[Changes in blood rheological properties and erythrocyte osmotic resistance in activation of free radical processes]. / Izmenenie reologicheskikh svoistv krovi i osmoticheskoi rezistentnosti éritrotsitov pri aktivatsii svobodnoradikal'nykh protsessov.

Relationship between serum oxidation of different degree and micro- and macrorheology of the blood and modification of this relationship in the presence of antioxidant alpha-tocopherol were studied. Lipid peroxidation affects blood rheology and erythrocyte osmotic resistance. Erythrocytes are the first to react to increased activity of free radical oxidation and to exhaust their compensatory potential. Plasma viscosity remains stable in serum oxidation of different degree, and therefore erythrocytes are responsible for changes in blood rheology during intensification of free radical oxidation. Moreover, erythrocytes are functionally resistant to oxidative stress in malonic dialdehyde concentrations under 3.62 +/- 0.41 nM/ml. alpha-Tocopherol increases functional resistance of erythrocytes and maybe of protein components of the plasma to damaging action of free radicals.

Effects of low-density lipoproteins on blood coagulation and fibrinolytic activity.

In vitro experiments showed that copper-oxidized low-density lipoproteins activate factors of the prothrombin complex in the whole blood and inhibit fibrin generation in both blood and plasma. Moreover, oxidized low-density lipoproteins inhibit fibrinolysis and impair the structure of fibrin clot, which results in hypercoagulation.

[Determination of bifonazole using HPLC in pharmacokinetic studies]. / Opredelenie bifonazola metodom VEZhKh pri farmakokineticheskikh issledovaniiakh.

A sensitive method for HPLC quantification of bifonazole, an antimycotic drug, in the skin and plasma was developed. The skin samples were homogenized with the use of a physiological solution (1:5) and then centrifuged at 2000 r.p.m. for 20 minutes. Bifonazole was extracted from the homogenates or plasma with methylene chloride. The organic phase was evaporated to dryness under nitrogen at 45 degrees C, the residue was redissolved in methanol and an aliquot of 0.03 ml was injected to the HPLC system for determination of the drug content. A Silasorb C column (30 cm x 4.6 mm, 10 microns) was used. The mobile phase consisted of acetonitrile, 0.12 M sodium acetate and methanol (84:15:1). The flow rate was 1.5 ml/min. The UV absorption was monitored at lambda 254 nm. The calibration plots were linear within the concentration ranges of 1 to 20 micrograms/g. The determination limit was 0.02 microgram/g. The bifonazole pharmacokinetics was studied with the developed method on rats after a single application of 1 per cent drug cream to the skin. The cream was manufactured by two different companies (formulations A and B). The skin and blood samples were collected 0.5, 1, 2, 6, 24 and 48 hours after the bifonazole cream application in a dose of 1 g/kg. The plasma levels of bifonazole were below the detection limit of the method throughout the observation period whereas the skin concentrations could be measured within 0.5-48 hours. Despite the faster skin penetration of bifonazole applied as formulation A the relative extent of the penetration was close to 1 (0.95) and the mean residence times were similar (14.9 and 14.5 hours for formulations A and B respectively). The developed analytical procedure is useful in pharmacokinetic studies with bifonazole.

[Correlation between pharmacokinetic parameters of rifampicin and its biologically active metabolite as related to estimation of the relative bioavailability of the antibiotic]. / Vzaimosviaz' mezhdu parametrami farmakokinetiki rifampitsina i ego biologicheski aktivnogo metabolita v kontekste otsenki otnositel'noi biodostupnosti antibiotika.

In the bioavailability studies with drugs biotransformed to biologically active metabolities only the concentrations of the parent drug (PD) are usually taken into account even when the pharmacokinetic data on the metabolite(s) (M) are available. However, such data may be useful as an alternative source for the bioavailability determination. Moreover, the clinical outcomes often depend on both the PD and M concentrations. The aim of the study performed with two rifampicin formulations, tablets and dragee, was to correlate the pharmacokinetic parameters of the PD and 25-O-deacetylrifampicin, a microbiologically active M of rifampicin, and to examine whether the bioavailability parameters based on the PD and M concentrations were compatible. The serum concentrations of the PD and M were determined in 8 healthy volunteers by HPLC. Despite different patterns of the PD and M pharmacokinetic profiles the PD peak concentration (Cmax) and especially the AUC correlated with Cmax or the AUC of the M (r = 0.76 and 0.92 respectively). Moreover, the extent of the absorption expressed as the AUC ratio for the PD correlated with the AUC ratio for the M (r = 0.86). However, neither the time to reach the maximum (tmax), nor the Cmax/AUC ratio, a measure of the absorption rate, based on the PD pharmacokinetic data correlated with the respective parameters calculated with using the M concentrations. Thus, only the estimates of the extent of the absorption and not of the absorption rate based on the PD and M data may be considered as compatible.

[Pharmacokinetics of protegentin, a combined preparation]. / Farmakokinetika kombinirovannogo preparata protégentin.

Protegentin is a combined preparation in the form of ointment containing 0.1 per cent of gentamicin, 0.25 per cent of erythromycin and 0.1 per cent of protease C. Pharmacokinetic studies on the preparation were conducted. Protegentin and gentamicin ointment, currently manufactured in this country, were applied to the surface of experimental pure cutaneous wounds in guinea pigs in a dose of 1 g. It was shown that inspite of the same contents of gentamicin in the ointments, the mean maximum concentration of the antibiotic in the underlying muscular tissue after the protegentin application was somewhat higher than that after the use of the gentamicin ointment. The differences in the drug concentration maintained during the whole observation period of 24 hours. However, they were not statistically significant. The gentamicin concentrations in serum after the use of protegentin were also somewhat higher than those after application of the gentamicin ointment (the differences were not statistically significant). Still, in no case the concentrations reached the potentially toxic ones. The erythromycin concentrations in the muscular tissue were much higher than those in the blood.

[Quantitative analysis of rifampicin and 25-desacetylrifampicin in the plasma using high performance liquid chromatography]. / Kolichestvennoe opredelenie rifampitsina i 25-dezatsetilrifampi- tsina v plazme s pomo'shchiu vysokoéffektivnoi zhidkostnoi khromatografii.

A procedure for determination of rifampicin and 25-desacetylrifampicin in plasma by HPLC was developed. The plasma proteins are precipitated by acetonitrile and the supernatant layer (50 microliters) is used for the assay under isocratic conditions on an analytical column 250 x 4.6 mm in size containing the reversed phase sorbent (C18). The size of the precolumn is 50 x 4.6 mm. An UV detector (at lambda 335 nm) is used. For preparing the mobile phase 630 ml of methanol and 370 ml of 0.058 M sodium nitrite solution are mixed. The flow rate of the mobile phase is 40.7 ml/min. The assay duration is about 10 min. The retention time is 9.6 min for rifampicin and 6.5 min for 25-desacetylrifampicin. The minimum detectable amount of the antibiotic and its metabolite is 0.10 micrograms/ml. The standard curves of rifampicin and 25-desacetylrifampicin are linear within the concentration ranges of 0.5-100 and 0.5-10 micrograms/ml respectively. The procedure is useful in studies on pharmacokinetics of rifampicin and 25-desacetylrifampicin.

[Interrelations in the changes in the pharmacokinetics and nephrotoxic effect of sisomycin as affected by cefazolin]. / Vzaimosviaz' izmenenii v farmakokinetike i nefrotoksicheskom éffekte sizomitsina pod vliianiem tsefazolina.

The action of cefazolin on the pharmacokinetics and nephrotoxic effect of sisomicin was studied on Wistar rats. Sisomicin in doses of 12.5 and 25 mg/kg alone or in combination with cefazolin in doses of 90 and 360 mg/kg was administered intramuscularly to the animals daily for 16 days. It was shown that in both the doses cefazolin had no noticeable action on the level of the functional and morphological changes in the kidneys. Consequently, there were no significant changes in the levels of sisomicin in serum and the site of the nephrotoxic effect (cortical layer of the kidneys) and in the half-life of the aminoglycoside in the kidney cortical layer under the action of cefazolin. At the same time there was observed a marked individual variability of the levels of urea nitrogen and sisomicin in serum of the rats treated with the aminoglycoside alone or in combination with cefazolin. Analysis of the dependence of the nephrotoxic effect on concentration of sisomicin in serum after its use alone or in combination with cefazolin revealed that the changes in the individual intensity of the effect in all the cases were mainly induced by the changes in the sisomicin blood levels. Therefore, control of the blood levels of the aminoglycoside should provide prevention of the development of its nephrotoxic effect not only in monotherapy but also in the use of aminoglycosides in combination with cefazolin.

[Decrease of sisomicin nephrotoxicity as affected by cephalothin: pharmacokinetic evaluation]. / Oslablenie nefrotoksichnosti sizomitsina pod vliianiem tsefalotina: popytka farmakokineticheskogo ob'iasneniia.

The effect of cephalothin on the nephrotoxicity and pharmacokinetics of sisomicin was studied on Wistar rats. Sisomicin was injected intramuscularly in doses of 12.5 and 25 mg/kg alone or in combination with cephalothin in a dose of 360 mg/kg once a day for 16 days. It was shown that the combined use of sisomicin and cephalothin resulted in less pronounced functional and morphological changes in the kidneys as compared to the use of sisomicin alone. The decrease in the nephrotoxic effect was accompanied by a decrease in the sisomicin concentration in the blood serum and the site of the nephrotoxic effect (the kidney cortical layer) and the period of the aminoglycoside half-life in the kidney cortical layer under the action of cephalothin. The analysis of the relation between the nephrotoxic effect and the concentration of sisomicin in the kidney cortical layer and blood serum demonstrates that the nephrotoxicity of the sisomicin combination with cephalothin is mainly due to a decrease in the aminoglycoside concentration in the zone of the nephrotoxic effect.