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Jasper Dingemanse - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan
Clinical Pharmacokinetics, 2015Co-Authors: P. N. Sidharta, A. Treiber, Jasper DingemanseAbstract:Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ET_A and ET_B Receptor Antagonist with high affinity and sustained Receptor binding is the first ET Receptor Antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug–drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.
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Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan
Clinical Pharmacokinetics, 2015Co-Authors: P. N. Sidharta, A. Treiber, Jasper DingemanseAbstract:Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ET_A and ET_B Receptor Antagonist with high affinity and sustained Receptor binding is the first ET Receptor Antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug–drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.
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Macitentan: entry-into-humans study with a new endothelin Receptor Antagonist
European Journal of Clinical Pharmacology, 2011Co-Authors: P. N. Sidharta, Paul L. M. Van Giersbergen, Atef Halabi, Jasper DingemanseAbstract:Purpose To study the pharmacokinetics, pharmacodynamics, and tolerability of rising single doses of macitentan, an endothelin Receptor Antagonist, in healthy male subjects.
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Tolerability, pharmacokinetics, and pharmacodynamics of clazosentan, a parenteral endothelin Receptor Antagonist
European Journal of Clinical Pharmacology, 2006Co-Authors: Paul L. M. Van Giersbergen, Jasper DingemanseAbstract:Objective The purpose of this study was to investigate in healthy male subjects the tolerability, pharmacokinetics, and pharmacodynamics of ascending doses of clazosentan, an intravenous endothelin Receptor Antagonist.
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Clinical Pharmacology of Bosentan, a Dual Endothelin Receptor Antagonist
Clinical Pharmacokinetics, 2004Co-Authors: Jasper Dingemanse, Paul L. M. Van GiersbergenAbstract:Bosentan, a dual endothelin Receptor Antagonist, is indicated for the treatment of patients with pulmonary arterial hypertension (PAH).
Tomoyuki Kanda - One of the best experts on this subject based on the ideXlab platform.
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In vitro pharmacological profile of the A_2A Receptor Antagonist istradefylline
Naunyn-Schmiedeberg's Archives of Pharmacology, 2013Co-Authors: Mayumi Saki, Koji Yamada, Etsuko Koshimura, Katsutoshi Sasaki, Tomoyuki KandaAbstract:Adenosine A_2A Receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A_2A Receptor Antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of istradefylline as an A_2A Receptor Antagonist. Istradefylline exhibited high affinity for A_2A Receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine Receptors (A_1, A_2B, and A_3) were lower than that for A_2A Receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter Receptors, including dopamine Receptors (D_1, D_2, D_3, D_4, and D_5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol- O -methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A_2A Receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A_2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A_2A Receptor Antagonist. The in vitro pharmacological profile of istradefylline helps to explain the in vivo profile of istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.
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In vitro pharmacological profile of the A2A Receptor Antagonist istradefylline.
Naunyn-Schmiedeberg's archives of pharmacology, 2013Co-Authors: Mayumi Saki, Koji Yamada, Etsuko Koshimura, Katsutoshi Sasaki, Tomoyuki KandaAbstract:Adenosine A2A Receptors are suggested to be a promising non-dopaminergic target for the treatment of Parkinson’s disease (PD). Istradefylline is an adenosine A2A Receptor Antagonist that has been reported to exhibit antiparkinsonian activities in PD patients as well as both rodents and nonhuman primate models of PD. The aim of this study was to evaluate the in vitro pharmacological profile of istradefylline as an A2A Receptor Antagonist. Istradefylline exhibited high affinity for A2A Receptors in humans, marmosets, dogs, rats, and mice. The affinities for the other subtypes of adenosine Receptors (A1, A2B, and A3) were lower than that for A2A Receptors in each species. Istradefylline demonstrated no significant affinity for other neurotransmitter Receptors, including dopamine Receptors (D1, D2, D3, D4, and D5). In addition, istradefylline hardly inhibited monoamine oxidase-A, monoamine oxidase-B, or catechol-O-methyl transferase. A kinetic analysis indicated that istradefylline reversibly binds to the human A2A Receptors: The association reached equilibrium within 1 min, and the binding was also almost completely dissociated within 1 min. Istradefylline inhibited the A2A agonist CGS21680-induced accumulation of cAMP in the cultured cells and then shifted the concentration–response curve of CGS21680 to the right without affecting the maximal response of the agonist. These results indicate that istradefylline is a potent, selective, and competitive A2A Receptor Antagonist. The in vitro pharmacological profile of istradefylline helps to explain the in vivo profile of istradefylline and may be useful for clinical pharmacokinetic–pharmacodynamic considerations of efficacy and safety.
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KF17837: a novel selective adenosine A2A Receptor Antagonist with anticataleptic activity.
European journal of pharmacology, 1994Co-Authors: Tomoyuki Kanda, Shizuo Shiozaki, Junichi Shimada, Fumio Suzuki, Joji NakamuraAbstract:KF17837 is a novel selective adenosine A2A Receptor Antagonist. Oral administration of KF17837 (2.5, 10.0 and 30.0 mg/kg) significantly ameliorated the cataleptic responses induced by intracerebroventricular administration of an adenosine A2A Receptor agonist, CGS 21680 (10 micrograms), in a dose-dependent manner. KF17837 also reduced the catalepsy induced by haloperidol (1 mg/kg i.p.) and by reserpine (5 mg/kg i.p.). These anticataleptic effects were exhibited dose dependently at doses from 0.625 and 2.5 mg/kg p.o., respectively. Moreover, KF17837 (0.625 mg/kg p.o.) potentiated the anticataleptic effects of a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-DOPA; 25 mg/kg i.p.) plus benserazide (6.25 mg/kg i.p.). These results suggested that KF17837 is a centrally active adenosine A2A Receptor Antagonist and that the dopaminergic function of the nigrostriatal pathway is potentiated by adenosine A2A Receptor Antagonists. Furthermore, KF17837 may be a useful drug in the treatment of parkinsonism.
Robert J. Padley - One of the best experts on this subject based on the ideXlab platform.
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Single‐Dose Pharmacokinetics of Atrasentan, an Endothelin‐A Receptor Antagonist
The Journal of Clinical Pharmacology, 2001Co-Authors: Emil Samara, Margaret S Dordal, G. Richard Granneman, Sandeep Dutta, Robert J. PadleyAbstract:Objective To determine the single- and multiple-dose pharmacokinetics of atrasentan, a highly selective endothelin-A Receptor Antagonist that is currently being investigated for the treatment of prostate cancer and cardiovascular disorders.
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single dose pharmacokinetics of atrasentan an endothelin a Receptor Antagonist
The Journal of Clinical Pharmacology, 2001Co-Authors: Emil Samara, Margaret S Dordal, G. Richard Granneman, Sandeep Dutta, Robert J. PadleyAbstract:Objective To determine the single- and multiple-dose pharmacokinetics of atrasentan, a highly selective endothelin-A Receptor Antagonist that is currently being investigated for the treatment of prostate cancer and cardiovascular disorders.
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multiple dose pharmacokinetics of atrasentan an endothelin a Receptor Antagonist
Clinical Drug Investigation, 2001Co-Authors: Sandeep Dutta, Philip T. Leese, Emil Samara, G. Richard Granneman, Robert J. PadleyAbstract:Objective To determine the single- and multiple-dose pharmacokinetics of atrasentan, a highly selective endothelin-A Receptor Antagonist that is currently being investigated for the treatment of prostate cancer and cardiovascular disorders.
Steven M. Opal - One of the best experts on this subject based on the ideXlab platform.
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Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration.
Critical care medicine, 2018Co-Authors: Nuala J. Meyer, John P. Reilly, Brian J. Anderson, Jessica A. Palakshappa, Tiffanie K. Jones, Thomas G. Dunn, Michael G. S. Shashaty, Rui Feng, Jason D. Christie, Steven M. OpalAbstract:OBJECTIVE Plasma interleukin-1 beta may influence sepsis mortality, yet recombinant human interleukin-1 Receptor Antagonist did not reduce mortality in randomized trials. We tested for heterogeneity in the treatment effect of recombinant human interleukin-1 Receptor Antagonist by baseline plasma interleukin-1 beta or interleukin-1 Receptor Antagonist concentration. DESIGN Retrospective subgroup analysis of randomized controlled trial. SETTING Multicenter North American and European clinical trial. PATIENTS Five hundred twenty-nine subjects with sepsis and hypotension or hypoperfusion, representing 59% of the original trial population. INTERVENTIONS Random assignment of placebo or recombinant human interleukin-1 Receptor Antagonist × 72 hours. MEASUREMENTS AND MAIN RESULTS We measured prerandomization plasma interleukin-1 beta and interleukin-1 Receptor Antagonist and tested for statistical interaction between recombinant human interleukin-1 Receptor Antagonist treatment and baseline plasma interleukin-1 Receptor Antagonist or interleukin-1 beta concentration on 28-day mortality. There was significant heterogeneity in the effect of recombinant human interleukin-1 Receptor Antagonist treatment by plasma interleukin-1 Receptor Antagonist concentration whether plasma interleukin-1 Receptor Antagonist was divided into deciles (interaction p = 0.046) or dichotomized (interaction p = 0.028). Interaction remained present across different predicted mortality levels. Among subjects with baseline plasma interleukin-1 Receptor Antagonist above 2,071 pg/mL (n = 283), recombinant human interleukin-1 Receptor Antagonist therapy reduced adjusted mortality from 45.4% to 34.3% (adjusted risk difference, -0.12; 95% CI, -0.23 to -0.01), p = 0.044. Mortality in subjects with plasma interleukin-1 Receptor Antagonist below 2,071 pg/mL was not reduced by recombinant human interleukin-1 Receptor Antagonist (adjusted risk difference, +0.07; 95% CI, -0.04 to +0.17), p = 0.230. Interaction between plasma interleukin-1 beta concentration and recombinant human interleukin-1 Receptor Antagonist treatment was not statistically significant. CONCLUSIONS We report a heterogeneous effect of recombinant human interleukin-1 Receptor Antagonist on 28-day sepsis mortality that is potentially predictable by plasma interleukin-1 Receptor Antagonist in one trial. A precision clinical trial of recombinant human interleukin-1 Receptor Antagonist targeted to septic patients with high plasma interleukin-1 Receptor Antagonist may be worthy of consideration.
P. N. Sidharta - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan
Clinical Pharmacokinetics, 2015Co-Authors: P. N. Sidharta, A. Treiber, Jasper DingemanseAbstract:Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ET_A and ET_B Receptor Antagonist with high affinity and sustained Receptor binding is the first ET Receptor Antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug–drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.
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Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan
Clinical Pharmacokinetics, 2015Co-Authors: P. N. Sidharta, A. Treiber, Jasper DingemanseAbstract:Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ET_A and ET_B Receptor Antagonist with high affinity and sustained Receptor binding is the first ET Receptor Antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug–drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.
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Macitentan: entry-into-humans study with a new endothelin Receptor Antagonist
European Journal of Clinical Pharmacology, 2011Co-Authors: P. N. Sidharta, Paul L. M. Van Giersbergen, Atef Halabi, Jasper DingemanseAbstract:Purpose To study the pharmacokinetics, pharmacodynamics, and tolerability of rising single doses of macitentan, an endothelin Receptor Antagonist, in healthy male subjects.
