Pharmacokinetics and pharmacodynamics of single dose of inhaled nebulized sodium nitrite in healthy and hemoglobin E/β-thalassemia subjects
| Autor: | Nathawut Sibmooh, Thanaporn Sriwantana, Kanjana Sirirat, Sirada Srihirun, Suthat Fucharoen, Kittiphong Paiboonsukwong, Tipparat Parakaw, Pornpun Vivithanaporn, Piyamitr Sritara, Garnpimol C. Ritthidej, Jirada Kaewchuchuen |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Cancer Research Physiology Hypertension Pulmonary Clinical Biochemistry Pulmonary Artery 030204 cardiovascular system & hematology Pharmacology Biochemistry Methemoglobin Nitric oxide 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Administration Inhalation Humans Medicine Arterial Pressure Platelet activation Nitrite Sodium nitrite Whole blood Sodium Nitrite Inhalation business.industry Hemoglobin E beta-Thalassemia Middle Aged Platelet Activation medicine.disease Pulmonary hypertension Oxidative Stress 030104 developmental biology chemistry Nitrosative Stress Female business |
| Zdroj: | Nitric Oxide. 93:6-14 |
| ISSN: | 1089-8603 |
| DOI: | 10.1016/j.niox.2019.09.001 |
| Popis: | Inhaled sodium nitrite has been reported to decrease pulmonary artery pressure in hemoglobin E/β-thalassemia (HbE/β-thal) patients with pulmonary hypertension. This study investigated the pharmacokinetics and pharmacodynamics of inhaled nebulized sodium nitrite in 10 healthy subjects and 8 HbE/β-thal patients with high estimated pulmonary artery pressure. Nitrite pharmacokinetics, fraction exhaled nitric oxide (FENO), estimated right ventricular systolic pressure (eRVSP) measured by echocardiography, and platelet activation were determined. Nebulized sodium nitrite at doses used in this study (37.5 and 75 mg for healthy subjects and 15 mg for HbE/β-thal patients) was well tolerated and did not cause changes in methemoglobin levels and systemic blood pressure. Absorption of inhaled nitrite was rapid with the absolute bioavailability of 18%. In whole blood, nitrite exhibited the dose-independent pharmacokinetics with clearance (CL) of 1.5 l/h/kg, volume of distribution (Vd) of 1.3 l/kg and half-life (t1/2) of 0.6 h. CL and Vd of nitrite was higher in red blood cells (RBC) than whole blood and plasma. HbE/β-thal patients had lower nitrite CL and longer t1/2 in RBC than healthy subjects. FENO increased immediately after inhalation. Following nitrite inhalation, eRVSP remained unchanged but platelet activation was suppressed as evidenced by inhibition of adenosine diphosphate (ADP)-induced P-selectin expression and increase in phosphorylated vasodilator-stimulated phosphoprotein (P-VASPSer239) in platelets. There were no changes in markers of oxidative and nitrosative stress after inhalation. Our results support further development of inhaled nebulized sodium nitrite for treatment of pulmonary hypertension in β-thalassemia. |
| Databáze: | OpenAIRE |
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