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At least 19 recordsLinked to original sources
PubMed1976

Pralidoxime as an insignificant reactivator in severe anticholinesterase (organophosphate insecticide) poisoning.

In acute severe anticholinesterase poisoning by organophosphate compounds, pralidoxime (P-2-AM, pyridine-2-aldoxime methiodide) used in the recommended doses, intravenously, has not been shown to reactivate the inhibited cholinesterase, as evidenced both clinically and biochemically. In vitro studies using pralidoxime iodide up to ten times the recommended concentrations, produced insignificant reactivation of cholinesterases inhibited by the organophosphate insecticide Bidrin (di-methyl-3-hydroxyl-N, N-dimethyl-crotonamide phosphate). This was even so despite prolonged exposure of the inhibited cholinesterases to the oxime. The value of pralidoxime as a reactivator of phosphorylated cholinesterases is therefore in doubt, and should not be used in preference to large doses of atropine and other supportive treatment in poisoning by organophosphate insecticides.

Acetylthiocholine↗
PubMedDate not supplied

Studies on the delayed neuropathic and anticholinesterase potential of quinalphos (diethyl 2-quinoxalyl phosphorothionate) in hens.

Incidence of numerous human poisonings by quinalphos (Ekalux, Bayrusil) in agricultural areas near Belgrade initiated this study on the ability of the compound to inhibit hen brain neuropathy target esterase, acetylcholinesterase and plasma butyrylcholinesterase in vivo. Hens were treated with a single oral dose ranging from 25 to 600 mg kg-1 quinalphos (LD50 = 72 mg kg-1) or 500 mg kg-1 triorthocresyl phosphate (positive control), sacrificed 24-96 h later for enzyme assays and monitored for 25 days for evaluation of walking impairments. High inhibition (> 80%) of both cholinesterases was obtained with 25 and 50 mg kg-1 quinalphos. Doses of 200 and 600 mg kg-1 of the agent inhibited up to 23 and 28% of hen brain neuropathy target esterase activity, respectively. Clinical signs of neuropathy were not seen. Quinalphos was slowly absorbed from the gastrointestinal tract, as indicated by the severity of the cholinergic symptoms and the inhibition of neuropathy target esterase, which reached its maximum 72 and 96 h after poisoning. The results suggest that quinalphos, at doses tested, has no ability to cause delayed neuropathy in hens without showing signs of severe cholinergic intoxication.

Animals↗
PubMed1986

Stability studies of bis(pyridiniumaldoxime) reactivators of organophosphate-inhibited acetylcholinesterase.

Relative stability studies of three organophosphate-inhibited acetylcholinesterase reactivators, 1-(2-hydroximinomethyl-1-pyridinium)-3-(4-carbamoyl-1-pyridinium)- 2-oxapropane dichloride (HI-6), 1,1'-methylenebis(4-hydroximinomethylpyridinium) dichloride (MMB-4), and 1,1'-trimethylenebis(4-hydroximinomethylpyridinium) dibromide (TMB-4) were carried out by semiquantitative TLC and NMR methods. TMB-4 appears to be the most, and HI-6 the least stable of the three compounds. The extent of hydrolysis of HI-6, MMB-4, and TMB-4 in 0.05 M, pH 7 phosphate buffer was approximately 50, 25, and less than 1%, respectively, after 20 d at room temperature. The hydrolysis products of HI-6 were identified by NMR and MS (electron impact) as 2-pyridinealdoxime, picolinamide, and isonicotinamide, whereas that of MMB-4 was identified as 4-pyridinealdoxime. The stability of these reactivators decreases with increasing pH. TMB-4 was stable under both neutral and basic conditions at room temperature. Deuterium exchange of the methylene protons of MMB-4 in D2O and of the protons at the 2- and 6-positions of the pyridinium ring of TMB-4 in NaOD/D2O were observed.

Acetylcholinesterase↗
PubMed2000

Efficacy of biperiden and atropine as anticonvulsant treatment for organophosphorus nerve agent intoxication.

The ability of the nerve agents tabun, sarin, soman, GF, VR, and VX to produce brain seizures and the effectiveness of the anticholinergics biperiden HCl or atropine SO4 as an anticonvulsant treatment were studied in a guinea-pig model. All animals were implanted a week prior to the experiment with cortical electrodes for electroencephalogram (EEG) recordings. On the day of exposure, the animals were pretreated with pyridostigmine (0.026 mg/kg, i.m.) 30 min prior to challenge with a 2 x LD50 dose (s.c.) of a given agent. In separate experiments, animals were challenged with 5 x LD50 (s.c.) of soman. One minute after agent challenge, the animals were treated intramuscularly (i.m.) with 2 mg/kg atropine SO4 admixed with 25 mg/kg 2-PAM Cl and then observed for the onset of seizure activity. Five minutes after the start of nerve agent-induced EEG seizures, animals were treated i.m. with different doses of biperiden HCl or atropine SO4 and observed for seizure termination. The anticonvulsant ED50 of biperiden HCl and atropine SO4 for termination of seizures induced by each nerve agent was calculated and compared. With equally toxic doses (2 x LD50) of these agents, continuous EEG seizures (status epilepticus) developed in all animals challenged with soman, tabun, or VR, and in more than 90% of the animals challenged with GF or sarin. In contrast, only 50% of the animals developed seizures when challenged with VX. The times to onset of seizures for soman, tabun, GF, and sarin were very similar (5-8 min) while for VR, it was about 10 min. In the case of VX, not only was the time to seizure development longer (20.7 min), but the seizure activity in 19% of the animals terminated spontaneously within 5 min after onset and did not return. Under these conditions, the anticonvulsant ED50s of biperiden HCl for soman, GF, VR, tabun, sarin, and VX were 0.57, 0.51, 0.41, 0.2, 0.1, and 0.09 mg/kg, respectively, while those of atropine SO4 for soman, VR, tabun, GF, sarin, and VX were 12.2, 11.9, 10.4, 10.3, 5.1, and 4.1 mg/kg, respectively. In separate experiments, the anticonvulsant ED50 doses of biperiden for animals challenged with 2 or 5 x LD50 of soman were 0.48 (95% confidence limits 0.25-0.73) or 0.57 (95% CI 0.38-0.84) mg/kg, respectively, while the anticonvulsant ED50s for atropine (12.2 mg/kg, i.m.) were identical under these same two challenge conditions. The present study demonstrates that all nerve agents can produce status epilepticus and that the therapeutic effectiveness of atropine and biperiden roughly paralleled the seizurogenic potential of these agents.

Animals↗
PubMed1999

Oxime reactivation of RBC acetylcholinesterases for biomonitoring.

A low-variability method to reactivate blood cholinesterases (ChEs) after prior exposure of mammals, including humans, to ChE-inhibiting organophosphate esters (OPs) is presented. A concentration of 10 mM pyridine 2-aldoxime methochloride (2-PAM Cl) was incubated with intact red blood cells (RBCs) and assayed virtually free of interfering oxime and hemoglobin (Hb). Variability was decreased by reducing the number of washing steps and sedimenting RBC ghosts through a 7% sucrose cushion. Statistically significant detections of reactivations as low as 5% with average "false positives" of 3.8% were achieved. Relative rates and extent of reactivation after OP treatment of rabbit RBC AChE in vitro were of the order dimethyl- (DDVP) > diethyl- (ethyl paraoxon) >, diisopropyl-substituted (diisopropyl fluorophosphate; DFP) OPs. Rabbit RBC AChE was reactivatable for up to 60 h following dermal exposure to ethyl parathion and reactivatable for only 12 to 24 h following exposure to methyl parathion. Reactivation of plasma ChEs with 0.1 mM 2-PAM Cl in the same animals was achievable for only 12 to 24 h after ethyl parathion and for only 1 to 4 h after methyl parathion.

Acetylcholinesterase↗
PubMed1986

In vitro studies on the reactivation by oximes of phosphylated acetylcholinesterase--II. On the formation of O,O-diethyl phosphorylated AChE and O-ethyl methylphosphonylated AChE and their reactivation by PS2.

The in vitro reactivation profiles of O,O-diethyl phosphorylated AChE and O-ethyl methyl phosphonylated AChE by P2S (2-hydroxy iminomethyl-1-methyl-pyridinium methane sulphonate) have been determined. Whilst reinhibition of the reactivated AChE by phosphorylated oxime (POX) is not important in determining the reactivation profile of O,O-diethyl phosphorylated AChE, reinhibition of the reactivated AChE by phosphonylated oxime can, however, be important in determining the reactivation profile of O-ethyl methylphosphonylated AChE and the extent of this reinhibition is determined by the initial concentration of phosphonylated AChE. Kinetic analysis of the reactivation profiles demonstrated that the generally accepted scheme for this reactivation process is incorrect and that phosphylated AChE cannot be considered as a single species although an adequate description of the present data is afforded by a model using a 1:1 mixture of two species each with its own rate of reactivation. In the case of O,O-diethyl phosphorylated AChE the main kinetic difference between these two species is found not in the formation or stability of the phosphorylated AChE-P2S complex but in its subsequent reaction. From results with O-ethyl methylphosphonylated AChE prepared from two pairs of enantiomers as well as from the racemic fluoridate it was concluded that phosphonylation of AChE may not always occur via a mechanism involving inversion of configuration at phosphorus but can also occur with retention of configuration. Reactivation by P2S of O-ethyl methylphosphonylated AChE prepared from (S) organophosphates proceeds with inversion of configuration at phosphorus. Inversion also occurs in the reinhibition of AChE by the POX produced in the initial reactivation.

Acetylcholinesterase↗
PubMed1978

Effects of cholinesterase inhibitors on the spasmogenic action of acetate esters on rat uterus.

Acetate esters, such as phenyl acetate and aspirin, induced atropine-sensitive contractions of isolated uterus only when choline was present. These contractions were selectively and reversibly inhibited by carbamate-type cholinesterase inhibitors, such as neostigmine and eserine, and quaternary ammonium compounds, such as tetraethylammonium and decamethonium. After treatment with organophosphorus cholinesterase inhibitors, such as di-isopropyl fluorophosphate and tetraethyl pyrophosphate, the uterus failed to respond to the acetate esters, even when high concentrations of choline were present. The inhibition of the response of the uterus by organophosphates was effectively removed by pyridine-2-aldoxime methiodide. Pretreatment of the uterus with neostigmine or simultaneous addition of high concentrations of quaternary ammonium compounds prevented the inhibition by organophosphates. The inhibition produced by neostigmine was also reduced by simultaneous addition of quaternary ammonium compounds. These findings suggest that some esterase having an anionic site and an esteratic site, probably cholinesterase, may mediate in the uterine contractions induced by acetate esters in the presence of choline, and that inhibition by organophosphates, carbamates and quaternary ammonium compounds of cholinesterase activity in the preparation may impede the initiation of contractions by the acetate esters in the presence of choline.

Acetates↗
PubMed1981

Effect of N-methylpyridinium-2-aldoxime methane sulphonate (P2S) on rat intestinal, (Na-K)ATPase and adenyl cyclase activities.

The effect of N-methylpyridinium-2-aldoxime methane sulphonate (P2S), a drug recommended for prophylactic and therapeutic purposes in organophosphate poisoning, on intestinal (Na-K) ATPase and adenyl cyclase activities, was tested in rats. Intestinal (Na-K) ATPase activity was determined 5 h after intragastric administration of either 0.15 M NaCl or P2S 200 mg/kg body weight. P2S decreased significantly jejunal and colonic (Na-K)ATPase activity, 17.1 +/- 4.8 (S.E.) and 13.5 +/- 3.0, as compared to that in saline-treated rats, 41.5 +/- 3.0 (S.E.) and 25.4 +/- 1.2 mumol Pi/mg protein per h, respectively. Pretreatment with methyl prednisolone did not prevent the decrease in enzyme activity induced by P2S. Mucosal PGE2 and cAMP contents, adenyl cyclase and phosphodiesterase activities, were similar in P2S and saline-treated rats. It is thus suggested that P2S-induced inhibition of intestinal (Na-K)ATPase activity might be among the mechanisms contributing to looseness of the stool frequently observed following P2S administration.

Adenylyl Cyclases↗
PubMed1992

Reduction by pyridostigmine pretreatment of the efficacy of atropine and 2-PAM treatment of sarin and VX poisoning in rodents.

This study concerned the effect of pyridostigmine pretreatment on (a) the antidotal efficacy of atropine and 2-PAM in sarin, tabun, and VX poisoning in mice and guinea pigs and on (b) the oxime-induced reactivation of VX-inhibited whole blood acetylcholinesterase (AChE) of guinea pigs. One hour prior to organophosphate (OP) challenge with sarin, tabun, or VX, animals were given oral doses of pyridostigmine to induce approximately 30 and 60% inhibition of whole blood AChE; controls received vehicle. Mice were challenged im and guinea pigs sc with the OP compounds. Treatment with atropine (11.2 mg/kg to mice; 32 mg/kg to guinea pigs) plus 2-PAM (25 mg/kg) was given im at 10 sec postchallenge in mice and 1 min postchallenge in guinea pigs. In the reactivation experiments, pyridostigmine or saline was given im to guinea pigs 30 min prior to VX (8.24 micrograms/kg, sc), atropine (16 mg/kg) was given im at 1 min, and 2-PAM (25 mg/kg) at 16 min postchallenge. Pyridostigmine significantly enhanced the efficacy of atropine and 2-PAM against tabun in both species. In contrast, pyridostigmine reduced or did not increase the efficacy of atropine and 2-PAM against sarin or VX in both species. Recovery of VX-inhibited AChE by 2-PAM was decreased significantly in pyridostigmine pretreated animals. The results suggest that pyridostigmine pretreatment may adversely effect the efficacy of atropine and 2-PAM as antidotes for VX and sarin intoxication.

Acetylcholinesterase↗