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Luigi Cervo - One of the best experts on this subject based on the ideXlab platform.

  • brain disposition metabolism and behavioral effects of the synthetic opioid ah 7921 in rats
    Neuropharmacology, 2018
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Luigi Cervo, Marco Gobbi
    Abstract:

    Abstract 3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (tmax 30 min) and large (Brain-to-Plasma Ratio 16), with active concentRation >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain tmax>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentRations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentRations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower Brain-to-Plasma Ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.

  • brain disposition of cis para methyl 4 methylaminorex cis 4 4 dmar and its potential metabolites after acute and chronic treatment in rats correlation with central behavioral effects
    Journal of Pharmacology and Experimental Therapeutics, 2017
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Marco Gobbi, Luigi Cervo
    Abstract:

    para-Methyl-4-methylaminorex (4,4′-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography—tandem mass spectrometry method to measure the compound’s concentRations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4′-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4′-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (tmax = 30–60 minutes) and large (Brain-to-Plasma Ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound’s effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,4′-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentRations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in the plasma longer and at higher concentRations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4′-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

Jacopo Lucchetti - One of the best experts on this subject based on the ideXlab platform.

  • brain disposition metabolism and behavioral effects of the synthetic opioid ah 7921 in rats
    Neuropharmacology, 2018
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Luigi Cervo, Marco Gobbi
    Abstract:

    Abstract 3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (tmax 30 min) and large (Brain-to-Plasma Ratio 16), with active concentRation >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain tmax>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentRations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentRations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower Brain-to-Plasma Ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.

  • brain disposition of cis para methyl 4 methylaminorex cis 4 4 dmar and its potential metabolites after acute and chronic treatment in rats correlation with central behavioral effects
    Journal of Pharmacology and Experimental Therapeutics, 2017
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Marco Gobbi, Luigi Cervo
    Abstract:

    para-Methyl-4-methylaminorex (4,4′-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography—tandem mass spectrometry method to measure the compound’s concentRations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4′-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4′-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (tmax = 30–60 minutes) and large (Brain-to-Plasma Ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound’s effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,4′-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentRations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in the plasma longer and at higher concentRations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4′-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

Marco Gobbi - One of the best experts on this subject based on the ideXlab platform.

  • brain disposition metabolism and behavioral effects of the synthetic opioid ah 7921 in rats
    Neuropharmacology, 2018
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Luigi Cervo, Marco Gobbi
    Abstract:

    Abstract 3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (tmax 30 min) and large (Brain-to-Plasma Ratio 16), with active concentRation >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain tmax>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentRations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentRations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower Brain-to-Plasma Ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.

  • brain disposition of cis para methyl 4 methylaminorex cis 4 4 dmar and its potential metabolites after acute and chronic treatment in rats correlation with central behavioral effects
    Journal of Pharmacology and Experimental Therapeutics, 2017
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Marco Gobbi, Luigi Cervo
    Abstract:

    para-Methyl-4-methylaminorex (4,4′-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography—tandem mass spectrometry method to measure the compound’s concentRations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4′-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4′-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (tmax = 30–60 minutes) and large (Brain-to-Plasma Ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound’s effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,4′-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentRations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in the plasma longer and at higher concentRations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4′-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

Renzo Bagnati - One of the best experts on this subject based on the ideXlab platform.

  • brain disposition metabolism and behavioral effects of the synthetic opioid ah 7921 in rats
    Neuropharmacology, 2018
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Luigi Cervo, Marco Gobbi
    Abstract:

    Abstract 3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (tmax 30 min) and large (Brain-to-Plasma Ratio 16), with active concentRation >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain tmax>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentRations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentRations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower Brain-to-Plasma Ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.

  • brain disposition of cis para methyl 4 methylaminorex cis 4 4 dmar and its potential metabolites after acute and chronic treatment in rats correlation with central behavioral effects
    Journal of Pharmacology and Experimental Therapeutics, 2017
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Marco Gobbi, Luigi Cervo
    Abstract:

    para-Methyl-4-methylaminorex (4,4′-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography—tandem mass spectrometry method to measure the compound’s concentRations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4′-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4′-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (tmax = 30–60 minutes) and large (Brain-to-Plasma Ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound’s effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,4′-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentRations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in the plasma longer and at higher concentRations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4′-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

Angelo Di Clemente - One of the best experts on this subject based on the ideXlab platform.

  • brain disposition metabolism and behavioral effects of the synthetic opioid ah 7921 in rats
    Neuropharmacology, 2018
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Luigi Cervo, Marco Gobbi
    Abstract:

    Abstract 3,4-Dichloro-N-benzamide (AH-7921) is a cyclohexyl-methylbenzamide derivative with analgesic activity, whose abuse was associated with several fatal intoxications, included in Schedule I of UN Single Convention on Narcotic Drugs. We validated an HPLC-MS/MS method to investigate its brain disposition and metabolism after single and repeated injections; in parallel, we evaluated its central behavioral effects. After an intraperitoneal injection of 10 mg/kg, the analgesic effect appeared after 5 min and persisted up to 4 h; brain absorption was rapid (tmax 30 min) and large (Brain-to-Plasma Ratio 16), with active concentRation >700 ng/g. By high-resolution MS we identified several metabolites in plasma and brain, the most important being N-demethylated and N,N-didemethylated metabolites; they showed high brain permeability, although they probably do not contribute to the analgesic effect of the parent compound (brain tmax>2 h). Starting 2 h after treatment, the two metabolites showed higher plasma and brain concentRations than the parent molecule, which persisted much longer, and could be used to evaluate drug intake in human consumers. Tolerance was observed after seven daily doses, when the compound's analgesic effect was 14% lower than after the first dose; since brain concentRations did not decrease in parallel, the development of pharmacodynamic tolerance can be suggested. However, pharmacokinetic tolerance is also likely, as brought to light by the data after a dose challenge, given after a 48 h washout period from the 7th dose, showing a lower Brain-to-Plasma Ratio. We also describe the rewarding effect of AH-7921 (conditioned place preference), suggesting a high risk of addiction in humans.

  • brain disposition of cis para methyl 4 methylaminorex cis 4 4 dmar and its potential metabolites after acute and chronic treatment in rats correlation with central behavioral effects
    Journal of Pharmacology and Experimental Therapeutics, 2017
    Co-Authors: Jacopo Lucchetti, Claudio Marcello Marzo, Alice Passoni, Federico Moro, Angelo Di Clemente, Renzo Bagnati, Marco Gobbi, Luigi Cervo
    Abstract:

    para-Methyl-4-methylaminorex (4,4′-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography—tandem mass spectrometry method to measure the compound’s concentRations in plasma, and we applied it to describe the pharmacokinetic properties of 4,4′-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,4′-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (tmax = 30–60 minutes) and large (Brain-to-Plasma Ratio = 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound’s effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,4′-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentRations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the para-methyl group (M2) persisted in the plasma longer and at higher concentRations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,4′-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.