A comparison of the therapeutic and reactivating efficacy of newly developed bispyridinium compounds (K206, K269) with currently available oximes against tabun in rats and mice

Figures & data

Figure 1.  Chemical structure of oximes.

Table I.  LD₅₀ values of oximes following i.m. administration in rats and mice.

	LD50 (mg/kg) ± 95% confidence limit
OXIMES	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)
K206	386.6 (332.2–449.9)	175.1 (164.1–186.9)
K269	113.5 (92.1–138.9)	43.9 (41.5–46.5)

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

	AChE activity (μkat/L or μkat/kg)
	Blood	Diaphragm	Brain
Atropine	3.93 ± 0.21^a	5.89 ± 1.25^a	11.7 ± 4.32^a
Atropine + obidoxime (% reactivation^b)	5.51 ± 0.34 (24.2^*^x)	8.78 ± 0.58 (19.2^*)	35.2 ± 6.97 (25.3^*^x)
Atropine + HI-6 (% reactivation)	4.50 ± 0.53 (8.7)	6.99 ± 1.97 (7.3)	13.6 ± 4.79 (2.1)
Atropine + trimedoxime (% reactivation)	4.91 ± 0.21 (15.0^*)	8.71 ± 1.01 (18.7^*)	25.0 ± 8.07 (14.4^*)
Atropine + K206 (% reactivation)	5.53 ± 0.27 (24.5*^x)	7.61 ± 0.85 (11.4)	19.0 ± 2.90 (7.8^*)
Atropine + K269 (% reactivation)	5.73 ± 0.24 (27.6*^x)	6.49 ± 1.23 (4.0)	11.0 ± 2.7 (0)

^a Means ± S.E.M., N = 8. The untreated control value (saline control) for rat blood AChE activity was 10.45 (μkat/L), for diaphragm AChE activity 20.99 μkat/kg and for brain AChE activity 104.7 μkat/kg

^b Percent reactivation was determined using the AChE activity values: {1- [((saline control) – (oxime + atropine))/((saline control) – (atropine control))]} x 100

^* Significantly different from the atropine group at a level of P < 0.05, ^x significantly different from the atropine + HI-6 group at a level of P < 0.05 as determined by the Student's test.

Table III.  The influence of the type of oxime on the potency of antidotal treatment to eliminate acute lethal effects of tabun in mice.

Treatment	LD50 (μg/kg) ± 95% confidence limit	Protective ratio
–	295.2 (275.5 – 317.9)	–
Obidoxime + atropine	435.7 (410.8 – 460.5)^*^x	1.47
HI-6+ atropine	318.8 (302.7 – 336.5)	1.08
Trimedoxime + atropine	504.8 (460.3 – 553.0)^*^x	1.71
K206+ atropine	436.9 (395.3 – 466.7)^*^x	1.48
K269+ atropine	431.0 (404.9 – 459.6)^*^x	1.46

^* significantly different from the untreated group at the level of P < 0.05, ^x significantly different from the group treated by atropine in combination with HI-6 at the level of P < 0.05.