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

NCT ID: NCT05798481

Last Updated: 2025-11-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 14 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-27
• Study Completion Date: 2025-10-05

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

Conditions

Hypertension; Cardiovascular Diseases

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

sodium nitrite and N-acetycysteine mixture

sodium nitrite 2.5mg + N-acetylcysteine 50mg

Sodium nitrite 5 mg + N-acetylcysteine 50mg

Group Type: EXPERIMENTAL

Mixture of Sodium Nitrite and N-acetylcysteine (NAC) crytals.

Intervention Type: DRUG

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.

Interventions

Mixture of Sodium Nitrite and N-acetylcysteine (NAC) crytals.

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.

Intervention Type: DRUG

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.

• Minimum Eligible Age: 21 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

University of Alabama at Birmingham

OTHER

Sponsor Role: lead

Responsible Party

Nagababu Enika

Assistant Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nagababu Enika, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Alabama at Birmingham

Brant Wagener, MD, PhD

Role: STUDY_DIRECTOR

University of Alabama at Birmingham

Locations

Anesthesiology and Perioperative Medicine

Birmingham, Alabama, United States

Countries

United States

References

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

PMID: 30621010 (View on PubMed)

Other Identifiers

IRB-300010325

Identifier Type: -

Identifier Source: org_study_id