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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Gastroparesis

Intervention / Treatment
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* Drug: Nizatidine
* Drug: Lisinopril
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nizatidine<br>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<br>* 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.<br>* Other names: Axid;|
| Experimental: Lisinopril<br>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<br>* 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.<br>* Other names: Prinivil;|
| Experimental: Nizatidine plus Lisinopril<br>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<br>* 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.<br>* Other names: Axid;Drug: Lisinopril<br>* 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.<br>* Other names: Prinivil;|
| Placebo Comparator: Placebo<br>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<br>* 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.<br>|

What is the study measuring?
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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 |