Paraoxon has only a minimal effect on pralidoxime brain concentration in rats

Abstract

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 micromol 2-PAM only (G(1)) or additionally 1 micromol POX ( approximately LD(75)) (G(2)). 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 (C(max)) in G(1) brain was 6% of plasma C(max), while in G(2) brains it was 8%. Similarly, the ratio of the area under the curve (AUC) brain to plasma was 8% in G(1) and 12% in G(2). Brain t(max) (15 min) was slightly higher than plasma t(max) (5 min). The AUC of plasma 2-PAM did not differ between G(1) and G(2). However, in G(1), AUC brain was significantly lower than in G(2), 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.

Entry of two new asymmetric bispyridinium oximes (K‐27 and K‐48) into the rat brain: comparison with obidoxime

“…This observation corroborates findings obtained in an older study employing radiolabeled obidoxime (Falb and Erdmann, 1969). Whereas slightly, but significantly, more pralidoxime enters the brain after administration of POX (Petroianu et al, 2007), the present results demonstrate that penetration of obidoxime, K-27 and K-48 through the blood-brain barrier is not affected by prior injection of POX.…”

Efficacy of Eight Experimental Bispyridinium Oximes Against Paraoxon-Induced Mortality: Comparison with the Conventional Oximes Pralidoxime and Obidoxime

“…The excellent in vivo protective capacity of K-27 becomes even more evident considering that this oxime is even efficacious when administered in a relatively lower concentration, i.e. 10% of the LD 01 , as compared to 50% of the LD 01 for all the other oximes, as demonstrated in several previous studies (Petroianu et al 2006(Petroianu et al , 2007a(Petroianu et al , 2007b(Petroianu et al , 2007cLorke et al 2007Lorke et al , 2008aLorke et al 2008c.…”

“…2-PAM, obidoxime, and K-48 dosages were the same as in earlier studies, which was half the LD 01 , as determined previously (Lorke et al 2008c). Dosage of K-27 (125 lmol) was also half the LD 01 , which was 2.5 times the dosage administered in previous studies (Petroianu et al 2006(Petroianu et al , 2007a(Petroianu et al , 2007cLorke et al 2007Lorke et al , 2008a (Table 1).…”

Minireview: does in‐vitro testing of oximes help predict their in‐vivo action after paraoxon exposure?

“…One example for the biological importance of hydrophilicity/ lipophilicity of an oxime is its passage through the blood-brain barrier (Lorke et al, 2007(Lorke et al, , 2008dPetroianu et al, 2007a). Diff usion of a substance into the brain depends upon its lipid solubility and is inversely related to its degree of ionization (Scherrmann, 2002).…”