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

Adil Bharucha24 enrolled

Overview

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.

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

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Enrollment

Conditions

Gastroparesis

Interventions

NizatidineDRUG

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.

LisinoprilDRUG

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.

PlaceboDRUG

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

Sex: ALLMin age: 18 YearsMax age: 65 YearsHealthy volunteers:

Medical Language ↔ Plain English

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.

Locations (2)

Mayo Clinic in Rochester

Rochester, Minnesota, United States

Mayo Clinic

Rochester, Minnesota, United States

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: Day 3, Day 10

Data from ClinicalTrials.gov

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