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Open SPR助力疫苗動物模型評估

Title: A synthetic opioid vaccine attenuates fentanyl-vs-food choice in male and female rhesus monkeys

題目：合成阿片類疫苗減弱了雄性和雌性恒河猴的芬太尼與食物選擇

Journal: Drug and Alcohol Dependence

IF:3.951

Date: 2020/10/20

Abstract

Aim: Opioid-targeted vaccines are under consideration as candidate Opioid Use Disorder medications. We recently reported that a fentanyl-targeted vaccine produced a robust and long-lasting attenuation of fentanyl-vsfood choice in rats. In the current study, we evaluated an optimized fentanyl-targeted vaccine in rhesus monkeys to determine whether vaccine effectiveness to attenuate fentanyl choice translated to a species with greater phylogenetic similarity to humans.

Methods: Adult male (2) and female (3) rhesus monkeys were trained to respond under a concurrent schedule of food (1 g pellets) and intravenous fentanyl (0, 0.032? 1 μg/kg/injection) reinforcement during daily 2 h sessions. Fentanyl choice dose-effect functions were determined daily and 7-day buprenorphine treatments (0.0032? 0.032 mg/kg/h IV; n = 4–5) were determined for comparison to vaccine effects. Subsequently, a fentanyl-CRM197 conjugate vaccine was administered at week 0, 3, 8, 15 over a 29-week experimental period during which fentanyl choice dose-effect functions continued to be determined daily.

Results: Buprenorphine significantly decreased fentanyl choice and reciprocally increased food choice. Vaccination eliminated fentanyl choice and increased food choice in four-of-the-five monkeys. A transient and less robust vaccine effect was observed in the fifth monkey. Fentanyl-specific antibody concentrations peaked after the third vaccination to approximately 50 μg/mL while anti-fentanyl antibody affinity increased to a sustained low nanomolar level.

Conclusion: These results translate fentanyl vaccine effectiveness from rats to rhesus monkeys to decrease fentanyl-vs-food choice, albeit with greater individual differences observed in monkeys. These results support the potential and further clinical evaluation of this fentanyl-targeted vaccine as a candidate Opioid Use Disorder medication.

目的

阿片類藥物靶向疫苗可能成為阿片類藥物使用障礙治療藥物。我們最近報(bào)道芬太尼疫苗能強(qiáng)而持久地讓小鼠減弱對芬太尼與食物選擇。在最近的研究中，我們在與人類有更相似的發(fā)育系統(tǒng)的恒河猴中對優(yōu)化后的芬太尼疫苗進(jìn)行評估，以確定疫苗是否能有效降低恒河猴對芬太尼的選擇。

方法

2只雄性和3只雌性成年恒河猴在每天2小時(shí)的會議時(shí)間內(nèi)進(jìn)行食物(1g丸劑)和靜脈內(nèi)芬太尼(0, 0.032? 1 μg/kg/注射)強(qiáng)化的同時(shí)做出反應(yīng)的訓(xùn)練。每天確定芬太尼選擇劑量，7天的丁丙諾啡治療(0.0032? 0.032 mg/kg/h IV; n = 4–5)作為疫苗效果的對照。隨后，在29周的實(shí)驗(yàn)中，在第 0、3、8、15 周接種芬太尼結(jié)合疫苗，在此期間每天繼續(xù)確定芬太尼選擇劑量。

結(jié)果

丁丙諾啡顯著減少了芬太尼的選擇并相應(yīng)地增加了食物的選擇。在五分之四的猴子中，接種疫苗消除了芬太尼的選擇并增加了食物的選擇。在第五只猴子中觀察到短暫且不太強(qiáng)烈的疫苗效果。芬太尼特異性抗體濃度在第三次接種后達(dá)到峰值50μg/mL，同時(shí)抗芬太尼抗體親和力提高到低納摩爾水平。

結(jié)論

這些結(jié)果將芬太尼疫苗減少芬太尼與食物的選擇的有效性從大鼠轉(zhuǎn)移到恒河猴，雖然在猴子中觀察到更大的個體差異。這些結(jié)果表明，芬太尼疫苗具有治療阿片類藥物濫用的潛力，有進(jìn)一步進(jìn)行臨床評估的意義。