The effect of phenazepam on the pancreatic excretory function in thermal stress

The excretory function of the pancreas was studied on albino rats during thermal stress and ACTH (corticotropine) administration. Stress inhibited the enzyme-synthesizing and enzyme-secreting functions of the gland. The tranquilizer phenazepam influencing the GABA-ergic brain systems exerted a protective effect on pancreatic exosecretion in stress and its strength depended on the administration regimen of the drug. Experiments with corticotropine have shown that the antistress effect of phenazepam, to a certain extent is related to its action on the level of ACTH production in the hypophysis.     

Characteristics of fenazepam excretion in rats and mice

Study of excretion of the tranquilizer phenazepam [7-bromo-1,3-dihydro-5-(2'-chlorophenyl)-2H-1,4-benzodiazepine-2-one] and its pharmacologically active metabolite 3-hydroxyphenazepam with urine and feces of rats and mice has shown that the drug is excreted unchanged in extremely negligible amounts. During 5 days, 11.4% of phenazepam with reference to the dose administered is excreted with mouse urine. In rats, this metabolite is detectable in the urine only after phenazepam administration in a dose of 100 mg/kg.     

The fenazepam demand by rats depending on the degree of alcoholic motivation

Phenazepam stimulates the drinking behaviour of rats. Under free-choice conditions ethanol-preferring rats drank significantly greater amount of phenazepam solution than those not preferring ethanol. Intraperitoneal administration of phenazepam and ethanol eliminated differences between the animals of the two groups in consumption of each substance but had no cross effect.     

Effect of stimulants on the tranquilizing, hypnotic and myorelaxant action of phenazepam

It has been established in experiments on mice and rats that sydnocarb, strychnine, corasol and thiosemicarbazide are correctors as regards the myorelaxant effect of phenazepam. The correcting effect of the drugs manifests to a greater degree under conditions of eliminating the side effects that developed. Electroencephalographic studies on the combined action of phenazepam and sydnocarb on the sleep cycles in rats have shown sydnocarb to reduce the hypnotic effect of the tranquilizer. Under conflict situation sydnocarb or strychnine exert no effect on the tranquilizing action of phenazepam. Conversely, corasol and thiosemicarbazide diminish the anxiolytic effect of the tranquilizer. The data obtained allowed one to recommend that sydnocarb and strychnine be introduced in medical practice as correctors of the side effects produced by phenazepam.     

Correlation of the clinical pharmacological action of a single dose of fenazepam with the EEG dynamics and pharmacokinetics

Interaction between the clinical, EEG-effects and phenazepam concentration in the blood was studied in 111 patients with neurotic disorders after intake of the test drug dose (2 mg) administered singly and on the 14th day of the treatment. It was established that EEG changes commonly induced by benzodiazepines supervene primarily within the interval of 1 to 3 h after a single intake which correlates with the maximal degree of the tranquilizing, somnolent and myorelaxant drug action. It was demonstrated that the clinical and EEG-effects occur before attainment of the maximal phenazepam concentration and then become less potent, with preservation of the high blood drug level. Intake of the test dose during the treatment course is characterized, as compared with the effect of a single intake, by less marked clinical action of the drug and the lack of significant changes on the EEG and in the blood phenazepam concentration.     

The role of bemitil pharmacokinetics in realizing its therapeutic efficacy]

The pharmacokinetics of a new psychotropic drug bemithil was studied after single and long-term administrations under monotherapy and in combination with phenazepam in patients with asthenoneurotic disturbances. A high degree of correlation for some pharmacokinetic parameters of bemithil following the administration of the drug test dose and its global therapeutic effect was established.     

Characteristics of the anticonvulsant effects of fenazepam

Studies of the new benzodiazepine drug phenazepam comparatively to diazepam, clonazepam, nitrazepam, phenobarbital and diphenylhydantoin have shown that by its anticonvulsant effects phenazepam is similar to clonazepam and differs from other antiepileptic agents. Phenazepam exhibits a pronounced capacity for removing paroxysmal epileptiform discharges induced by cobalt application to the surface of the brain cortex. Prolonged administration induces tolerance to phenazepam as shown by antagonism to strychnine and by capacity for preventing convulsions in maximal electric shock.     

The immunotropic properties of fenazepam]

The effect of phenazepam (0.25-10.0 mg/kg) on the humoral immune response, antibody-dependent cellular cytotoxicity (ADCC), the ability of macrophages to induce the humoral immune response at a single administration to Wistar rats and CBA mice was studied. It was found that when administered in doses of 1.0-5.0 mg/kg phenazepam exerts the stimulating effect on the formation of antibodies to the thymus-dependent antigen (ram erythrocytes). When administered in a dose of 2.5 mg/kg the drug increases the titer of antibodies to Vi antigen, ADCC, the ability of macrophages to induce the humoral immune response and also abolishes the studied manifestations of the postintoxication immunodeficiency state caused by anticholinesterase agent.     

Effect of phenazepam on the peripheral catecholaminergic systems in immobilization stress

Fluorescent microscopy and spectrofluorometry of biogenic amines were used to study adrenergic innervation of the dura mater, vas deferens and medullary substance of the adrenals in immobilized rats treated with phenazepam. It was established that phenazepam (1 mg/kg, i. p.) prevented the decrease in the level of the adrenergic transmitter at the stage of anxiety and promoted its stabilization throughout the entire period of body adaptation to immobilization. The stress-protective effect of the drug appeared reduced at the stage of cachexia.     

Analysis of phenazepam and 3‐hydroxyphenazepam in post‐mortem fluids and tissues

Phenazepam is a benzodiazepine that is predominantly used clinically in the former Soviet states but is being abused throughout the wider world. This study reports the tissue distribution and concentration of both phenazepam and 3‐hydroxyphenazepam in 29 cases quantitated by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) in a variety of post‐mortem fluids (subclavian blood, femoral blood, cardiac blood, urine, vitreous humour) and tissues (thalamus, liver and psoas muscle). In 27 cases, the cause of death was not directly related to phenazepam (preserved (fluoride/oxalate) femoral blood phenazepam concentrations 0.007 mg/L to 0.360 mg/L (median 0.097 mg/L). In two cases, phenazepam was either a contributing factor to, or the certified cause of death (preserved (fluoride/oxalate) femoral blood 0.97 mg/L and 1.64 mg/L). The analysis of phenazepam and 3‐hydroxyphenazepam in this study suggests that they are unlikely to be subject to large post‐mortem redistribution and that there is no direct correlation between tissues/fluid and femoral blood concentrations. Preliminary investigations of phenazepam stability comparing femoral blood phenazepam concentrations in paired preserved (2.5% fluoride/oxalate) and unpreserved blood show that unpreserved samples show on average a 14% lower concentration of phenazepam and we recommend that phenazepam quantitation is carried out using preserved samples wherever possible. Copyright © 2015 John Wiley & Sons, Ltd.     

Effect of nicergoline on learning and memory

The anti-amnestic action of nicergoline was studied using the following experimental methods for learning and memory impairment, based on passive avoidance response: amnesia induced by maximal electroshock in mice, scopolamine-induced amnesia in mice and amnesia by paradoxical sleep deprivation in rats. Piracetam, meclofenoxate, pyritinol, deanol and phenazepam were used as reference drugs. The results show that nicergoline demonstrates well-expressed anti-amnestic effect manifested by reducing the amnestic effect of maximal electroshock, scopolamine or paradoxical sleep deprivation, its effect being equal to or more pronounced than piracetam, meclofenoxate, pyritinol, deanol and phenazepam.     

Mechanism of the anti-alcohol action of fenazepam

Experiments were performed on 64 albino male rats selected according to their ethanol preference. A long-term administration of ethanol produced a number of specific changes in the activity of the enzymes involved in metabolism of ethanol, lipid peroxidation, enzymes of metabolism of xenobiotics. At the continuous ethanol administration, phenazepam was found to normalize the activity of ethanol-metabolizing enzymes, both in vivo and in vitro. Phenazepam also normalized reaction of lipid peroxidation both in vivo and in vitro. The drug was shown to be an inductor with respect to enzymes of xenobiotic metabolism.     

Correlations between the pharmacokinetic indices of the tranquilizer fenazepam in single and long-term administration to patients

A high degree of correlation between experimentally established and theoretically calculated constant concentrations of phenazepam was revealed in blood plasma of patients. Due to experimental findings the employment of a single-dose drug administration with regard to previously stated effective-dose interval during dosage build-up made possible estimating the maximum allowable individual dosage which should yield a good therapeutic result without side effects.     

Behavior disorder in rats induced by Madopar and its pharmacological correction

Administration to rats of madopar in a dose of 125 mg/kg produced stereotypy, decrease in the exploration activity in the open field test, loss of the ability to decide the extrapolation problem (escape out of acute stressful situation). The latter type of behavioral pathology alone was selectively averted by administering the classical neuroleptics fluorophenazine, haloperidol and its analog azaperone. Atypical neuroleptics and the the antidepressant imipramine were less effective and reduced but animals' motor excitation induced by madopar according to the extrapolation avoidance test. The tranquilizer phenazepam did not influence behavioral pathology in this test. The data obtained suggest that impairment of the animals' behavioral pattern in the extrapolation avoidance test on madopar administration in a dose of 125 mg/kg may serve an experimental model for evaluating the neuroleptic effect of the drugs.     

Effects of cholesterol and its esters on transdermal penetration of phenazepam

Cholesterol and its esters with aliphatic acids were studies as agents increasing the transdermal penetration of phenazepam when given transdermally in mice. Drug penetration was measured in terms of its pharmacological action (anticonvulsive effect on intravenous administration of 1% corasole). These studies showed that of the compounds studied, cholesteryl pelargonate had the greatest enhancing effect. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 1, pp. 3–10, January, 2009.     

Effect of benzodiazepine tranquilizers on the development of toxic brain edema

Experimental nicotinic brain edema in rats was made use of to examine the action of the benzodiazepine tranquilizers, diazepam and phenazepam. It was disclosed that these agents have antiedematous properties. It is suggested that the GABA-ergic mechanisms might participate in the realization of the effect under consideration.     

Increasing the solubility of phenazepam by forming solid dispersions

The effect of solid dispersion (SD) formation on the solubility of phenazepam has been studied. Phenazepam and its SDs with poly(ethyleneglycol)-1500 (PEG), poly(vinylpyrrolidone)-10000 (PVP), and β-cyclodextrin were studied. The SD with PVP increases both the solubility and the dissolution rate of phenazepam. Results obtained by a complex of physical and chemical methods suggest that the improved release of phenazepam from the SD with PVP is due to solubilization, amorphization, and formation of a colloidal dispersion of the parent drug substance.     

Metabolism and Testicular Toxicity of 1 ,3-Dinitrobenzene in the Rat: Effect of Route of Administration

Studies investigating the testicular toxicity of 1,3-dinitrobenzene(1,3-DNB) have utilized both the oral (po) and intraperitoneal(ip) routes of administration. These two administration routescould be expected to produce different pharmacokinetic profilesand, potentially, different degrees of toxicity. In the presentwork, the effect of route of administration upon 1,3-DNB dispositionand susceptibility to testicular damage has been investigated.Male Sprague–Dawley rats were given 25 mg/kg 1,3-DNB eitherip or po. Metabolites were quantitated in blood, urine, andfeces, and methemoglobin levels were determined. Peak bloodlevels of 1,3-DNB and its major metabolite were three timeshigher in ip-dosed rats than in po-dosed rats. While the lowerblood levels seen after po administration were maintained forgreater than 6 hr, blood levels fell rapidly after ip dosing,reaching po levels at 6 hr postadministration. Peak methemoglobinlevels in ip-dosed animals were twice that of po-dosed animals.Route of administration had a minor effect on the levels ofurinary metabolites, while there was a significantly higherexcretion of metabolites in the feces of po-dosed animals. Despitethe markedly higher 1,3-DNB blood levels after ip administration,there were only subtle differences in testicular damage. Thedata raise the possibility that above a threshold level of 1,3-DNBin the blood, only the duration of testicular exposure to thetoxicant may govern susceptibility to testicular toxicity.     

Hypoglycemic effect of aqueous extract of Ammi visnaga in normal and streptozotocin-induced diabetic rats

The effect of the aqueous extract of Ammi visnaga (Apiaceae) on blood glucose levels was investigated in fasting normal and streptozotocin-induced diabetic rats after single and repeated oral administration. The aqueous extract of Ammi visnaga (AV) at a dose of 20 mg/kg significantly reduced blood glucose in normal rats six hours after a single oral administration (P < 0.005) and nine days after repeated oral administration (P < 0.05). This hypoglycemic effect is more pronounced in streptozotocin (STZ) diabetic rats (P < 0.001). Acute toxicity (LD50) and general behavioural effects of an aqueous extract of AV fruits was studied in mice. The LD50 of intraperitoneal (i.p.) and oral administration was 3.6 and 10.1 g/kg, respectively. These findings suggest that the aqueous extract of AV possess significant hypoglycemic effect in both normal and STZ diabetic rats and support, therefore, its claimed clinical use by the Moroccan population.     

Experimental model of heuristic decision making in experiments on rats for pharmacologic screening

In experiments on 399 rats the authors developed a method permitting the evaluation of the rate and probability of solving the task demanding from the experimental animals to survive after immersion in cold water. Each animal was exposed to stress only once in life. The task was solved by the animals with the probability rate of approximately 80-100% within 2 min. The pharmacological agents with the depriming effects (morphine, aminazine, sodium oxybutyrate, phenazepam) decreased the aim-oriented behavioral reactions of experimental animals. Caffeine (5-10 mg/kg) decreased the reaction time necessary for solving the task and phenazepam (5 mg/kg) blocked the decision made by the exposed rats to eliminate the stress situation. Nootropil and strychnine exerted no effects on the probability and quickness of the exposed rats to solve the stressful task.