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

Gastroparesis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02232308
• Other study ID #: 14-004137
• Secondary ID: UL1RR024150P01DK
• Status: Completed
• Phase: Phase 1
• First received: June 23, 2014
• Last updated: April 28, 2015
• Start date: July 2014
• Est. completion date: September 2014

Study information

• Verified date: April 2015
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 24
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Gastroparesis

Intervention

Drug:
• 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.
• 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.
• 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.

Locations

Country	Name	City	State
United States	Mayo Clinic	Rochester	Minnesota
United States	Mayo Clinic in Rochester	Rochester	Minnesota

Sponsors (3)

Lead Sponsor	Collaborator
Adil Bharucha	National Center for Research Resources (NCRR), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No