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Romano Deghenghi - One of the best experts on this subject based on the ideXlab platform.
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growth hormone releasing activity of hexarelin in humans a dose response study
European Journal of Clinical Pharmacology, 1994Co-Authors: Bruno Pietro Imbimbo, Vincent Lenaerts, Francois Boutignon, Timothy G K Mant, D. Amin, N Dalton, M Edwards, Patrick Wuthrich, Romano DeghenghiAbstract:Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·μg·kg−1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng·ml−1 after 0, 0.5, 1 and 2 μg·kg−1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0–180) were 0.135, 1.412, 2.918 and 3.695 μg·min·ml−1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 μg·kg−1 for Cmax and AUC0–180, respectively. The corresponding Emaxs were 55.1 ng·ml−1 and 3936 ng·min·ml−1, thus indicating that the effect after the 2 μg·kg−1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.
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growth hormone releasing activity of hexarelin in humans a dose response study
European Journal of Clinical Pharmacology, 1994Co-Authors: Bruno Pietro Imbimbo, Vincent Lenaerts, Francois Boutignon, Timothy G K Mant, D. Amin, N Dalton, M Edwards, Patrick Wuthrich, Romano DeghenghiAbstract:Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·μg·kg−1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng·ml−1 after 0, 0.5, 1 and 2 μg·kg−1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0–180) were 0.135, 1.412, 2.918 and 3.695 μg·min·ml−1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 μg·kg−1 for Cmax and AUC0–180, respectively. The corresponding Emaxs were 55.1 ng·ml−1 and 3936 ng·min·ml−1, thus indicating that the effect after the 2 μg·kg−1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.
Byron J Gajewski - One of the best experts on this subject based on the ideXlab platform.
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bayesian Emax model with a mixture of normal distributions for dose response in clinical trials
Contemporary Clinical Trials, 2021Co-Authors: Fengming Tang, Susan E Carlson, Jo Wick, Byron J GajewskiAbstract:Abstract When a dose–response relationship is monotonic, the Emax model has been shown to provide a good empirical fit for designing and analyzing dose–response data across a wide range of pharmaceutical studies. However, the Emax model has never been applied to a finite mixture distribution. Motivated by a proposal investigating DHA dose effect on preterm birth (PTB, 41 weeks gestation) using the same model. We compared our proposed Emax mixture model with an Emax logistic model and an independent doses logistic model for a dichotomized endpoint using extensive simulations. Across the scenarios under consideration, the Emax mixture model achieved higher power than the Emax logistic model and the independent doses logistic model in detecting the effect of DHA supplementation on the PTB rate. The Emax mixture model also resulted in smaller mean squared errors (MSE) in PTB rate estimates.
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comparison of hierarchical Emax and ndlm models in dose response for early phase clinical trials
BMC Medical Research Methodology, 2020Co-Authors: Xiaqing Huang, Byron J GajewskiAbstract:Phase II clinical trials primarily aim to find the optimal dose and investigate the relationship between dose and efficacy relative to standard of care (control). Therefore, before moving forward to a phase III confirmatory trial, the most effective dose is needed to be identified. The primary endpoint of a phase II trial is typically a binary endpoint of success or failure. The Emax model, ubiquitous in pharmacology research, was fit for many compounds and described the data well, except for a single compound, which had nonmonotone dose–response (Thomas et al., Stat Biopharmaceutical Res. 6:302-317 2014). To mitigate the risk of nonmonotone dose response one of the alternative options is a Bayesian hierarchical Emax model (Gajewski et al., Stat Med. 38:3123-3138 2019). The hierarchical Emax adapts to its environment. When the dose-response curve is monotonic it enjoys the efficiency of Emax. When the dose-response curve is non-monotonic the additional random effect hyperprior makes the hierarchical Emax model more adjustable and flexible. However, the normal dynamic linear model (NDLM) is a useful model to explore dose-response relationships in that the efficacy at the current dose depends on the efficacy of the previous dose(s). Previous research has compared the Emax to the hierarchical Emax (Gajewski et al., Stat Med. 38:3123-3138 2019) and the Emax to the NDLM (Liu et al., BMC Med Res Method 17:149 2017), however, the hierarchical Emax has not been directly compared to the NDLM. The focus of this paper is to compare these models and discuss the relative merit for each of their uses for an ongoing early phase dose selection study.
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bayesian hierarchical Emax model for dose response in early phase efficacy clinical trials
Statistics in Medicine, 2019Co-Authors: Byron J Gajewski, Caitlyn Meinzer, Scott M Berry, Gaylan L Rockswold, William G Barsan, Frederick K Korley, Renee H MartinAbstract:A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses. One very successful alternate model improves power using a pre-specified dose-response structure. Past research indicates that Emax models are broadly successful and therefore attractive for designing dose-response trials. However, there may be instances of slight risk of nonmonotone trends that need to be addressed when planning a clinical trial design. We propose to add hierarchical parameters to the Emax model. The added layer allows information about the treatment effect in one dose to be "borrowed" when estimating the treatment effect in another dose. This is referred to as the hierarchical Emax model. Our paper compares three different models (independent, Emax, and hierarchical Emax) and two different design strategies. The first design considered is Bayesian with a fixed trial design, and it has a fixed schedule for randomization. The second design is Bayesian but adaptive, and it uses response adaptive randomization. In this article, a randomized trial of patients with severe traumatic brain injury is provided as a motivating example.
Silveira, Alessandra Cristina De Paula - One of the best experts on this subject based on the ideXlab platform.
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Avaliação in vitro da adaptação marginal e interna de coroas de cerâmica e resina composta fabricadas com o sistema CAD/CAM utilizando duas câmeras intraorais de moldagem digital
2016Co-Authors: Silveira, Alessandra Cristina De PaulaAbstract:O objetivo deste estudo in vitro foi avaliara adaptação marginal e interna de coroas totais obtidas a partir de blocos pré-fabricados de Lava Ultimate 3M ESPE (resina nanocerâmica) e IPS e.max CAD IvoclarVivadent(cerâmica de dissilicato de lítio) com dois tipos de moldagem digital, câmera intraoralBluecam e câmera intraoralOmnicam, por meio do microtomógrafo. Métodos: Dez terceiros molares humanos hígidos foram preparados para receber coroas totais. Para cada molar preparado, foram realizadas duas impressões ópticas, uma com a Bluecam e a outra com a Omnicam, onde foram fresadas quatro diferentes coroas. Os quatro grupos formados foram: Grupo1 (Lava Ultimate+Bluecam); Grupo 2 (Emax+Bluecam); Grupo 3 (Lava Ultimate+Omnicam); Grupo 4 (Emax+Omnicam). A avaliação da adaptação marginal e interna sem ajuste foi realizada com a simulação da cimentação de cada coroa em seu respectivo dente com um silicone leve. O conjunto foi levado a um microtomógrafo e a discrepância marginal foi avaliada bidimensional e tridimensional para as variáveis gap axial (GA), gap oclusal (GO), gap marginal (GM), desadaptação marginal absoluta (DMA) e desadaptação entre a coroa e preparo (DCP). A significância estatística foi avaliada com o teste Shapiro-Wilk e ANOVA (p
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Avaliação in vitro da adaptação marginal e interna de coroas de cerâmica e resina composta fabricadas com o sistema CAD/CAM utilizando duas câmeras intraorais de moldagem digital
'Biblioteca Central da UNB', 2015Co-Authors: Silveira, Alessandra Cristina De PaulaAbstract:Dissertação (mestrado)—Universidade de Brasília, Faculdade de Ciências da Saúde, Programa de Pós-Graduação em Ciências da Saúde, 2015.O objetivo deste estudo in vitro foi avaliara adaptação marginal e interna de coroas totais obtidas a partir de blocos pré-fabricados de Lava Ultimate 3M ESPE (resina nanocerâmica) e IPS e.max CAD IvoclarVivadent(cerâmica de dissilicato de lítio) com dois tipos de moldagem digital, câmera intraoralBluecam e câmera intraoralOmnicam, por meio do microtomógrafo. Métodos: Dez terceiros molares humanos hígidos foram preparados para receber coroas totais. Para cada molar preparado, foram realizadas duas impressões ópticas, uma com a Bluecam e a outra com a Omnicam, onde foram fresadas quatro diferentes coroas. Os quatro grupos formados foram: Grupo1 (Lava Ultimate+Bluecam); Grupo 2 (Emax+Bluecam); Grupo 3 (Lava Ultimate+Omnicam); Grupo 4 (Emax+Omnicam). A avaliação da adaptação marginal e interna sem ajuste foi realizada com a simulação da cimentação de cada coroa em seu respectivo dente com um silicone leve. O conjunto foi levado a um microtomógrafo e a discrepância marginal foi avaliada bidimensional e tridimensional para as variáveis gap axial (GA), gap oclusal (GO), gap marginal (GM), desadaptação marginal absoluta (DMA) e desadaptação entre a coroa e preparo (DCP). A significância estatística foi avaliada com o teste Shapiro-Wilk e ANOVA (p
Bruno Pietro Imbimbo - One of the best experts on this subject based on the ideXlab platform.
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growth hormone releasing activity of hexarelin in humans a dose response study
European Journal of Clinical Pharmacology, 1994Co-Authors: Bruno Pietro Imbimbo, Vincent Lenaerts, Francois Boutignon, Timothy G K Mant, D. Amin, N Dalton, M Edwards, Patrick Wuthrich, Romano DeghenghiAbstract:Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·μg·kg−1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng·ml−1 after 0, 0.5, 1 and 2 μg·kg−1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0–180) were 0.135, 1.412, 2.918 and 3.695 μg·min·ml−1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 μg·kg−1 for Cmax and AUC0–180, respectively. The corresponding Emaxs were 55.1 ng·ml−1 and 3936 ng·min·ml−1, thus indicating that the effect after the 2 μg·kg−1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.
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growth hormone releasing activity of hexarelin in humans a dose response study
European Journal of Clinical Pharmacology, 1994Co-Authors: Bruno Pietro Imbimbo, Vincent Lenaerts, Francois Boutignon, Timothy G K Mant, D. Amin, N Dalton, M Edwards, Patrick Wuthrich, Romano DeghenghiAbstract:Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·μg·kg−1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng·ml−1 after 0, 0.5, 1 and 2 μg·kg−1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0–180) were 0.135, 1.412, 2.918 and 3.695 μg·min·ml−1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 μg·kg−1 for Cmax and AUC0–180, respectively. The corresponding Emaxs were 55.1 ng·ml−1 and 3936 ng·min·ml−1, thus indicating that the effect after the 2 μg·kg−1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.
Timothy G K Mant - One of the best experts on this subject based on the ideXlab platform.
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growth hormone releasing activity of hexarelin in humans a dose response study
European Journal of Clinical Pharmacology, 1994Co-Authors: Bruno Pietro Imbimbo, Vincent Lenaerts, Francois Boutignon, Timothy G K Mant, D. Amin, N Dalton, M Edwards, Patrick Wuthrich, Romano DeghenghiAbstract:Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·μg·kg−1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng·ml−1 after 0, 0.5, 1 and 2 μg·kg−1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0–180) were 0.135, 1.412, 2.918 and 3.695 μg·min·ml−1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 μg·kg−1 for Cmax and AUC0–180, respectively. The corresponding Emaxs were 55.1 ng·ml−1 and 3936 ng·min·ml−1, thus indicating that the effect after the 2 μg·kg−1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.
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growth hormone releasing activity of hexarelin in humans a dose response study
European Journal of Clinical Pharmacology, 1994Co-Authors: Bruno Pietro Imbimbo, Vincent Lenaerts, Francois Boutignon, Timothy G K Mant, D. Amin, N Dalton, M Edwards, Patrick Wuthrich, Romano DeghenghiAbstract:Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH2) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·μg·kg−1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (Cmax) were 3.9, 26.9, 52.3, 55.0 ng·ml−1 after 0, 0.5, 1 and 2 μg·kg−1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC0–180) were 0.135, 1.412, 2.918 and 3.695 μg·min·ml−1. The theoretical maximum response (Emax) and the dose that produces half of the maximum response (ED50) were estimated using logistic regression. The calculated ED50 values were 0.50 and 0.64 μg·kg−1 for Cmax and AUC0–180, respectively. The corresponding Emaxs were 55.1 ng·ml−1 and 3936 ng·min·ml−1, thus indicating that the effect after the 2 μg·kg−1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.