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

Adil Bharucha

Status and phase: Completed; Phase 1

Conditions: Gastroparesis

Treatments: Drug: Lisinopril; Drug: Nizatidine; Drug: Placebo

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02232308

14-004137

UL1RR024150 (U.S. NIH Grant/Contract)

P01DK068055 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 24 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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24 participants in 4 patient groups, including a placebo group

Nizatidine

Experimental group

Description:

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.

Treatment:

Drug: Nizatidine

Lisinopril

Experimental group

Description:

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.

Treatment:

Drug: Lisinopril

Nizatidine plus Lisinopril

Experimental group

Description:

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.

Treatment:

Drug: Nizatidine

Drug: Lisinopril

Placebo

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo