Department of BioMolecular Sciences, University of Mississippi, Oxford, Mississippi, 38677, USA.
Department of Microbiology and Immunology, University of Mississippi Medical Center, Jackson, Mississippi, 39216, USA.
Pharm Res. 2022 Mar;39(3):541-551. doi: 10.1007/s11095-022-03191-4. Epub 2022 Mar 2.
Intranasally administered unfractionated heparin (UFH) and other sulfated polysaccharides are potential prophylactics for COVID-19. The purpose of this research was to measure the safety and pharmacokinetics of clearance of intranasally administered UFH solution from the nasal cavity.
Double-blinded daily intranasal dosing in C57Bl6 mice with four doses (60 ng to 60 μg) of UFH was carried out for fourteen consecutive days, with both blood coagulation measurements and subject adverse event monitoring. The pharmacokinetics of fluorescent-labeled UFH clearance from the nasal cavity were measured in mice by in vivo imaging. Intranasal UFH at 2000 U/day solution with nasal spray device was tested for safety in a small number of healthy human subjects.
UFH showed no evidence of toxicity in mice at any dose measured. No significant changes were observed in activated partial thromboplastin time (aPTT), platelet count, or frequency of minor irritant events over vehicle-only control. Human subjects showed no significant changes in aPTT time, international normalized ratio (INR), or platelet count over baseline measurements. No serious adverse events were observed. In vivo imaging in a mouse model showed a single phase clearance of UFH from the nasal cavity. After 12 h, 3.2% of the administered UFH remained in the nasal cavity, decaying to background levels by 48 h.
UFH showed no toxic effects for extended daily intranasal dosing in mice as well as humans. The clearance kinetics of intranasal heparin solution from the nasal cavity indicates potentially protective levels for up to 12 h after dosing.
鼻腔内给予未分级肝素（UFH）和其他硫酸多糖是 COVID-19 的潜在预防药物。本研究旨在测量鼻腔内给予 UFH 溶液的安全性和药代动力学，以清除鼻腔。
连续 14 天对 C57Bl6 小鼠进行每日双盲鼻腔内给药，给予 4 个剂量（60ng 至 60μg）的 UFH，同时进行凝血测量和受试者不良事件监测。通过体内成像测量荧光标记的 UFH 从鼻腔清除的药代动力学。用鼻腔喷雾装置将 2000U/天的鼻腔内 UFH 溶液进行了少量健康人体受试者的安全性测试。
在任何测量剂量下，UFH 在小鼠中均未显示出毒性迹象。与仅用载体对照相比，激活部分凝血活酶时间（aPTT）、血小板计数或轻微刺激性事件的频率均无明显变化。与基线测量相比，人体受试者的 aPTT 时间、国际标准化比值（INR）或血小板计数均无明显变化。未观察到严重不良事件。在小鼠模型中的体内成像显示 UFH 从鼻腔中呈单相清除。12 小时后，鼻腔中仍有 3.2%的给予 UFH，48 小时后降至背景水平。
UFH 在小鼠和人体中进行延长的每日鼻腔内给药均无毒性作用。鼻腔内肝素溶液从鼻腔清除的清除动力学表明，给药后 12 小时内可能具有保护作用。
