Spence A M, Edmondson S W, Krohn K A, Grunbaum Z, Rasey J S, Steele J E
Int J Radiat Oncol Biol Phys. 1986 Sep;12(9):1653-60. doi: 10.1016/0360-3016(86)90292-0.
The radioprotective capacity of the phosphorothioate compounds, WR2721, WR77913, and WR3689, in the CNS is being evaluated following injection of the drugs into the lateral cerebral ventricle or the cisterna magna of F-344 rats. This approach circumvents the blood-brain barrier and permits an assessment of the CNS toxicity and regional distribution of these compounds. Following intraventricular injection in 150-200 gm female rats, the LD50 doses for WR2721, WR77913, and WR3689 were respectively 0.60 +/- 0.07 mg (S.E.), 2.36 +/- 0.13 mg, and 3.56 +/- 0.26 mg. Following intracisternal injection the LD50 doses were 0.71 +/- 0.18 mg, 4.12 +/- 1.09 mg and 3.03 +/- 0.68 mg, respectively. WR 2721 produced lethargy, unsteady gait, and dishevelment but these signs all resolved completely within 1-3 days in survivors. In addition to these signs, WR77913 and WR3689 produced severe convulsions. At high doses, following intraventricular administration, all three drugs were associated with cerebral and diencephalic periventricular necrosis and ipsilateral necrosis of the lateral hippocampus. Biodistribution studies were performed with [S-35]-labeled derivatives of the drugs and tissue sampling. The three drugs demonstrated similar patterns. Forty-five minutes following either the intraventricular or intracisternal route of drug delivery the highest drug concentrations were in the brainstem, cerebellum, and cervical cord. Additional studies with autoradiography revealed that intraventricular injection was associated with high drug uptake in the cerebral white matter, the periventricular diencephalon, and the periaqueductal mesencephalon. The biodistribution and toxicity data together suggest that the drugs can be ranked, WR3689 greater than WR77913 greater than WR2721, according to the level of drug thiol that can be achieved in the CNS tissues with intraventricular or intracisternal injection. Tissue levels achievable with WR2721 following these two routes of administration are as high as levels others have reported as radioprotective in rodent skin and gut.
在将硫代磷酸酯化合物WR2721、WR77913和WR3689注射到F-344大鼠的侧脑室或大池后，正在评估它们在中枢神经系统中的辐射防护能力。这种方法绕过了血脑屏障，并允许评估这些化合物的中枢神经系统毒性和区域分布。在150 - 200克雌性大鼠进行脑室内注射后，WR2721、WR77913和WR3689的半数致死剂量分别为0.60±0.07毫克（标准误）、2.36±0.13毫克和3.56±0.26毫克。在脑池内注射后，半数致死剂量分别为0.71±0.18毫克、4.12±1.09毫克和3.03±0.68毫克。WR2721会导致嗜睡、步态不稳和毛发凌乱，但这些症状在存活者中均在1 - 3天内完全消失。除了这些症状外，WR77913和WR3689还会引发严重惊厥。在高剂量脑室内给药后，所有三种药物都与大脑和间脑脑室周围坏死以及同侧海马外侧坏死有关。使用药物的[S-35]标记衍生物和组织采样进行了生物分布研究。这三种药物表现出相似的模式。在通过脑室内或脑池内途径给药45分钟后，药物浓度最高的部位是脑干、小脑和颈髓。放射自显影的进一步研究表明，脑室内注射与大脑白质、脑室周围间脑和导水管周围中脑的高药物摄取有关。生物分布和毒性数据共同表明，根据通过脑室内或脑池内注射在中枢神经系统组织中可达到的药物硫醇水平，这些药物的排序为WR3689＞WR77913＞WR2721。通过这两种给药途径，WR2721可达到的组织水平与其他研究报道的在啮齿动物皮肤和肠道中具有辐射防护作用的水平一样高。
