Biotransformation of the 14C-hydrogenated analog of phenazepam in inbred mice

The elimination of 14C-hydrogenated analogue of phenazepam and its metabolites was studied in inbred C57B1/6 (B/6), BALB-c (C) and CBA mice. The kinetics of two-phase elimination of 14C-compounds with urine and feces was similar in all the above mouse strains. The excretion was realized mainly with feces, exceeding elimination with urine 5-6-fold in B6 mice and 10-11-fold in C and CBA mice. Some interstrain quantitative differences in metabolite composition were found. No metabolite was detected whose concentration would indicate a predominating direction of biotransformation of 14C-hydrogenated phenazepam analogue or distinguish it from other mouse strains. In the organism of mice, 14C-hydrogenated phenazepam analogue undergoes active aromatic hydroxylation and methoxylation via heterocycle (and possibly via chlorine-containing ring). At the same time dehydrogenation of 14C-hydrogenated phenazepam analogue molecule was not recorded.     

Onset of a dissociative state--reversible amnesia as affected by phenazepam

Dissociation is produced by injections of phenazepam (a benzodiazepine tranquilizer) before daily sessions of rat learning in a T-maze. The drinking reflex is seen only after the administration of benzodiazepine. The dissociation depth is linked with the dose of phenazepam: the higher the dose the more pronounced dissociation. Besides, it depends on the time between the administration of phenazepam and the reflex registration. One may assume that learning in the presence of phenazepam gives rise to new interrelations that form the basis for a new functional system which warrants the activity with the drug in the body.     

Kinetics of phenazepam-14C excretion from the body of white rats in the single and prolonged administration of the preparation]

During 5 days after intraperitoneal injection of 14C-phenazepam into albino rats, about 77% of the total radioactivity was excreted with urine and feces in both intact animals and in those premedicated with phenazepam for 15 days. The excretory processes are described by the first order equations. The rates of phenazepam total excretion are identical in single and repeated injections. At the same time, phenazepam injected into the animals at a single dose is predominantly excreted with urine, while in multiple administration it is excreted with feces. Excretion of phenazepam with urine acquires the biexponential features, provided it is injected in multiple doses.     

Comparative evaluation of anticonvulsant and anti-arrhythmic effects of phenazepam, a benzodiazepine receptor agonist

It was established on white mice that benzodiazepine receptor agonist phenazepam possessed a high anticonvulsant activity to antagonize bicuculline, corrasol, picrotoxin and thiosemicarbazide. It was also shown that phenazepam had a potent antiarrhythmic effect on ischemic and reperfusion cardiac arrhythmias in Wistar rats in situ. The effect was of a central nature since it was irreproducible in isolated heart. It seems to be due to the potentiating effect of phenazepam on the realization of GABA inhibitory control of centers of the heart regulation. The facts obtained evidence a possibility of using phenazepam not only as an anticonvulsant but also as an antiarrhythmic means.     

Effect of the antioxidant dibunol and its combination with phenazepam on the behavior of rats in a conflict situation

The influence of dibunol, phenazepam used alone and combined on rat conflict behavior and rat blood and brain malonic dialdehyde content was studied. It was shown that dibunol exerts an unmarked anticonflict action that can be removed by bicuculline. Combined administration of dibunol and phenazepam potentiates appreciably the anticonflict effect. This permits reducing the doses of the drugs. The anxiolytic effect of dibunol alone and combined with phenazepam is attended by a decrease in the content of malonic dialdehyde in rat blood and brain, evidence of the reduction of the lipid peroxidation intensity.     

Cross tolerance when benzodiazepines are administered with other substances

It has been demonstrated in experiments on rats that only the drugs of benzodiazepine structure are responsible for complete cross tolerance as regards the myorelaxant effect under application with phenazepam. Other substances such as neuroleptics (chlorpromazine, triftazin), ethanol, phenobarbital, tranquilizers of non-benzodiazepine structure (meprobamate, ataractic), and an agonist of GABA receptors, muscimol, in doses that produce myorelaxation are not capable to replace phenazepam under conditions of this drug tolerance development. Partial cross tolerance under application with phenazepam arises from the use of supposed endogenous ligands of benzodiazepine receptors, nicotinamide and inosine, as well as of the use of the GABA-mimetic calcium valproate. The mechanisms of benzodiazepine tolerance development are discussed.     

Pharmacological action of phenazepam and caffeine on emotional sphere changes ethanol preference in Wistar male rats

Earlier we showed that direction of changes in the initial anxiety level during compulsory alcoholization was more essential for development of alcohol preference than the initial anxiety level per se. The goal of this work was to study effect of the anxiety level changes on development of ethanol preference in Wistar male rats pharmacologically affected by phenazepam and caffeine. Out of four groups (60 rats) over the period of 4 months, group I had access to 10% ethanol, group II-to 10% ethanol with 0.4 g/l caffeine, group III-to 10% ethanol with 0.5 mg/l phenazepam, and group IV (control)—to water only. The anxiety level and behavioral parameters were evaluated before the onset of the experiment and every 5 weeks thereafter by using the open field test. The ethanol preference was determined by the 2-glass test before the onset of the experiment and every 4 weeks thereafter. In the experimental groups, the long-term consumption of ethanol, ethanol with caffeine, and ethanol with phenazepam led to an increase in alcohol preference as compared with control. A decrease in motor activity under compulsory alcoholization was found to correlate positively with the low level of alcohol preference. Rats that consumed ethanol with caffeine sensitive to this anxiety-enhancing psychostimulant developed ethanol preference faster. The rats insensitive to caffeine developed no alcohol preference. The rats sensitive to the sedative effect of phenazepam were less anxious and did not prefer alcohol subsequently. In rats insensitive to phenazepam, anxiety increased and alcohol preference developed.     

Effect of benzodiazepines on 5'-nucleotidase activity in rat brain

Experiments on 330 rats were made to study the influence of benzodiazepines (diazepam, dormicum and phenazepam) on 5'-nucleotidase activity in brain homogenates. It was discovered that diazepam and dormicum in doses of 3 and 4 mg, phenazepam in doses of 3.75 and 5 mg per 200 g bw provoked a 16-20% reduction in 5'-nucleotidase activity. The maximal effect of diazepam (3 and 4 mg doses) was attained 1 h after intraperitoneal injection, that of dormicum (3 mg) 30 min and of phenazepam (5 mg) 1 h after intraperitoneal injection. It is assumed that benzodiazepines are involved in AMP metabolism.     

Hydroxylation of the aromatic nuclei and heterocyclic ring of the fenazepam molecule in the endoplasmic reticulum of white rats and mice

The reactions of 14C- and 3H-phenazepam hydroxylation by liver microsomes of mice and rats were examined to detect the formation of 3-hydroxymetabolite and products of aromatic hydroxylation of phenazepam molecule. The kinetics of the appearance of these products was studied. It was established that enzyme complex of mouse microsomes rather produced 3C-hydroxylation of the drug, while microsomes of rats produced reactions of hydroxylation of phenazepam aromatic rings.     

Effect of phenazepam on the ethanol demand of rats]

The new Soviet tranquilizer phenazepam given to rats intraperitoneally at a dose of 1 mg/kg daily was shown to be capable of suppressing ethanol addiction produced by 2-month intake of 5% ethanolic solution as the only source of liquid. The mechanism of this effect is likely to be related to the changes in the activity of the neurosecretory centers of the hypothalamus. The phenazepam in the treatment of chronic alcoholism.     

Innate forms of behavior and energy metabolism in the brain of the rat after phenazepam administration in the presence of inescapable painful stimulation

Initially low level of motor search activity in test situations ("open field", maze) in rats previously grouped according to their passive behaviour with a partner-victim (Simonov method), does not essentially change after 3-week administration of phenazepam; the activity level of cytochrome oxidase in the cortex and hypothalamus is lowered. Phenazepam administration in conditions of prolonged unavoidable painful stimulation brings to a sharp increase of motor search activity and aggressive behaviour. Simultaneously the cytochrome oxidase activity increases in the same way as during a stress without phenazepam. This fact points to the independence of behavioural and biochemical effects in this case.     

Effect of psychotropic preparations on the behavior of inbred mice under emotional stress]

The effect of phenazepam and sydnocarb in doses of 0.05, 0.07 and 0.1 mg/kg or 6, 12 and 24 mg/kg, respectively, on the behaviour of C57BL/6, CBA and BALB/c mice, was studied in the "open field" test. Interlinear difference in the reaction of inbred animals to emotional stress and its phenazepam or sydnocarb correction were established.     

Effector modeling of the action of GABA-receptor complex ligands. Functional interactions of subunits of the complex

The distribution of the minimum effective doses of bicuculline, corasole and picrotoxin was studied in intact mice and in mice administered different doses of 1.4-benzodiazepines (phenazepam and its 1,2,4,5-tetrahydroxy derivatives) and sodium barbital. The changes in the "dose-response" relationship for thiosemicarbazide have been observed with the administration of the increasing doses of phenazepam and sodium barbital. The effects registered correspond to the modifications of the GABA-receptor complex by exogenous ligands. The forms of the "dose-response" relationship observed, the types of the antagonism between pharmacological agents and the cooperation of their interaction correspond to the indices obtained from the "quartet" model of the receptor-channel complex.     

Role of GABA-ergic and dopaminergic mechanisms in the withdrawal syndrome after discontinuation of long-term phenazepam administration

It has been shown that depakin, a GABA-ergic agonist, and alpha-methyl-DOPA that inhibits catecholamine synthesis are capable of removing the withdrawal syndrome (disturbed pavlovian behavior pattern and aggressiveness) occurring after discontinuance of long-term administration (30 days) of phenazepam to rats in a dose of 2 mg/kg. In contrast, bicucullin, a blocker of GABA-ergic receptors, thiosemicarbazide that inhibits GABA synthesis by the brain, disulfiram and 3,4-dioxyphenylalanine that increase dopamine and noradrenaline content in the barain aggravate the withdrawal syndrome after phenazepam is discontinued. The data obtained suggest a role of GABA-ergic and dopaminergic mechanisms in the emergence of the withdrawal syndrome after discontinuance of long-term administration of benzdiazepins.     

Modifying action of drug preparations on the effect of promutagen compounds

The Ames test has shown that the action of nitrosomorpholine and cyclophosphane promutagens on bacteria of Salmonella typhimurium TA 1950 increases while using S-9 liver fraction of rats treated with pharmaceuticals of amidopyrine, reserpine and pyrazidol and decreases while using those treated with phenazepam.     

Effect of drugs of the nootropic class on rat behavior after deprivation of the paradoxical stage of sleep

Pharmacological analysis was used for studying the influence of 24-hour deprivation of paradoxical sleep by Jouvet method on retention of conditioned reaction of passive avoidance in rats. Psychotropic substances of different action were used for the analysis: nootropes as anti-amnestic--pyracetam (400 mg/kg), kleregil (100 mg/kg), centrofenoxin (50 mg/kg) and watersoluble salt of 3-oxypiridin derivative (3-OP) (50 mg/kg) and tranquilizer of bensodiazepine series phenazepam (1 mg/kg) as antistress and antiphobic. It was established that 24-hour deprivation disturbed the elaborated reaction but did not change the rate of emotionality and orienting-investigating behaviour of rats in the open field. Nootropes effectively restored the conditioned passive avoidance reaction while phenazepam had no effect. This allows to suggest that Jouvet method of paradoxical sleep deprivation elicits amnesia and its cause is not only stress but deficit of paradoxical sleep.     

Effect of subchronic administration of phenazepam and synthetic antioxidants on the functional status of synaptic membranes in the cerebral cortex of rats subjected to prolonged stress

Monoamine oxidase activity, lipid peroxidation and membrane structure were tested after chronic stress and 7-day treatment with drugs in the brain cortex synaptosomal membranes of rats. The most potent corrector of stress-induced changes, as compared to hydrophobic antioxidant dibunol and tranquilizer phenazepam, was compound 3-OP, a hydrophilic antioxidant.     

Embryotropic action of phenazepam in mini pigs, a new species of experimental animals

It has been established in experiments on mini pigs of Siberian origin that phenazepam given at a dose of 1 mg/kg per os during organogenesis has no embryotoxic or teratogenic action. The drug content in the blood of pregnant animals was determined simultaneously. A conclusion is drawn about perspectiveness of using mini pigs for testing embryotoxic activity of drugs.     

Protective effect of phenazepam and sodium oxybutyrate on somatic manifestations in immobilization stress

The effects of phenazepam and sodium hydroxybutyrate on the somatic manifestations, ultrastructure of the cortex and lipid content of the adrenals in rats exposed to immobilization were examined. Both the drugs had the stress-protective effect, decreasing the stress manifestations at alarm and resistance stages.     

Effect of caffeine and phenazepam on the quantitative parameters of the EEG and ultraslow electrical processes in the brain

A comparative study of the power and coherence of the ultraslow phasic processes (USPPs) of the brain in the frequency range 0.05–0.5 Hz and the EEG (1.5–50 Hz) at rest with the eyes opened or closed before and after the administration of caffeine and phenazepam, a benzodiazepine tranquilizer, was performed. Caffeine and phenazepam caused similarly directed changes in the EEG pattern. The differences between the effects of these drugs were expressed in a different topography of changes in the EEG pattern. Different locations of such changes are supposed to reflect differences in the behavioral effects of drugs (stimulating or sedative). According to the USPP data, the differences in the drug effects are accompanied not only by a different topography of changes in the USPP pattern, but also by an opposite direction of these changes. This fact makes it possible to suppose that, during pharmacological tests, the differential sensitivity of USPPs as an indicator of CNS sensitivity may be higher than that of the EEG, in view of the closer relationship between the behavioral and electrographic changes.