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Pharmacokinetics of Neostigmine and Glycopyrrolate

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ClinicalTrials.gov Identifier: NCT04027972
Recruitment Status : Recruiting
First Posted : July 22, 2019
Last Update Posted : July 22, 2019
Sponsor:
Information provided by (Responsible Party):
Dr. Mark Korsten, Bronx VA Medical Center

Brief Summary:
A group of 6 able-bodied healthy volunteers will receive Neostigmine (NEO) and Glycopyrrolate (GLY) intravenously and via 3 different methods of Iontophoresis (ION) with subsequent blood draws over 1 hour in order to measure the pharmacokinetic behavior of the drugs en-vivo.

Condition or disease Intervention/treatment Phase
Pharmacokinetic Behavior of Neostigmine and Glycopyrrolate After Administration Via Different Routes Drug: Combination of Neostigmine and Glycopyrrolate Device: I-Box by Dynatronics Early Phase 1

Detailed Description:

The maximum dose of NEO is limited to 10.0 mg and the dose of GLY to 2.0 mg per subject per administration. Subjects will be asked to arrive at the Spinal Cord Research Center at the JJP VAMC (Room 7A-13) on the day of their appointment. On Day 1, following the obtainment the subject's consent, filling out a MoCA cognitive assessment and establishing an IV access point, administration of the medications via IV will be performed. The study design will consist of a Day 1to determine the pharmacokinetic profiles of the IV doses of NEO and GLY. During the second visit, at least 24 hours later, two patches with separately-applied NEO (0.035mg/kg) and GLY (0.007mg/kg) on separate patches will be simultaneously delivered by transdermal administration by ION for 20 minutes. Due to the doubling of cumulative current delivered, the dosage applied has been halved in an attempt to deliver approximately the same dose of medications systemically. During the third and final visit, at least 24 hours following the second visit, a single patch containing 0.07mg/kg of NEO and 0.0014mg/kg of GLY will be applied to the skin and delivered by transdermal administration by ION for 20 minutes..

Heart rate, bowel sounds, blood pressure and symptoms will be recorded at 0, 2, 4, 7, 10, 20, 40, 60 minutes of the initiation of the IV push and at 0, 10, 20, 40 and 60 minutes after the initiation of ION. Bowel evacuation time and time after the completion of delivery (by either ION or IV) will be recorded throughout the study visit, as described in Table 2. The subject will assume his/her normal bowel evacuation (BE) position until a bowel movement occurs; privacy draping and privacy will be provided at the time of BE. The subjects will be monitored for a minimum of 60 minutes. A minimum of two research personnel will be present during the study visit to record all of data and perform the tasks required.

After the start a 30 second IV push of NEO which will be followed by a NS flush (12mL), and then a 30 second IV push of GLY which will be followed by a NS flush (12mL), venous blood (2 mL) will be drawn into a gold-topped vial at 2, 4, 7, 10, 20, 40 and 60 minutes. Identical technique blood draws will be performed at 10, 20, 30, 40 and 60 minutes after the start of ION. Upon drawing, the blood will be placed in an ice bath and spun using a cooled centrifuge within 5 minutes of collection. Upon completion of 5 minutes of centrifugation, the resulting serum will be aliquoted into two separate vials, with equal volumes and labelled with date, time of draw, associated procedure, NEO or GLY testing destination and the subject's unique identifier. The transfer vials will be inserted into dry ice for at least 10 minutes, after which they will be placed into the -80 degrees Celsius freezer. Plasma levels of NEO and of GLY will be batched and measured at a later date. A file designating the tubes with random numbers associated with the draw times will be created for each subject to conceal the sequence of draw and to attempt the removal of possible bias during the measurement and recording of the concentrations of NEO (SUNY Downstate Albany Research Laboratory using GE LC-MRM detector) and GLY (JJPVAMC SCI Research Laboratory by ELISA).

Proposed Doses:

Day 1.: 0.02 mg/kg NEO and 0.004 mg/kg GLY via IV Day 2.: 0.035mg/kg NEO and 0.007mg/kg GLY via ION Day 3.: 0.07 mg/kg NEO and 0.014 mg/kg GLY via ION Day 4.: 0.07 mg/kg NEO and 0.014 mg/kg GLY via ION


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Same group receives all 4 treatments but in a randomized order after the IV phase.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pharmacokinetics of Neostigmine and Glycopyrrolate After Intravenous and Transcutaneous Administration by Iontophoresis
Actual Study Start Date : April 22, 2019
Estimated Primary Completion Date : December 28, 2019
Estimated Study Completion Date : December 30, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Primary
6 Subjects will receive all 4 types of medication administration in random sequence
Drug: Combination of Neostigmine and Glycopyrrolate
Intravenous or transdermal

Device: I-Box by Dynatronics
Electric field conducting drugs through the skin without compromising its integrity
Other Name: Iontophoresis




Primary Outcome Measures :
  1. Pharmacokinetic profile of Neostigmine and Glycopyrrolate within 1 hour post-administration via the measurement of the concentrations of Neostigmine and Glycopyrrolate in the serum of human subjects [ Time Frame: Within Two Hours ]
    Measurement of serum concentration of Neostigmine and of Glycopyrrolate


Secondary Outcome Measures :
  1. Safety (Presence of and graded severity of headache, dry mouth, muscle twitching and abdominal cramps.) [ Time Frame: Within 1 hour of administration ]
    Presence of and graded severity of headache, dry mouth, muscle twitching and abdominal cramps as reported by the subjects on the scale of 0 to 10



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male or Female
  • Age 18-70 years

Exclusion Criteria:

  • Previous adverse reaction or hypersensitivity to electrical stimulation,
  • Known sensitivity to neostigmine or glycopyrrolate,
  • History of mechanical obstruction of the GI or urinary tract,
  • Myocardial infarction within 6 months of trial,
  • Malignant and/or Uncontrollable Hypertension Defined by a blood pressure reading of 160/100 mmHg or higher with or without taking 3 or more different classes of anti-hypertensive medications,
  • Organ damage (heart & kidney) and/or TIA-CVA as a result of hypertension,
  • Known past history of coronary artery disease or bradyarrhythmia,
  • Symptomatic orthostatic hypotension
  • Deep brain stimulation
  • Pregnancy (women who are sexually active and of childbearing potential must utilize a method of contraception and agree to maintain a contraceptive method until completion of the study),
  • Lactating, nursing females
  • Inability to provide informed consent signaled by MoCA cognitive test score of 20 or less,
  • History of ingrown hair folliculitis,
  • Concurrent illness and fever,
  • Concurrent participation in a research study,
  • VA employee.

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): NCT04027972


Contacts
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Contact: Anton Sabiev, MD 917 717 4643 anton.sabiev@va.gov
Contact: Mark Korsten, MD 718 584 5000 ext 6753 mark.korsten@va.gov

Locations
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United States, New York
James J Peters VA Medical Center Recruiting
Bronx, New York, United States, 10468
Contact: Anton Sabiev    917-717-4643    sabiev@hotmail.com   
Sponsors and Collaborators
James J. Peters Veterans Affairs Medical Center

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Responsible Party: Dr. Mark Korsten, Chief of Gastroenterology, Bronx VA Medical Center
ClinicalTrials.gov Identifier: NCT04027972     History of Changes
Other Study ID Numbers: KOR-18-16
First Posted: July 22, 2019    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Pediatric Postmarket Surveillance of a Device Product: No
Keywords provided by Dr. Mark Korsten, Bronx VA Medical Center:
Neostigmine, Glycopyrrolate, Transdermal, Intravenous, Pharmacokinetic, Constipation, Bowel Control, Mass Spectroscopy, Stool Incontinence
Additional relevant MeSH terms:
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Glycopyrrolate
Neostigmine
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Parasympathomimetics
Autonomic Agents
Peripheral Nervous System Agents
Adjuvants, Anesthesia
Muscarinic Antagonists
Cholinergic Antagonists