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Modulation of Heme Oxygenase 1 by Nizatidine and Lisinopril in Healthy Subjects

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ClinicalTrials.gov Identifier: NCT02232308
Recruitment Status : Completed
First Posted : September 5, 2014
Last Update Posted : April 30, 2015
Sponsor:
Collaborators:
National Center for Research Resources (NCRR)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by (Responsible Party):
Adil Bharucha, Mayo Clinic

Brief Summary:
To assess if oral nizatidine or lisinopril alone and in combination will increase heme oxygenase 1 (HO-1) protein concentration and activity compared to placebo in healthy subjects.

Condition or disease Intervention/treatment Phase
Gastroparesis Drug: Nizatidine Drug: Lisinopril Drug: Placebo Phase 1

Detailed Description:
Current therapeutic options for gastroparesis are limited to dietary modifications and pharmacological (i.e., prokinetic and symptomatic) agents. Exciting and novel preliminary data from our programs demonstrate that (i) reduced expression of heme oxygenase 1 (HO-1) is responsible for loss of interstitial cells of Cajal and delayed gastric emptying in non-obese diabetic (NOD) mice, (ii) upregulation of (HO-1) reverses delayed gastric emptying in this model, perhaps by generating carbon monoxide (CO), which has anti-apoptotic and cytoprotective actions, and may relax smooth muscle, and (iii) hemin upregulates HO-1 in humans. However, hemin is exorbitant and can only be administered intravenously. A large throughput screening assay uncovered that the histamine H2 receptor antagonist nizatidine and the ACE inhibitor lisinopril upregulate HO-1 in Human Embryonic Kidney (HEK) cells. Hence, this double-blind placebo-controlled study will randomly assign 24 healthy subjects to one of 4 arms, and HO-1 protein activity and concentration will be assessed.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: Modulation of Heme Oxygenase 1 by Nizatidine and Lisinopril in Healthy Subjects
Study Start Date : July 2014
Actual Primary Completion Date : September 2014
Actual Study Completion Date : September 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Nizatidine
Nizatidine (150 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
Drug: Nizatidine
Nizatidine (150 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
Other Name: Axid

Experimental: Lisinopril
Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
Drug: Lisinopril
Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
Other Names:
  • Zestril
  • Prinivil

Experimental: Nizatidine plus Lisinopril
Nizatidine (150 mg) and Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
Drug: Nizatidine
Nizatidine (150 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
Other Name: Axid

Drug: Lisinopril
Lisinopril (10 mg) will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
Other Names:
  • Zestril
  • Prinivil

Placebo Comparator: Placebo
Placebo capsules to match active drug will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.
Drug: Placebo
Placebo capsules to match active drug will be administered once daily for the first 3 days, then twice daily for days 4-9, and once on day 10.




Primary Outcome Measures :
  1. Change in plasma heme oxygenase 1 (HO-1) protein concentration [ Time Frame: Day 3, Day 10 ]
    Heme oxygenase (HO-1) degrades heme and protects against oxidative stress. HO-1 concentration was measured by a blood test; the units are ng/ml.

  2. Change in Monocyte HO-1 activity [ Time Frame: Day 3, Day 10 ]
    Heme oxygenase (HO-1) degrades heme and protects against oxidative stress. When HO-1 is induced, more heme is removed, and end products of heme metabolism (i.e., carbon monoxide, iron, and bilirubin) are generated. HO-1 activity was measured by a blood test, the units are pmol bilirubin/mg/h.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion criteria:

  • Healthy subjects without clinical evidence of significant cardiovascular, gastrointestinal, hematological, neurological, psychiatric or other disease that may interfere with the objectives of the study and/or pose safety concerns
  • Normal serum potassium and estimated glomerular filtration rate (eGFR) > 60 ml/minute
  • Baseline systolic BP ≥ 110 mmHg
  • No known hypersensitivity to lisinopril or nizatidine
  • Able to provide written informed consent before participating in the study
  • Able to communicate adequately with the investigator and to comply with the requirements for the entire study.

Exclusion criteria:

  • Pregnant
  • Breast feeding
  • Current smoker
  • Symptoms of functional GI disorder as assessed by a validated questionnaire
  • Previous history of peptic ulcer disease.

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): NCT02232308


Locations
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United States, Minnesota
Mayo Clinic in Rochester
Rochester, Minnesota, United States, 55905
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Adil Bharucha
National Center for Research Resources (NCRR)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
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Principal Investigator: Adil Bharucha, MBBS, MD Mayo Clinic
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Responsible Party: Adil Bharucha, Professor of Medicine, Mayo Clinic
ClinicalTrials.gov Identifier: NCT02232308    
Other Study ID Numbers: 14-004137
UL1RR024150 ( U.S. NIH Grant/Contract )
P01DK068055 ( U.S. NIH Grant/Contract )
First Posted: September 5, 2014    Key Record Dates
Last Update Posted: April 30, 2015
Last Verified: April 2015
Additional relevant MeSH terms:
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Gastroparesis
Stomach Diseases
Gastrointestinal Diseases
Digestive System Diseases
Paralysis
Neurologic Manifestations
Lisinopril
Nizatidine
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antihypertensive Agents
Cardiotonic Agents
Protective Agents
Physiological Effects of Drugs
Anti-Ulcer Agents
Gastrointestinal Agents
Histamine H2 Antagonists
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents