V. G. Zin'kovskii

Character of correlation between the anticonvulsant action of phenazepam and its level in the mouse brain

: The effect of low doses of haloperidol was studied by means of screening and electrophysiological tests. In doses of 0.05--0.15 mg/Kg haloperidol exerts an activating effect which manifests in the elevation of motility, in the potentiation of the convulsant effect of bicuculline, EEG desynchronization and decrement of test response depression in the recovery cycle of the somatosensory primary response. The data obtained suggest that the activating effect of haloperidol is due to the weakening of inhibitory processes in the brain.

Determination of tranquilizers of the 1,4-benzodiazepine series and their metabolites in biological media

Among the vast group of tranquilizers the derivatives of 1,4-benzodiazepine have received wide reputation and application in medical practice. The pharmacological activity of 1,4-benzodiazepines depends on a series of factors among which an important place is occupied by metabolism, absorption, distribution, and elimination from the organism. All these points are the main links of the problem of the molecular-biological search for, the direct preparation of, and the study of the mechanism of action of this group of drugs. Special methods are necessary for their solution with the aid of which it is possible to extract the benzodiazepines from biological test samples, to separate them from coextracted substances, to separate metabolites formed in the organism and finally to establish their structure and their amount. The enumerated points are considered in the present paper. The methods under consideration may be applied with success in toxicology, clinical medicine, pharmacy, and chemistry.

Analysis of the structure of components of the convulsant action of metrazol in mice receiving sulazepam and its metabolites

The relationship between minimal effective doses of pseudoclonic and clonico-tonic convulsions (DPCC, DCTC) and also of tonic extension (DTE), evoked by intravenous injection of metrazol into mice and the effect of the anticonvulsant action of sulazepam and its metabolites (diazepam, desmethyldiazepam, and oxazepam) were investigated. All the compouds tested were shown to increase the values of the minimal effective doses based on recorded indices of the seizure, and anticonvulsant activity reached a maximum 15 min after injection of desmethyldiazepam, 15–30 min after injection of sulazepam and oxazepam, and 5–30 min after injection of diazepam. Clear correlation was established between the minimal effective doses of the recorded indices of the seizure in the animals of the control group and it continued after injection of the drugs. It is postulated that sulazepam and its metabolites increase the minimal effective doses of metrazol for the recorded effect but do not change the general pattern of the seizure and do not affect dispersion of the dose—effect curves of metrazol.

Kinetics of [14C]phenazepam excretion in albino rats after single and repeated injections of the drug

During the 5 days after intraperitoneal injection of [14C] phenazepam into albino rats, both intact animals and animals previously receiving phenazepam injections for 15 days, about 77% of the total radioactivity was excreted with the urine and feces. The excretion processes can be described by a first-order equation. The rate of total excretion of phenazepam was identical after single or repeated injections of the drug. Meanwhile, after a single injection of phenazepam into the animals, it was excreted mainly with the urine, whereas after repeated injections it was excreted mainly with the feces. The process of excretion of phenazepam with the urine after repeated injection is biexponential in character.

Estimation Fast-Reversible of Effects of Ethanol and Pharmacokinetic Forecast

The alternative and graduated methods for estimation of fast-reversible effects of ethanol are compared. Estimation of the myorelaxing and anticonvulsive effects of ethanol by the alternative method can be used with some limitations for the effector analysis of ethanol pharmacokinetics. It is shown that the effector expectation of pharmacokinetic profile for ethanol based on the minimal effective doses of bicuculline inducing clonic convulsions and tonic extension is comparable to experimentally determined brain contents of14C-ethanol.

BIOKINETICS OF A NEW PROTODRUG HYDAZEPAM AND ITS METABOLITE

: Pharmacodynamics and pharmacokinetics of a novel tranquilizing agent--gidazepam (I), a prodrug, and its physiologically active metabolite--7-bromo-5-phenyl-1,2-di-hydro-3H-1,4- benzodiazepine-2-one (II) in mice organism were studied. The form of relationship was determined between the dynamics of the anticonvulsant effect of labelled (2-14C-) I and II and the kinetics of the content of 14C-compounds in the experimental animals brain. It was noted that the biophase of the effect and the effector fragment of the scheme of biokinetics for I and II are identical. The effector prognosis of pharmacokinetics of I was realized. The comparison of the main characteristics of biokinetics for the prodrug (I) and drug (II) allowed us to reveal the nature of the quantitative differences of these pharmacological effects.

Effector modeling of the action of GABA-receptor complex ligands: Functional interaction of muscimol and exogenous modulators of the complex

Muscimol (ML) is widely used in molecular-biochemical investigations of the supramolecular GABA-receptor-ionophore complex (GABA-RC) as agonist of the GABA-receptor [4, 6, 9]. Unlike GABA muscimol can pass through the blood--brain barrier, so that it can be used in pharmacological research [6, 12, 13]. However, data obtained in vivo are quite contradictory. It has been found that ML induces a significant anticonvulsant effect when accompanied by administration of 3-mercaptopropionic acid, a compound analogous with thiosemicarbazide (TS), which competitively inhibits GABA synthesis in vivo, and protects animals, although not significantly, against seizures evoked by metrazol (MZ) and bicuculline (BC) [6]. In one study [13] ML was used as a compound potentiating the sedative effect; of barbiturates (BB); in another study [11] it was used as a convulsant, with an action antagonistic to the effects of 1,4-benzodiazepine (BD) derivatives. The aim of this investigation was to study the functional state of GABA-RC when modified by ML and other exogenous ligands of the complex, on the level of integrity of the biosystem.

Synthesis and pharmacokinetics of14C-methyl N-(2-amino-5-bromobenzhydryl)glycine

One of the most promising areas in the search for new tranquilizers is the creation of precursor-drugs (pro-drugs) whose biotransformation results in the formation of active metabolites [4, 9]. In the present study we have investigated the distribution kinetics of 14C-methyl N-(2-amino-5-bromobenzhydryl)glycine (I) and its excretion from mice. The pharmacological effects of this compound may be due to the formation of active metabolites, i.e., derivatives of 1,4-benzdiazepine [5].

Biokinetics of peptidamidobenzophenones — Precursors of benzodiazepines

Egg PC, purified by column chromatography on aluminum oxide and silica gel and egg PC ; hydrogenated in the presence of palladium on charcoal [6] was used in the experiment. The s~ of the lipids from the erythrocyte phages was obtained by extraction with a 2:1 chloroformmethanol mixture from previously lyophilized stromal mass (waste obtained during the production of Hb). Human Hb, separated by method [5], contained 2% meta form and was used in the oxygenated form.

Prediction of the biotransformation of peptidamidobenzophenones on the basis of effector analysis

The quantitative indices of the biological activity of derivatives of peptidamidobenzophenone (PABP) depend on the structure of the peptide fragment of their molecule [i0]. In the organism [9] and in vitro [8] in the process of hydrolysis of PABP and subsequent intramolecular condensation of the hydrolysis products (2-glycylamidobenzophenones), the derivatives of 1,4-benzdiazepine (BD) --exogenous ligands of GABAA2 -the receptor-channel assembly of neuronal membranes [7], combined with pronounced anxiolytic and anticonvulsive properties, are formed [7, 8, i0]. PABP do not interact directly with the benzdiazepine receptors of GABAA2 -the receptor-channel assembly [8]. Consequently, PABP can be classed among the drug precursors whose action is due to their biotransformation into biologically active metabolites (BD). Evidently the observed differences in the physiological activity of a number of PABP [8, i0] are determined by the parameters of the kinetics of their conversion to the corresponding metabolites in the bodies of experimental animals.