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

Condition(s) targeted: Gastroparesis

Intervention: Nizatidine (Drug); Lisinopril (Drug); Placebo (Drug)

Phase: Phase 1

Status: Completed

Sponsored by: Adil Bharucha

Official(s) and/or principal investigator(s):
Adil Bharucha, MBBS, MD, Principal Investigator, Affiliation: Mayo Clinic

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.

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

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Primary outcome:

Change in plasma heme oxygenase 1 (HO-1) protein concentration

Change in Monocyte HO-1 activity

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.

Minimum age: 18 Years. Maximum age: 65 Years. Gender(s): Both.

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.

Mayo Clinic, Rochester, Minnesota 55905, United States

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

Starting date: July 2014
Last updated: April 28, 2015