Tepper Jeffrey, Ochoa Ricardo, Rix Peter, Elliott Gary, Hoglen Niel, Poulin Dominic, Parsley Ed, Masamune Hiroko
Tepper Nonclinical Consulting, San Carlos, CA, USA
Pre-Clinical Safety Inc, Niantic, CT, USA.
Int J Toxicol. 2014 May;33(3):162-174. doi: 10.1177/1091581814531801. Epub 2014 May 6.
Historically, nitrogen oxides (NO) in food, drinking water, as well as in the atmosphere have been believed to be associated with adverse health consequences. More recently, NO have been implicated in normal homeostatic regulation, and exogenous administration has been associated with health benefits. One such potential health benefit is the prospect that inhaled nitrite will lower pulmonary blood pressure (BP) in patients with pulmonary arterial hypertension (PAH), a disease with poor prognosis due to the lack of effective treatment. To characterize potential chronic toxicity associated with inhaled AIR001 (sodium nitrite) for use in the treatment of PAH, 26-week exposures to AIR001 were carried out by inhalation administration in rats and by intravenous infusion in dogs. The studies revealed that methemoglobinemia was the primary adverse effect in both species. Methemoglobin levels less than 40% were well tolerated in both species, while levels greater than 50% methemoglobin caused death in some rats. Additionally, a decrease in systemic BP was also observed with inhaled AIR001 exposure in dogs. These acute secondary and exaggerated pharmacological effects occurred daily throughout the 26-week treatment period. Chronic exposure did not alter the magnitude of either methemoglobinemia or hypotension or result in additional toxicity or compensatory responses. Based on the exposure levels that produced these pharmacodynamic responses in animals, relative to those measured in early clinical studies, it appears that an adequate margin of safety exists to support the continued clinical development of inhaled AIR001.
从历史上看，人们一直认为食物、饮用水以及大气中的氮氧化物（NO）与不良健康后果有关。最近，NO被认为参与正常的稳态调节，并且外源性给予NO已被证明具有健康益处。其中一个潜在的健康益处是，吸入亚硝酸盐有望降低肺动脉高压（PAH）患者的肺血压（BP），PAH是一种因缺乏有效治疗而预后较差的疾病。为了表征与用于治疗PAH的吸入式AIR001（亚硝酸钠）相关的潜在慢性毒性，通过吸入给药对大鼠进行了为期26周的AIR001暴露实验，并通过静脉输注对犬进行了实验。研究表明，高铁血红蛋白血症是这两个物种的主要不良反应。两个物种对高铁血红蛋白水平低于40%都有良好的耐受性，而高铁血红蛋白水平高于50%会导致一些大鼠死亡。此外，在犬中吸入AIR001暴露后也观察到全身血压下降。在整个26周的治疗期间，这些急性继发性和过度的药理作用每天都会出现。慢性暴露并未改变高铁血红蛋白血症或低血压的程度，也未导致额外的毒性或代偿反应。根据在动物中产生这些药效学反应的暴露水平，相对于早期临床研究中测得的水平，似乎存在足够的安全边际来支持吸入式AIR001的持续临床开发。
