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Comparative Study
.2009 Dec;331(3):1014-24.
doi: 10.1124/jpet.109.160028. Epub 2009 Sep 9.

Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine

Affiliations
Comparative Study

Effectiveness of donepezil, rivastigmine, and (+/-)huperzine A in counteracting the acute toxicity of organophosphorus nerve agents: comparison with galantamine

Yasco Aracava et al. J Pharmacol Exp Ther.2009 Dec.

Abstract

Galantamine, a centrally acting cholinesterase (ChE) inhibitor and a nicotinic allosteric potentiating ligand used to treat Alzheimer's disease, is an effective and safe antidote against poisoning with nerve agents, including soman. Here, the effectiveness of galantamine was compared with that of the centrally active ChE inhibitors donepezil, rivastigmine, and (+/-)huperzine A as a pre- and/or post-treatment to counteract the acute toxicity of soman. In the first set of experiments, male prepubertal guinea pigs were treated intramuscularly with one of the test drugs and 30 min later challenged with 1.5 x LD(50) soman (42 microg/kg s.c.). All animals that were pretreated with galantamine (6-8 mg/kg), 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A survived the soman challenge, provided that they were also post-treated with atropine (10 mg/kg i.m.). However, only galantamine was well tolerated. In subsequent experiments, the effectiveness of specific treatment regimens using 8 mg/kg galantamine, 3 mg/kg donepezil, 6 mg/kg rivastigmine, or 0.3 mg/kg (+/-)huperzine A was compared in guinea pigs challenged with soman. In the absence of atropine, only galantamine worked as an effective and safe pretreatment in animals challenged with 1.0 x LD(50) soman. Galantamine was also the only drug to afford significant protection when given to guinea pigs after 1.0 x LD(50) soman. Finally, all test drugs except galantamine reduced the survival of the animals when administered 1 or 3 h after the challenge with 0.6 or 0.7 x LD(50) soman. Thus, galantamine emerges as a superior antidotal therapy against the toxicity of soman.

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Figures

Fig. 1.
Fig. 1.
Pretreatment with galantamine prevents the acute toxicity of 1.5 × LD50 soman in guinea pigs post-treated with atropine. A, dose-response relationship for galantamine to afford 24-h survival of guinea pigs challenged with 1.5 × LD50 soman (42 μg/kg s.c.) and post-treated with atropine (10 mg/kg i.m.). Galantamine (0.5–8 mg/kg i.m.) was injected in one of the hind limbs of the animals 30 min before soman. Atropine was injected in the other hind limb 1 min after the nerve agent. Each group consisted of 8 to 12 animals. “% survival” represents the percentage of animals that were kept alive at 24 h after the soman challenge because they presented no life-threatening symptoms. B, body weight of animals subjected to different treatments. Body weights are expressed as percentage of the weights measured 1 h before the first treatment. Experimental groups consist of animals that were treated with 1) saline (0.5 ml/kg i.m.), 2) atropine (10 mg/kg i.m.), 3) galantamine (8 mg/kg i.m.), or 4) galantamine (8 mg/kg i.m.) followed 30 min later by 1.5 × LD50 soman (42 μg/kg s.c.), and atropine (10 mg/kg i.m.) 1 min after soman. Each experimental group consisted of five to eight animals. Data points and error bars represent mean and S.E.M., respectively. Solid, dotted, and dashed lines are the linear regression of each data set. Adapted from Albuquerque EX, Pereira EFR, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano JA Jr, and Adler M (2006) Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents.Proc Natl Acad Sci USA 103:13220–13225. Copyright © 2006. National Academy of Sciences, U.S.A.
Fig. 2.
Fig. 2.
Effectiveness of donepezil in preventing toxicity of 1.5 × LD50 soman in atropine-treated guinea pigs. A, dose-response relationship for donepezil to afford 24-h survival of guinea pigs challenged with 1.5 × LD50 soman (42 μg/kg s.c.) and post-treated with atropine (10 mg/kg i.m.). Donepezil (0.05–3 mg/kg i.m.) was injected in one of the hind limbs of the animals at 30 min before soman. Atropine (10 mg/kg i.m.) was injected in the other hind limb 1 min after the nerve agent. Each group consisted of 8 to 12 animals. “% survival” represents the percentage of animals that were kept alive at 24 h after the soman challenge because they presented no life-threatening symptoms. B, survival of guinea pigs treated with donepezil alone (1 or 3 mg/kg). C, body weight of animals subjected to different treatments. Body weights are expressed as percentage of the weights measured 1 h before the first treatment. Experimental groups consist of animals that were treated with 1) saline (0.5 ml/kg i.m.), 2) donepezil (3 mg/kg i.m.), or 3) donepezil (3 mg/kg i.m.) followed 30 min later by 1.5 × LD50 soman (42 μg/kg s.c.) and atropine (10 mg/kg i.m.). Data points and error bars represent mean and S.E.M., respectively, of results obtained from 18 animals in the saline group and 5 to 8 animals in the other two experimental groups. Solid, dotted, and dashed lines are the linear regression of each data set;r2 ranged from 0.96 to 0.98.
Fig. 3.
Fig. 3.
Effectiveness of (±)huperzine A in preventing the acute toxicity of 1.5 × LD50 soman in atropine-treated guinea pigs. A, dose-response relationship for (±)huperzine A to afford 24-h survival of guinea pigs challenged with 1.5 × LD50 soman (42 μg/kg s.c.) and post-treated with atropine (10 mg/kg i.m.). Animals were pretreated with (±)huperzine A (1–500 μg/kg i.m.), challenged with 1.5 × LD50 soman (subcutaneously) 30 min later and subsequently treated with atropine (10 mg/kg i.m.). Each group consisted of 8 to 12 animals. B, survival (1–7 days) of guinea pigs treated with (±)huperzine A alone (300 μg/kg i.m.). “% survival” represents the percentage of animals that were kept alive at 24 h after the treatment as they presented no life-threatening symptoms. C, body weight of animals subjected to different treatments. Body weights are expressed as percentage of the weights measured 1 h before the first treatment. Experimental groups consist of animals that were treated with 1) saline (0.5 ml/kg i.m.), 2) (±)huperzine A (300 μg/kg i.m.), or 3) (±)huperzine A (300 μg/kg i.m.) followed 30 min later by 1.5 × LD50 soman (42 μg/kg s.c.) and atropine (10 mg/kg i.m.). Data points and error bars represent mean and S.E.M., respectively, of results obtained from 18 animals in the saline group and from 5 to 8 animals in the other two experimental groups. Solid, dotted, and dashed lines are the linear regression of each data set;r2 ranged from 0.96 to 0.98.
Fig. 4.
Fig. 4.
Effectiveness of rivastigmine in preventing toxicity of 1.5 × LD50 soman in atropine-treated guinea pigs. A, dose-response relationship for rivastigmine to afford 24-h survival of guinea pigs challenged with 1.5 × LD50 soman (42 μg/kg s.c) and post-treated with atropine (10 mg/kg i.m.). Animals were pretreated with rivastigmine (0.1–16 mg/kg i.m.), challenged with 1.5 × LD50 soman (subcutaneously) 30 min later and subsequently treated with atropine (10 mg/kg i.m.). Each group consisted of 8 to 12 animals. B, survival (24 h) of guinea pigs treated with rivastigmine alone. “% survival” represents the percentage of animals that were kept alive at 24 h after the treatment because they presented no life-threatening symptoms. C, D, long-term survival of guinea pigs that were pretreated with rivastigmine, challenged with 1.5 × LD50 soman and treated with 10 mg/kg atropine (C) or injected with rivastigmine alone (D). Each treatment group had 8 to 10 animals. E, F, body weight of animals subjected to different treatments. Results presented in E are from animals treated with rivastigmine (0.5 or 8 mg/kg i.m.) followed 30 min later by the subcutaneous challenge with 1.5 × LD50 soman and treatment with 10 mg/kg i.m. atropine. Results in F are from animals treated with 8 mg/kg i.m. rivastigmine alone or saline. As in Fig. 3, body weights are expressed as percentage of the weights measured 1 h before the first treatment. Data points and error bars represent mean and S.E.M., respectively, of results obtained from 18 animals in the saline group and from 5 to 8 animals in the other two experimental groups. Solid, dotted, and dashed lines are the linear regression of each data set;r2 ranged from 0.96 to 0.98.
Fig. 5.
Fig. 5.
Effectiveness of pretreatment with galantamine, donepezil, (±) huperzine A, or rivastigmine in preventing acute toxicity of 1.0 × LD50 soman in guinea pigs in the absence of atropine. A, dose-response relationship illustrating the ability of galantamine to afford 24-h survival of guinea pigs challenged with 1.0 × LD50 soman (28 μg/kg s.c.). Soman was injected 30 min after galantamine. Each point represents data from 8 to 12 animals. B, survival (24 h) of guinea pigs pretreated with donepezil (3 mg/kg i.m.), (±)huperzine A (0.3 mg/kg i.m.), or rivastigmine (6 mg/kg i.m.), and challenged 30 min later with 1.0 × LD50 soman. Each experimental group consisted of eight guinea pigs. Ordinates in A and B represent the percentage of animals that were kept alive at 24 h after the treatment because they presented no life-threatening symptoms.
Fig. 6.
Fig. 6.
Effectiveness of post-treatment with galantamine or donepezil in counteracting the acute toxicity of 1.0 × LD50 soman in guinea pigs. A, B, survival (24 h) of guinea pigs treated with 8 mg/kg i.m. galantamine (A) or 1 to 3 mg/kg i.m. donepezil (B) at the indicated times after the challenge with soman (28 μg/kg s.c.). C, D, seven-day survival of guinea pigs challenged with 1.0 × LD50 soman and 5 or 15 min later treated im with 8 mg/kg galantamine or 1 or 5 min later with 3 mg/kg donepezil. “% Survival/day” represents the percentage of animals that were kept alive at days 1–7 after treatment because they presented no life-threatening symptoms. Each experimental group in A to D consisted of 8 to 12 animals. E, F, body weight of animals subjected to different treatments. Body weights are expressed as percentage of the weights measured 1 h before the first treatment. Experimental groups consist of animals that were treated with 1) saline (0.5 ml/kg i.m.) alone, 2) saline (0.5 ml/kg i.m.) injected 5 min after soman (1.0 × LD50, s.c.), 3) galantamine (8 mg/kg i.m.) injected 15 min after the soman, or 4) donepezil (3 mg/kg i.m.) injected 5 min after the soman challenge. In E and F, data points and error bars represent mean and S.E.M., respectively, of results obtained from 18 animals in the control (saline) group and from 4 to 8 animals in the other experimental groups. Solid, dotted, and dashed lines are the linear regression of each data set;r2 ranged from 0.96 to 0.98.
Fig. 7.
Fig. 7.
Effectiveness of post-treatment with rivastigmine or (±)huperzine A in counteracting the acute toxicity of 1.0 × LD50 soman in guinea pigs. A and B, survival (24 h) of guinea pigs treated im with 6 mg/kg rivastigmine (A) or 0.3 mg/kg (±)huperzine A (B) at the indicated times after the challenge with soman (28 μg/kg s.c.). Each experimental group consisted of 10 to 12 animals. C, seven-day survival of guinea pigs challenged with 1.0 × LD50 soman and 1, 5, or 15 min later treated im with 6 mg/kg rivastigmine. “% survival” represents the percentage of animals that were kept alive at any given day after the treatment because they presented no life-threatening symptoms. D, body weight of animals subjected to different treatments. Body weights are expressed as percentage of the weights measured 1 h before the first treatment. Experimental groups consisted of animals that were treated with 1) saline (0.5 ml/kg i.m.) alone, 2) saline (0.5 ml/kg i.m.) at 5 min after the soman (1.0 × LD50, sc), or 3) (±)huperzine A (0.3 mg/kg i.m.) at 5 min after the soman. Data points and error bars represent mean and S.E.M., respectively, of results obtained from 18 animals in the control (saline) group and from 4 to 6 animals in the other experimental groups. Solid, dotted, and dashed lines are the linear regression of each data set;r2 ranged from 0.96 to 0.98.
Fig. 8.
Fig. 8.
Effectiveness of post-treatment with galantamine, donepezil, (±)huperzine A, or rivastigmine administered 1 or 3 h after an acute challenge of guinea pigs with sublethal doses of soman. Survival (24 h) of guinea pigs treated im with 8 mg/kg galantamine (A), 3 mg/kg donepezil (C), 0.3 mg/kg (±)huperzine A (E), or 6 mg/kg rivastigmine (G) at 1 or 3 h after challenge with sublethal doses of soman (16.8 or 19.6 μg/kg s.c.). “% survival” represents the percentage of animals that were kept alive at any given day after the treatment because they presented no life-threatening symptoms. Each experimental group consisted of 10 to 12 animals. B, D, body weight of animals subjected to different treatments. Body weights are expressed as percentage of the weights measured 1 h before the first treatment. Experimental groups consisted of animals that were challenged with 0.7 × LD50 soman (19.6 μg/kg s.c.) and treated 1 or 3 h later with 8 mg/kg galantamine, 3 mg/kg donepezil, or saline. Data points and error bars represent mean and S.E.M., respectively, of results obtained from four to six animals per treatment. Solid, dotted, and dashed lines are the linear regression of each data set;r2 ranged from 0.96 to 0.98. F, seven-day survival of the guinea pigs that were challenged with 0.7 × LD50 soman and 1 or 3 h later treated with 0.3 mg/kg (±)huperzine A. H, seven-day survival of the guinea pigs that were challenged with 0.6 × LD50 soman and 1 or 3 h later treated with 6 mg/kg rivastigmine.
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