Clinical experience with oximes, cholinesterase reactivators used in organophosphorus poisoning, has been disappointing. Their major anatomic site of therapeutic action and their ability to pass the blood-brain barrier (BBB) are controversial. Although their physico-chemical properties do not favour BBB penetration, access of oximes to the brain may be facilitated by organophosphates. The effect of the organophosphate paraoxon (POX) on pralidoxime (2-PAM) brain entry was therefore determined. Rats either received 50 μmol 2-PAM only (G1) or additionally 1 μmol POX (≈ LD75) (G2). Three animals each were killed after 5, 15, 30, 60, 90, 120, 180, 240, 360, 480 min, and 2-PAM concentrations in the brain and plasma were measured using HPLC. Moreover, the effect of brain perfusion with isotonic saline on subsequent 2-PAM measurements was assessed. The maximal 2-PAM concentration (Cmax) in G1 brain was 6% of plasma Cmax, while in G2 brains it was 8%. Similarly, the ratio of the area under the curve (AUC) brain to plasma was 8% in G1 and 12% in G2. Brain tmax (15 min) was slightly higher than plasma tmax (5 min). The AUC of plasma 2-PAM did not differ between G1 and G2. However, in G1, AUC brain was significantly lower than in G2, the differences probably being clinically irrelevant. In perfused brains, 2-PAM concentrations were very close to those of non-perfused brains. The results indicate that brain penetration of 2-PAM is poor and that organophosphates only have a modest effect on 2-PAM BBB penetration. Brain perfusion does not significantly alter 2-PAM measurements and is therefore considered unnecessary.
- Blood-brain barrier
ASJC Scopus subject areas