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Effects of Lipid Emulsion on the Pharmacokinetic and Pharmacodynamic Properties of Metoprolol.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02924454
Recruitment Status : Completed
First Posted : October 5, 2016
Last Update Posted : April 12, 2017
Sponsor:
Information provided by (Responsible Party):
Mikkel Bring Christensen, University Hospital Bispebjerg and Frederiksberg

Brief Summary:
The aim of this study is to investigate whether intravenous lipid emulsion is effective in attenuating the clinical effects of a cardioactive drug, exemplified by the beta-blocking agent metoprolol. In addition, the investigators will clarify how intravenous lipid emulsion affects the pharmacokinetic parameters of metoprolol.

Condition or disease Intervention/treatment Phase
Drug Overdose Overdose of Beta-adrenergic Blocking Drug Blood Pressure Drug: metoprolol Drug: intravenous lipid emulsion Drug: Sodium chloride 0.9% solution - lipid emulsion dummy Drug: Sodium chloride 0.9% solution - metoprolol dummy Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: An Investigation Into the Effects of Intravenous Lipid Emulsion (ILE) on the Pharmacokinetic and Pharmacodynamic Properties of Metoprolol.
Actual Study Start Date : September 2016
Actual Primary Completion Date : March 10, 2017
Actual Study Completion Date : March 10, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Metoprolol-Lipid emulsion
intervention 1: metoprolol Intervention 2: intravenous lipid emulsion
Drug: metoprolol
One hundred and twenty ml, 0.5 mg metoprolol/ml (as metoprolol tartrate) is administered as an intravenous bolus injection followed by a continuous infusion. Infusion is halted if heart rate drops below 35 bpm or systolic blood pressure drops below 80 mm Hg, or the participant experiences subjective side effects. Infusion stops at T=30 minutes.
Other Names:
  • metoprolol tartrate
  • Seloken
  • ATC: C07AB02

Drug: intravenous lipid emulsion
Intravenous lipid emulsion 20 % is administered as an intravenous bolus infusion (1.5 ml/kg) followed by continuous infusion (infusion rate: 0.25 ml/kg/min). Lipid emulsion infusion is stopped at T = 30 minutes.
Other Names:
  • Intralipid
  • ATC: B05BA02

Experimental: Metoprolol - normal saline
intervention 1: metoprolol intervention 2: Sodium chloride 0.9% solution - lipid emulsion dummy
Drug: metoprolol
One hundred and twenty ml, 0.5 mg metoprolol/ml (as metoprolol tartrate) is administered as an intravenous bolus injection followed by a continuous infusion. Infusion is halted if heart rate drops below 35 bpm or systolic blood pressure drops below 80 mm Hg, or the participant experiences subjective side effects. Infusion stops at T=30 minutes.
Other Names:
  • metoprolol tartrate
  • Seloken
  • ATC: C07AB02

Drug: Sodium chloride 0.9% solution - lipid emulsion dummy
Isotonic 0.9 % sodium chloride solution is administered as an intravenous bolus infusion (1.5 ml/kg), followed by continuous infusion (infusion rate: 0.25 ml/kg/min). Infusion is stopped at T = 30 minutes.
Other Name: Normal saline

Experimental: Normal saline-Lipid emulsion
intervention 1: Sodium chloride 0.9% solution - metoprolol dummy intervention 2: intravenous lipid emulsion
Drug: intravenous lipid emulsion
Intravenous lipid emulsion 20 % is administered as an intravenous bolus infusion (1.5 ml/kg) followed by continuous infusion (infusion rate: 0.25 ml/kg/min). Lipid emulsion infusion is stopped at T = 30 minutes.
Other Names:
  • Intralipid
  • ATC: B05BA02

Drug: Sodium chloride 0.9% solution - metoprolol dummy
Saline solution is administered as an intravenous bolus injection followed by a continuous infusion to T=30 minutes.
Other Name: Normal saline

Experimental: Normal saline-normal saline
intervention 1: Sodium chloride 0.9% solution - metoprolol dummy intervention 2: Sodium chloride 0.9% solution - lipid emulsion dummy
Drug: Sodium chloride 0.9% solution - lipid emulsion dummy
Isotonic 0.9 % sodium chloride solution is administered as an intravenous bolus infusion (1.5 ml/kg), followed by continuous infusion (infusion rate: 0.25 ml/kg/min). Infusion is stopped at T = 30 minutes.
Other Name: Normal saline

Drug: Sodium chloride 0.9% solution - metoprolol dummy
Saline solution is administered as an intravenous bolus injection followed by a continuous infusion to T=30 minutes.
Other Name: Normal saline




Primary Outcome Measures :
  1. Change in heart rate from baseline compared between study days [ Time Frame: From baseline to + 120 minutes. ]
    Arterial catheter connected to a pressure transducer records heart rate (beats per minute).


Secondary Outcome Measures :
  1. Area under the plasma concentration versus time curve (AUC) of metoprolol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo. [ Time Frame: 0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose. ]
    Blood samples drawn from an antecubital vein.

  2. Peak plasma concentration (Cmax) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo. [ Time Frame: 0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose. ]
    Paracetamol is used as a tool for measuring gastric emptying time.

  3. Area under the plasma concentration versus time curve (AUC) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo. [ Time Frame: 0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose. ]
    Paracetamol is used as a tool for measuring gastric emptying time.

  4. Time to peak plasma concentration (Tmax) of paracetamol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo. [ Time Frame: 0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose. ]
    Paracetamol is used as a tool for measuring gastric emptying time.

  5. Percent change in plasma levels of standard biochemical measurements from baseline compared between study days. [ Time Frame: Changes at +30 and +60 minutes from baseline. ]
    Blood samples drawn from an antecubital vein measuring alanine aminotransferase, aspartate aminotransferase, albumin, bilirubin, alkaline phosphatase, calcium, creatine kinase, creatinine, C-reactive protein, high density lipoprotein, potassium, sodium, glucagon, lactate dehydrogenase, haptoglobin, triglycerides, and whole blood glucose levels(measured with a glucose meter).

  6. Peak Plasma Concentration (Cmax) of metoprolol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo. [ Time Frame: +0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose. ]
    Blood samples drawn from an antecubital vein measuring plasma metoprolol.

  7. Time to peak plasma concentration (Tmax) of metoprolol on days with co-administration of intravenous lipid emulsion compared to days with lipid emulsion placebo. [ Time Frame: +0, +10, +20, +30, +40, +50, +60, +90, +120 minutes post metoprolol dose. ]
    Blood samples drawn from an antecubital vein measuring plasma metoprolol.

  8. Cardiac conductivity between days with metoprolol and/or intravenous lipid emulsion compared with placebo. [ Time Frame: T-10, T-5, T 0, T 10, T 20, T 30, T 40, T 50, T 60, T 90, T 120 minutes. ]
    12-lead ECG

  9. Effects of metoprolol and lipid emulsion on stroke volume compared to days with placebo. [ Time Frame: T-10, T-5, T 0, T 10, T 20, T 30, T 40, T 50, T 60, T 90, T 120 minutes. ]
    Stroke volume (mL) derived from arterial pulse contour analysis.

  10. Effect of metoprolol on systolic, diastolic and mean arterial pressure on days with co-administration of intravenous lipid emulsion compared to days with placebo. [ Time Frame: T-10, T-5, T 0, T 10, T 15, T 20, T 30, T 40, T 50, T 60, T 90, T100, T110, T 120 minutes. ]
    Arterial catheter connected to a pressure transducer records blood pressure in mm Hg.

  11. Change in systolic, diastolic and mean arterial pressure from baseline compared between study days. [ Time Frame: Changes at +5, +10, +15, +20, +30, +40, +50, +60, +90, +95, +100, +105, +110, +115, +120 minutes from baseline. ]
    Arterial catheter connected to a pressure transducer records blood pressure in mm Hg.

  12. Change in heart rate from baseline compared between study days. [ Time Frame: Changes at +5, +10, +15, +20, +30, +40, +50, +60, +90, +95, +100, +105, +110, +115, +120 minutes from baseline. ]
    Arterial catheter connected to a pressure transducer records heart rate (beats per minute).

  13. Change in stroke volume (ml) from baseline compared between study days. [ Time Frame: Changes at +5, +10, +15, +20, +30, +40, +50, +60, +90, +95, +100, +105, +110, +115, +120 minutes from baseline. ]
    Stroke volume (ml) derived from arterial pulse contour analysis.



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Ages Eligible for Study:   20 Years to 30 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

- healthy male.

Exclusion Criteria:

  • Abnormal blood levels of sodium, potassium, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, albumin, bilirubin, hemoglobin, HbA1c, cholesterol fractions.
  • Abnormal urine albumin to creatinine ratio.
  • Abnormal function of CYP2D6 metabolism (ultrarapid or slow metabolizer)
  • Any heart disease or hypertension
  • Sinoatrial block
  • Second or third degree atrioventricular block
  • Heart failure
  • profound bradycardia or hypotension
  • sinoatrial node disease
  • metabolic acidosis
  • untreated pheochromocytoma
  • asthma
  • chronic obstructive pulmonary disease
  • intermittent claudicatio
  • diabetes
  • Allergy to egg, soy or peanut protein and allergy to any active or inactive ingredients contained in metoprolol (Seloken) or the lipid emulsion (Intralipid)
  • Raynaud's syndrome
  • Prinzmetal's angina

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02924454


Locations
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Denmark
Bispebjerg University Hospital Copenhagen
Copenhagen NW, Capital Region of Denmark, Denmark, 2400
Sponsors and Collaborators
Mikkel Bring Christensen
Investigators
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Principal Investigator: Mikkel B Christensen, MD, PhD Bispebjerg University Hospital, Copenhagen

Publications:
Hoffman RS, Howland MA, Lewin NA, Nelson L, Goldfrank LR, Flomenbaum N, editors. Goldfrank's toxicologic emergencies. Tenth edition. New York: McGraw-Hill Education; 2015. 1882 p.

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Responsible Party: Mikkel Bring Christensen, MD, PhD, University Hospital Bispebjerg and Frederiksberg
ClinicalTrials.gov Identifier: NCT02924454    
Other Study ID Numbers: Intralipid-Metoprolol
First Posted: October 5, 2016    Key Record Dates
Last Update Posted: April 12, 2017
Last Verified: April 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Mikkel Bring Christensen, University Hospital Bispebjerg and Frederiksberg:
metoprolol
lipid emulsion
pharmacodynamics
pharmacokinetics
Additional relevant MeSH terms:
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Drug Overdose
Substance-Related Disorders
Chemically-Induced Disorders
Metoprolol
Fat Emulsions, Intravenous
Pharmaceutical Solutions
Anti-Arrhythmia Agents
Antihypertensive Agents
Sympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Parenteral Nutrition Solutions