Efficacy of antidotal treatment against sarin poisoning: the superiority of benactyzine and caramiphen.

Sarin, a potent cholinesterase inhibitor, induces an array of toxic effects including convulsions and behavioral impairments. We report here on the protection provided by post-exposure antidotal treatments against a lethal dose of sarin (1.2xLD50) by scopolamine, benactyzine, trihexyphenidyl or caramiphen, administered 5, 10 or 20 min after the initiation of convulsions. A mixture of the oxime TMB4 and atropine (TA) was injected 1 min following poisoning a paradigm that may represent a scenario reminiscent of a terror incident. Surviving TA-treated rats exhibited marked tonic-clonic convulsions, weight loss, poor clinical status and abnormal cognitive performance as assessed by the Morris water maze. Additionally, a dramatic increase in the density of peripheral benzodiazepine receptors (PBRs), a faithful marker for neuronal damage, was noted. Animals treated 5 min after the development of toxic signs with benactyzine, trihexyphenidyl or caramiphen demonstrated control levels of PBR values, whereas scopolamine produced binding densities significantly above basal levels. Examined at the 10-min time point, scopolamine and trihexyphenidyl afforded no protection against brain damage and did not differ from TA-injected rats. All four drugs failed to significantly prevent the alterations when applied 20 min after onset of convulsions. Assessment of learning processes yielded similar results, where caramiphen exibited some protection at the 20-min time point. Our results show that caramiphen and benactyzine, agents with combined anticholinergic and antiglutamatergic pharmacological profiles, offer considerable shielding against sarin, even when their administration is delayed.

Therapeutic and neuroprotective efficacy of pharmacological pretreatment and antidotal treatment of acute tabun or soman poisoning with the emphasis on pretreatment drug PANPAL.

A good knowledge of the basic mechanisms of acute toxicity of organophosphorus compounds has lead to the development of specific antidotes able to counteract their acute toxic effects. Unfortunately, there are still some highly toxic organophosphorus compounds, called nerve agents, that are resistant to standard antidotal treatment. Relatively unsatisfactory antidotal treatment of acute poisonings with some nerve agents has prompted studies of pretreatment possibilities that would increase the resistance of organisms exposed to nerve agents. Current protection against nerve agent poisoning is pyridostigmine, but its prophylactic efficacy is rather limited. To increase the effectiveness of pharmacological pretreatment of soman or tabun poisoning, a prophylactic mixture called PANPAL and consisting of pyridostigmine and two anticholinergic drugs - benactyzine and trihexyphenidyle was developed, produced and introduced into the Czech Army to protect soldiers against nerve agent exposure. This review describes the evaluation of the potency of PANPAL to counteract acute soman or tabun poisoning and to increase the therapeutic and neuroprotective efficacy of current post-exposure antidotal treatment in comparison with pyridostigmine given alone as pretreatment.

Acute experimental tabun-induced intoxication and its therapy in rats.

Pharmacological pretreatment and antidotal treatment on tabun-induced neurotoxicity were studied in male albino rats that were poisoned with a lethal dose of tabun (280 microg/kg i.m.; 100% of LD50 value) and observed at 24 hours and 7 days following tabun challenge. The neurotoxicity of tabun was evaluated using a Functional observational battery and an automatic measurement of motor activity. Pharmacological pretreatment as well as antidotal treatment were able to reverse most of tabun-induced neurotoxic signs observed at 24 hours following tabun poisoning. However, there was not significant difference between the efficacy of profylaxis and antidotal treatment to eliminate tabun-induced neurotoxicity. The combination of profylactic pretreatment and antidotal treatment seems to be slightly more effective in the elimination of tabun-induced neurotoxicity in rats at 24 hours following tabun challenge in comparison with the administration of profylactic pretreatment or antidotal treatment alone. At 7 days following tabun poisoning, very few neurotoxic signs in tabun-poisoned rats were observed regardless of administration of pharmacological pretreatment or antidotal treatment. Thus, our findings confirm that the combination of pharmacological pretreatment and antidotal treatment is not only able to protect the experimental animals from the lethal effects of tabun but also to eliminate most of tabun-induced signs of neurotoxicity in tabun-poisoned rats.

Therapeutic efficacy of different antidotal mixtures against poisoning with GF-agent in mice.

The toxicity of cyclohexyl methylphosphonofluoridate (GF-agent; cyclosarin) and therapeutic efficacy of four oximes (trimedoxime, methoxime, obidoxime and HI-6) in combination with atropine or benactyzine (BNZ) was studied in mice. The oxime therapy combined with anticholinergic drug was administered intramusculary (i.m.) 1 or 2 min after i.m. GF-agent challenge. All the drugs were applied in dose of 20% of LD50. Obidoxime and trimedoxime that were combined with atropine were less effective than methoxime and HI-6 in combination with BNZ when applied 2 minutes after GF-agent poisoning. When the drugs were administered 1 min after GF-agent challenge already, in case of methoxime, the faster application of therapy resulted in significantly higher protective ratio, while for obidoxime the therapeutic effectivity did not depend significantly on the seasonableness of therapeutic intervention. The present findings show that all four combinations of oxime with anticholinergic drug decrease the GF-agent toxicity more than twofold regardless of the time of treatment administration.

Neuroprotective efficacy of pharmacological pretreatment and antidotal treatment in tabun-poisoned rats.

To study the influence of pharmacological pretreatment (PANPAL) and antidotal treatment (obidoxime plus atropine) on tabun-induced neurotoxicity, male albino rats were poisoned with a lethal dose of tabun (280 microg/kg i.m.; 100% of LD(50) value) and observed at 24 h and 7 days following tabun challenge. The neurotoxicity of tabun was evaluated using a functional observational battery (FOB) and an automatic measurement of motor activity. Pharmacological pretreatment as well as antidotal treatment were able to eliminate most of tabun-induced neurotoxic effects observed at 24 h following tabun poisoning. However, there was not significant difference between the efficacy of PANPAL and antidotal treatment to eliminate tabun-induced neurotoxicity in rats. The combination of PANPAL pretreatment and antidotal treatment seems to be slightly more effective in the elimination of tabun-induced neurotoxicity in rats at 24 h following tabun challenge in comparison with the administration of PANPAL pretreatment or antidotal treatment alone. At 7 days following tabun poisoning, very few neurotoxic signs in tabun-poisoned rats were observed regardless of administration of pharmacological pretreatment or antidotal treatment. Thus, our findings confirm that the combination of pharmacological pretreatment and antidotal treatment is not only able to protect the experimental animals from the lethal effects of tabun but also to eliminate most of tabun-induced signs of neurotoxicity in tabun-poisoned rats.

A comparison of the efficacy of new monopyridinium oximes with the oxime HI-6 against mevinphos in mice.

1. The therapeutic efficacy of three new monopyridinium oximes (2,4-PAEtM, 2,5-PAEtM, 2,5-PAAM) and the bispyridinium oxime HI-6 was evaluated in combination with benactyzine against acute poisoning with the organophosphorus insecticide mevinphos in mice. 2. When mice were treated two min after mevinphos poisoning, no significant differences in the therapeutic effectiveness of tested oximes were observed. They increased the 24h LD50 values of mevinphos about three times in comparison with non-treated intoxicated animals. 3. On the other hand, there were significant differences in their therapeutic efficacy when they were administered 30 sec following mevinphos challenge. The monopyridinium oxime 2,5-PAEtM seems to be the most efficacious against mevinphos toxicity. 4. Use of new monopyridinium oxime 2,5-PAEtM appears to be the improvement in the antidotal treatment of poisoning with organophosphorus insecticide mevinphos in comparison with HI-6.

Effect of Panpal pretreatment and antidotal treatment (HI-6 plus benactyzine) on respiratory and circulatory function in soman-poisoned rats.

1 The effect of pharmacological pretreatment (pyridostigmine, benactyzine and trihexyphenidyle), designated Panpal, and antidotal treatment (the oxime HI-6 plus benactyzine) in soman poisoning was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. 2 Soman poisoning caused a high decrease in respiratory rate as well as minute respiratory volume and an increase in mean arterial pressure from 30-120 min following soman challenge. Soman at sublethal dose also significantly inhibited acetylcholinesterase activity in diaphragm and various brain parts. 3 Panpal pretreatment as well as antidotal treatment were effective in improving the respiratory and circulatory function disturbed by soman without the ability to increase significantly soman-inhibited acetylcholinesterase activity in all brain parts studied. 4 The efficacy of combined Panpal pretreatment and antidotal treatment against sublethal soman poisoning was not different from the efficacy of Panpal pretreatment or antidotal treatment alone. 5 The results of this investigation suggest that Panpal pretreatment as well as antidotal treatment are able to restore respiratory and circulatory function in soman-poisoned rats without significant reactivation of brain acetylcholinesterase.

The influence of pharmacological pretreatment on efficacy of HI-6 oxime in combination with benactyzine in soman poisoning in rats.

1. The influence of pharmacological pretreatment (pyridostigmine, benactyzine and trihexyphenidyle), designated PANPAL, on soman-induced cholinergic and stressogenic effects as well as on the efficacy of antidotal treatment (HI-6 plus obidoxime) in rats was studied. 2. PANPAL prophylaxis significantly decreased soman-induced cholinesterase inhibition in blood, brain and diaphragm as well as stressogenic effects of soman (an increase in plasma corticosterone level and liver tyrosine aminotransferase activity). 3. PANPAL pretreatment did not improve the efficacy of HI-6 in combination with benactyzine on soman-induced anticholinesterase and stressogenic effects. 4. These findings confirm that PANPAL prophylaxis can improve prognosis of soman poisoning especially by protection of cholinesterases.

[Comparison of the effect of HI-6 oxime and its derivatives in combination with benactyzine on cholinergic and stress effects of soman in rats]. / Srovnání vlivu oximu HI-6 a jeho derivátu v kombinaci s benaktyzinem na cholinergní a stresogenní ucinky somanu u potkana.

In male rat experiments, the therapeutic effect of oxime HI-6 and its derivatives (HI-6 ester and amide) in combination with benactyzine on the cholinergic and stressogenic effects of a sublethal dose of soman was compared. Cholinergic effects were investigated by monitoring the changes in the activity of cholinesterases in the whole blood, brain and diaphragm, stressogenic effects by monitoring the changes in the level of corticosterone in the plasma and the activity of tyrosine aminotransferase in the liver. The monitoring of the changes in the selected parameters of cholinergic and stressogenic effects of soman has demonstrated that neither of the derivatives of oxime HI-6 under study achieves its therapeutic effect and thus seems to be a suitable substitute of oxime HI-6 for the therapy of acute intoxications with the organophosphate soman, which are difficult to treat.

[Biological age, adrenoreception and lipid peroxidation in patients with ischemic heart disease]. / Biologicheskii vozrast, adrenoretseptsiia i perekisnoe okislenie lipidov u bol'nykh ishemicheskoi bolezn'iu serdtsa.

The article deals with electro-kinetic potential of cellular nucleus considered as an indicator of unspecific reactivity and presents some data on molecular and cellular mechanisms of adreno- and muscarino-receptive interactions, such as adrenalin, noradrenaline and DOPA blood levels, lipid peroxidation, erythrocyte resistance to peroxidation. The attempt is made to comprehend directions and trends of aforementioned processes in patients with stable and unstable stenocardia as well as in myocardial infarction with regard to sex and influence of central M-cholinoblockader amizyl. The drug provides adaptive effect, corrects affected adreno-reception, protects biomembranes from lesion, promotes their "fluidity" and reduces rigidity.

[The possible role of presynaptic effects in realizing the protective action of M-cholinolytics in dimethyl dichlorovinyl phosphate poisoning]. / Vozmozhnaia rol' presinapticheskikh éffektov v osushchestvlenii zashchitnogo deistviia M-kholinolitikov pri otravlenii dimetildikhlorvinilfosfatom.

Under the conditions of the constancy of the postsynaptic effect of two M-cholinolytics atropine and amizil the relationship between the presynaptic and protective effects of the drugs in DDVF intoxication was studied. The indication of the level of the postsynaptic activity was the suppression by the cholinolytics of tremor reaction in rats induced by the action of arecoline. The presynaptic effect of the drugs was judged by the charge of the "bound" acetylcholine content in the brains of the animals. It was found that when administered in the equieffective by the choline-blocking activity doses, atropine to a greater extent reduced the content of the "bound" acetylcholine which was increased due to the action of DDVF and at the same time it possessed the less pronounced protective activity in intoxication with DDVF than amizil. It is supposed that the removal of the presynaptic suppression of acetylcholine release due to the anticholinesterase substance action deteriorates the prognosis of the course of DDVF intoxication.

Actions and interactions of cholinolytics and cholinesterase reactivators in the treatment of acute organophosphorus toxicity.

Different drug combinations consisting of cholinolytic and a cholinesterase (ChE) reactivator provide greater therapeutic efficacy in acute organophosphorus (OP) poisoning in mice than when used alone. Maximum protection, as determined by a shift of the LD50 for the two OP agents, was observed with the cholinolytic benactyzine. A protection index (P.I.) of 42 was obtained when benactyzine was given along with obidoxime in diisopropylphosphorofluoridate (DFP) intoxication. With the more toxic OP agent soman (o-pinacolylmethylphosphonofluoridate), the same cholinolytic only offered a maximum P.I. of 3.2 when administered with HS-6, another bispyridinium ChE reactivator. This beneficial effect of benactyzine is possibly due to its greater antimuscarinic effect in the central nervous system than atropine or dexetimide.

[Experience with amysil treatment of patients with vascular parkinsonism]. / Opyt lecheniia amizilom bo'lnykh sosudistym parkinsonizmom.

The results of treatment of 45 patients with vascular parkinsonism are reported. To the majority of the patients, daily amysil administration (1-2 mg 2-4 times a day) was prescribed. Most pronounced was the drug effect in patients with combined syndromes in which predominated bradikynesia (79.3%), rigidity (75%), and to a lesser extent, tremor (66.6%). In some patients, the sedative effect was evident. In most of the patients, the positive EMG changes were noticeable, especially in those with stage I of the disease.

[Duration of the antihypothermic action of the antidepressant ftoratsizin in galanthamine-induced hypothermia]. / O dlitel'nosti antigipotermicheskogo deistviia antidepressanta ftoratsizina pri gipotermii, vyzvannoi galantaminom.

The presence of m-anticholinergic properties in ftoratsizin was confirmed in experiments of rats. Ftoratsizin was found to possess the ability of preventing galanthamine-induced hypothermia. Unlike ftoratsizin, amizil exhibited an incomplete and transient antagonistic effect towards galanthamine (within an hour) not depending on the dose.

[Effect of neuroleptic, adreno- and cholinolytic agents on cerebral cortical function in edema]. / Vliianie neirolepticheskikh, adreno- i kholinoliticheskikh sredstv na funktsional'noe sostoianie kory mozga pri ego oteke.

Experiments on rats with experimental brain edema under water intoxication were made to study the effects of the neuroleptics aminazine and propazine, the central M-cholinoblocker amizyl and the alpha-adrenoblocker phentolamine on the time-course of the recovery of cortical electric activity after passing of the wave of Leao's spreading depression (SD). The drugs under study were demonstrated to have antiedematous properties under water intoxication and to make to a considerable degree for disorders in the processes of the recovery of cortical electrogenesis after SD. It is assumed that the action of the drugs on the electrophysiological parameters under study is associated with their effects on metabolic processes and with the presence of antiedematous properties.

[The GABA-ergic system and brain edema]. / GAMK-ergicheskaia sistema i otek golovnogo mozga.

It has been shown in rats with experimental toxic and traumatic edemas that picrotoxin (1 mg/kg) removes the antiedematous action of diazepam, phenazepam, phenibut and amizyl and reduces the action of phentolamine. When the dose of picrotoxin is minimized to 0.5 mg/kg such an effect is not observed. Prolonged daily administration of picrotoxin in a dose of 1 mg/kg results in the development of brain edema. It is recommended that GABA-positive drugs be included into a complex of treatment measures for edema.

Efficacy and toxicity of drug combinations in treatment of physostigmine toxicosis.

Atropine, in combination with 1 of 6 other drugs, was tested in mice for the ability to prevent death by an otherwise lethal dose of the cholinesterase inhibitor, physostigmine. The atropine dose (4 mg/kg, i.p.) was kept constant, while the dose of the other drug in the pair was tested in 5 geometrically spaced doses, ranging down to 1/16 of the maximum dose (which caused no gross behavioral signs). Atropine alone saved 20% of the mice. The combination of atropine and benactyzine saved 100% of the mice at all 5 doses of benactyzine; similar complete protection was afforded by the combination of atropine and the largest dose of an oxime, TMB4 (15 mg/kg). Over 80% survivals were achieved with the larger doses of atropine combinations involving hexamethonium, mecamylamine, and diazepam. No enhanced protection occurred with atropine combinations with the oxime, 2-PAM. The toxicity of the effective combinations, when used in high doses without physostigmine challenge, revealed that deaths occurred over a narrow range of doses of all combinations except atropine/diazepam. An additive toxic effect of atropine was suggested with its combinations with TMB4, mecamylamine, and diazepam, whereas no additive toxicity occurred with combinations involving hexamethonium or benactyzine (i.e., the LD50 of the combinations was about the same as for hexamethonium or benzactyzine alone). The combinations with the best therapeutic safety ratio were with diazepam (no deaths at a dose 10 times that which saved 100% of mice) and benactyzine (no deaths at a more than 50-fold dose).

[Effect of N- and M- cholinoblockaders on experimental epileptogenesis]. / Vliianie N- i M-kholinoblokatorov na éksperimental'nyi épileptogenez.

It has been shown in chronic experiments on rabbits with epileptogenic foci provoked by microinjections of penicillin into the dorsal hippocamp that the N-cholinoblockers gangleron (3 mg/k, intravenously) and etherophen (5-10mg/kg, intravenously) possess marked anticonvulsant activity. Diphenin (50 mg/kg, intraperitoneally) was less potent. The M-cholinoblocker methamizil (1 mg/kg, intravenously), on the contrary, potentiated the epileptiform seizures. Emphasis is laid on the necessity of the goal-oriented synthesis and search for agents that would exhibit a "purely" central N-cholinoblocking action with a purpose of applying such agents as antiepileptic drugs. It is not recommended using the M-cholinoblockers for such purposes.