PDF(Pubmed)
Abstract：
The aim of this study is to determine if extended-release, bioabsorbable, subcutaneous naltrexone (NTX) implants can mitigate respiratory depression after an intravenous injection (IV) of fentanyl. Six different BIOabsorbable Polymeric Implant Naltrexone (BIOPIN) formulations, comprising combinations of Poly-d,l-Lactic Acid (PDLLA) and/or Polycaprolactone (PCL-1 or PCL-2), were used to create subcutaneous implants. Both placebo and naltrexone implants were implanted subcutaneously in male dogs. The active naltrexone implants consisted of two doses, 644 mg and 1288 mg. A challenge with IV fentanyl was performed in 33 male dogs at 97-100 days after implantation. Following the administration of a 30 μg/kg intravenous fentanyl dose, the placebo cohort manifested a swift and profound respiratory depression with a ~50% reduction in their pre-dose respiratory rate (RR). The BIOPIN NTX-implanted dogs were exposed to escalating doses of intravenous fentanyl (30 μg/kg, 60 μg/kg, 90 μg/kg, and 120 μg/kg). In contrast, the dogs implanted with the BIOPIN naltrexone implants tolerated doses up to 60 μg/kg without significant respiratory depression (<50%) but had severe respiratory depression with fentanyl doses of 90 μg/kg and especially at 120 μg/kg. Bioabsorbable, extended-release BIOPIN naltrexone implants are effective in mitigating fentanyl-induced respiratory depression in male canines at about 3 months after implantation. This technology may also have potential for mitigating fentanyl-induced respiratory depression in humans.
摘要：
这项研究的目的是确定是否延长释放，生物可吸收，皮下纳曲酮（NTX）植入物可以减轻静脉注射（IV）芬太尼后的呼吸抑制。六种不同的生物可吸收聚合物植入物纳曲酮（BIOPIN）配方，包含Poly-d的组合，l-乳酸(PDLLA)和/或聚己内酯(PCL-1或PCL-2),被用来制造皮下植入物。安慰剂和纳曲酮植入物均皮下植入雄性犬。活性纳曲酮植入物由两个剂量组成，644mg和1288mg。在植入后97-100天对33只雄性狗进行IV芬太尼攻击。在给予30μg/kg静脉内芬太尼剂量后，安慰剂组表现出迅速而严重的呼吸抑制,给药前呼吸频率(RR)降低约50%.将植入BIOPINNTX的狗暴露于递增剂量的静脉注射芬太尼（30μg/kg，60μg/kg,90μg/kg,和120μg/kg)。相比之下,植入BIOPIN纳曲酮植入物的犬耐受剂量高达60μg/kg,无明显呼吸抑制(<50%),但芬太尼剂量为90μg/kg,尤其是120μg/kg时出现严重呼吸抑制.生物可吸收，缓释BIOPIN纳曲酮植入物在植入后约3个月可有效缓解芬太尼引起的雄性犬呼吸抑制.该技术还可能具有减轻芬太尼引起的人类呼吸抑制的潜力。
