVF to DZP, via an open ring intermediate (ORI). A second derivative UV spectroscopic method was developed to simultaneously monitor DZP solution concentration and the time course of DZP phase separation. Fitting a kinetic model, with prior knowledge of the enzyme kinetic parameters, the rate constant for conversion of ORI to DZP was found to be 0.470 ± 0.012 min−1. Kinetics and supersaturated solution stability were studied as a function of formulation parameters, including temperature, pH, buffering agent, AVF concentration, and enzyme concentration. The maximum aqueous solution concentration for DZP at 32 °C was determined to be 1.22 ± 0.03 mM DZP (S = 9.38) and was insensitive to changes in formulation parameters, excepting temperature. Supersaturated solutions of DZP could be maintained at the maximum concentration for >24 h, even in the presence of phase separated DZP. Polarized light microscopy, PXRD, and DSC analysis indicated that the phase separated DZP was amorphous upon formation and remained so for >24 h. Our findings suggest that co-administration of AVF with a suitable human converting enzyme will provide a viable mechanism for IN delivery of DZP and result in very rapid and complete absorption to quickly terminate seizure emergencies.
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Chirally Pure Prodrugs and Their Converting Enzymes Lead to High Supersaturation and Rapid Transcellular Permeation of Benzodiazepines.
Journal of pharmaceutical sciences, 2016Co-Authors: Mamta Kapoor, Gunda I. Georg, Davin Rautiola, Narsihmulu Cheryala, James C. Cloyd, Ronald A. SiegelAbstract:Water-soluble prodrugs can be rapidly converted by enzymes to hydrophobic drugs, whose aqueous thermodynamic solubilities are low, but are maintained in aqueous solution at supersaturated concentrations due to slow precipitation kinetics. Recently, we investigated Avizafone (AVF) in combination with Aspergillus oryzae protease as a prodrug/enzyme system intended to produce supersaturated diazepam (DZP). Several fold enhancement of permeation of supersaturated DZP across Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers was observed, compared to saturated DZP solutions. However, prodrug conversion was incomplete, putatively due to partial racemization of AVF and stereoselectivity of A oryzae protease. Here we report synthesis of chirally pure AVF, and demonstrate complete conversion to supersaturated DZP followed by complete DZP permeation at enhanced rates across MDCKII-wt cell monolayers. We also synthesized, for the first time, a chirally pure prodrug of midazolam (MDZ-pro) and carried out the same sequence of studies. A oryzae protease was identified as a benign and efficient activating enzyme for MDZ-pro. The MDZ-pro/A oryzae protease system showed greater than 25-fold increase in absorption rate of MDZ across MDCKII-wt monolayers, compared to saturated MDZ. Such chirally pure prodrug/enzyme systems are promising candidates for efficient intranasal delivery of benzodiazepine drugs used in the treatment of seizure emergencies.
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Pharmaceutics, Drug Delivery and Pharmaceutical Technology Chirally Pure Prodrugs and Their Converting Enzymes Lead to High Supersaturation and Rapid Transcellular Permeation of Benzodiazepines
2016Co-Authors: Mamta Kapoor, Gunda I. Georg, Davin Rautiola, Narsihmulu Cheryala, James C. Cloyd, Ronald A. SiegelAbstract:Water-soluble prodrugs can be rapidly converted by enzymes to hydrophobic drugs, whose aqueous thermodynamic solubilities are low, but are maintained in aqueous solution at supersaturated concentrations due to slow precipitation kinetics. Recently, we investigated Avizafone (AVF) in combination with Aspergillus oryzae protease as a prodrug/enzyme system intended to produce supersaturated diazepam (DZP). Several fold enhancement of permeation of supersaturated DZP across Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers was observed, compared to saturated DZP solutions. However, prodrug conversion was incomplete, putatively due to partial racemization of AVF and stereoselectivity of A oryzae protease. Here we report synthesis of chirally pure AVF, and demonstrate complete conversion to supersaturated DZP followed by complete DZP permeation at enhanced rates across MDCKII-wt cell monolayers. We also synthesized, for the first time, a chirally pure prodrug of midazolam (MDZ-pro) and carried out the same sequence of studies. A oryzae protease was identified as a benign and efficient activating enzyme for MDZ-pro. The MDZ-pro/A oryzae protease system showed greater than 25-fold increase in absorption rate of MDZ across MDCKII-wt monolayers, compared to saturated MDZ. Such chirally pure prodrug/enzyme systems are promising candidates for efficient intranasal delivery of benzodiazepine drugs used in the treatment of seizure emergencies. © 2016 American Pharmacists Association
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Rapid Delivery of Diazepam from Supersaturated Solutions Prepared Using Prodrug/Enzyme Mixtures: Toward Intranasal Treatment of Seizure Emergencies
The AAPS Journal, 2014Co-Authors: Mamta Kapoor, Tate Winter, Lev Lis, Gunda I. Georg, Ronald A. SiegelAbstract:Current treatments for seizure emergencies, such as status epilepticus, include intravenous or rectal administration of benzodiazepines. While intranasal delivery of these drugs is desirable, the small volume of the nasal cavity and low drug solubility pose significant difficulties. Here, we prepared supersaturated diazepam solutions under physiological conditions and without precipitation, using a prodrug/enzyme system. Avizafone, a peptide prodrug of diazepam, was delivered with— Aspergillus oryzae ( A.O. ) protease , an enzyme identified from a pool of hydrolytic enzymes in assay buffer, pH 7.4 at 32°C. This enzyme converted Avizafone to diazepam at supersaturated concentrations. In vitro permeability studies were performed at various prodrug/enzyme ratios using Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers, a representative model of the nasal epithelium. Monolayer integrity was examined using TEER measurement and the lucifer yellow permeability assay. Prodrug/drug concentrations were measured using HPLC. Enzyme kinetics with Avizafone- protease mixtures revealed K _M = 1,501 ± 232 μM and V _max = 1,369 ± 94 μM/s. Prodrug- protease mixtures, when co-delivered apically onto MDCKII-wt monolayers, showed 2–17.6-fold greater diazepam flux ( S = 1.3–15.3) compared to near-saturated diazepam ( S = 0.7). Data for prodrug conversion upstream (apical side) and drug permeability downstream (basolateral side) fitted reasonably well to a previously developed in vitro two compartment pharmacokinetic model. Avizafone- protease mixtures resulted in supersaturated diazepam in less than 5 min, with the rate and extent of supersaturation determined by the prodrug/enzyme ratio. Together, these results suggest that an intranasal Avizafone- protease system may provide a rapid and alternative means of diazepam delivery.
B. Broxup - One of the best experts on this subject based on the ideXlab platform.
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Efficacy of diazepam and Avizafone against soman-induced neuropathology in brain of rats.
Neurotoxicology, 1993Co-Authors: J. G. Clement, B. BroxupAbstract:The purpose of this investigation was to compare the efficacy of diazepam and a water soluble pro-diazepam drug, Avizafone (lysyl, peptido-aminobenzophenone diazepam pro-drug) in preventing or reducing the severity of soman-induced neuropathology in rats and to determine the temporal relationship between seizure initiation, anticonvulsant administration and the incidence and severity of soman-induced neuropathology. Brains from rats, treated with a convulsant dose of soman (pinacolyl methylphosphonofluoridate) and anticonvulsants such as diazepam and Avizafone, were evaluated by light microscopy for evidence of neuropathology. All rats received atropine methyl nitrate (20 mg/kg, ip)+the bispyridinium acetylcholinesterase reactivator HI-6 (125 mg/kg, ip; 1-(((4-(aminocarbonyl)pyridinio) methoxy)methyl)-2-((hydroxyimino)methyl)-pyridinium dichloride) in the same solution 10 min before soman (130 micrograms/kg,sc). Three days later the rats were perfused and the tissue fixed for histological evaluation. Necrosis and/or malacia (degenerative changes) and hemorrhage were observed in some groups. The sites where pathology was most frequently observed and with greater severity were the piriform cortex, amygdala and (dorsal) thalamus. Less severe changes were observed in the cerebral cortex and hippocampus. There were no changes in the hypothalamus. Diazepam given 10 minutes before soman prevented the occurrence of soman-induced convulsions and neuropathology (i.e. degenerative changes were not then seen). Diazepam given at the start of the soman-induced convulsions reduced considerably the convulsions and the degree of neuropathology. Avizafone given 10 minutes before soman reduced slightly the effect of soman. Other treatments (diazepam given 30, 60 and 120 minutes after the start of the convulsions and Avizafone given at the start of convulsions) showed little or no effect on the neuropathology associated with soman administration. The results of this study have demonstrated that the use of an anticonvulsant, such as diazepam, must be initiated shortly after soman exposure in order for any therapeutic benefit to be realized.
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Efficacy of diazepam and Avizafone against soman-induced neuropathology in brain of rats.
Neurotoxicology, 1993Co-Authors: J. G. Clement, B. BroxupAbstract:The purpose of this investigation was to compare the efficacy of diazepam and a water soluble pro-diazepam drug, Avizafone (lysyl, peptido-aminobenzophenone diazepam pro-drug) in preventing or reducing the severity of soman-induced neuropathology in rats and to determine the temporal relationship between seizure initiation, anticonvulsant administration and the incidence and severity of soman-induced neuropathology. Brains from rats, treated with a convulsant dose of soman (pinacolyl methylphosphonofluoridate) and anticon vulsants such as diazepam and Avizafone, were evaluated by light microscopy for evidence of neuropathology
Guy Lallement - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic analysis of pralidoxime after its intramuscular injection alone or in combination with atropine-Avizafone in healthy volunteers
British journal of pharmacology, 2010Co-Authors: Chadi Abbara, J.-m. Rousseau, Alain Turcant, Guy Lallement, Isabelle Bardot, Bénédicte Lelièvre, Séverine Férec, Bertrand DiquetAbstract:BACKGROUND AND PURPOSE Treatment of organophosphate poisoning with pralidoxime needs to be improved. Here we have studied the pharmacokinetics of pralidoxime after its intramuscular injection alone or in combination with Avizafone and atropine using an auto-injector device. EXPERIMENTAL APPROACH The study was conducted in an open, randomized, single-dose, two-way, cross-over design. At each period, each subject received either intramuscular injections of pralidoxime (700 mg), or two injections of the combination: pralidoxime (350 mg), atropine (2 mg), Avizafone (20 mg). Pralidoxime concentrations were quantified using a validated LC/MS-MS method. Two approaches were used to analyse these data: (i) a non-compartmental approach; and (ii) a compartmental modelling approach. KEY RESULTS The injection of pralidoxime combination with atropine and Avizafone provided a higher pralidoxime maximal concentration than that obtained after the injection of pralidoxime alone (out of bioequivalence range), while pralidoxime AUC values were equivalent. Pralidoxime concentrations reached their maximal value earlier after the injection of the combination. According to Akaike and to goodness of fit criteria, the best model describing the pharmacokinetics of pralidoxime was a two-compartment with a zero-order absorption model. When Avizafone and atropine were injected with pralidoxime, the best model describing pralidoxime pharmacokinetics becomes a two-compartment with a first-order absorption model. CONCLUSIONS AND IMPLICATIONS The two approaches, non-compartmental and compartmental, showed that the administration of Avizafone and atropine with pralidoxime results in a faster absorption into the general circulation and higher maximal concentrations, compared with the administration of pralidoxime alone.
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Bioavailability of diazepam after intramuscular injection of its water-soluble prodrug alone or with atropine–pralidoxime in healthy volunteers
British journal of pharmacology, 2009Co-Authors: Chadi Abbara, J.-m. Rousseau, Alain Turcant, Guy Lallement, Emmanualle Comets, Isabelle Bardot, Pascal Clair, Bertrand DiquetAbstract:Background and purpose: The aim of this study was to assess the relative bioavailability of diazepam after administration of diazepam itself or as a water-soluble prodrug, Avizafone, in humans. Experimental approach: The study was conducted in an open, randomized, single-dose, three-way, cross-over design. Each subject received intramuscular injections of Avizafone (20 mg), diazepam (11.3 mg) or Avizafone (20 mg) combined with atropine (2 mg) and pralidoxime (350 mg) using a bi-compartmental auto-injector (AIBC). Plasma concentrations of diazepam were quantified using a validated LC/MS‐MS assay, and were analysed by both a non-compartmental approach and by compartmental modelling. Key results: The maximum concentration (Cmax) of diazepam after Avizafone injection was higher than that obtained after injection of diazepam itself (231 vs. 148 ng·mL -1 ), while area under the curve (AUC) values were equal. Diazepam concentrations reached their maximal value faster after injection of Avizafone. Injection of Avizafone with atropine‐pralidoxime (AIBC) had no effect on diazepam Cmax and AUC, but the time to Cmax was increased, relative to Avizafone injected alone. According to the Akaike criterion, the pharmacokinetics of diazepam after injection as a prodrug was best described as a twocompartment with zero-order absorption model. When atropine and pralidoxime were injected with Avizafone, the best pharmacokinetic model was a two-compartment with a first-order absorption model. Conclusion and implications: Diazepam had a faster entry to the general circulation and achieved higher Cmax after injection of prodrug than after the parent drug. Administration of Avizafone in combination with atropine and pralidoxime by AIBC had no significant effect on diazepam AUC and Cmax. British Journal of Pharmacology (2009) 157, 1390‐1397; doi:10.1111/j.1476-5381.2009.00330.x
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High-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) method for the simultaneous determination of diazepam, atropine and pralidoxime in human plasma.
Journal of chromatography. B Analytical technologies in the biomedical and life sciences, 2008Co-Authors: Chadi Abbara, Alain Turcant, Guy Lallement, Isabelle Bardot, Pascal Clair, A. Cailleux, Anne Le Bouil, Bertrand DiquetAbstract:A high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (LC/MS/MS) procedure for the simultaneous determination of diazepam from Avizafone, atropine and pralidoxime in human plasma is described. Sample pretreatment consisted of protein precipitation from 100microl of plasma using acetonitrile containing the internal standard (diazepam D5). Chromatographic separation was performed on a X-Terra MS C8 column (100mmx2.1mm, i.d. 3.5microm), with a quick stepwise gradient using a formate buffer (pH 3, 2mM) and acetonitrile at a flow rate of 0.2ml/min. The triple quadrupole mass spectrometer was operated in positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated over the concentration ranges of 1-500ng/ml for diazepam, 0.25-50ng/ml for atropine and 5-1000ng/ml for pralidoxime. The coefficients of variation were always
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compared efficacy of diazepam or Avizafone to prevent soman induced electroencephalographic disturbances and neuropathology in primates relationship to plasmatic benzodiazepine pharmacokinetics
Archives of Toxicology, 2000Co-Authors: Guy Lallement, F Renault, Dominique Baubichon, Michel Peoch, Mariefrance Burckhart, Monique Galonnier, Didier Clarencon, N JourdilAbstract:We performed an experiment to characterize the toxicity of soman in cynomolgus monkeys in which organophosphorus intoxication was followed by treatment with either the current three-drug therapy atropine/pralidoxime/diazepam or a combination of atropine/pralidoxime/Avizafone, Avizafone being the water soluble prodrug of diazepam. Clinical, electrophysiological, and histological approaches were combined. When benzodiazepines were injected at the similar molar dose of 0.7 µmol/kg, the protection against soman toxicity was better with the atropine/pralidoxime/diazepam combination than with the atropine/pralidoxime/Avizafone one. Pharmacokinetic studies demonstrated that this difference of efficacy could be explained by a lower plasmatic load of diazepam obtained after injection of Avizafone at 0.7 µmol/kg, compared to the administration of diazepam at the same molar dose. Moreover, after injection of Avizafone, plasmatic levels of diazepam were achieved faster and declined more rapidly than after administration of diazepam. Compared to diazepam given at a dose of 0.7 µmol/kg, injection of 1 µmol Avizafone/kg gave a similar plasmatic load of benzodiazepine, but with a lower time to maximum plasma concentration (tmax) and a higher maximum plasma concentration (Cmax) for plasmatic diazepam. We therefore went on to demonstrate that administration of the atropine/pralidoxime/Avizafone combination at a dose 1 µmol benzodiazepine/kg to intoxicated monkeys afforded electrophysiological and histological protection similar to that obtained after administration of atropine/pralidoxime/diazepam at a dose of 0.7 µmol diazepam/kg. Reflections on the possible incorporation of Avizafone in three-drug emergency treatment are presented.
