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PubMed1991

Effectiveness of oximes 2-PAM and HI-6 in recovery of muscle function depressed by organophosphate agents in the rat hemidiaphragm: an in vitro study.

Phrenic nerve diaphragm muscles of young adult rats were used to study the ability of the oximes 2-PAM and HI-6 to recover muscle function depressed by organophosphate (OP) agents. The single twitch of diaphragm muscles which were exposed to soman (0.2 microM) recovered after washing with saline for 3 hr, but the muscles pretreated with sarin (0.4 microM), VX (0.2 microM), or tabun (0.4 microM) showed only partial recovery. In addition, after 3 hr washing, the muscles pretreated with soman as well as with tabun did not recover the tetanus sustaining ability (TSA), yet complete recovery was observed with muscles pretreated with sarin and VX. These results indicate that the OPs have different effects on muscle contractile properties and that VX- and sarin-pretreated muscles recover equally well after wash with physiological solution. The recovery of twitch tension of diaphragm muscles by 2-PAM and HI-6 was similar to that achieved by washing with saline for 3 hr for sarin- and soman-exposed muscles. The most remarkable differences were seen in the recovery of TSA. Both 2-PAM and HI-6 recovered the TSA of muscles that were pretreated with sarin and VX. Although 2-PAM recovered the TSA after tabun pretreatment, HI-6 had no discernible effect. On the other hand, HI-6 recovered the TSA of soman-pretreated muscles but 2-PAM did not. The effectiveness of muscle function recovery was not related to the oximes' ability to reactivate AChE, thus indicating that the recovery of muscle contractility may be attributed to a direct effect of these compounds on the muscle.

Animals↗
PubMed2004

Inhibition of plasma butyrylcholinesterase activity in the lizard Gallotia galloti palmae by pesticides: a field study.

A field study was performed to evaluate the effect of exposure to organophosphorus (OP) and carbamate (CB) pesticides on the lizard Gallotia galloti palmae. Butyrylcholinesterase (BChE) activity was measured in the plasma of 420 lizards collected from agricultural and reference areas on the Island of La Palma (Canary Islands, Spain) in two sampling periods. Exposure to cholinesterase-inhibiting pesticides was evaluated by a statistical criterion based on a threshold value (two standard deviations below the mean enzyme activity) calculated for the reference group, and a chemical criterion based on the in vitro reactivation of BChE activity using pyridine-2-aldoxime methochloride (2-PAM) or after water dilution of the sample. Mean (+/- SD) BChE activity for lizards from agricultural areas was significantly lower (Fuencaliente site = 2.00 +/- 0.98 micromol min(-1) ml(-1), Tazacorte site = 2.88 +/- 1.08) than that for lizards from the reference areas (Los Llanos site = 3.06 +/- 1.17 micromol min(-1) ml(-1), Tigalate site = 3.96 +/- 1.62). According to the statistical criterion, the number of lizards with BChE depressed was higher at Fuencaliente (22% of males and 25.4% of females) than that sampled at Tazacorte (7.8% of males and 6.2% of females). According to the chemical criterion, Fuencaliente also yielded a higher number of individuals (112 males and 47 females) with BChE activity inhibited by both OP and CB pesticides. CBs appeared to be the pesticides most responsible for BChE inhibition because most of the samples showed reactivation of BChE activity after water treatment (63.3% from Fuencaliente and 29% from Tazacorte). We concluded that the use of reactivation techniques on plasma BChE activity is a better and more accurate method for assessing field exposure to OP/CB pesticides in this lizard species than making direct comparisons of enzyme activity levels between sampling areas.

Animals↗
PubMed2005

Signs of cyclosarin-induced neurotoxicity and its pharmacological treatment with quaternary pyridinium-oximes reactivators.

Cyclosarin (GF-agent; O-cyclohexylmethylfluorophosphonate) belongs to highly toxic organophosphorus compounds. Potential for exposure to chemical warfare organophosphosphorus nerve agents, such as cyclosarin exists on the battlefield, or in the civilian sector as a threat by a terrorist group, as well as an accident as part of current demilitarization efforts. Cyclosarin was not in a front of scientific interest for long time. The research interest was increased after Operation Desert Shield and Desert Storm with the possibility (later confirmed by the UN special commission) that cyclosarin constituted the Iraqi chemical agent inventory. In this study, the neurotoxicity of cyclosarin and therapeutic efficacy of three oximes [HI-6(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxa-propane dichloride), BI-6(2-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)-but-2-ene dibromide), HS-6(2-hydroxyiminomethylpyridinium)-3-(3-carbamoylpyridinium)-2-oxa-propane dichloride)] as acetylcholinesterase reactivators in combination with atropine was studied in rats. The therapy was administered intramusculary (i.m.) 1 min after i.m. GF-agent challenge (1 LD50). Testing of cyclosarin-induced neurotoxicity progress was carried out using the method of Functional observational battery (FOB). The experimental animals were observed at 24 h and 7 days following cyclosarin administration. The results were compared to the condition of control rats that received physiological solution instead of cyclosarin and treatment. All tested antidotal compounds induced neuroprotective efficacy, because decrease of neurotoxicity signs was recorded. There were no poisoned experimental group treated with atropine only, because our preliminary study showed no therapeutical effect of atropine alone. Cyclosarin caused a marked statistically significant change in most of the neurobehavioral parameters (FOB) at 24 h and 7 days after exposure, compared to the saline control group. Survival was 7/10 at 24 h and 5/10 at 7 days. Oxime (BI-6, HS-6 or HI-6) + atropine treatment caused a progressing recovery of the neurobehavioral disturbances caused by cyclosarin at 24 h and 7 days after exposure.

Animals↗
PubMed2004

Mutant cholinesterases possessing enhanced capacity for reactivation of their phosphonylated conjugates.

Selective mutants of mouse acetylcholinesterase (AChE; EC 3.1.1.7) phosphonylated with chiral S(P)- and R(P)-cycloheptyl, -3,3-dimethylbutyl, and -isopropyl methylphosphonyl thiocholines were subjected to reactivation by the oximes HI-6 and 2-PAM and their reactivation kinetics compared with wild-type AChE and butyrylcholinesterase (EC 3.1.1.8). Mutations in the choline binding site (Y337A, Y337A/F338A) or combined with acyl pocket mutations (F295L/Y337A, F297I/Y337A, F295L/F297I/Y337A) were employed to enlarge active center gorge dimensions. HI-6 was more efficient than 2-PAM (up to 29000 times) as a reactivator of S(P)-phosphonates (k(r) ranged from 50 to 13000 min(-1) M(-1)), while R(P) conjugates were reactivated by both oximes at similar, but far slower, rates (k(r) < 10 min(-1) M(-1)). The Y337A substitution accelerated all reactivation rates over the wild-type AChE and enabled reactivation even of R(P)-cycloheptyl and R(P)-3,3-dimethylbutyl conjugates that when formed in wild-type AChE are resistant to reactivation. When combined with the F295L or F297I mutations in the acyl pocket, the Y337A mutation showed substantial enhancements of reactivation rates of the S(P) conjugates. The greatest enhancement of 120-fold was achieved with HI-6 for the F295L/Y337A phosphonylated with the most bulky alkoxy moiety, S(P)-cycloheptyl methylphosphonate. This significant enhancement is likely a direct consequence of simultaneously increasing the dimensions of both the choline binding site and the acyl pocket. The increase in dimensions allows for optimizing the angle of oxime attack in the spatially impacted gorge as suggested from molecular modeling. Rates of reactivation reach values sufficient for consideration of mixtures of a mutant enzyme and an oxime as a scavenging strategy in protection and treatment of organophosphate exposure.

Acetylcholinesterase↗
PubMed1975

The management of organophosphate intoxication.

This review attempts to reiterate the problem of organophosphate intoxication and the pathophysiologic problems created by these compounds. A discussion of management is included. The case reported of a two-year old child serves to illustrate the tremendously high doses of atropine which may be required to block the acetylcholine accumulated at cholinergic synapses as a result of phosphorylation of acetylcholinesterase by organophosphorus compounds.

Acetylcholinesterase↗
PubMed2004

Diagnosis in an acute organophosphate poisoning: report of three interesting cases and review of the literature.

Organophosphates may cause serious life-threatening conditions, such as an initial acute cholinergic crisis and intermediate syndrome. Each of these conditions has a potential for respiratory failure requiring ventilatory support. For this reason, it is very important to recognize them early, especially to institute appropriate management. The diagnosis of organophosphate poisoning is based essentially on a clinical assessment, followed by laboratory examinations. Sometimes the diagnosis may be difficult, as in case 1, identified initially as brainstem stroke. However, if neurological syndromes associated with organophosphate poisoning are well known, they can easily be distinguished from other conditions that resemble them. Two cases displayed the symptoms and signs of intermediate syndrome; however, one case (no. 2) did not have severe poisoning on admission but needed artificial ventilation. Each case recovered completely from organophosphate poisoning as a result of early diagnosis and appropriate therapy. Therefore, we would like to describe the clinical and laboratory features of these syndromes, observed in three interesting cases, and to emphasize the importance of early and accurate diagnosis for the appropriate management of acute organophosphate poisoning.

Acetylcholinesterase↗
PubMed1979

Effect of toxogonin and P2S on the toxicity of carbamates and organophosphorus compounds.

Toxogonin (80 mg/kg intraperitoneally) given 15 min. prior to the administration of organophosphorus insecticides dimethoate, malathion, parathion and azinphos-methyl, organophosphorus warfare agents soman and tabun, or carbamates physostigmine, pyridostigmine and aldicarb, reduced the toxicity in mice of these agents by increasing their LD50 dose 1.5-3 fold. The toxicity of the carbamate insecticide carbaryl, however, was significantly increased by toxogonin. Similar results were obtained for P2S (150 mg/kg intraperitoneally) with respect to the toxicity of dimethoate, soman and pyridostigmine, whereas no effect could be detected on the toxicity of tabun. Only a slight reduction in the toxicity of physostigmine was observed. The acetylcholinesterase activity in erythrocytes, cerebrum and diaphragm of surviving mice 20 hours after organophosphate intoxication was similar both in toxogonin and P2S treated animals and untreated animals.

Animals↗
PubMed2001

The use of carbamates, atropine, and 2-pyridine aldoxime methoiodide in the protection of Artemia salina against poisoning by carbophenothion.

The acute toxicity of carbophenothion to three age classes of Artemia salina was evaluated. An increase in toxicity of carbophenothion was found following longer development of A. salina. The effect of pretreatment with the nonselective muscarinic antagonist atropine, the two reversible acetylcholinesterase-inhibitors physostigmine and pyridostigmine, and the cholinesterase-reactivating oxime 2-pyridine aldoxime methochloride (2-PAM) on carbophenothion-induced lethality in 24-h-old A. salina was also investigated. The lethal action of carbophenothion was completely prevented by pretreatment of A. salina with 2-PAM. Atropine and pyridostigmine afforded a maximal protection of approximately 87% and 72%, respectively, compared to control values. In contrast, physostigmine was ineffective. The inhibitory effects of combinations of 10(-5) M atropine with physostigmine, pyridostigmine, or 2-PAM were greater than those elicited by either drug alone, with the maximum protection afforded being 92.58%, 100%, and 100%, respectively. In the presence of 10(-7) M atropine, neither pyridostigmine nor 2-PAM provided additional inhibition of the lethality compared to that with either drug alone, whereas the protection afforded by 10(-7) M atropine plus physostigmine increased as the concentration of carbamate increased (up to 10(-3) M). Pretreatment with pyridostigmine or physostigmine plus 2-PAM (10(-6) M) slightly enhanced the maximal inhibition of carbophenothion lethality compared to that with either drug alone. It is suggested that the most active combined pretreatment studied here was physostigmine plus atropine.

Animals↗
PubMed2005

Effectivity of new acetylcholinesterase reactivators in treatment of cyclosarin poisoning in mice and rats.

The present study was performed to assess and compare a therapeutic efficacy of obidoxime, HI-6, BI-6 and HS-6 administered in equimolar doses and combined with atropine in cyclosarin-poisoned mice and rats. It was demonstrated that all the therapeutic regimens tested, were able to decrease the cyclosarin-induced toxicity significantly - at least 1.5 times. Higher therapeutic ratios, almost three times, were achieved in rats in comparison with mice. The highest therapeutic ratio was achieved for therapeutic regimen consisting of HI-6 and atropine in both mice and rats. Obidoxime was the least effective oxime in the treatment of cyclosarin intoxication. The BI-6 oxime was significantly more efficacious than obidoxime (in both mice and rats) and HS-6 (in rats) but its effectiveness did not reach the efficacy of HI-6.

Animals↗
PubMed1987

Protective effects of oximes HI-6 and PAM-2 applied by osmotic minipumps in quinalphos-poisoned rats.

Protective and reactivating effects of oximes HI-6 and PAM-2, combined with atropine and diazepam, were investigated in quinalphos-poisoned rats. In protective experiments, atropine and diazepam decreased acute toxicity of the insecticide 3.3 times. Later administration of a single injection of oximes led to further improvement of protective indexes which were 1.45 (PAM-2) and 1.52 (HI-6) times larger. Plasma HI-6 concentrations below 1 microgram/ml, continuously maintained by osmotic minipumps and supported by a single administration of atropine and diazepam, protected animals from 18.6 LD50 of quinalphos, while its higher concentrations (ranging from 1 to 5.4 micrograms/ml) provided markedly better protection (up to 72 LD50). Corresponding plasma PAM-2 concentrations were even more effective in overcoming toxic effects of quinalphos. PAM-2 concentrations, continuously maintained in plasma, were distinctly better in protecting and reactivating peripheral cholinesterase activity than corresponding HI-6 concentrations in the case of quinalphos poisoning. On the basis of our findings we suggest that continuous maintenance of low oxime concentrations is preferred to single oxime administration in the therapy of organophosphate intoxications.

Animals↗