Astrocyte Pharmaceuticals Inc, Cambridge, MA (T.E.L., R.B.P., W.S.K.).
Hamamatsu Pharma Research Inc, Japan (A.H., I.H., T.N., H.T.).
Stroke. 2022 Jan;53(1):238-248. doi: 10.1161/STROKEAHA.121.036396. Epub 2021 Nov 22.
Treatment with A1R/A3R (adenosine A1 and A3 receptor) agonists in rodent models of acute ischemic stroke results in significantly reduced lesion volume, indicating activation of adenosine A1R or A3R is cerebroprotective. However, dosing and timing required for cerebroprotection has yet to be established, and whether adenosine A1R/A3R activation will lead to cerebroprotection in a gyrencephalic species has yet to be determined.
The current study used clinical study intervention timelines in a nonhuman primate model of transient, 4-hour middle cerebral artery occlusion to investigate a potential cerebroprotective effect of the dual adenosine A1R/A3R agonist AST-004. Bolus and then 22 hours intravenous infusion of AST-004 was initiated 2 hours after transient middle cerebral artery occlusion. Primary outcome measures included lesion volume, lesion growth kinetics, penumbra volume as well as initial pharmacokinetic-pharmacodynamic relationships measured up to 5 days after transient middle cerebral artery occlusion. Secondary outcome measures included physiological parameters and neurological function.
Administration of AST-004 resulted in rapid and statistically significant decreases in lesion growth rate and total lesion volume. In addition, penumbra volume decline over time was significantly less under AST-004 treatment compared with vehicle treatment. These changes correlated with unbound AST-004 concentrations in the plasma and cerebrospinal fluid as well as estimated brain A1R and A3R occupancy. No relevant changes in physiological parameters were observed during AST-004 treatment.
These findings suggest that administration of AST-004 and combined A1R/A3R agonism in the brain are efficacious pharmacological interventions in acute ischemic stroke and warrant further clinical evaluation.
在急性缺血性卒中的啮齿动物模型中，A1R/A3R（腺苷 A1 和 A3 受体）激动剂的治疗导致病变体积显著减小，表明激活腺苷 A1R 或 A3R 具有脑保护作用。然而，仍需确定脑保护所需的剂量和时间，并且还需要确定在脑回动物中激活腺苷 A1R/A3R 是否会导致脑保护。
本研究在短暂性 4 小时大脑中动脉闭塞的非人灵长类动物模型中使用临床研究干预时间线，以研究双重腺苷 A1R/A3R 激动剂 AST-004 的潜在脑保护作用。在短暂性大脑中动脉闭塞后 2 小时开始进行 AST-004 的推注和 22 小时静脉输注。主要结局指标包括病变体积、病变生长动力学、半影体积以及在短暂性大脑中动脉闭塞后 5 天内测量的初始药代动力学-药效学关系。次要结局指标包括生理参数和神经功能。
AST-004 的给药导致病变生长率和总病变体积的快速且具有统计学意义的降低。此外，与载体治疗相比，AST-004 治疗下的半影体积随时间的下降明显减少。这些变化与血浆和脑脊液中未结合的 AST-004 浓度以及估计的大脑 A1R 和 A3R 占有率相关。在 AST-004 治疗期间未观察到生理参数的相关变化。
这些发现表明，AST-004 的给药和大脑中联合的 A1R/A3R 激动作用是急性缺血性卒中的有效药物干预措施，值得进一步的临床评估。
