Lorke D E, Hasan M Y, Nurulain S M, Sheen R, Kuca K, Petroianu G A
Department of Anatomy, FMHS, UAE University, Al Ain, United Arab Emirates.
J Appl Toxicol. 2007 Sep-Oct;27(5):482-90. doi: 10.1002/jat.1229.
In the search for new oximes with higher reactivation potency and a broader spectrum, K-27 and K-48, have recently been synthesized. To test if their superior efficacy was related to better penetration across the blood-brain barrier, their brain entry was compared with that of obidoxime, when administered either alone or after the organophosphate paraoxon (POX). Rats received 50 micromol obidoxime, K-27 or K-48, either alone or in addition to 1 micromol POX. Oxime concentrations at various points in time in brain and plasma were measured using HPLC. The obidoxime C(max) in brain was 1.3% of the plasma C(max) when injected alone, and 1.5% when injected following POX. The ratio of the area under the curve (AUC) brain to plasma for obidoxime was around 6%, irrespective of whether it was administered alone or after POX. For K-27, C(max) (brain) was 0.6% of C(max) (plasma) when injected alone, and 0.7% when injected after POX (no significant difference). The AUC (brain) was 2% of AUC (plasma) for both K-27 groups. K-48, when injected alone reached 1.4% of C(max) (plasma) in the brain and 1.2% of C(max) (plasma), when injected following POX. The AUC (brain) was 5% of the AUC (plasma), both when K-48 was administered alone and in combination with POX. Entry of all three oximes into the brain is minimal and cannot explain the better therapeutic efficacy of K-27 and K-48. As already observed for pralidoxime, injection of POX before oxime administration had no influence upon penetration across the blood-brain barrier.
为了寻找具有更高重活化效力和更广泛谱的新型肟类化合物，最近合成了K - 27和K - 48。为了测试它们的卓越疗效是否与更好地穿透血脑屏障有关，将它们单独给药或在给予有机磷酸酯对氧磷（POX）后给药时，将它们的脑内进入情况与氯解磷定进行了比较。大鼠接受50微摩尔氯解磷定、K - 27或K - 48，单独给药或除了1微摩尔POX之外给药。使用高效液相色谱法测量脑和血浆中不同时间点的肟类化合物浓度。单独注射时，氯解磷定在脑中的C(max)是血浆C(max)的1.3%，注射POX后为1.5%。氯解磷定的脑曲线下面积（AUC）与血浆的比值约为6%，无论其单独给药还是在POX后给药。对于K - 27，单独注射时C(max)（脑）是C(max)（血浆）的0.6%，注射POX后为0.7%（无显著差异）。两个K - 27组的AUC（脑）都是AUC（血浆）的2%。单独注射K - 48时，脑中达到C(max)（血浆）的1.4%，注射POX后为C(max)（血浆）的1.2%。当K - 48单独给药和与POX联合给药时，AUC（脑）都是AUC（血浆）的5%。所有三种肟类化合物进入脑内的量都极少，无法解释K - 27和K - 48更好的治疗效果。正如已经观察到的解磷定的情况一样，在肟类化合物给药前注射POX对穿过血脑屏障的穿透没有影响。
