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Paolo Baroldi - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetics of the Dual Melatonin Receptor Agonist Tasimelteon in Subjects With Hepatic or Renal Impairment
2016Co-Authors: Rosarelis Torres, William G. Kramer, Paolo BaroldiAbstract:Tasimelteon is a circadian regulator that resets themaster clock in the suprachiasmatic nuclei of the hypothalamus by binding to bothMelatonin MT1 and MT2 Receptors making it a dual Melatonin Receptor Agonist. Tasimelteon has been approved by the United States Food and Drug Administration for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). Two prospective, single-center, open-label studies evaluated the pharmacokinetics of tasimelteon and its main metabolites after a single 20mg dose administered to subjects with mild or moderate hepatic impairment or severe renal impairment, including subjects on dialysis compared to healthy controls. In subjects with mild or moderate hepatic impairment, exposure to tasimelteon after a single 20mg dose, as measured by area under the plasma concentration-time curve to infinity, was increased by approximately 2-fold. There was no apparent relationship between tasimelteon clearance and renal function. No safety concerns were apparent in either study. Based on these results, the changes in the pharmacokinetics of tasimelteon due to mild or moderate hepatic or severe renal impairment are not considered clinically relevant, and no dose adjustment is necessary in these patients. Keywords tasimelteon, dual Melatonin Receptor Agonists, pharmacokinetics, renal function impairment, hepatic function impairment The endogenous circadian pacemaker resides in the suprachiasmatic nucleus (SCN) of the hypothalamus, and its function is to regulate biological functions in a
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clinical assessment of drug drug interactions of tasimelteon a novel dual Melatonin Receptor Agonist
The Journal of Clinical Pharmacology, 2015Co-Authors: Brian W Ogilvie, Rosarelis Torres, William G. Kramer, Marlene Dressman, Paolo BaroldiAbstract:Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual Melatonin Receptor Agonist that demonstrates specificity and high affinity for Melatonin Receptor types 1 and 2 (MT1 and MT2 Receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug–drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%.
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Clinical assessment of drug–drug interactions of tasimelteon, a novel dual Melatonin Receptor Agonist
Journal of clinical pharmacology, 2015Co-Authors: Brian W Ogilvie, Rosarelis Torres, William G. Kramer, Marlene Dressman, Paolo BaroldiAbstract:Tasimelteon ([1R-trans]-N-[(2-[2,3-dihydro-4-benzofuranyl] cyclopropyl) methyl] propanamide), a novel dual Melatonin Receptor Agonist that demonstrates specificity and high affinity for Melatonin Receptor types 1 and 2 (MT1 and MT2 Receptors), is the first treatment approved by the US Food and Drug Administration for Non-24-Hour Sleep-Wake Disorder. Tasimelteon is rapidly absorbed, with a mean absolute bioavailability of approximately 38%, and is extensively metabolized primarily by oxidation at multiple sites, mainly by cytochrome P450 (CYP) 1A2 and CYP3A4/5, as initially demonstrated by in vitro studies and confirmed by the results of clinical drug–drug interactions presented here. The effects of strong inhibitors and moderate or strong inducers of CYP1A2 and CYP3A4/5 on the pharmacokinetics of tasimelteon were evaluated in humans. Coadministration with fluvoxamine resulted in an approximately 6.5-fold increase in tasimelteon's area under the curve (AUC), whereas cigarette smoking decreased tasimelteon's exposure by approximately 40%. Coadministration with ketoconazole resulted in an approximately 54% increase in tasimelteon's AUC, whereas rifampin pretreatment resulted in a decrease in tasimelteon's exposure of approximately 89%.
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Pharmacokinetics of the dual Melatonin Receptor Agonist tasimelteon in subjects with hepatic or renal impairment.
The Journal of Clinical Pharmacology, 2015Co-Authors: Rosarelis Torres, William G. Kramer, Paolo BaroldiAbstract:Tasimelteon is a circadian regulator that resets the master clock in the suprachiasmatic nuclei of the hypothalamus by binding to both Melatonin MT1 and MT2 Receptors making it a dual Melatonin Receptor Agonist. Tasimelteon has been approved by the United States Food and Drug Administration for the treatment of Non-24-Hour Sleep-Wake Disorder (Non-24). Two prospective, single-center, open-label studies evaluated the pharmacokinetics of tasimelteon and its main metabolites after a single 20 mg dose administered to subjects with mild or moderate hepatic impairment or severe renal impairment, including subjects on dialysis compared to healthy controls. In subjects with mild or moderate hepatic impairment, exposure to tasimelteon after a single 20 mg dose, as measured by area under the plasma concentration-time curve to infinity, was increased by approximately 2-fold. There was no apparent relationship between tasimelteon clearance and renal function. No safety concerns were apparent in either study. Based on these results, the changes in the pharmacokinetics of tasimelteon due to mild or moderate hepatic or severe renal impairment are not considered clinically relevant, and no dose adjustment is necessary in these patients.
Ferdinando Nicoletti - One of the best experts on this subject based on the ideXlab platform.
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chronic agomelatine treatment corrects behavioral cellular and biochemical abnormalities induced by prenatal stress in rats
Psychopharmacology, 2011Co-Authors: Sara Morleyfletcher, Elisabeth Mocaer, Jerome Mairesse, Amelie Soumier, Mounira Banasr, Francesca Fagioli, Cecilia Gabriel, Annie Daszuta, Bruce S Mcewen, Ferdinando NicolettiAbstract:Rationale and objectives The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 Melatonin Receptor Agonist/5-HT2c serotonin Receptor antAgonist.
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Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats
Psychopharmacology, 2011Co-Authors: Sara Morley-fletcher, Elisabeth Mocaer, Jerome Mairesse, Amelie Soumier, Mounira Banasr, Francesca Fagioli, Cecilia Gabriel, Annie Daszuta, Bruce Mcewen, Ferdinando NicolettiAbstract:Rationale and objectives The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 Melatonin Receptor Agonist/5-HT_2c serotonin Receptor antAgonist. Results Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate Receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40–50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a “disease-dependent” drug. Conclusions These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders.
Chen Youxi - One of the best experts on this subject based on the ideXlab platform.
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Synthesis of the Melatonin Receptor Agonist Ramelteon using a tandem C–H activation–alkylation/Heck reaction and subsequent asymmetric Michael addition
Tetrahedron: Asymmetry, 2013Co-Authors: Fu Xiaodan, Guo Xingqun, Li Xingwei, Yushe Yang, Chen YouxiAbstract:Abstract An asymmetric synthesis of the Melatonin Receptor Agonist Ramelteon 1 has been achieved, which involved a tandem C–H activation–alkylation/Heck reaction and subsequent highly diastereoselective asymmetric Michael addition to generate the corresponding chiral intermediate, which was readily converted into Ramelteon 1 in 19% overall yield in 15 linear steps.
Youxi Chen - One of the best experts on this subject based on the ideXlab platform.
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synthesis of the Melatonin Receptor Agonist ramelteon using a tandem c h activation alkylation heck reaction and subsequent asymmetric michael addition
Tetrahedron-asymmetry, 2013Co-Authors: Xingqun Guo, Yushe Yang, Youxi ChenAbstract:Abstract An asymmetric synthesis of the Melatonin Receptor Agonist Ramelteon 1 has been achieved, which involved a tandem C–H activation–alkylation/Heck reaction and subsequent highly diastereoselective asymmetric Michael addition to generate the corresponding chiral intermediate, which was readily converted into Ramelteon 1 in 19% overall yield in 15 linear steps.
Elisabeth Mocaer - One of the best experts on this subject based on the ideXlab platform.
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Chronic agomelatine treatment corrects behavioral, cellular, and biochemical abnormalities induced by prenatal stress in rats
Psychopharmacology, 2011Co-Authors: Sara Morley-fletcher, Elisabeth Mocaer, Jerome Mairesse, Amelie Soumier, Mounira Banasr, Francesca Fagioli, Cecilia Gabriel, Annie Daszuta, Bruce Mcewen, Ferdinando NicolettiAbstract:Rationale and objectives The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 Melatonin Receptor Agonist/5-HT_2c serotonin Receptor antAgonist. Results Adult PRS rats showed behavioral, cellular, and biochemical abnormalities that were consistent with an anxious/depressive phenotype. These included an increased immobility in the forced swim test, an anxiety-like behavior in the elevated plus maze, reduced hippocampal levels of phosphorylated cAMP-responsive element binding protein (p-CREB), reduced hippocampal levels of mGlu2/3 and mGlu5 metabotropic glutamate Receptors, and reduced neurogenesis in the ventral hippocampus, the specific portion of the hippocampus that encodes memories related to stress and emotions. All of these changes were reversed by a 3- or 6-week treatment with agomelatine (40–50 mg/kg, i.p., once a day). Remarkably, agomelatine had no effect in age-matched control rats, thereby behaving as a “disease-dependent” drug. Conclusions These data indicate that agomelatine did not act on individual symptoms but corrected all aspects of the pathological epigenetic programming triggered by PRS. Our findings strongly support the antidepressant activity of agomelatine and suggest that the drug impacts mechanisms that lie at the core of anxious/depressive disorders.
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chronic agomelatine treatment corrects behavioral cellular and biochemical abnormalities induced by prenatal stress in rats
Psychopharmacology, 2011Co-Authors: Sara Morleyfletcher, Elisabeth Mocaer, Jerome Mairesse, Amelie Soumier, Mounira Banasr, Francesca Fagioli, Cecilia Gabriel, Annie Daszuta, Bruce S Mcewen, Ferdinando NicolettiAbstract:Rationale and objectives The rat model of prenatal restraint stress (PRS) replicates factors that are implicated in the etiology of anxious/depressive disorders. We used this model to test the therapeutic efficacy of agomelatine, a novel antidepressant that behaves as a mixed MT1/MT2 Melatonin Receptor Agonist/5-HT2c serotonin Receptor antAgonist.
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Chronic exposure to Melatonin Receptor Agonists does not alter their effects on suprachiasmatic nucleus neurons
European Journal of Pharmacology, 1998Co-Authors: Shui-wang Ying, Benjamin Rusak, Elisabeth MocaerAbstract:Abstract Previous studies have demonstrated that Melatonin and a novel Melatonin Receptor Agonist, S20098 (N-[2-(7-methoxy-1-naphthyl) ethyl] acetamide), regulate neuronal firing activity of photically responsive cells in the suprachiasmatic nucleus in vivo. In the present study, we used several different methods to investigate the effects of chronic daily treatment with Melatonin, S20098 (1.0 mg/kg, s.c.) or control vehicle for 14 d on responsiveness of suprachiasmatic nucleus cells to these Agonists. Both chronic and acute application of drugs were carried out during the day–night transition period. We confirmed that suprachiasmatic nucleus cells from control animals were most sensitive at this circadian phase. Chronic drug treatments did not alter sensitivity of photically responsive suprachiasmatic nucleus cells to S20098 or Melatonin given intraperitoneally (i.p.) or iontophoretically in vivo. Suprachiasmatic nucleus cells studied in brain slice preparations also responded similarly to micropressure ejections of Melatonin Receptor Agonists regardless of drug pretreatment. These results indicate that chronic Melatonin Receptor Agonist pretreatment does not result in desensitization of suprachiasmatic nucleus neuronal responses to these Agonists during the daily phase of maximum Melatonin sensitivity.