Efficacy of an organophosphorus hydrolase enzyme (OpdA) in human serum and minipig models of organophosphorus insecticide poisoning

Figures & data

Figure 1. In vitro determination of enzyme kinetics in human serum. Determination of the rate of OP insecticide hydrolysis by 2 nM to 2 μM OpdA for eight OP insecticides.

Table 1. Activity of OpdA enzyme in human serum and in buffer against WHO Class II OP insecticides.

Pesticide	Chemistry	Activity in human serum (mol/sec/ mol enzyme)	Activity in buffer (mol/sec/ mol enzyme)
Quinalphos	Diethyl	856 ± 44	190,000
Diazinon	Diethyl	465 ± 34	150,000
Chlorpyrifos	Diethyl	58.3 ± 1.5	18,000
Profenofos	S-alkyl	15.3 ± 1.3	ND
Malathion	Dimethyl	0.833 ± 0.049	48
Fenthion	Dimethyl	0.406 ± 0.027	ND
Dimethoate	Dimethyl	0.161 ± 0.025	9.0
Phenthoate	Dimethyl	0.107 ± 0.010	ND

The buffer activity data are unpublished from CSIRO Entomology; the buffer was 50 mM Tris-HCl (pH 8.0). ND: not done. Human serum data are mean ± SD, n = 3.

Figure 2. Clinical effect of OpdA on OP insecticide poisoning. Heart rate, mean arterial pressure, arterial blood lactate concentrations, and noradrenaline requirements in pigs after poisoning with dimethoate EC40 (n = 9), methyl-parathion EC60 (n = 4), or saline placebo (n = 9), with (triangles) or without (circles) OpdA. Note that the dosing of OpdA varied between the control and dimethoate EC40 studies and the methyl parathion EC60 study, in which the duration of therapy infusion was extended (from total dose over 1 h, to half dose of 1 h and half dose over 8 h). OpdA dosing was started 1 h after oral gavage. The timing of administration is indicated by black bars in the mean arterial pressure panels. Values are group means ± SD.

Figure 3. Toxicodynamic effect of OpdA on OP insecticide poisoning. Plasma OP insecticide concentration, red cell AChE activity, and plasma BuChE activity in pigs after poisoning with dimethoate EC40, methyl-parathion EC60, or saline placebo, with or without OpdA. Symbols as in Figure 2 with addition of omethoate concentrations with (triangles) or without (circles) OpdA. Note that the dosing of OpdA varied between the control and dimethoate EC40 studies and the methyl parathion study, increasing the duration of therapy infusion in the latter (from total dose over 1 h, to half dose of 1 h and half dose over 8 h). OpdA dosing was started 1 h after oral gavage. Values are group means ± SD.

Figure 4. Pharmacodynamic effect of OpdA on profenofos poisoning. Plasma profenofos concentration, red cell AChE activity, and plasma BuChE activity in pigs (n = 8) after poisoning with profenofos EC50, with or without OpdA. OpdA was started 1 h after oral gavage and administered as half dose of 1 h and half dose over 8 h. Due to the lack of clinical effect of profenofos in anaesthetised pigs, noradrenaline was not required as a vasopressor. Symbols as for Figure 2. Values are group means ± SD.