A comparison of reactivating and therapeutic efficacy of the oxime K203 and its fluorinated analog (KR-22836) with currently available oximes (obidoxime, trimedoxime, HI-6) against tabun in rats and mice

Figures & data

Figure 1.  Chemical structures of oximes.

Table 1.  LD₅₀ values of oximes following intramuscular administration in rats and mice.

Oxime	LD50 (mg/kg) (95% confidence limits)
	Rats	Mice
Obidoxime	211.1 (176.4–252.6)	188.4 (156.3–208.0)
HI-6	781.3 (738.4–826.6)	671.3 (627.4–718.3)
Trimedoxime	150.5 (142.1–159.4)	149.3 (124.1–184.5)
K203	326.4 (285.4–373.2)	95.0 (88.4–102.2)
KR-22836	>600	107.2 (86.0–134.0)

Table 2.  Percent reactivation of tabun-inhibited AChE by oximes in rat blood, diaphragm, and brain in vivo.

Treatment	AChE activity (μkat/L or μkat/kg)
	Blood	Diaphragm	Brain
Atropine	6.74 ± 0.02^a	1.79 ± 0.80^a	11.89 ± 2.68^a
Atropine + obidoxime (% reactivation^b)	10.19 ± 0.64 (29.9^*†)	3.32 ± 0.57 (25.2^*)	15.47 ± 1.94 (2.9)
Atropine + HI-6 (% reactivation)	7.38 ± 0.58 (5.6)	2.50 ± 0.88 (8.9)	15.35 ± 3.43 (2.9)
Atropine + trimedoxime (% reactivation)	9.79 ± 0.79 (26.3^*†)	5.36 ± 1.47 (44.5^*†)	21.71 ± 4.66 (8.1^*)
Atropine + K203 (% reactivation)	11.07 ± 0.48 (37.5^*†)	5.28 ± 1.98 (43.5^*†)	29.34 ± 2.75 (14.6^*†)
Atropine + KR-22836 (% reactivation)	9.44 ± 0.36 (23.4^*†)	5.48 ± 0.62 (45.9^*†)	12.36 ± 1.71 (0.3)

Note. ^*Significantly different from the atropine group at a level of p < 0.05, ^†significantly different from the atropine + HI-6 group at a level of p < 0.05 as determined by Student’s t-test.

^aMean ± SEM, n = 8. The untreated control value for rat blood AChE activity was 18.29 ± 1.33 µkat/L, for diaphragm AChE activity 9.83 ± 2.38 µkat/kg, and for brain AChE activity 131.4 ± 7.46 µkat/kg.

^bPercent reactivation was determined using the AChE activity values: {1 – [((saline) – (oxime + atropine))/((saline) – (atropine control))]} × 100.

Table 3.  Influence of type of oxime on the potency of antidotal treatment to reduce acute lethal effects of tabun in mice.

Treatment	LD50 (µg/kg) (95% confidence limits)	Protective ratio
—	331.5 (272.9–396.6)	—
Atropine	334.5 (272.0–381.1)	1.01
Obidoxime + atropine	565.6 (521.2–594.8)^*	1.71
HI-6 + atropine	450.2 (394.2–543.6)	1.36
Trimedoxime + atropine	598.4 (495.5–681.5)^*	1.81
K203 + atropine	564.2 (441.5–623.2)^*	1.70
KR-22836 + atropine	504.7 (420.8–598.5)^*	1.52

Note. ^*Significantly different from the untreated group at a level of p < 0.05.