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In Vitro Optimization of Oxytocin-induced Myometrial Contractility by Propranolol

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ClinicalTrials.gov Identifier: NCT03434444
Recruitment Status : Recruiting
First Posted : February 15, 2018
Last Update Posted : July 18, 2019
Sponsor:
Information provided by (Responsible Party):
Samuel Lunenfeld Research Institute, Mount Sinai Hospital

Brief Summary:

The rates of cesarean deliveries (CD) and postpartum hemorrhage (PPH) are on the rise, with failed induction and augmentation of labor as major contributing factors. Oxytocin is commonly used for labor induction, as well as during the third stage of labor to minimize the risk of primary PPH. At delivery, it is imperative that the uterus responds effectively to parenteral oxytocin. Poor response to oxytocin following delivery is commonly due to prolonged labor with oxytocin augmentation that is known to "desensitize" the myometrium. Despite the option of several second line uterotonic agents, none of them are as effective as oxytocin in controlling PPH. Given that poor uterine muscle contraction is the root cause of both failed induction or augmentation (leading to a CD in labor) and uterine atony (leading to PPH), there is an urgent and clinically important need to investigate novel methods to enhance oxytocin-induced myometrial contractions.

Propranolol, a beta adrenergic receptor agonist, has the potential to improve myometrial contractions by virtue of its ability to inhibit catecholamine production. The investigators plan to investigate the effects of propranolol in both naive and desensitized myometrium, in order to better understand its potential role in improving labor induction and reducing the risk of PPH following oxytocin exposure during labor.

The investigators hypothesize that propranolol is likely to potentiate the action of oxytocin upon human myometrium, to ultimately help improve the success of labor induction/augmentation and treatment of PPH.


Condition or disease Intervention/treatment Phase
Postpartum Hemorrhage Drug: Oxytocin Drug: Propranolol Not Applicable

Detailed Description:

Myometrial samples will be used to investigate the effect of propranolol on uterine contractions when exposed to high and low doses of oxytocin (to simulate PPH treatment and labor induction respectively).

The tissue will also be frozen at the end of the experiment, and Western blotting will be used to investigate the effect of propranolol on the expression patterns and cellular distribution of the oxytocin receptor and beta-adrenergic receptor and their signaling pathways in desensitized myometrium.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: In Vitro Optimization of Oxytocin-induced Myometrial Contractility by Propranolol - Potential Applications in Induction of Labour and Treatment of Postpartum Hemorrhage
Actual Study Start Date : September 8, 2017
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Low Dose Oxytocin
The myometrial samples are bathed in an oxytocin solution at increasing concentrations (from 10 -15M to 10 -10M)
Drug: Oxytocin
Oxytocin in solution, ranging from 10 -15M to 10 -5M
Other Name: pitocin

Active Comparator: Propranolol
The myometrial samples are bathed in a propranol solution at 10 -7M
Drug: Propranolol
Propranolol in solution, 10-7M

Active Comparator: Propranolol + low dose oxytocin
The myometrial samples are bathed in an oxytocin solution at increasing concentrations (from 10 -15M to 10 -10M) plus propranol (10 -7M)
Drug: Oxytocin
Oxytocin in solution, ranging from 10 -15M to 10 -5M
Other Name: pitocin

Drug: Propranolol
Propranolol in solution, 10-7M

Active Comparator: High Dose Oxytocin
The myometrial samples are bathed in an oxytocin solution (10 -5M), followed by increasing concentrations of oxytocin (from 10 -10M to 10 -5M)
Drug: Oxytocin
Oxytocin in solution, ranging from 10 -15M to 10 -5M
Other Name: pitocin

Active Comparator: High Dose Oxytocin, Propranolol-pretreated
The myometrial samples are bathed in an oxytocin solution (10 -5M) plus propranolol (10 -7M), followed by increasing concentrations of oxytocin (from 10 -10M to 10 -5M)
Drug: Oxytocin
Oxytocin in solution, ranging from 10 -15M to 10 -5M
Other Name: pitocin

Drug: Propranolol
Propranolol in solution, 10-7M

Active Comparator: High dose oxytocin + propranolol
The myometrial samples are bathed in an oxytocin solution (10 -5M), followed by increasing concentrations of oxytocin (from 10 -10M to 10 -5M) plus propranolol (10 -7M)
Drug: Oxytocin
Oxytocin in solution, ranging from 10 -15M to 10 -5M
Other Name: pitocin

Drug: Propranolol
Propranolol in solution, 10-7M




Primary Outcome Measures :
  1. Motility index [ Time Frame: 3 hours ]

    Motility index (MI) takes into account both the amplitude and frequency of the myometrial contraction. It is a calculated outcome, based on the formula: frequency/(10 x amplitude).

    The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.



Secondary Outcome Measures :
  1. Amplitude of contraction [ Time Frame: 3 hours ]
    The maximum extent of uterine muscle contraction, measured in grams (g). The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.

  2. Frequency of contraction [ Time Frame: 3 hours ]

    The number of contractions in uterine muscle (myometrium) over 10 minutes, spontaneously and in response to an agonist.

    The analysis is undertaken by attaching myometrial strips between an isometric force transducer and the base of an organ bath chamber.


  3. Integrated area under response curve (AUC) [ Time Frame: 3 hours ]


Information from the National Library of Medicine

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Ages Eligible for Study:   16 Years to 40 Years   (Child, Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Patients who give written consent to participate in this study
  • Patients with gestational age 37-41 weeks
  • Non-laboring patients, not exposed to exogenous oxytocin
  • Patients requiring primary Cesarean delivery or first repeat Cesarean delivery

Exclusion Criteria:

  • Patients who refuse to give written informed consent
  • Patients who require general anesthesia
  • Patients who had previous uterine surgery or more than one previous Cesarean delivery
  • Patients with any condition predisposing to uterine atony and postpartum hemorrhage, such as abnormal placentation, multiple gestation, preeclampsia, macrosomia, polyhydramnios, uterine fibroids, bleeding diathesis, chorioamnionitis, or a previous history of postpartum bleeding
  • Emergency Cesarean section in labor
  • Patients on medications that could affect myometrial contractility, such as nifedipine, labetolol or magnesium sulfate

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): NCT03434444


Contacts
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Contact: Mrinalini Balki 416-586-5270 mrinalini.balki@uhn.ca

Locations
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Canada, Ontario
Mount Sinai Hospital Recruiting
Toronto, Ontario, Canada, M5G1X5
Contact: Mrinalini Balki, MD    416-586-5270    mrinalini.balki@uhn.ca   
Principal Investigator: Mrinalini Balki, MD         
Sub-Investigator: Jose CA Carvalho, MD         
Sub-Investigator: Gayani Jayasooriya, MD         
Sub-Investigator: Alice Luca, MSc         
Sub-Investigator: John Kingdom, MD         
Sponsors and Collaborators
Samuel Lunenfeld Research Institute, Mount Sinai Hospital
Investigators
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Principal Investigator: Mrinalini Balki, MD MOUNT SINAI HOSPITAL

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Responsible Party: Samuel Lunenfeld Research Institute, Mount Sinai Hospital
ClinicalTrials.gov Identifier: NCT03434444     History of Changes
Other Study ID Numbers: 18-04
First Posted: February 15, 2018    Key Record Dates
Last Update Posted: July 18, 2019
Last Verified: July 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Samuel Lunenfeld Research Institute, Mount Sinai Hospital:
propranolol
oxytocin
uterine contraction
Additional relevant MeSH terms:
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Propranolol
Postpartum Hemorrhage
Hemorrhage
Pathologic Processes
Obstetric Labor Complications
Pregnancy Complications
Puerperal Disorders
Uterine Hemorrhage
Oxytocin
Pharmaceutical Solutions
Oxytocics
Reproductive Control Agents
Physiological Effects of Drugs
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents