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Applicability of the "pharmacokinetic time" concept in animal scale-up was evaluated by the findings of the pharmacokinetic study of doxycycline after its bolus intravenous administration to rats in doses of 9 and 18 mg/kg and to cats as 1-hour constant rate infusion in doses of 3.8 and 7.6 mg/kg. Analysis of the pharmacokinetic profiles in the plot of the logarithmic ratio of concentration/dose to "pharmacokinetic time" i. e. time related to body weight raised to the power 0.25 showed that the slopes of the curves for rats, cats and humans (the literature data, intravenous bolus administration in a dose of 2.9 mg/kg) were practically similar. However, no complete coincidence of the curves was observed. When expressed in the "pharmacokinetic time" scale the half lives were equal to 4.6-5.4, 3.5-3.7 and 5.2 h.kg-0.25 respectively. The difference was 1.5-fold while with using the chronological time the difference was about 5-fold (3.1 hours in rats and 15.1 hours in humans). Therefore, with using the "pharmacokinetic time" 10-fold species differences in the total clearance (0.55 and 0.056 l.h-1.kg-1 in rats and humans respectively) transformed into 2-fold differences (0.37 and 0.16 l.h-1.kg-0.75 respectively). Prediction of doxycycline half lives in humans by the experimental findings was successful.

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Seasonal changes in sensitivity to acetylcholine were studied on the isolated frog ventricle. The highest sensitivity was observed in autumn and winter (November-January). In spring, from the period of reproduction, the sensitivity to acetylcholine drops to-threefold and remains at a low level until September. Seasonal changes were more obvious in females. The observed seasonal changes are discussed with reference to ecology, state of reproductive system, etc.

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Cephalothin and cefazolin pharmacokinetics was studied in cats after intravenous administration in doses of 20 and 75 mg/kg. The antibiotic serum concentrations were determined microbiologically. It was shown that the antibiotic pharmacokinetics within the above dose ranges was linear. The data on the antibiotic pharmacokinetics were described by bioexponential equations. Various methods for estimating population pharmacokinetic parameters were compared. Two approaches were used in estimating the population parameters: (1) averaging of individual concentrations followed by determining a single set of the parameters (naive pooled data approach) and (2) calculating of the parameters for an individual concentration/time set followed by the parameter averaging (two-stage approach). With the use of every approach the geometric mean of the parameters was calculated along with the arithmetic one. When the two-stage approach was used the population parameters were estimated with two procedures: averaging of the hybrid parameters (macroconstants) and averaging of the microconstants. Estimation of the population parameters as a geometric mean of the individual parameters, proved to be the most preferable approach.

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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.

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The pharmacokinetics and safety of the lincomycin ointment and gel were studied. It was shown that diffusion of lincomycin through the skin was satisfactory. Investigation of their general toxicity and organotropic properties revealed neither irritating effect nor changes in the internal organs associated with the toxic effect of the drugs. On the basis of the data on the stability of the lincomycin ointment and gel obtained on their storage the lincomycin ointment was recommended for industrial production.

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The pharmacokinetics of sisomicin in the blood, infection foci and urine of patients with wound infections was studied comparatively. Higher blood levels of the antibiotic after intravenous injection as compared to those after intramuscular injection provided its more intensive penetration into the tissues of the wound edges and bottom. After intravenous injection the sisomicin concentration in the tissues was sufficient for inhibition of the strains of Staphylococcus, E. coli and Ps. aeruginosa detected in the patients, while after intramuscular injection the antibiotic levels were sufficient only for inhibition of the first two causative agents. Comparison of the data on the sisomicin pharmacokinetics in the blood and tissues of the wounds provided the characteristics of the level of the drug penetration into the focus of the infection ("therapeutic availability"). Since the levels of sisomicin in the blood and infection foci were highly variable in different individuals. It is recommended that the antibiotic be used under the control of its concentrations in patients. It was shown that the data on the sisomicin renal excretion might be used for the purposes of the pharmacokinetic control.

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The pharmacokinetics of ampicillin was studied in 30 children with diseases of the upper respiratory tracts. The data obtained with a single administration of anhydrous ampicillin in a dose of 25 mg/kg were estimated on one-compartment model. It was shown that the maximum antibiotic levels in the serum were attained in 1.52 hours and averaged to 4.56 micrograms/ml. The antibiotic half-life was 1.24 hours. The period of half-absorption of the antibiotic was 0.66 hours. Comparison of the experimental results with the literature data showed that the pharmacokinetic properties of anhydrous ampicillin and ampicillin trihydrate were close.

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Nephrotoxicity and pharmacokinetics of gentamicin were studied on rats treated with the antibiotic for 30 days in doses of 6.25, 12.5 and 25 mg/kg administered daily. The pharmacokinetics of gentamicin and the time course of changes in the urea nitrogen levels of the blood serum were studied after the 1st, 5th, 8th and 30th injection. The analysis of the respective curves was used for calculation of the average integral values of the concentrations of the antibiotic (C) and urea nitrogen (E). After that the average integral values of these parameters ((CAVG and EAVG respectively) within the whole treatment couse with the use of every dose were calculated in the same way by using the curves of the dynamics of C and E changing. Comparison of the diagrams of E dependence on C for gentamicin and sisomycin showed that nephrotoxicity of sisomycin was 1.48 times higher than that of gentamicin.

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The pharmacokinetics of cephalexin monohydrate after its oral administration in a single dose was studied on rats and dogs. The analysis of the pharmacokinetic data obtained with the one-compartmental model showed that the rate of the antibiotic absorption in the rats was higher than that in the dogs. The periods of the cephalexin half-absorption and maximum concentration were 0.2 and 1.1 hour in the rats and 0.64 and 1.9 hours in the dogs respectively. The period of the antibiotic half-life was almost the same in both animal species. Selective localization of cephalexin in the kidney and liver tissues was noted. The antibiotic was mainly excreted by the kidneys (98.8 per cent for 24 hours).

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Seasonal changes in ACh sensitivity have been studied on isolated cardiac muscle of the bivalve molluscs together with ATP content of the hemolymph and the heart. The lowest ACh sensitivity of the heart was found in August and October (KACh in August was equal to 44.0.10(-6) M). Maximum sensitivity was observed in March and at the end of August--the beginning of September (KACh in March was equal to 1.27 X X 10(-6) M); at this period of year, ATP content of the hemolymph decreases approximately 100-fold, the release of ATP from the heart in the presence of ACh being also decreased. Maximum level of ATP in cardiac muscle was found in July. It was demonstrated that most significant changes in ACh sensitivity take place during spawning, especially when sex cells are transported from the gonads into the gills, as well as during the release of glochidia from the latter. Possible causes of seasonal changes in ACh sensitivity of cardiac muscle and the role of ATP in this process are discussed.

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