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Markus A Weigand - One of the best experts on this subject based on the ideXlab platform.

  • continuous infusion of Physostigmine in patients with perioperative septic shock a pharmacokinetic pharmacodynamic study with population pharmacokinetic modeling
    Biomedicine & Pharmacotherapy, 2019
    Co-Authors: Nadine Pinder, Johannes B Zimmermann, Silke Gastine, Gudrun Wurthwein, Georg Hempel, Torsten Hoppetichy, Markus A Weigand, Thomas Bruckner, Stefanie Swoboda
    Abstract:

    Abstract Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive Physostigmine Salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on Physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for Physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state Physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during Physostigmine Salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by Physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of Physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

  • Continuous infusion of Physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2019
    Co-Authors: Nadine Pinder, Johannes B Zimmermann, Silke Gastine, Gudrun Wurthwein, Georg Hempel, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefanie Swoboda
    Abstract:

    Abstract Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive Physostigmine Salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on Physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for Physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state Physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during Physostigmine Salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by Physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of Physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

  • effect of Physostigmine on recovery from septic shock following intra abdominal infection results from a randomized double blind placebo controlled monocentric pilot trial anticholium per se
    Journal of Critical Care, 2019
    Co-Authors: Nadine Pinder, Torsten Hoppetichy, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Phillip Knebel, Jan Larmann, Thomas Bruckner, Markus A Weigand
    Abstract:

    Abstract Purpose The cholinergic anti-inflammatory pathway has been shown to be accessible by Physostigmine Salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated. Materials and methods In this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The Physostigmine group received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days. Results Administration of Physostigmine Salicylate was well tolerated. Mean SOFA scores were 8.9 ± 2.5 and 11.3 ± 3.6 (mean ± SD) for Physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (−2.37, 95% CI: −5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the Physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability. Conclusions Treatment with Physostigmine Salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock. Trial registration EudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322 .

  • Adjunctive use of Physostigmine Salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se)
    Trials, 2017
    Co-Authors: Johannes B Zimmermann, Nadine Pinder, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefan Hofer
    Abstract:

    Background Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor Physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Methods Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with Physostigmine Salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of Physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. Discussion This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of Physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. Trial registration EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

  • Adjunctive use of Physostigmine Salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se).
    Trials, 2017
    Co-Authors: Johannes B Zimmermann, Nadine Pinder, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefan Hofer
    Abstract:

    Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor Physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with Physostigmine Salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of Physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of Physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

Nadine Pinder - One of the best experts on this subject based on the ideXlab platform.

  • continuous infusion of Physostigmine in patients with perioperative septic shock a pharmacokinetic pharmacodynamic study with population pharmacokinetic modeling
    Biomedicine & Pharmacotherapy, 2019
    Co-Authors: Nadine Pinder, Johannes B Zimmermann, Silke Gastine, Gudrun Wurthwein, Georg Hempel, Torsten Hoppetichy, Markus A Weigand, Thomas Bruckner, Stefanie Swoboda
    Abstract:

    Abstract Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive Physostigmine Salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on Physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for Physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state Physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during Physostigmine Salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by Physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of Physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

  • Continuous infusion of Physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2019
    Co-Authors: Nadine Pinder, Johannes B Zimmermann, Silke Gastine, Gudrun Wurthwein, Georg Hempel, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefanie Swoboda
    Abstract:

    Abstract Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive Physostigmine Salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on Physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for Physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state Physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during Physostigmine Salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by Physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of Physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

  • effect of Physostigmine on recovery from septic shock following intra abdominal infection results from a randomized double blind placebo controlled monocentric pilot trial anticholium per se
    Journal of Critical Care, 2019
    Co-Authors: Nadine Pinder, Torsten Hoppetichy, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Phillip Knebel, Jan Larmann, Thomas Bruckner, Markus A Weigand
    Abstract:

    Abstract Purpose The cholinergic anti-inflammatory pathway has been shown to be accessible by Physostigmine Salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated. Materials and methods In this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The Physostigmine group received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days. Results Administration of Physostigmine Salicylate was well tolerated. Mean SOFA scores were 8.9 ± 2.5 and 11.3 ± 3.6 (mean ± SD) for Physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (−2.37, 95% CI: −5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the Physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability. Conclusions Treatment with Physostigmine Salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock. Trial registration EudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322 .

  • Adjunctive use of Physostigmine Salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se)
    Trials, 2017
    Co-Authors: Johannes B Zimmermann, Nadine Pinder, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefan Hofer
    Abstract:

    Background Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor Physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Methods Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with Physostigmine Salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of Physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. Discussion This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of Physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. Trial registration EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

  • Adjunctive use of Physostigmine Salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se).
    Trials, 2017
    Co-Authors: Johannes B Zimmermann, Nadine Pinder, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefan Hofer
    Abstract:

    Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor Physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with Physostigmine Salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of Physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of Physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

Stefanie Swoboda - One of the best experts on this subject based on the ideXlab platform.

  • continuous infusion of Physostigmine in patients with perioperative septic shock a pharmacokinetic pharmacodynamic study with population pharmacokinetic modeling
    Biomedicine & Pharmacotherapy, 2019
    Co-Authors: Nadine Pinder, Johannes B Zimmermann, Silke Gastine, Gudrun Wurthwein, Georg Hempel, Torsten Hoppetichy, Markus A Weigand, Thomas Bruckner, Stefanie Swoboda
    Abstract:

    Abstract Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive Physostigmine Salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on Physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for Physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state Physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during Physostigmine Salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by Physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of Physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

  • Continuous infusion of Physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2019
    Co-Authors: Nadine Pinder, Johannes B Zimmermann, Silke Gastine, Gudrun Wurthwein, Georg Hempel, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefanie Swoboda
    Abstract:

    Abstract Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive Physostigmine Salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on Physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for Physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state Physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during Physostigmine Salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by Physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of Physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

  • effect of Physostigmine on recovery from septic shock following intra abdominal infection results from a randomized double blind placebo controlled monocentric pilot trial anticholium per se
    Journal of Critical Care, 2019
    Co-Authors: Nadine Pinder, Torsten Hoppetichy, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Phillip Knebel, Jan Larmann, Thomas Bruckner, Markus A Weigand
    Abstract:

    Abstract Purpose The cholinergic anti-inflammatory pathway has been shown to be accessible by Physostigmine Salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated. Materials and methods In this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The Physostigmine group received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days. Results Administration of Physostigmine Salicylate was well tolerated. Mean SOFA scores were 8.9 ± 2.5 and 11.3 ± 3.6 (mean ± SD) for Physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (−2.37, 95% CI: −5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the Physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability. Conclusions Treatment with Physostigmine Salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock. Trial registration EudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322 .

  • Adjunctive use of Physostigmine Salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se)
    Trials, 2017
    Co-Authors: Johannes B Zimmermann, Nadine Pinder, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefan Hofer
    Abstract:

    Background Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor Physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Methods Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with Physostigmine Salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of Physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. Discussion This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of Physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. Trial registration EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

  • Adjunctive use of Physostigmine Salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se).
    Trials, 2017
    Co-Authors: Johannes B Zimmermann, Nadine Pinder, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefan Hofer
    Abstract:

    Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor Physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with Physostigmine Salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of Physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of Physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

Thomas Bruckner - One of the best experts on this subject based on the ideXlab platform.

  • continuous infusion of Physostigmine in patients with perioperative septic shock a pharmacokinetic pharmacodynamic study with population pharmacokinetic modeling
    Biomedicine & Pharmacotherapy, 2019
    Co-Authors: Nadine Pinder, Johannes B Zimmermann, Silke Gastine, Gudrun Wurthwein, Georg Hempel, Torsten Hoppetichy, Markus A Weigand, Thomas Bruckner, Stefanie Swoboda
    Abstract:

    Abstract Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive Physostigmine Salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on Physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for Physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state Physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during Physostigmine Salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by Physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of Physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

  • Continuous infusion of Physostigmine in patients with perioperative septic shock: A pharmacokinetic/pharmacodynamic study with population pharmacokinetic modeling.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2019
    Co-Authors: Nadine Pinder, Johannes B Zimmermann, Silke Gastine, Gudrun Wurthwein, Georg Hempel, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefanie Swoboda
    Abstract:

    Abstract Background In the context of the cholinergic anti-inflammatory pathway, the clinical trial Anticholium® per Se (EudraCT Number: 2012-001650-26, ClinicalTrials.gov NCT03013322) addressed the possibility of taking adjunctive Physostigmine Salicylate treatment in septic shock from bench to bedside. Pharmacokinetics (PK) are likely altered in critically ill patients; data on Physostigmine PK and target concentrations are sparse, particularly for continuous infusion. Our objective was to build a population PK (popPK) model for Physostigmine, and further evaluate pharmacodynamics (PD) and concentration-response relationship in this setting. Methods In the randomized, double-blind, placebo-controlled trial, 20 patients with perioperative septic shock either received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for up to 120 h, or equivalent volumes of 0.9% sodium chloride (placebo group). Physostigmine plasma concentrations and acetylcholinesterase (AChE) activity were measured; concentration-response associations were evaluated, and popPK and PD modeling was performed with NONMEM. Results Steady state Physostigmine plasma concentrations reached 7.60 ± 2.81 ng/mL (mean ± standard deviation [SD]). PK was best described by a two-compartment model with linear clearance. Significant covariate effects were detected for body weight and age on clearance, as well as a high inter-individual variability of the central volume of distribution. AChE activity was significantly reduced to 30.5%–50.6% of baseline activity during Physostigmine Salicylate infusion. A sigmoidal direct effect PD model best described enzyme inhibition by Physostigmine, with an estimated half maximal effective concentration (EC50) of 5.99 ng/mL. Conclusions PK of Physostigmine in patients with septic shock displayed substantial inter-individual variability with body weight and age influencing the clearance. Physostigmine inhibited AChE activity with a sigmoidal concentration-response effect.

  • effect of Physostigmine on recovery from septic shock following intra abdominal infection results from a randomized double blind placebo controlled monocentric pilot trial anticholium per se
    Journal of Critical Care, 2019
    Co-Authors: Nadine Pinder, Torsten Hoppetichy, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Phillip Knebel, Jan Larmann, Thomas Bruckner, Markus A Weigand
    Abstract:

    Abstract Purpose The cholinergic anti-inflammatory pathway has been shown to be accessible by Physostigmine Salicylate in animal models. However, the cholinesterase inhibitor is not approved for adjunctive therapy in sepsis, and tolerability and safety of high initial doses followed by continuous infusion have not been investigated. Materials and methods In this trial, 20 patients with perioperative septic shock due to intra-abdominal infection were eligible. The Physostigmine group received an initial dose of 0.04 mg/kg Physostigmine Salicylate, followed by continuous infusion of 1 mg/h for 120 h; the placebo group was treated with 0.9% sodium chloride. Primary outcome was the mean Sequential Organ Failure Assessment (SOFA) score during treatment and up to 14 days. Results Administration of Physostigmine Salicylate was well tolerated. Mean SOFA scores were 8.9 ± 2.5 and 11.3 ± 3.6 (mean ± SD) for Physostigmine and placebo group, respectively. Adjusted for age, difference between means was not statistically significant (−2.37, 95% CI: −5.43 to 0.70, p = 0.121). Norepinephrine doses required only appeared lower in the Physostigmine group (p = 0.064), along with a more rapid reduction from an elevated heart rate possibly indicating less hemodynamic instability. Conclusions Treatment with Physostigmine Salicylate was feasible and safe. Further studies are justified to assess the effect on recovery from septic shock. Trial registration EudraCT Number 2012-001650-26, ClinicalTrials.gov identifier NCT03013322 .

  • Adjunctive use of Physostigmine Salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se)
    Trials, 2017
    Co-Authors: Johannes B Zimmermann, Nadine Pinder, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefan Hofer
    Abstract:

    Background Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor Physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Methods Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with Physostigmine Salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of Physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. Discussion This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of Physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. Trial registration EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

  • Adjunctive use of Physostigmine Salicylate (Anticholium®) in perioperative sepsis and septic shock: study protocol for a randomized, double-blind, placebo-controlled, monocentric trial (Anticholium® per Se).
    Trials, 2017
    Co-Authors: Johannes B Zimmermann, Nadine Pinder, Stefanie Swoboda, Monika Lehmann, Jean Motsch, Thorsten Brenner, Markus A Weigand, Thomas Bruckner, Torsten Hoppe-tichy, Stefan Hofer
    Abstract:

    Severe sepsis and septic shock remain a major challenge, even in modern intensive care. In Germany, about 68,000 patients die annually because of septic diseases, characterized by a complex systemic inflammatory response. Causal treatment of the underlying infection is essential for successful management of sepsis, but the course can be positively influenced by supportive and adjuvant measures. The cholinergic anti-inflammatory pathway (CAP) represents a new approach to adjunctive therapy of septic diseases and can be pharmacologically activated by the acetylcholinesterase inhibitor Physostigmine (Anticholium®). Promising effects can be found in several in vitro and in vivo models of sepsis, such as a reduction in pro-inflammatory cytokines and improved survival. Anticholium® per Se is a randomized, double-blind, placebo-controlled, monocentric trial to assess whether the CAP can be transferred from bench to bedside. In this pilot study, 20 patients with perioperative sepsis and septic shock as a result of intra-abdominal infection are enrolled. According to randomization, participants are treated with Physostigmine Salicylate (verum group) or 0.9% sodium chloride (placebo group) for up to 5 days. The mean Sequential Organ Failure Assessment (SOFA) score during treatment and subsequent intensive care of up to 14 days is used as surrogate outcome (primary endpoint). Secondary outcome measures include 30- and 90-day mortality. An embedded pharmacokinetics and pharmacodynamics study investigates plasma concentrations of Physostigmine and its metabolite eseroline. Further analyses will contribute to our understanding of the role of various cytokines in the pathophysiology of human sepsis. A computer-generated list is used for block randomization. This randomized, controlled, monocentric trial investigates for the first time the adjunctive use of Physostigmine (Anticholium®) in patients with perioperative sepsis and septic shock and may be a pivotal step toward the clinical use in this indication. EudraCT Number: 2012-001650-26 (entered 14 August 2012), ClinicalTrials.gov identifier: NCT03013322 (registered on 1 Jan 2017).

Leon J Thal - One of the best experts on this subject based on the ideXlab platform.