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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.

Prenatal administration of the n-cholinolytic ganglerone to pregnant female rats at different periods of gestation was found to lead to long-term changes in sexual behavior in pubescent offspring: there was a reduced dynamic of acquiring sexual experience and a very low level of sexual activity, with significant impairment to the motivational and ejaculatory components of sexual behavior. The number of males with reduced sexual activity in the experimental groups was significantly greater than that in control offspring. The results obtained here provide evidence that impairments of sexual function in adult offspring induced by prenatal administration of the n-cholinolytic ganglerone at 9-11 and 12-14 days of gestation and, to a lesser extent, the m-cholinolytic metamyzil at 9-11 days of gestation, were due to impairment to the central mechanisms regulating sexual function due to stable changes in neurotransmitter activity in the hippocampus and hypothalamus, along with a significant reduction in the blood testosterone level.

The data obtained have shown that prenatal exposure of pregnant rat females of 9-19-day pregnancy to N-cholinolytics as compared to M-cholinolytics produce long-term behavioural changes in pubescent rat progeny. Pubescent rat progeny had low dynamics of gaining sexual experience and decreased sexual activity with equal disturbance of motivation and coitus. The number of males with absence of sexual activity was above that of the control group. We suggest that sexual dysfunction of offspring adulthood was provoked by introduction of ganglerone (N-cholinolytic) which had been injected on 9-11 and 12-14 days of gestation, and metamyzil (M-cholinolytic) injected on 9-11 days of gestation. Apparently, regulation of neuronal mechanisms for sexual function is disturbed as a consequence of lasting change in neurotransmitter activity. It is suggested that dopaminergic activity in brain limbic structures was affected the most. The significant decrease in blood testosterone values has also been elucidated.

In chronic experiments on cats with unilateral ablations of the motor cortical area, recovery of motor function of the contralateral forelimb was observed in average on the 31-th day after ablation. Stimulation of M-cholinoreactive brain biosystems by galantamine in combination with simultaneous suppression of N-cholinoreactive biosystems by ganglerone, shortened the period of complete compesation up to 10 days. Suppression of M-cholinoreactive systems and simultaneous stimulation of N-cholinoreactive ones by metamisil combined with galantamine prolonged the recovery period up to several months. A conclusion is drawn of an important role of M- and N-cholinergic mechanisms in providing compensatory possibilities of the brain.

It was shown in experiments in vitro that hydrocortisone, gangleron and benzohexonium at a concentration of 10(-6) M increase the resistance of rat red cells to hypoosmotic hemolysis. Diplacin, d-tubocurarin, methamysil and methacin at the same concentration produce no effect on the resistance. Repeated injections of hydrocortisone to rats decrease the osmotic resistance of red cells, while diplacin and d-tubocurarin increase it. Combined use of hydrocortisone and cholinolytics made it possible to reveal the ability of diplacin and d-tubocurarin to reduce the effect of the steroid on the osmotic resistance of red cells both in vitro and in vivo.

The influence of alpha- and beta-receptor antagonists combined with drugs which act as antagonists at muscarinic and nicotinic receptor sites on epileptic focus produced by topic penicillin application was investigated. The beta-receptor blocking agent caused a faster and more intense activity of epileptogenic focus in comparison with activity in control animals, but the number of seizures decreased relatively for 25%. N-receptor antagonists diminished the facilitating effect of the beta-receptor antagonist on focal activity. Combination of m- and beta-receptor antagonists did not influence the spike activity of the focus. Treatment with alpha-receptor antagonists enhanced spikes and number of seizures only insignificantly. The combination of alpha- and n-receptor blocking substances does not influence the development of the epileptic process. The alpha-receptor antagonist together with the m-receptor blocking drug induces a facilitation of spike activity.

In experiments on rats learned to passive avoidance reaction in one trial with subsequent administration of electroconvulsive shock (two hours after learning), the influence of different factors on the retrieval of the lost reaction was tested after three days. The greatest restoring capacity was exhibited by a non-specific reminding agent, the bell, gamma-amino-butyric acid (200 mg/kg) and etimizol (1.5 mg/kg). In animals with a preserved reaction, a number of pharmacological agents impaired retrieval of the habit (caffeine 5 mg/kg, carbocholine 0.01 mg/kg and metamizil 0.5 mg/kg). Optimal conditions for the restoration of the lost reaction were formed by etimizol and gamma-aminobutyric acid. Cholinergic mechanisms play a certain role in the functioning of the retrieval apparatus.

The paper is concerned with a study of the effect of metamizil in 45 patients with different forms of vascular parkinsonism. It was established that metamizil exerts a positive effect on the development of neurological symptoms (rigidity, bradykinesia, tremor) in mild and moderately expressed degrees of lesions. In most of the cases the drugs appeared effective in doses of 0.001 g thrice daily, and in separate cases 0.001 g 6 times daily. In the majority of patients metazil was tolerated without significant side effects. In some patients the side effects (vertigo, dryness in the mouth) were slightly expressed. The effect of treatment was seen after 2 days up to 2 weeks and lasted during the whole course of treatment and sometimes after it. Metamizil possessing a moderate sedative action, as well as spasmolytical and hypotensive is indicated for patients with vascular parkinsonism.

It has been established in chronic experiments on rabbits that acute alcohol intoxication increased the after-discharge thresholds in response to electrical stimulation of dorsal hippocampus. It has been shown that neurotropic agents selectively blocking M- or N-cholinoceptors exerted various effects. M-cholino-blocker methamizol (1 mg/kg, i. p.) decreased the excitability of dorsal hippocampus, potentiated EEG and behavioural effects of alcohol intoxication. N-cholinoblocker etherophen (IEM-506, 20 mg/kg, i. p.), on the contrary, increased the excitability of dorsal hippocampus and reduced behavioural effects of alcohol administration.

Chronic experiments on rabbits with penicillin epilepsy have shown that intravenous injections of the ACHE inhibitor galanthamine (1 mg/kg), and N-cholinergic-blockers, ganglerone (3 mg/kg) and eterofen (8 mg/kg), decreased or suppressed completely epileptogenesis manifestations. Combination of galanthamine with one of the N-cholinergic-blockers markedly increased their anticonvulsive actions. On the contrary, combination of galanthamine with the M-cholinergic-blocker metamizil (0.5 mg/kg) enhanced epileptogenesis activity. It is postulated that both M- and N-cholinergic mechanisms take part in the genesis of penicillin epilepsy. The use of N-cholinergic-blockers and their combinations with M-cholinomimetics as anticonvulsants seems expedient.

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).

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.

Treatment of hemicastrated adult female rats with nicotine increased the compensatory ovarian hypertrophy (COH) while central n-cholinolytic IEM-506 decreased COH and prevented the estrogen-induced suppression of COH. Administration of L-DOPA abolished the effect of IEM-506, and disulfiram blocked gonadotropic action of nicotine. Elevation of the dose of arecoline decreased COH and the sensitivity of hypothalamo-gonadotropic complex to estrogen suppression. Treatment of rats with L-DOPA and disulfiram abolished the late effect of arecoline. Central m-cholinolytic metamizyl decreased COH, potentiated the effect of estrogen and prevented the gonadotropic effect of L-DOPA. The regulatory role of m-cholinergic systems in noradrenaline mediation of gonadotropic function and n-cholinergic system in dopamine ones are suggested.

The synthesis and pharmacological evaluation of conformationally restricted analogues of certain anticholinergic agents is a powerful method for probing the topography of the muscarinic receptor. In the present study, clues as to the binding conformation of structurally flexible anticholinergics are provided by approximating certain conformations of benactyzine by synthetic analogues 1-6, which are structurally locked into desired conformations. The pharmacological activity of each analogue is an indication of how well particular conformational models are accommodated by the receptor. The conformation of benactyzine in which an intramolecular hydrogen bond may exist between the hydroxyl group and the carbonyl oxygen of the ester group (conformation I) is approximated by the synthetic analogue 2,2-diphenyl-3-tetrahydrofuranyl (diethylamino)ethyl ether (1) and related analogues. Pharmacological evaluation using dose-response experiments on isolated rat ileum tissue demonstrated that these compounds noncompetitively inhibited acetylcholine-induced ileum contractions. Restriction of the conformational freedom of the amino side chain of 1 by synthesis of the hexahydro[3,4-b]furan derivative 3 provided a weak but competitive inhibitor at low concentration. The conformation of benactyzine in which an intramolecular hydrogen bond may exist between the hydroxyl group and the ether oxygen of the ester group (conformation II) is approximated by 2,2-diphenyl-4-[2-(diethylamino)ethyl]-3-tetrahydrofuranone (4). Pharmacological studies showed that this compound competitively inhibited acetylcholine-induced ileum contractions. These experiments provide evidence that receptor-bound conformation II for benactyzine is preferred over conformation I in providing competitive binding with the muscarinic receptor.

It was established in experiments on unanesthetized rats given intraventricular injections of drugs that hyperthermic effect of prostaglandin E2 (PGE2) was markedly weakened by administering clofelin while isoproterenol had no appreciable effect on PGE2 effects were not prevented by noradrenaline, 5-hydroxytryptamine, phenoxybenzamine, propranolol, deseril, nicotine, metamyzyl and IEM-506. Preliminary administration of oxotremorine and hemicholinium-3 averted PGE2 effect. The disorders of the thermo-regulation centers caused by excess PGE2 are likely to be counterbalanced by the central effect of some synaptically active drugs which affect in particular the function of cholinergic synapses and alpha-adrenoreceptors.

The effects of physostigmine and m-cholinolytics on emotional reactivity, aggressiveness, exploratory behavior, along with simultaneous influence on the endogenous serotonin metabolism, enhanced by 1-tryptophan serotonin metabolism in the brain, were studied. Upon blocking the peripheral effects with methylatropine-physostigmine exerted a tranquillizing action on emotional reactions without producing any significant changes in the serotonin metabolism. Physostigmine acted as an antagonist to the traquillizing effect of 1-tryptophan, facilitating the catabolism of serotonin. M-cholinolytics--atropine and benactyzine exercised a tranquillizing action on emotional reactions, increasing the serotonin level in the forebrain and diencephalon.