Pharmacokinetics, pharmacodynamics, safety, and tolerability of nebulized sodium nitrite (AIR001) following repeat-dose inhalation in healthy subjects.

INTRODUCTION: The efficacy of nebulized sodium nitrite (AIR001) has been demonstrated in animal models of pulmonary arterial hypertension (PAH), but it was not known if inhaled nitrite would be well tolerated in human subjects at exposure levels associated with efficacy in these models. METHODS: Inhaled nebulized sodium nitrite was assessed in three independent studies in a total of 82 healthy male and female subjects. Study objectives included determination of the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) under normal and mildly hypoxic conditions, and following co-administration with steady-state sildenafil, assessment of nitrite pharmacokinetics, and evaluation of the fraction exhaled nitric oxide (FENO) and concentrations of iron-nitrosyl hemoglobin (Hb(Fe)-NO) and S-nitrosothiols (R-SNO) as biomarkers of local and systemic NO exposure, respectively. RESULTS: Nebulized sodium nitrite was well tolerated following 6 days of every 8 h administration up to 90 mg, producing significant increases in circulating Hb(Fe)-NO, R-SNO, and FENO. Pulmonary absorption of nitrite was rapid and complete, and plasma exposure dose was proportional through the MTD dosage level of 90 mg, without accumulation following repeated inhalation. At higher dosage levels, DLTs were orthostasis (observed at 120 mg) and hypotension with tachycardia (at 176 mg), but venous methemoglobin did not exceed 3.0 % at any time in any subject. Neither the tolerability nor pharmacokinetics of nitrite was impacted by conditions of mild hypoxia, or co-administration with sildenafil, supporting the safe use of inhaled nitrite in the clinical setting of PAH. CONCLUSION: On the basis of these results, nebulized sodium nitrite (AIR001) has been advanced into randomized trials in PAH patients.

The state of health hardware in Aboriginal communities in rural and remote Australia.

INTRODUCTION: Many of the health problems faced by rural and remote Aboriginal people have been attributed to a poor living environment. In the mid 1980s we began a process of defining problems with the immediate living environment that would affect health. These related particularly to safety, washing and hygiene practice. METHODS: Between January 1999 and November 2006 we undertook a standardised and detailed assessment of housing in Aboriginal communities. This involved an initial assessment of 250 items in each house and living area, focusing on performance and their impact on these healthy living practices. At the first survey-fix we implemented a limited cost repair of non-functioning health hardware and then six months later returned to the communities for a repeat assessment to examine improvement in performance. RESULTS: Between January 1999 and November 2006 we assessed 4,343 houses in 132 communities in four States and the Northern Territory during survey-fix 1 (SF1) and have repeated that survey-fix assessment (SF2) in 3,448 houses in 112 of those communities. This survey demonstrates extraordinarily poor performance of Aboriginal houses. In the survey period, 71,869 items referred for repair by survey teams were inspected by licensed electricians or plumbers and 49,499 of these have so far been fixed. Only 10% of these house items requiring repair were due to vandalism or misuse. CONCLUSION: Improvements in the living environment for Aboriginal people will require a sustained commitment to the planning, funding and implementation of maintenance programs in addition to adherence to the design, construction and supervision detail outlined in the National Indigenous Housing Guide.