[The age-related dynamics of mortality and the Gompertz-Makeham law]. / Vozrastnaia dinamika smertnosti i zakon Gompertsa--Meikema.

Using the statistics of mortality of Caucasian population of 48 states of the USA (1969-1971) it was demonstrated that the real age dynamics of human mortality may differ significantly both from the Gompertz law and from the Gompertz-Makeham law. Using of the Gompertz-Makeham formula leads to appearance of negative A value in 77 cases out of 96. This makes it difficult to interpret this parameter as a "background" component of mortality. Using of the Gompertz formula in different age groups leads uncoordinated changes in alpha and R0 values in every state. Hence, it is impossible to plot geographically stable characters for Gompertz parameters alpha for subsequent epidemiological analysis. The "aging rate", estimated by parameter is not stable throughout the life span of 30-92 years, but changes with certain pattern.

Actuarial aging rate is not constant within the human life span.

It is often believed that the mortality intensity in the modern human population undergoes an exponential growth after 40 years, i.e. the actuarial aging rate is regarded to be constant after 40 years. To check this assumption we have calculated local aging rate values for 13 age ranges (within the interval of 30-92 years) for the male and female population of 48 states of the US (1969-1971). It was found that generally the male aging rate is not constant but lowers monotonically with time, while for females the aging rate has a pronounced approximately-shaped character with a minimum in the range of 45-60 years and a maximum within the range of 70-80 years. The results obtained are a warning to those who boldly use Gompertz or Gompertz-Makeham formulas when describing human aging on the population level.

[Correlation between the pharmacokinetic indices and the pharmacological effects of fenazepam in an experiment]. / Korreliatsiia mezhdu farmakokineticheskimi pokazateliami i farmakologicheskimi éffektami fenazepama v éksperimente.

A good agreement was established between the anxiolytic (tranquilizing) effect of phenazepam after administration to rats per os and the rate of its supply to the systemic blood flow. The magnitude of the myorelaxant effect of phenazepam in rats after its oral and intravenous administration correlated well with the drug concentration in blood only at the late periods of time.

[Pharmacokinetics of fenazepam and its metabolite 3-oxyfenazepam in animals of different species and in man]. / Farmakokinetika fenazepama i ego metabolita 3-oksifenazepama u zhivotnykh raznykh vidov i cheloveka.

It has been established that phenazepam is rapidly absorbed from the gastrointestinal tract of animals and man. The maximal concentrations of the unchanged drugs are reached 1, 0.5, 2 and 4 hours in rats, dogs, cats and man, respectively. The half-life of phenazepam in animal and human blood decreases in the following order: man greater than cat greater than dog greater than rat. The metabolite 3 + hydroxyphenazepam was identified in appreciable amounts in cat and rat blood.

[Characteristics of fenazepam excretion in rats and mice]. / Osobennosti ékskretsii fenazepama u krys i myshei.

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.

[Simulation of kinetics of phenazepam and its metabolite 3-hydroxyphenazepam in cat blood]. / Modelirovanie kinetiki fenazepama i ego metabolita 3-oksifenazepama v krovi koshek.

The pharmacokinetics of the tranquilizer phenazepam and its high-active metabolite 3-hydroxyphenazepam in the cat blood was studied in experiments using gas liquid chromatography and mathematic simulation. The experimental findings were computer-processed. An appreciable quantity of 3-hydroxyphenazepam was found in the blood in addition to the unchanged drug at any times after oral administration of phenazepam (2 mg/kg). Joint modelling of the kinetics of phenazepam and 2-hydroxyphenazepam within the same metabolic model allowed calculating the kinetic parameters of both the compounds. The elimination constant of the metabolite in cats was found to be twice as high on the average as compared to that of the unchanged drug.

Species differences in phenazepam kinetics and metabolism.

The kinetic profiles of phenazepam and its hydroxylated derivative were compared in rat, dog, cat and man after administration of single oral doses of the parent compound. The absorption of phenazepam was reasonably rapid in all the species studied. Blood peak concentrations (Cmax) were reached at 1 h in rats (0.32 +/- 0.03 microgram/ml), at 0.5 h in dogs 0.54 +/- 0.10 microgram/ml), at about 2 h in cats (1.65 +/- 0.23 microgram/ml), about only at 4 h in man (0.038 microgram/ml) at the highest dose tested. The largest normalized (value/dose) Cmax and area under the curve (AUC) were observed in man, while the rat gave the lowest values. The half-life of phenazepam was about 60 h in man, 13.72 +/- 2.09 h in the cat, 6.35 +/- 2.32 h in the dog and 7.49 +/- 1.88 h in the rat (beta-half-life). 3-OH-phenazepam was rapidly detected in cat, rat, and dog blood but no measurable amounts (less than 3 ng/ml) were found in human blood. At the oral doses tested, the ratio of the AUC for 3-OH-phenazepam to phenazepam was 0.01, 0.48, and 0.53 in the dog, rat, and cat, respectively. The half-life of the metabolite was shorter than that of the parent compound in the dog, but it was comparable in the rat and longer in the cat. The results suggest that 3-OH-phenazepam might contribute to the overall pharmacological effects of the parent compound in those species in which it accumulates in significant amounts.

[Gas chromatographic method for the quantitative determination of ftoratsizin and its N-dealkylated metabolites in animal and human biological material]. / Gazokhromatograficheskii metod kolichestvennogo opredeleniia ftoratsizina i ego N-dezalkilirovannykh metabolitov v biologicheskom materiale zhivotnykh i cheloveka.

Conditions have been selected, providing the most complete transformation of ftoracizin 10-(beta-diethylaminopropionyl)-2-trifluoromethylphenothiazine and its two dealkylated metabolites--deethylftoracizin 10-(beta-ethylaminopropionyl)-2-trifluoromethylphenothiazine and dediethylftoracizin 10-(beta-aminoprpiony 17-2-trifluoromethylphenothiazine to 10-akryloyl-2-trifluoromethylphenothiazine in the injector of a chromatograph. The detector for electrons 63Ni uptake was extremely sensitive to the above substance. A method has been developed for quantitative determination of ftoracizin, diethylftoracizin and dediethylftoracizin in animal and human bioloigcal material.

7-Bromo-5-(2'-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (I), a new tranquillizing agent: metabolism in rats.

1. After intraperitoneal injection of rats with the new benzodiazepine (compound I), four metabolites (compounds II, III, IV and V) were found in the urine. 2. Compound II was identified as 7-bromo-5-(2'-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one by comparison of g.l.c. and mass spectral properties of the metabolite and synthetic compound. 3. Mass spectra of compound III and its acid hydrolysis products indicate that compound III contains a hydroxyl group in the C(5)-phenyl ring. 4. Compounds IV and V were identified by mass spectrometry as products of simultaneous aromatic hydroxylation and methoxylation of the diazepine I. 5. The major urinary excretion products are compounds III, IV and V. Only very small amounts of compounds I and II were detected.