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

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.

Study Overview

• Status: Completed
• Conditions: Gastroparesis
• Intervention / Treatment: Drug: Nizatidine; Drug: Lisinopril; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / 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 Names: 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: Prinivil; Zestril
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 Names: 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: Prinivil; Zestril
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in plasma heme oxygenase 1 (HO-1) protein concentration	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.	Day 3, Day 10
Change in Monocyte HO-1 activity	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.	Day 3, Day 10

Collaborators and Investigators

• Sponsor: Adil Bharucha
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Research Resources (NCRR)
• Investigators: Principal Investigator: Adil Bharucha, MBBS, MD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: June 23, 2014
• First Submitted That Met QC Criteria: September 2, 2014
• First Posted (Estimate): September 5, 2014

Study Record Updates

• Last Update Posted (Estimate): April 30, 2015
• Last Update Submitted That Met QC Criteria: April 28, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neurologic Manifestations; Gastrointestinal Diseases; Stomach Diseases; Paralysis; Gastroparesis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Gastrointestinal Agents; Protease Inhibitors; Protective Agents; Cardiotonic Agents; Anti-Ulcer Agents; Histamine Antagonists; Histamine Agents; Angiotensin-Converting Enzyme Inhibitors; Histamine H2 Antagonists; Lisinopril; Nizatidine
• Other Study ID Numbers: 14-004137; UL1RR024150 (U.S. NIH Grant/Contract); P01DK068055 (U.S. NIH Grant/Contract)