hs-6 and asoxime-chloride

The oximes 4-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HI-6) and 3-carbamoyl-1-[({2-[(E)-(hydroxyimino) methyl] pyridinium-1-yl} methoxy) methyl] pyridinium (known as HS-6) are isomers differing from each other only by the position of the carbamoyl group on the pyridine ring. However, this slight difference was verified to be responsible for big differences in the percentual of reactivation of acetylcholinesterase (AChE) inhibited by the nerve agents tabun, sarin, cyclosarin, and VX. In order to try to find out the reason for this, a computational study involving molecular docking, molecular dynamics, and binding energies calculations, was performed on the binding modes of HI-6 and HS-6 on human AChE (HssAChE) inhibited by those nerve agents.

Topics: Acetylcholinesterase; Chemical Warfare Agents; Cholinesterase Inhibitors; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Nerve Agents; Organophosphates; Organophosphorus Compounds; Organothiophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Sarin

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.

Topics: Animals; Antidotes; Behavior, Animal; Chemical Warfare Agents; Injections, Intramuscular; Male; Molecular Structure; Neurotoxicity Syndromes; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Wistar

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.

Topics: Animals; Cholinesterase Reactivators; Female; Mice; Obidoxime Chloride; Organophosphate Poisoning; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats

Topics: Acetylcholinesterase; Animals; Brain; Carbamates; Cattle; Erythrocytes; Humans; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rabbits; Trimedoxime

1 The ability of various bis-pyridinium oximes to restore organophosphate-inhibited neuromuscular transmission in vitro was compared in human intercostal and marmoset diaphragm muscles. 2 HI-6 (2-hydroxyiminomethyl-pyridinium-1-methyl-4'-carbamoyl-pyridinium-1'-methyl ether dichloride monohydrate) appeared very effective against VX (O-ethyl S-2-diisopropylaminoethyl methylphosphonothioate) and sarin in both muscles, whereas obidoxim was quite effective against tabun. 3 Against soman, HI-6, HS-6 (2-hydroxyiminomethyl-pyridinium-1-methyl-3'-carbamoyl-pyridinium-1'-methyl ether dichloride dihydrate) and obidoxim had little effect in the human muscle and only slight activity in the marmoset muscle; HGG-12 (2-hydroxyiminomethyl-pyridinium-1-methyl-3'-phenylcarbonyl-pyridinium-1'-methy l ether dichloride) and benzyl-P2A (1-benzyl-2-hydroxyiminomethyl-pyridinium methanesulphonate) were ineffective. 4 Anaesthetized, atropinized marmosets were poisoned with soman (4 X LD50, i.v.) and subsequently treated with HI-6, HS-6 or HGG-12. Only HI-6 and HS-6 were marginally effective in restoring respiration and neuromuscular transmission. 5 Marmoset muscle is a reasonable model for human muscle for the study of organophosphate poisoning and therapy.

Topics: Animals; Antidotes; Callithrix; Cardiovascular System; Humans; In Vitro Techniques; Insecticides; Models, Biological; Neuromuscular Junction; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Soman; Synaptic Transmission

HI-6 and TMB-4 were the most effective and safe of 7 cholinesterase reactivators tested as agents for the prophylaxis of proserine poisoning of male mice. The reactivator HI-6 strongly potentiated the prophylactic efficacy of a mixture of atropine and arpenal administered in the doses sufficient for the blockade of both the m- and h-cholinoreactive systems of mice. As demonstrated by experiments in vitro, HI-6 and TMB-4 did not reacivate proserine-inhibited cholinesterase. The natural anticholinesterase activity of HI-6 was negligible. Based on the correlation of the data obtained to the reported data indicating that HI-6 has a low ganglioblocking activity it is inferred that the direct effect on the receptor is of no importance for the potentiating effect. It is assumed that HI-6 modulates the cholinoreactive systems, which leads to a dramatic increase of the efficacy of cholinolytics.

Topics: Animals; Antidotes; Atropine; Butanones; Cholinesterase Reactivators; Diphenylacetic Acids; Drug Synergism; Male; Mice; Neostigmine; Obidoxime Chloride; Oximes; Parasympatholytics; Pralidoxime Compounds; Pyridinium Compounds; Trimedoxime

Topics: Animals; Antidotes; Carboxylic Ester Hydrolases; Cholinesterases; Male; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Inbred Strains; Soman; Tritolyl Phosphates

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Brain; Cholinesterases; Male; Mice; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Soman; Structure-Activity Relationship

Previous results had shown that bis-pyridinium oximes, particularly HI-6 are quite effective therapeutically in soman-poisoned rats and mice in vivo and in the rat diaphragm preparation in vitro. The aim of the present study was to investigate the efficacy of bis-pyridinium oximes on soman-inhibited neuromuscular transmission in muscle preparations from several species including man. The muscles tested were preparations of rat diaphragm and intercostal muscle, guinea-pig diaphragm, dog external intercostal muscle and human external interscotal muscle. These muscles were stimulated indirectly with field stimulation. With a few exceptions the preparations were exposed to soman for 2.5 or 15 min. In some cases different exposure times were employed or the organophosphate sarin was administered instead of its analogue soman. After the degree of inhibition of neuromuscular transmission had been established, oximes were added to the bath fluid. After washout 15 min later, recovery of neuromuscular transmission was tested. Subsequently, a second dose of soman was administered to investigate whether the recovery observed had been caused by cholinesterase reactivation. The results of these experiments indicate that the oximes tested, mostly HI-6, were quite effective as soman antidotes in muscle preparations of rats, guinea-pigs and dogs. In the human preparation while these oximes were quite effective after sarin intoxication they were essentially without effect against soman.

Topics: Adult; Aged; Animals; Antidotes; Chorionic Gonadotropin; Dogs; Electric Stimulation; Female; Guinea Pigs; Humans; In Vitro Techniques; Male; Middle Aged; Neuromuscular Junction; Organophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Sarin; Soman; Species Specificity; Synaptic Transmission

The bispyridinium oximes HS6 and HI6 were tested in vitro for their ability to restore neuromuscular function in soman-poisoned tissue, using diaphragm and intercostal muscle of the rat and guinea pig and intercostal muscle of man. It was found that the oxime-mediated recovery of function in both tissues of the rat and guinea pig was composed of direct oxime actions, AChE reactivation and adaptation. In the human intercostal muscle, however, only adaptation was observed. These findings might suggest that HS6 and HI6 may have only limited value in the treatment of soman poisoning in man. However, recovery of function in rodent tissues was consistently greater in the diaphragm than in the intercostal muscle and, since human diaphragm tissue was not included in this study the therapeutic efficacy of these oximes in this tissue remains unknown.

Topics: Aged; Animals; Diaphragm; Guinea Pigs; Humans; In Vitro Techniques; Intercostal Muscles; Male; Middle Aged; Neuromuscular Junction; Organ Specificity; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Soman; Species Specificity; Synaptic Transmission; Time Factors

Monkeys were exposed to varying doses of soman and given therapy. Therapy consisted of pyridostigmine, clonazepam, atropine and HS-6 or HI-6. Cerebral electrical activity, heart rate, respiration, systemic blood pressure and cholinesterase activity were recorded thoughtout the experiment. The animals in the HS-6 series were divided into 4 groups depending upon the dose of soman; one group received 30 microgram/kg of soman, the second group received 40 microgran/kg. All animals in the HI06 series survived while only one of three monkeys in the fourth group survived. Administration of therapy immediately suppressed all seizure activity and convulsions and the animals appeared awake throughout the experiment. All animals exhibited bradycardia and hypotension following the adminstration of therapy. The cholinesterase activity was depressed after administration of HS-6 therapy. Three of the four monkey that received therapy consisting of HI-6 at a dose of 15 mg/kg survived, while one of two that received HI-6 at a dose of 30 mg/kg survived. The animals that received HI-6 at a dose of 15 mg/kg did not exhibit as severe a decrease in blood pressure as the animals in either the HS-6 series or the monkeys that received HI-6 at 30 mg/kg. In addition, these monkeys were awake and appeared alert throughout the experiment and were up within 4-6 hr post-exposure to soman. The animals that received 30 mg/kg exhibited severe hypotension and did poorly.

Topics: Animals; Atropine; Cholinesterases; Clonazepam; Electroencephalography; Female; Heart Rate; Macaca mulatta; Male; Organophosphate Poisoning; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Pyridostigmine Bromide; Respiration; Soman