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PubMed1969

An in vitro study of the intestinal absorption of pyridinium aldoximes.

1. The transfer rates of three pyridinium aldoximes, a non-quaternary pyridine aldoxime and choline across the wall of sacs from the jejunum of rats were measured in vitro.2. The transfer rates observed for any one of the quaternary compounds could be inversely correlated with the transmural potential of the particular sac studied, but there was no correlation with the rates of water or glucose transfer.3. 2-hydroxyiminomethyl-N-methylpyridinium iodide (PAM) had a transfer rate seven times less than that of its non-quaternary analogue, 2-hydroxyiminomethyl pyridine.4. Neither neostigmine nor EDTA affected the transfer rate of PAM in the conditions used.5. It was concluded that the transfer of the quaternary compounds could be explained by diffusion through aqueous pores.

Animals↗
PubMedDate not supplied

Assessment of motor performance decrement following soman poisoning in mice.

A simple motor performance test, the inverted screen test, was used to assess the incapacitating effects of soman in mice and to evaluate the effectiveness of carbamate pretreatment and/or treatment with atropine plus 2-PAM on soman-induced debilitation. The test requires minimal equipment and personnel training, and can be done rapidly on untrained animals. Mice were placed individually on wire mesh screens which were horizontally mounted on a metal rod. The rod was rotated 180 degrees so that the mice were oriented upside down on the bottom of the screen. The animals were observed for their ability to climb to the top of the screen within one minute. Mice exhibited significant disruption of performance on the screen test 24 hours after soman doses of 0.71 LD50 or more. Treatment with atropine and 2-PAM i.m. 10 sec post-soman (1.1 x LD50) did not improve screen test performance when measured at 24 hours. Pretreatment with pyridostigmine or physostigmine in combination with post-soman therapy with atropine and 2-PAM significantly improved screen test performance as early as 2 hours after soman. The results suggest that the inverted screen test may be useful as a first-line assessment of the efficacy of pretreatment and treatment compounds against nerve agent-induced incapacitation.

Animals↗
PubMed1983

Differential effects of di-isopropylfluorophosphate poisoning and its treatment on opioid antinociception in the mouse.

Compounds which enhance cholinergic activity have been reported to interact with opioid drugs. We have shown, using the hot-plate test in mice that di-isopropylfluorophosphate potentiates the antinociceptive activity of alfentanil but has no effect on the activity of morphine or fentanyl. Administration of atropine and pralidoxime as a treatment for DFP poisoning does not reverse this effect, and itself potentiates morphine antinociception. The results suggest that a cholinergic/opioid interaction is dependent on the opioid studied, and may have clinical importance when opioid drugs are required in patients poisoned by irreversible anticholinesterases.

Animals↗
PubMed1959

Oximes of alpha omega-diquaternary alkane salts as antidotes to organophosphate anticholinesterases.

Sixteen compounds of the general structure {HON: CH.C(5)H(4)N(+).[CH(2)](n).R(+)}2Br(-) have been synthesized in which the position of the oxime group in the pyridine ring, the second charged group R(+) and the number of methylene groups between the charged atoms have been varied. The rate at which these compounds reactivate cholinesterase inhibited by ethyl pyrophosphate has been studied and a number have been found which are more active than 2-hydroxyiminomethyl-N-methylpyridinium methanesulphonate. Since considerable variation in structure was found among those compounds which are better reactivators than the latter, the concept that 2-hydroxyiminomethyl-N-methylpyridinium salts are unique in their ability to fit the surface of the inhibited enzyme is no longer tenable. The reactivating power of these oximes correlated well with their ability, when given in conjunction with atropine, to save the lives of mice poisoned by ethyl pyrophosphate. The most effective compounds, NN'-trimethylenebis-(4-hydroxyiminomethylpyridinium bromide) and NN'-hexamethylenebis(2-hydroxyiminomethylpyridinium bromide), contained a further oxime group in R(+), but the second oxime group was not essential for high activity. These new oximes were also superior in saving the lives of mice poisoned with sarin (isopropyl methylphosphonofluoridate), but the improvement was not as dramatic as when the mice were poisoned with ethyl pyrophosphate. The toxicity of the compounds varied with both n and R(+) and was unrelated to the therapeutic potency.

Alkanes↗
PubMed1987

[Effect of cholinesterase (ChE) reactivators on hemodynamics in animals. I. Reactions of the circulatory and respiratory systems of rabbits after administration of ChE reactivators].

Studies on the dynamics of changes in the circulatory and respiratory system in rabbits were carried out after intravenous injection of ChE reactivators used in treatment of poisoning with phosphoorganic compounds (FO). Blood flow in the carotid artery, arterial pressure, frequency and amplitude of breathing were measured. From the above data pulse rate and coefficient of vesself resistance were calculated. The results obtained indicate that the reactions in the circulatory and respiratory system depend on the kind of the reactivator, the size of its dose and time of action. Pralidoxim--PAM (at a dose of 10, 20, 40 mg/kg) acts cholinergically on the muscular coat o blood vessels, causing their shrinkage, which is proved by decreased blood flow with simultaneous increase of vessel resistance. The increase of vessel resistance was directly proportional to the dose of pralidoxim and often caused an increase in arterial pressure. Pralidoxim did not show a larger effect on the function of the heart. The action of obidoxim--Toxogonin or Toxobidin--does not only depend on the size of the dose but on the time of action as well. At small doses (10 mg/kg), obidoxim increases blood flow after 15 min, then causes shrinkage of blood vessels and decreases blood flow with increased vessel resistance. At larger doses (20, 40 mg/kg) a constant increase of blood flow is maintained, despite frequently decreased arterial pressure with simultaneously decreased vessel resistance. This accounts for blood vessel dilatation. The reactivators studied stimulate the function of the respiratory system by increased frequency of breathing, but its amplitude was effected to a lesser extent. It was also shown that ChE activity in blood was not changed significantly. The action of the indoxims studied was similar to that of Toxobidin (Polfa) and Toxogonin (E. Merck).

Animals↗
PubMed1988

In vivo protection against soman toxicity by known inhibitors of acetylcholine synthesis in vitro.

Soman inhibits the enzyme acetylcholinesterase, essentially irreversibly, producing an accumulation of acetylcholine (ACh) which is responsible for many of its toxic effects. Current approaches to treatment include: (1) atropine, a muscarinic receptor blocker; (2) pyridine-2-aldoxime methylchloride (2-PAM), an enzyme reactivator; and (3) carbamate protection of the enzyme. However, no fully satisfactory regimen has been found, primarily because of the rapid aging process. In this study, compounds known to inhibit ACh synthesis in vitro were evaluated in combination with atropine and 2-PAM so as to assess their potential utility in protection against soman toxicity in rats. Acetylsecohemicholinium (100 micrograms/kg, i.c.v.t., 30 min prior to soman), an inhibitor of high affinity choline uptake (HAChU) and cholineacetyltransferase (ChAT) activity in vitro, enhanced the protective effects of atropine and 2-PAM, reducing the mortality within the first 2 hr following soman. N-Hydroxyethylnaphthylvinylpyridine (NHENVP), a quaternary ChAT inhibitor (1.7 mumol/kg, i.m.), significantly reduced the overall percent mortality due to soman from 80% to 20%. The compound was most effective when administered 2-3 min prior to soman and was effective only by the intramuscular route. N-Allyl-3-quinuclidinol, a potent HAChU inhibitor (1 mumol/kg, i.m.) was the most effective quinuclidine analog evaluated, also reducing the percent mortality for a 24-hr period. Unlike NHENVP, it was most effective when given 30-60 min prior to soman. It is suggested from the data that compounds that disrupt presynaptic ACh synthesis in vitro may prove effective in treating organophosphate poisoning. The results demonstrate interesting differences among the compounds studied and provide insight for the design of protectants against soman toxicity. These findings further underscore the need to examine the structure activity and pharmacokinetic properties of these compounds, i.e. comparison of routes of administration, dose-response relationships, and time to effect.

Acetylcholine↗
PubMed1965

Effects of a combination of atropine, metaraminol and pyridine aldoxime methanesulfonate (AMP therapy) on normal human subjects.

Four hundred and seventeen medical students at the University of Toronto were used as both subjects and observers in a series of double-blind experiments to determine possible toxic effects following oral ingestion of various combinations of 2 mg. atropine, 10 mg. metaraminol and 1 g. pyridine aldoxime methanesulfonate (P(2)S). Heart rate, blood pressure, pupil diameter, and visual accommodation were measured before and at 20-minute intervals after drug administration for 100 minutes. A visual and memory perceptual test (Mackworth) was performed before and 100 minutes after drug ingestion.No toxic effects were observed following administration of the triple combination of atropine, metaraminol and P(2)S (AMP therapy). The AMP combination might be useful prophylactically for persons facing exposure to organophosphorus anticholinesterase compounds. It must not be considered an adequate substitute for treatment should poisoning occur.

Atropine↗
PubMed1983

Direct and indirect effects of an organophosphorus acetylcholinesterase inhibitor and of an oxime on a neuro-neuronal synapse.

The action of an irreversible inhibitor of acetylcholinesterase (AChE), the organophosphorus compound, ecothiopate iodide, and of a reactivator of phosphorylated AChE, contrathion, were analysed on acetylcholine (ACh) receptors and cholinergic synaptic transmission in the buccal ganglion of Aplysia. At high concentration (above 10(-4)mol X 1(-1), both compounds exerted a curare-like depression on ACh receptors which was reversible with washing. Both compounds reversibly facilitated the current response to ionophoretic application of ACh and increased the evoked postsynaptic current (PSC) as well as the miniature postsynaptic currents (MPSCs). All responses also showed an increase in decay time. These modifications, when induced by ecothiopate iodide were irreversible by washing; however they could be reversed if first washed with contrathion. Neither the organophosphate compound or the oxime did change the number of quanta released per impulse. The current response to ionophoretic application of carbachol also increased after ecothiopate iodide was added. In the limits of the method used, the conductance and opening time of postsynaptic ionic channels opened by ACh were not found to be modified by the two compounds. It was concluded that the facilitatory action of the organophosphorus inhibitors cannot be solely explained by the inhibition of ACh hydrolysis.

Acetylcholine↗
PubMed1984

PAM-2 Cl, HI-6, and HGG-12 in soman and tabun poisoning.

Acute sc toxicity of soman increased in the order, mice----rats----guinea pigs----dogs, being 12.6 times more toxic to dogs (LD50 = 0.05 mumol/kg) than to mice. It was 2.8 times more toxic than tabun to mice and 35 times more toxic to dogs. HI-6 was the least toxic and had similar toxicity values to the four animal species studied and HGG-12 the most toxic of the three oximes used. HGG-12 has shown the greatest interspecies variation (rats:dogs = 1:19.5). HI-6, HGG-12, and PAM-2 Cl (in conjunction with atropine and diazepam) revealed the best protective effect in soman-poisoned dogs, with the respective protective indices of 9, 6.3, and 3.5, followed by guinea pigs. In tabun poisoning the best, but relatively low, protective effect was found only in guinea pigs. The introduction of diazepam increased the protective effects of atropine-oxime combination in soman and tabun poisoning by 10 to 80%. We suggest that the high toxicity of soman and low toxicity of HI-6 may be anticipated in man. The inefficiency of HI-6, HGG-12, and PAM-2 Cl in tabun poisoning points either to the search of new compounds or to the use of the mixture of the oximes found to be effective against the known chemical warfare nerve agents.

Acetylcholinesterase↗
PubMedDate not supplied

Treatment of organophosphate poisoning. Experience of nerve agents and acute pesticide poisoning on the effects of oximes.

Organophosphate (OP) compounds have been used as pesticides and in chemical warfare (nerve agents). Two nerve agents, tabun and sarine, were used by the Iraqi army against Iranian troops and innocent people. Hundreds of the exposed combatants died in the field. Atropine sulphate has been used successfully in large doses to counteract the muscarinic effects of OP poisoning. The effects of oximes in human OP poisoning have not been well studied. Our aim was to study the effects of obidoxime and pralidoxime in OP pesticide poisoning. The patients were divided into three groups: atropine (A), obidoxime + atropine (OA) and pralidoxime + atropine (PA). Sixty-three patients (33 males, 30 females) with a mean age of 25 years were studied in different groups (43 A, 22 OA and 8 PA). There were no statistical significant differences in major clinical findings and acetylcholinesterase (AChE) activity on admission between the groups. Significant changes were observed during the treatment. Notwithstanding the severity of intoxication--particularly respiratory complications were more observed in the OA and PA groups--there were no fatalities in the PA group, whereas 4 (9%) and 6 (50%) patients in the A and OA groups died, respectively. AChE reactivation was only observed in the PA group, although it was not statistically significant (r = 0.4747). There was a good relationship between the AChE reactivation and outcome of the patients. High doses of obidoxime (8 mg/kg followed by 2 mg/kg/h) were found to be hepatotoxic and should be avoided. High doses of pralidoxime (30 mg/kg followed by 8 mg/kg/h) did not induce serious side effects and may be effective in some OP pesticides poisoning.

Adolescent↗
PubMed2001

Aldicarb poisoning by an illicit rodenticide imported into the United States: Tres Pasitos.

OBJECTIVE: Although intentional and unintentional rodenticide poisoning is common, most readily available agents are of relatively low acute toxicity. A four-year long epidemic of severe toxicity from rodenticide exposure continues among patients predominantly of Dominican descent living in New York City. This study characterizes the ongoing epidemic of acute cholinesterase inhibitor poisoning due to an illicit rodenticide and identifies its etiology. METHODS: A prospectively collected case series of poisoned patients referred to the New York City Poison Control Center. The main outcome measures include the clinical characteristics upon presentation, antidotal and other therapeutic requirements, and patient outcome. Product analysis was performed with paper chromatography, gas chromatography/mass spectrometry, and high-performance liquid chromatography. A murine model assessing both clinical effect and cholinesterase activity was also performed. RESULTS: Thirty-five patients were referred following exposure to Tres Pasitos. Patients developed signs of cholinergic hyperactivity and many required high doses of atropine (>10 mg) to control these symptoms. The source was identified as a rodenticidal compound sold illicitly in local groceries primarily within the Dominican community. Murine cholinesterase activity fell significantly following exposure to the rodenticide. High-performance liquid chromatography identified aldicarb, an extremely potent carbamate-type cholinesterase inhibitor, not licensed for rodenticidal use in this country. CONCLUSION: Illicit sale of undocumented compounds poses a substantial public health threat. Despite several public health interventions, the epidemic continues.

Adolescent↗
PubMed1959

Protection against lethal organophosphate poisoning by quaternary pyridine aldoximes.

The effect of 18 pyridinium aldoximes on diethylphosphoryl-acetocholinesterase in vitro and the protection against lethal poisoning by ethyl pyrophosphate (TEPP) in mice pretreated with 0.095 m.mole/kg. of these oximes was investigated. Monoximes and dioximes of polymethylenebispyridinium compounds were studied in greater detail since they were up to 22 times more potent than pyridine-2-aldoxime methiodide (2-hydroxyiminomethyl-N-methylpyridinium iodide) in reactivating diethylphosphoryl-acetocholinesterase in vitro and protected mice against lethal poisoning by up to 15 LD100 of ethyl pyrophosphate. These oximes were also up to 52 times more potent than pyridine-2-aldoxime methiodide in reactivating di-isopropylphosphoryl-acetocholinesterase in vitro and were effective in preventing lethal poisoning by dyflos (di-isopropyl phosphorofluoridate). The antidotal action against diethyl phosphostigmine (Ro 3-0340) was even greater than that against ethyl pyrophosphate. Some of the most effective oximes had antidotal actions in poisoning by ethyl pyrophosphate, diethyl phosphostigmine and dyflos when given in 0.0095 m.mole/kg. and this effect was enhanced by 1 mg./kg. atropine sulphate. In vivo reactivation of diethylphosphoryl-acetocholinesterases by 0.0095 or 0.095 m.mole/kg. of oximes of polymethylenebispyridinium compounds was demonstrated in blood but not in brain. Atropine-like and neuromuscular blocking activities were studied on isolated organs and protection against lethal doses of neostigmine and related anticholinesterases were also investigated. Some of the oximes of polymethylenebispyridinium compounds have, relative to pyridine-2-aldoxime methiodide, a higher therapeutic ratio in mice and considerably greater water-solubility. The possible advantages to be gained from their use in preference to pyridine-2-aldoxime methiodide are discussed.

Animals↗
PubMed2005

New evidences for old biomarkers: effects of several xenobiotics on EROD and AChE activities in Zebra mussel (Dreissena polymorpha).

The biomarker approach is widely used both in vertebrates and invertebrates for environmental biomonitoring, because it can supply an integrated response for multi-xenobiotics contamination. However, the use of biomarkers requires the identification of every possible variation that can influence the biochemical response, because ecosystems are generally subject to a mixture of pollutants, which can create additive, opposite or competitive effects. In recent years, there has been considerable interest in the use of biomarkers within marine bivalves, while very few data are available for freshwater molluscs. The aim of this research was to investigate changes on EROD and AChE activities in the freshwater bivalve Zebra mussel (Dreissena polymorpha) exposed to different pollutants (Arochlor 1260, CB 153 and 126, pp'DDT, chlorpyrifos, carbaryl) at laboratory conditions, in order to standardize the analytical procedures and to highlight eventual interferences on enzyme activities. Chemical concentrations in the mussel soft tissues were analyzed by GC/MS-MS. Main results showed a significant induction of EROD activity when mussels were exposed to 100 ng/l of PCB mixture of Arochlor 1260 and dioxin-like CB 126, but this congener showed also a clear competitive inhibition after 48 h of exposure. Surprisingly, pp'DDT determined a significant decrease of basal EROD activity after only 24 h of exposure, even if it was not possible to discriminate between the effect of the parent compound and that of its metabolites (DDD, DDE). We also found an interaction between the organophosphate insecticide chlorpyrifos, which does not directly decrease the AChE activity, and terbutilazine. This herbicide increased the biotransformation of the organophosphate compound to its oxidized metabolite (oxon), a much stronger AChE inhibitor. The possible use of the oxime Pyridine-2-Aldoxime Methochloride (2-PAM) to bring back the catalytic activity to basal levels was also demonstrated.

Acetylcholinesterase↗
PubMed1976

Biological responsiveness to cholinesterase inhibition: a test for exploring the developmental maturity of the cholinergic system.

The acute mortality caused by two irreversible inhibitors of cholinesterases [diisopropylfluorophosphate (DFP) and diethoxyphosphorylthiocholine, 217 MI-phospholine iodide] has been investigated on chick embryos at different stages of development. The results demonstrate that the above compounds do not show any acute lethal action when administered before the 9th day of incubation; on the other hand, the administration is regularly followed by death after the 9th day of incubation. The doses are comparable to those causing death in hatched chicks. It has also been observed that no appreciable difference exists in DFP uptake from the yolk before and after the 9th day of incubation and that drug-induced cholinesterase inhibition is of the same order of magnitude at any developmental stage; the compound pyridine-2-aldoxime methanesulfonate (2-PAM) was a good antidote against DFP acute lethality. It seems likely that between the 8th and the 9th day of incubation the target system of organophosphorus inhibitors, that is, the cholinesterase enzymatic system, reaches a new point of maturation.

Animals↗
PubMedDate not supplied

Chlorpyrifos toxicosis in two cats.

Organophosphate compounds are widely employed for control of external parasites in cats and for control of insects in homes and yards. Chlorpyrifos is a long-acting organophosphate (OP) available for use as a systemically and topically acting parasiticide and insecticide in cattle. Its use on cats is not recommended, and no previous clinical cases of toxicosis have been described. Two cases of chronic chlorpyrifos toxicosis in cats are presented and pathophysiology as well as treatment are discussed. The cats had been showing signs of chronic organophosphate toxicosis before diazepam administration. Signs of acute organophosphate toxicosis were precipitated after diazepam was given. Treatment with pralidoxime chloride (2-PAM) and atropine was attempted. Response to treatment was dramatic and complete recovery was achieved with six injections of pralidoxime and atropine administration.

Animals↗