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PubMed1986

Pharmacokinetics of pralidoxime chloride in the rat.

The pharmacokinetics of pralidoxime chloride (2-PAM) was studied in rats. Different groups of rats were given an intramuscular injection of 2-PAM at one of three doses (20, 40, or 80 mg/kg). This range of doses is used commonly in studies concerned with the efficacy of 2-PAM against poisoning by potent organophosphorus inhibitors of cholinesterase enzyme. Individual, sequential blood samples were collected during the course of the experiment. From these blood samples the plasma concentrations of 2-PAM were determined over time for each animal. Next the relationship of plasma concentration to time was expressed in terms of a standard pharmacokinetic model. Estimates of various pharmacokinetic parameters were calculated using an open, one-compartment model: volume of distribution (Vd), maximal plasma concentration (Cmax), elimination rate constant (k10), absorption rate constant (k01), area under the curve (AUC) and clearance (CL). Of the pharmacokinetic estimates, only Cmax and AUC were found to be statistically significant (p less than 0.0001) when compared across all the doses; these pharmacokinetic estimates were highly correlated with doses with r = 0.998 and r = 0.997, respectively. However, when AUC and Cmax were normalized by dividing through by dose, no significant differences were found in the transformed data. The results of this study in rat indicate that the pharmacokinetics of 2-PAM is linearly related to dose in a range employed in therapeutic studies of 2-PAM.

Animals↗
PubMed1987

Oxime-induced decarbamylation and atropine/oxime therapy of guinea pigs intoxicated with pyridostigmine.

The generally accepted explanation for the effects of oximes in countering organophosphorus (OP) anticholinesterase is reactivation of the inhibited acetylcholinesterase (AChE). With soman, the inhibited AChE rapidly becomes resistant to oxime reactivation due to a phenomenon called aging. Thus, pretreatment with pyridostigmine (Py) or physostigmine (Ph) followed by atropine sulfate therapy is required to achieve significant protection against soman; the effectiveness of a pretreatment/therapy (P/T) regimen can be further increased against certain OPs (e.g. sarin and VX) by including an oxime in the therapy regimen. The P/T regimen is clouded by a controversy concerning the use of oximes in the treatment of carbamate intoxication, because 2-PAM has been reported to exacerbate intoxication by some carbamates and to have no effect on decarbamylation rates. To better understand the role of oxime therapy in the theory of pretreatment of OP intoxication we examined the effects of 2-PAM and HI-6 on the rate of decarbamylation of Py-inhibited erythrocyte AChE in vitro and in vivo, and studied the effects of atropine plus 2-PAM or HI-6 on Py toxicity. In decarbamylation experiments, Py-inhibited guinea pig erythrocytes were washed free of excess Py and incubated with vehicle or oxime (2 X 10(-4) M, pH 7.3 and 37 degrees C). Aliquots were assayed for AChE activity at various times during a 60 min incubation period. Rate constants were calculated and compared to determine whether the presence of oxime affected decarbamylation. The data from in vitro and in vivo experiments revealed that oximes accelerated the decarbamylation (p less than 0.05) of inhibited AChE. Lethality data for Py-treated guinea pigs showed that treatment with atropine (23 mumoles/kg, im) plus 2-PAM or HI-6 (145 mumoles/kg, im) at one min after injection of Py increased the protective ratio from 4.2 (atropine only) to 5.1 and 12.2, respectively. It is suggested that the enhanced therapeutic efficacy of atropine by oximes against Py intoxication is related to oxime-induced reactivation.

Acetylcholinesterase↗
PubMed1986

Protection by phenytoin and calcium channel blocking agents against the toxicity of diisopropylfluorophosphate.

Pretreatment of male Swiss-Webster mice with phenytoin, 25 mg/kg, verapamil, 25 to 3.0 mg/kg, nifedipine, 0.05 to 0.1 mg/kg, nitrendipine, 0.1 mg/kg, and nimodipine, 1 to 2.5 mg/kg, elevated the LD50 of diisopropylfluorophosphate (DFP) to a significant degree. In addition, these agents enhanced the protection that can be obtained from atropine and 2-pralidoxime. The protective effects of phenytoin cannot be attributed to an anticonvulsant action, per se, since carbamazepine, phenobarbital, and diphenylbarbituric acid in anticonvulsant doses did not influence DFP lethality. The mechanism of action of phenytoin and the other effective calcium channel blockers in providing protection over and above that achieved with atropine and 2-pralidoxime appears to be due to a protective action of the former agents on central respiratory centers and peripheral nicotinic sites and may involve the movement of calcium into excitable membranes.

Animals↗
PubMed1987

Comparison of serum concentrations of the acetylcholinesterase oxime reactivators HI-6, obidoxime, and PAM to efficacy against sarin (isopropyl methylphosphonofluoridate) poisoning in rats.

A comparison of serum concentrations of the oximes HI-6 [1-(((4-aminocarbonyl)-pyridino)methoxy)methyl)-2(hydroxy imino)methyl- pyridinium dichloride], PAM [2-[hydroxyimino)methyl-1-methylpyridinium chloride], and obidoxime [1,1'-(oxybis(methylene]bis(4-((hydroxyimino) methyl)-pyridinium dichloride] to the efficacy against sarin (350 micrograms/kg; sc) lethality was evaluated in rats. The oximes were administered prophylactically by means of Alzet osmotic minipumps. Atropine (17.4 mg/kg; im) was administered immediately following sarin (350 micrograms/kg; sc) administration. At serum concentrations of 3.6, 3.6, and 3.3 micrograms/ml for HI-6, obidoxime, and PAM, respectively, the 24-hr mortality following sarin poisoning was 0, 90, and 20%. The serum oxime concentrations (ED50 values) for HI-6, obidoxime, and PAM against a 3 LD50 dose of sarin were 0.72, 9.05, and 2.56 micrograms/ml, respectively. HI-6 was determined to be the most efficacious oxime when combined with atropine against sarin poisoning followed in order by PAM and obidoxime.

Acetylcholinesterase↗
PubMed1989

The relationship between oxime-induced reactivation of carbamylated acetylcholinesterase and antidotal efficacy against carbamate intoxication.

The efficacy of the oximes pyridinium-2-aldoxime methochloride (2-PAM) and 1-[[[(4-aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydro xyimino) methyl]pyridinium dichloride (HI-6), in combination with atropine (At), against lethality by either carbaryl (CA) or physostigmine (Phy) was investigated in rats. The protection by At, 8 mg/kg, iv, against CA intoxication was reduced by 2-PAM (22 mg/kg, iv) and HI-6 (50 mg/kg, iv) from a protective ratio (PR) of 6.6 to 3.5 and 2.3, respectively. However, in Phy-intoxicated rats, the administration, iv, of At alone, At + 2-PAM, or At + HI-6 at 1 min following Phy provided good protection and resulted in PRs of 7.2, 8.8, and 23.3, respectively. In experiments on decarbamylation of inhibited acetylcholinesterase (AChE), HI-6 and 2-PAM accelerated (p less than 0.05) the decarbamylation of Phy-inhibited AChE in vitro, and HI-6 decreased (p less than 0.05) the inhibition of whole blood AChE in Phy-intoxicated rats. These findings show that the protection was increased substantially by the use of either 2-PAM or HI-6 against Phy-induced lethality, whereas the use of oximes against carbaryl poisoning was contraindicated. Furthermore, even though CA and Phy are both N-methyl carbamates, the data indicate that there is no adverse interaction between 2-PAM or HI-6 and Phy.

Acetylcholinesterase↗
PubMed1982

Effects of PAM, proPAM, and DFP on behavior, thermoregulation, and brain AChE in rats.

The effects of pyridine-2 aldoxime methyl iodide (PAM), N-methyl-1,6-dihydro-pyridine-2-carbaldoxime hydrochloride (proPAM), and diisopropyl phosphorofluoridate (DFP) on performance of a conditioned avoidance response (CAR), body temperature, and in vivo acetylcholinesterase (AChE) activity in five brain regions in the rat were examined. Sublethal doses of DFP (1.5 to 2.5 mg/kg, IP) markedly degraded CAR performance. This effect was antagonized by 5 mg/kg, subcutaneously injected (SC) atropine. A 50 mg/kg, SC dose of PAM had no effect on the CAR, but an equal dose of proPAM caused a transient deterioration of performance. Given 10 min or 2 hr after DFP, 50 mg/kg proPAM initially exacerbated the behaviorally toxic effects of DFP. Neither PAM nor proPAM antagonized DFP-induced hypothermia. PAM did not reactivate DFP-inhibited brain AChE, and proPAM reactivated it by only 6 to 12% of control activity.

Acetylcholinesterase↗