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A 26-Week Toxicity Assessment of AIR001 (Sodium Nitrite) by Inhalation Exposure in Rats and by Intravenous
Jeffrey Tepper1, Ricardo Ochoa2, Peter Rix3
1Tepper Nonclinical Consulting, San Carlos, CA, USA TepperTox@gmail.com.
International Journal of Toxicology
|May 8, 2014
Summary
Inhaled sodium nitrite (AIR001) may treat pulmonary arterial hypertension. Chronic toxicity studies in rats and dogs showed methemoglobinemia and decreased blood pressure, but a sufficient safety margin supports further clinical development.
Area of Science:
- Pharmacology
- Toxicology
- Cardiovascular Medicine
Background:
- Nitrogen oxides (NOx), including nitrite, are increasingly recognized for roles in physiological regulation and potential therapeutic benefits.
- Pulmonary arterial hypertension (PAH) is a severe condition lacking effective treatments, presenting an unmet medical need.
- Inhaled nitrite is being investigated as a potential treatment to reduce pulmonary blood pressure in PAH patients.
Purpose of the Study:
- To assess the chronic toxicity of inhaled AIR001 (sodium nitrite) over 26 weeks in animal models.
- To determine the safety profile of AIR001 for potential therapeutic use in pulmonary arterial hypertension (PAH).
Main Methods:
- 26-week inhalation exposure to AIR001 in rats.
- 26-week intravenous infusion of AIR001 in dogs.
- Monitoring for adverse effects, including methemoglobinemia and blood pressure changes.
Main Results:
- Methemoglobinemia was the primary adverse effect in both rats and dogs.
- Methemoglobin levels below 40% were tolerated; levels above 50% were lethal in some rats.
- Systemic blood pressure decreased in dogs, an exaggerated pharmacological effect.
- Chronic exposure did not increase the severity of methemoglobinemia or hypotension.
Conclusions:
- AIR001 (sodium nitrite) administration via inhalation demonstrated a manageable safety profile in preclinical studies.
- Observed adverse effects, methemoglobinemia and hypotension, were dose-dependent and predictable.
- The identified safety margins support the continued clinical investigation of inhaled AIR001 for PAH treatment.
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