Repetitive antidotal treatment is crucial in eliminating eye pathology, respiratory toxicity and death following whole-body VX vapor exposure in freely moving rats.

Exposure to the chemical warfare nerve agent VX is extremely toxic, causing severe cholinergic symptoms. If not appropriately treated, death ultimately ensues. Based on our previously described whole-body vapor exposure system, we characterized in detail the clinical outcome, including respiratory dynamics, typical of whole-body exposure to lethal doses of VX vapor in freely moving rats. We further evaluated the efficacy of two different antidotal regimens, one comprising a single and the other repeated administration of antidotes, in countering the toxic effects of the exposure. We show that a 15 min exposure to air VX concentrations of 2.34-2.42 mg/m3 induced a late (15-30 min) onset of obvious cholinergic signs, which exacerbated over time, albeit without convulsions. Marked eye pathology was observed, characterized by pupil constriction to pinpoint, excessive lacrimation with red tears (chromodacryorrhea) and corneal damage. Respiratory distress was also evident, characterized by a three-fourfold increase in Penh values, an estimate of lung resistance, and by lung and diaphragm histological damage. A single administration of TAB (the oxime TMB-4, atropine and the anticholinergic and antiglutamatergic benactyzine) at the onset of clinical signs afforded only limited protection (66% survival), with clinical deterioration including weight loss, chromodacryorrhea, corneal damage, increased airway resistance and late death. In contrast, a combined therapy of TAB at the onset of clinical signs and repeated administration of atropine and toxogonin (ATOX) every 3-5 h, a maximum of five i.m. injections, led to 100% survival and a prompt recovery, accompanied by neither the above-described signs of eye pathology, nor by bronchoconstriction and respiratory distress. The necessity of recurrent treatments for successful elimination of VX vapor toxicity strongly supports continuous penetration of VX following termination of VX vapor exposure, most likely from a VX reservoir formed in the skin due to the exposure. This, combined with the above-described eye and respiratory pathology and absence of convulsions, are unique features of whole-body VX vapor exposure as compared to whole-body vapor exposure to other nerve agents, and should accordingly be considered when devising optimal countermeasures and medical protocols for treatment of VX vapor exposure.

[Tolerance of prostate biopsy with use of local anesthesia and benzodiazepines: a randomized, prospective study]. / Tolerancia a la biopsia prostática con el uso de anestesia local y benzodiacepinas: estudio prospectivo aleatorizado.

INTRODUCTION: Prostate biopsy is an uncomfortable procedure, and attempts are therefore being constantly made to try and decrease biopsy-related pain. MATERIALS AND METHODS: A randomized, prospective study including 160 procedures was designed. Inclusion criteria were: first biopsy, PSA < 15 ng/mL, and age under 75 years. Patients were randomized into 4 groups. Group A was the control group, while group B received intracapsular anesthesia (8 mL of 2% lidocaine), group C 5 mg of oral clorazepate dipotassium one hour before biopsy, and group D both local anesthesia and clorazepate. Each patient completed a questionnaire including three 10-point visual analog scales for pain immediately after the procedure and 30 minutes later. RESULTS: Mean pain scores were 5.17 (group A), 1.72 (group B), 2.43 (group C), and 0.88 (group D) in the first questionnaire, and 1.71, 0.25, 0.75 and 0.35 respectively in the second questionnaire. Statistically significant differences were found in the ANOVA test. Group comparisons showed the following: 1. A vs B: statistically significant differences in both questionnaires (p = 0.006 and 0.011). 2. A vs C: a significant difference was found in the first questionnaire (0.051), but not in the second (0.012). 3. A vs D: significant differences in both questionnaires (0.001 and 0.010). No statistically significant differences were seen in both questionnaires (0.825 and 0.685) when benzodiazepines where added to local anesthesia (B vs D). CONCLUSION: Use of benzodiazepines as a single method to decrease biopsy-related pain is not warranted.

A comparison of the neuroprotective efficacy of pharmacological pretreatment and antidotal treatment in soman-poisoned rats.

1. To study the influence of pharmacological pretreatment (PANPAL or pyridostigmine combined with biperiden) and antidotal treatment (the oxime HI-6 plus atropine) on soman-induced neurotoxicity, male albino rats were poisoned with a lethal dose of soman (54 (g/kg i.m.; 100% of LD50 value) and observed at 24 hours and 7 days following soman challenge. The neurotoxicity of soman was evaluated using a Functional observational battery and an automatic measurement of motor activity. 2. Pharmacological pretreatment as well as antidotal treatment were able to eliminate some of soman-induced neurotoxic effects observed at 24 hours following soman poisoning. The combination of pharmacological pretreatment (PANPAL or pyridostigmine combined with biperiden) and antidotal treatment was found to be more effective in the elimination of soman-induced neurotoxicity in rats at 24 hours following soman challenge in comparison with the administration of pharmacological pretreatment or antidotal treatment alone. To compare both pharmacological pretreatments, the combination of pyridostigmine with biperiden seems to be more efficacious to eliminate soman-induced signs of neurotoxicity than PANPAL. 3. At 7 days following soman poisoning, the combination of pharmacological pretreatment involving pyridostigmine and biperiden with antidotal treatment was only able to completely eliminate soman-induced neurotoxic signs. 4. Thus, our findings confirm that the combination of pharmacological pretreatment and antidotal treatment is able not only to protect the experimental animals from the lethal effects of soman but also to eliminate most soman-induced signs of neurotoxicity in poisoned rats. The pharmacological pretreatment containing pyridostigmine and biperiden appears to be more efficacious to eliminate soman-induced neurotoxic sings than PANPAL.

Effect of methoxime combined with anticholinergic, anticonvulsant or anti-HCN drugs in tabun-poisoned mice.

The effect of methoxime combined with a) atropine, b) benactyzine, c) atropine and natrium thiosulphate, d) atropine and diazepam on antidotal treatment effectiveness was studied in tabun-poisoned mice. In addition, the influence of pretreatment consisiting of pyridostigmine, benactyzine and trihexyphenidyle (PANPAL) administered 2 hours before tabun intoxication on the treatment effectivity of methoxime combined with e) atropine or f) benactyzine was tested. The most efficacious therapeutic mixture in non-pretreated mice was methoxime, atropine and diazepam. Natrium thiosulphate did not significantly increase neither decrease the antidotal treatment efficacy in comparison with methoxime and atropine alone. Pretreatment with PANPAL significantly decreased tabun toxicity (nearly 4 times in methoxime and benactyzine combination and more than 4 times in atropine and methoxime mixture). The present study demonstrates that the tabun toxicity in mice is more effectively reduced when PANPAL prophylactically is administered than in case of treatment with methoxime and cholinergic drug alone. We established that anticholinergic drug option in the therapeutic mixture of methoxime and anticholinergic drug did not cause the difference in the antidotal treatment effectivities.

[The effect of pharmacologic prophylaxis with Panpal on acetylcholinesterase activity in the diaphragm and various parts of the brain in rats during treated and untreated Soman poisoning]. / Vliv farmakologické profylaxe Panpalem na aktivitu acetylcholinesterázy v bránici a ruzných cástech mozku potkana v prubehu nelécené a lécené intoxikace somanem.

BACKGROUND: The pharmacological prophylaxis protecting the organism against organophosphorus compounds could increase the effect of antidotal treatment of poisoning with organophosphates. METHODS AND RESULTS: The influence of the pharmacological prophylaxis with Panpal (pyridostigmine in combination with benaetyzine and trihexyphenidyle) on acetylcholinesterase activity in diaphragm and various parts of brain at 1 and 3 h following non-treated and treated (the oxime HI-6 in combination with atropine) soman poisoning was tested on male rats. While Panpal did not significantly influence the acetylcholinesterase activity in brain following non-treated as well as treated soman poisoning. Panpal increased so many-induced acetylcholinesterase inhibition following non-treated poisoning and decreased the reactivating effect of the oxime HI-6 following treated soman poisoning in diaphragm. CONCLUSIONS: Our data confirm the importance of the combination of reversible acetylcholinesterase inhibitor pyridostigmine with anticholinergic drugs in the pharmacological prophylaxis of soman poisoning because of the elimination of consequences of pyridostigmine-induced increasing in acetylcholinesterase inhibition in the peripheral compartment.

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.

Evaluation of combined toxic effects of GB/GF and efficacy of jielin injection against combined poisoning in mice.

A computer program (Q-test) was used to evaluate the combined toxic effects of nerve agent GF and its combined form with sarin (GB/GF) in mice. Efficacy of Jielin Injection, the 2-PAM-containing antidote used successfully in China for the treatment of organophosphate pesticide poisoning, was also evaluated and compared with HI-6 against single and combined poisonings. The two agents were basically additive in toxicity when combined. However, toxic signs (convulsions) appeared later in combined poisoning than after exposure to each agent alone. The protective ratio of Jielin Injection against GF poisoning was low but significantly higher when against poisoning by GB or combined agent. When HI-6 was substituted for 2-PAM, the antidote was more effective against poisoning by both single and combined agents. Results of in vitro reactivation of GF-inhibited human erythrocyte acetylcholinesterase by these oximes agreed with the in vivo antidotal efficacy.

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.

[Correction of apathetic-abulic manifestations of schizophrenia with cholinotropic drugs]. / Korrektsiia apatoabulicheskikh proiavlenii protsessual'nogo defekta kholinotropnymi preparatami.

The authors describe the results of the treatment of 30 patients suffering from schizophrenia with the well-defined apatho-abulic manifestations. The patients received anticholin-esterase agents (galanthamine and deoxypeganin) combined with the M-cholinolytic drug benactyzine. The treatment lasted 3 to 4 weeks. Satisfactory compensation for the deficiency manifestations was attained in 18 patients (60%). The therapeutic dynamics appeared the best in patients with predominant anergic disorders accompanied by well-defined impoverishment of motor functions. The presence of roductive psychotic disorders in the syndromal structure noticeably decreased the treatment efficacy. The deranged capacity for behavioral initiation classified by the authors with the fundamental deficiency manifestations turned out most refractory to the treatment. The polymediator model of the schizophrenic defect is reviewed, according to which the deficiency manifestations represent adaptive stability states with emergence to a lower energy level. In such a case the neuronal populations with different mediator modality become deactivated. On the one hand, this gives rise to a decrease of psychotic productive disorders, on the other one, to the occurrence of the negative manifestations.

[Effect of amizil and the ACTH4-10 fragment on the ability of mice to extrapolate the direction of movement]. / Vliianie amizila i fragmenta AKTG4-10 na sposobnost' myshei k ékstrapoliatsii napravleniia dvizheniia.

Mice possessing the ability to extrapolate the direction of movement (100% of correct choices) were injected i.p. with different doses of m-cholinolytic amizil 2 hours before experiment. Doses of 2-5 mg/kg reduced the percentage of correct choices, the adequate solving strategy being replaced by stereotyped unidirectional reactions or stereotyped alternating responses. Doses of 8-12 mg/kg induced "refusals" to solve extrapolation problem. When amizil treated mice were intraventricularly injected with 1 mg/kg of ACTH4-10, their extrapolation ability was restored. This compensatory action of peptide could be mediated by its influence on cholinergic as well as on other neurotransmitter systems.

[Effect of an estrogen-progestin preparation alone and in combination with amizil on the structure and electrophoretic parameters of oocytes and early rat embryos]. / Vliianie estrogen-progestinovogo preparata i ego kombinatsii s amizilom na strukturu i élektrofiziologicheskie parametry ootsitov i rannikh émbrionov krys.

An increasing contraceptive effect at a combined administration of steroid drugs with neurotropic substances--M-cholinolytic benactyzine, makes the problem on the character and mechanism of their action. In the experiments performed in rats, under effect of ethinyl estradiol and norethisteron acetate, and especially at their combination with benactyzine, the first signs of overmaturation are revealed in oocytes situating in the follicular cavity. Therefore, oocytes revealed in the rat fallopian tubes leave behind the development of the control oocytes. The drugs investigated, influencing maturation and ovulation mechanisms of oocytes, produce certain physiological and morphological changes in ovaries of the test rats. This, evidently, defines the mechanism of their elevated contraceptive action. Overmaturation of oocytes in follicles, ovulation at later developmental stages results in increasing amount of degenerative forms of embryos and in disturbance of their development.

[Method of treating parkinsonism with metamizil in combination with galanthamine (clinico-experimental basis)]. / Sposob lecheniia parkinsonizma metamizilom v sochetanii s galantaminom (kliniko-eksperimental'noe obosnovanie).

Using experimental models of parkinsonism, imitating the hypertonus of the parasympathetic system (hypokinesia, rigidity and tremor) following the intraperitoneal injection of the acetylcholinesterase inhibitor galanthamin (15 mg/kg) to mice, the authors showed that the m-cholinoblocker metamisyl (2 mg/kg) blocks all manifestations of the CNS parasympathetic hypertonus whereas the n-cholinoblocker eterofen (30 mg/kg) increases them. Based on the theory developed by the authors as to the reciprocity of interaction between the m- and n-cholinergic mechanisms within the framework of the single cholinergic system of the body, they offered the treatment of parkinsonism by the combined use of metamisyl (1-2 mg) and galanthamin (5-10 mg). Forty-five patients were treated with metamisyl alone and 40 patients with metamisyl coupled with galanthamin. The latter method of treatment proved to be more effective. The patients responded to the treatment immediately. It lasted 2-4 weeks. The follow-up showed that in some patients, the effect of the treatment stabilized and persisted for 4 weeks to 12 months without the use of the antiparkinsonian drugs. The authors emphasize that in cases of parkinsonism it is necessary to study and take into account the nature of changes in both intersystemic mediator interaction (between ACh and NA, ACh and D, ACh and 5-HT, etc.) and the intrasystemic one (between m- and n-cholino, alpha- and beta-adreno, D1 and D2, 5-HT1 and 5-HT2-ergic mechanisms).

[Neurochemical mechanisms of the effect of ACTH on aggressive-defensive behavior in rats]. / Neirokhimicheskie mekhanizmy vliianiia AKTG na agressivno-oboronitel'noe povedenie krys.

It was found that ACTH increased fear and aggressive-defensive behavior in pairs of male rats in response to electrical stimulation. The parameters were the threshold values of squeak reactions, risings and fights, the frequency of fights and the duration of standing in a posture of threat. The ACTH influence was similar to the M-cholinomimetic effect. It increased against the background of M-cholinoreceptors' excitation but did not change in essential under the action of H-cholinoreceptors. An assumption has been made of the extraadrenal action of ACTH on affective aggression. The mechanism of the effect involves facilitation of excitation of the central M-cholinoreceptors.

[Certain biochemical and behavioral effects of morphine in rats following amyzil administration]. / Nekotorye biokhimicheskie i povedencheskie éffekty morfina na fone amizila u krys.

Motional excitement (ME), dopamine (DA) and homovanillic acid (HVA) content in the caudate nucleus of rats who were injected with morphine in doses of 2 and 10 mg/kg intraperitoneally after amyzil (40 mg/kg) given via the same route were studied to clarify the character of the action of narcotic analgetics on animals' behavior and DAN metabolism under conditions of imbalance between the cholinergic and dopaminergic neuromediator systems of the striatum, induced by central cholinolytics. Amyzil injection was shown to lower HVA level with no changes in DA content (the mediator turnover rate seems to decrease) and to start ME. Under these conditions morphine, in the presence of the induced imbalance of the mediator systems, exhibits a correcting action, elevating HVA level and apparently speeding DA turnover. The biochemical shifts described are accompanied by ME abolition. Possible mechanisms of the action of narcotic analgetics on dopaminergic mediation in the striatum are discussed.

[Central choline-potentiating effect of amizil]. / O tsentral'nom kholinopotentsiruiushchem deistvii amizila.

The effect of the central anticholinergic agent benactizin on cholinoreactivity of rats was evaluated by determination of ED50 of arecolin. ED50 of arecoline rose with increase in the dose of benactizin from 1 to 40 mg/kg. In a dose of 0.2 mg/kg benactizin elicited a pronounced statistically significant cholinopotentiating action that lasted about 5 hours. In a dose of 1 mg/kg the drug exerted an anticholinergic effect followed by cholinopotentiating action.