Modulation of Heme Oxygenase 1 by Nizatidine and Lisinopril in Healthy Subjects
Keywords
Abstract
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.
Dates
| Last Verified: | 03/31/2015 |
| First Submitted: | 06/22/2014 |
| Estimated Enrollment Submitted: | 09/01/2014 |
| First Posted: | 09/04/2014 |
| Last Update Submitted: | 04/27/2015 |
| Last Update Posted: | 04/29/2015 |
| Actual Study Start Date: | 06/30/2014 |
| Estimated Primary Completion Date: | 08/31/2014 |
| Estimated Study Completion Date: | 08/31/2014 |
Condition or disease
Intervention/treatment
Drug: Nizatidine
Drug: Lisinopril
Drug: Placebo
Phase
Arm Groups
| 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. | |
| 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. | |
| 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. | |
| 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. |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| 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. |
Outcome
Primary Outcome Measures
1. Change in plasma heme oxygenase 1 (HO-1) protein concentration [Day 3, Day 10]
2. Change in Monocyte HO-1 activity [Day 3, Day 10]
