Effect of Sublingually Generated S-nitroso-N-acetylcysteine on Systemic Blood Pressure.

Study Overview
=================
Brief Summary
-----------------
The purpose of the study is to increase the in vivo levels of nitric oxide by generating nitric oxide donor compound S-nitrosoacetylcysteine (SNOAC) using the mixture of sodium nitrite and N-acetylcysteine crystals in the sublingual space. The generated SNOAC rapidly diffuses into blood circulation thereby decrease the systemic blood pressure. This compound can be an alternative to organic nitrate NO donor drugs without developing tolerance in patients.

Detailed Description
-----------------
It is well established that increasing the bioavailability of endogenous nitric oxide (NO) protects against cardiovascular diseases. Administering exogenous NO donors is one option to increase endogenous NO levels. Organic nitrates like nitroglycerin have been used as NO donors to protect against angina and ischemic heart failure for over a century. However, their therapeutic value is compromised by rapid development of tolerance during sustained therapy. Hence, these drugs cannot be used as sustain sources of NO. Low-molecular-weight S-nitrosothiols are proven NO donors that have potent vasodilatory, antithrombotic, and anti-inflammatory activities. However, their prophylactic use is hindered by instability after preparation. Inorganic nitrite is emerging as a hypoxic vasodilator, but recent clinical studies indicate that high oral doses of >100 mg/day are required to improve vascular tone. To solve the problems of organic nitrates tolerance, S-nitrosothiol instability, and high nitrite dose requirements, the technique of generating S-nitrosoacetylcysteine (SNOAC) sublingually or in the stomach by reacting sodium nitrite with N-acetylcysteine (NAC) in rodent models was developed. This SNOAC is rapidly absorbed into circulation and increases plasma S-nitrosothiols and reduces systemic systolic and diastolic blood pressure. The major objective of the proposed pre-phase 1 study is to confirm the preclinical findings, including whether the procedure used to generate and deliver NO is feasible in humans using optimal levels of nitrite (2.5mg and 5mg) and NAC (50mg) and a minimum number of subjects. The study will assess the feasibility of using nitrite and NAC mixture sublingually, generation and absorption of SNOAC into circulation, and blood pressure response to the optimum doses of nitrite and NAC. This study will lay the groundwork for determining whether this NO delivery technique can be implemented to initiate comprehensive clinical studies. S-nitrosothiols, nitrite, and nitrate in plasma will be measured by highly sensitive chemiluminescence assay and monitor cardiovascular hemodynamics by FDA-approved mobil-O-graph for ambulatory subjects

Official Title
-----------------
A Pilot Pre-Phase 1 Clinical Trial to Study How Administering Sublingual Nitric Oxide Donor S-nitroso-N-acetylcysteine Affects the Systemic Blood Pressure in Healthy Human Volunteers.

Conditions
-----------------
Hypertension, Cardiovascular Diseases

Intervention / Treatment
-----------------
* Drug: Mixture of Sodium Nitrite and N-acetylcysteine (NAC) crytals.


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male and female subjects who are at least 21 years old and who consent to participate in the study. Participants must be willing to have approximately 15 mL of blood drawn via venipuncture and undergo blood pressure measurement. Exclusion Criteria: Individuals who are below 21 years of age, pregnant, have major cardiovascular problems or sickle cell disease, incarcerated individuals or are unable to give consent will be excluded. Those whose blood pressure is below normal (i.e., 120/80) and those who have cardiovascular problems and taking organic nitrates and sildenafil-based drugs will also be excluded.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Intervention Model: Single Group Assignment
Interventional Model Description: The optimum levels of 2.5 mg and 5mg mg sodium nitrite and fixed amount of 50 mg N-acetylcysteine are used for this study. Total of 14 subjects are divided to two groups.Group 1 is tested with the low dose of 2.5 mg sodium nitrite. If no adverse effects are noticed in this group, the study is proceed for 2nd group with 5mg sodium nitrite.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: sodium nitrite and N-acetycysteine mixture<br>sodium nitrite 2.5mg + N-acetylcysteine 50mg Sodium nitrite 5 mg + N-acetylcysteine 50mg | Drug: Mixture of Sodium Nitrite and N-acetylcysteine (NAC) crytals.<br>* Exactly 2.5 mg or 5 mg sodium nitrite and 50 mg N-acetylcysteine are weighed and mixed together just before use. The mixture is placed under the participant's tongue. The powder slowly dissolves in saliva and generate S-nitrosoacetylcysteine. Investigators will ask the subjects not to swallow the drug at least for 30 min. Administration of nitrite and N-acetylcysteine individually at these concentrations is not expected to change any blood NO chemistry or the systemic blood pressure. Hence, investigators will not investigate the effects of nitrite and N-acetylcysteine individually in this study. Placebo control is not needed for this study because the baseline parameters will serve as control. Investigators will assess the drug effect based on the difference between pre-treatment and post-treatment values.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Measurement of plasma nitrite, nitrate and S-nitrosothiols in the study participants. | Plasma level of nitrite, nitrate and S-nitrosothiols species (nanomol/L) will be measured by highly validated ozone-based chemiluminescience assay before, during and the end of sublingual administration of S-nitrosoacetylcysteine in study participants The drug effect will be assessed based on the change in the nitrite, nitrate and S-nitrosothiol values from the baseline levels following the administration of the drug. | up to 18 months | 
| Measurement of Systemic systolic and diastolic blood pressure | The FDA approved Mobil-O-Graph blood pressure (BP) apparatus will be used to measure the BP parameters. BP is measured in units of millimeters of mercury (mmHg). The cuff will be wrapped around the left arm and the measurement time will be set for 120 minutes. Blood pressure parameters will be automatically measured at 2-minute intervals. | up to 11 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nitric oxide, Sodium nitrite, N-acetylcysteine, S-nitrosothiols, systemic blood pressure, Vasodilators, Hypertension