[Experimental study of human recombinant insulin]. / Eksperimental'noe izuchenie rekombinantnogo insulina cheloveka.

The experimental study of recombinant human insulin revealed its high specific activity. The kinetics of the hypoglycemic effect of various dosage forms of the insulin developed at the National Research Centre of Antibiotics and the dosage forms manufactured by Eli Lilly was similar. The pharmacological investigation of the dosage forms showed that they had no side effects on the vitally important organs and systems. It was concluded that the dosage forms of the gene engineered human insulin developed at the National Research Centre of Antibiotics did not differ by their characteristics from the analogous dosage forms manufactured in other countries.

[Study of general toxic and organotropic properties of clindamycin in long-term experiments]. / Izuchenie obshchetoksicheskikh i organotropnykh svoistv klindamitsina v khronicheskikh éksperimentakh.

The action of clindamycin monohydrate on the general state and weight rise, liver and kidney functions, peripheral blood count and pathomorphological state of the viscera was studied on rats in chronic experiments. Clindamycin was administered to laboratory animals orally in doses of 50, 100, 150 and 300 mg/kg. It was shown that some adverse reactions to the drug and in particular disorders in blood coagulation and morphological changes in the intestine did not depend on its dose and were due to duration of the drug use and probable development of dysbacteriosis. At the same time the disorders in the liver and kidney functions though transitory did depend, to a greater extent, on the dose and were evident after the antibiotic overdosage.

[Study of general toxic and organotropic properties of ampicillin combined with sulbactam]. / Izuchenie obshchetoksicheskikh i organotropnykh svoistv kombinatsii ampitsillina s sul'baktamom.

The effect of sulacillin, a combination of sulbactam and ampicillin (1:2), on the functions of the liver and kidneys, peripheral blood count, cardiovascular and central nervous systems was studied in acute and chronic experiments on animals of various species. The allergenic and local irritating properties of the combination were also studied. It was shown that the combination was low toxic and the interaction of sulbactam and ampicillin by the lethal effect was additive. When the combination was administered intravenously to mice, its LD50 amounted to 6 g/kg. In chronic experiments on rats parenterally given the combination in doses equivalent to the therapeutic ones there were no changes in the examined systems and organs. When used in the doses exceeding the therapeutic ones, sulacillin used during long periods induced a transitory elevation of blood levels of transaminases and alkaline phosphatases, an increase in the relative weight of the liver and kidneys, elongation the typhlon and an increase in glycogen levels in the hepatocytes without morphological changes. The combination had no significant effect of sulacillin and the painful injections alleviated by local anesthesia were recorded. The allergenic properties of the combination were moderate and did not differ from those of ampicillin. The data indicate that the combined sulacillin preparation greatly resembles its foreign analogue.

[Biologic activity and tolerance of a preparation of polyunsaturated fatty acids, obtained by a microbiological route ["biopolyene"]]. / Biologicheskaia aktivnost' i perenosimost' preparata polinenasyshchennykh zhirnykh kislot, poluchaemykh mikrobiologicheskim putem ["biopoliena"].

Biopolyene is a mixture of ethyl ethers of polyunsaturated fatty acids isolated from biomass of Entomophthora virulenta, a mycelial fungus. Its acute and chronic toxicity was studied on rats and guinea pigs. After oral administration of the preparation in single doses exceeding 50 g/kg there were no disorders in the general state of the rats. In chronic experiments with oral biopolyene in doses of 100 and 500 mg/kg and its local application to the intact skin of the animals in a dose of 1 g/kg there were no significant changes in the functional state of the liver and kidneys as well as the peripheral blood count. Insignificant changes in the serum levels of liver enzymes and coagulation were transient. The preparation showed no allergenic or immunomodulating effects. It had neither embryotoxic, teratogenic nor mutagenic action.

[Experimental study of protease C--proteolytic enzyme of microbial origin]. / Eksperimental'noe izuchenie proteazy C--proteoliticheskogo fermenta mikrobnogo proiskhozhdeniia.

The specific activity of protease C, a proteolytic enzyme isolated from Acremonium chrysogenum was studied under experimental conditions. Protease C was shown to lyse necrotic biological substrates (dry crusts of burn wounds) and blood clots. By the nature of the effect protease C was analogous to terrilytin and by the level of the effect it was superior in some experiments. Protease C was low toxic and had no mutagenic action.

[Tolerance of gentacycol--a local dosage form of gentamicin based on collagen--animal experiments]. / Perenosimost' gentatsikola--mestnoi lekarstvennoi formy gentamitsina na osnove kollagena--v éksperimentakh na zhivotnykh.

Gentacycol is a local dosage form of gentamicin based on collagen for implantation to wounds in treatment of patients with infections of soft tissues and prevention of contamination of open injuries of the bones and soft tissues. General toxic and organotropic properties of gentacycol were studied on animals with subcutaneous implantation of the dosage form in doses equivalent to the therapeutic dose for man and exceeding it 2-fold. The study showed that the dosage form had no unfavourable side effects on the animal general state, hearing, the functional state of the liver and kidneys and the peripheral blood. In the doses tested gentacycol did not influence the indices of the cardiovascular system and neuromuscular conduction. Morphological examination of the skin and hypodermic tissues in the implantation site revealed no damaging action of the dosage form on the surrounding tissues.

[Experimental study of a novel formulation for local application based on gentamicin, erythromycin and protease C]. / Eksperimental'noe issledovanie novogo lekarstvennogo preparata dlia mestnogo primeneniia na osnove gentamitsina, éritromitsina i proteazy C.

A novel formulation for local application based on an enzyme of microbial origin, C protease, and two antibiotics, gentamicin and erythromycin, was studied on various experimental models in rats with respect to its effect on necrotic tissues and recovery of the skin and hypodermic tissue defects due to wounds. It was found that even within the first days of the application the formulation induced lysis of the primary crust, lowered exudation and promoted debridement, reduced the wound size and completely closed it. By its effect the formulation was similar to iruxol. In chronic experiments on animals with long-term application of the formulation to the skin and wound surfaces it showed no unfavourable general toxic or organotropic properties. The local irritating action was insignificant.

[Hypotension caused by intravenous infusion of rifampicin and its relation to the administration schedule]. / Gipotenziia, vyzyvaemaia vnutrivennym vvedeniem rifampitsina, i ee zavisimost' ot rezhima primeneniia antibiotika.

It was shown in studies on animals that bolus administration of rifampicin induced hypotension whose severity depended on the rate of the antibiotic administration. When the antibiotic was administered in the 5-, 10- or 15-minute regimen in a dose of 10 mg/kg the maximum decrease in blood pressure was 44, 34 or 21% of the initial level and the maximum antibiotic concentration attained in the blood was 34.4, 27.2 or 22.6 micrograms/ml, respectively. With the infusion for 30 minutes, the maximum antibiotic concentration in the blood was 17.6 micrograms/ml and the blood pressure did not undergo any significant changes. When the rate of the antibiotic infusion was high there was pharmacokinetic heterogeneity of the blood serum and biophase which could lead to unpredictable results. After repeated administrations of rifampicin to the same animals pronounced tachyphylaxis to the antibiotic was noted, which manifested itself in decreasing of hypotension, though the serum antibiotic level was 1.5 to 2 times higher that the initial one. It was concluded that administration of rifampicin in the therapeutic dose equal to 10 mg/kg for 30 minutes was the most sparing regimen for the antibiotic bolus intravenous infusion. Gradual increase in the antibiotic dose and administration rate in patients is possible under careful control of blood pressure and pharmacokinetic studies.

[General toxic and organotropic properties of cefotaxime in acute and chronic experiments]. / Izuchenie obshchetoksicheskikh i organotropnykh svoistv tsefotaksima v ostrykh i khronicheskikh éksperimentakh.

The action of cefotaxime on the functions of the liver and kidneys, the peripheral blood count, growth and development of young animals, blood circulation, respiration and the central nervous system was studied in acute and chronic experiments on mice and rats. Allergenic, immunomodulating, embryotoxic and teratogenic properties of the antibiotic were also studied. Cefotaxime was shown to be low toxic. After intravenous administration to mice, its LD50 amounted to 7000 (6295-7805) mg/kg. In the chronic experiments on rats with intramuscular and intravenous administration of the antibiotic in doses equivalent by the body surface to the course doses for humans there were no significant shifts in the function of the liver and kidneys, the count of the blood formed elements and the histologic pattern of the viscera. In the therapeutic doses the antibiotic had no action on hemopoiesis, respiration and the central nervous system. The allergenic properties of cefotaxime were slightly pronounced and similar to those of klaforan. The antibiotic had no action on the host immunity and showed no embryotoxic and teratogenic properties. After intravenous and intramuscular administration, cefotaxime had a slight irritating action on the tissues which was similar to that of klaforan.

[Mechanism of hypotension induced by rifampicin during intravenous administration]. / K mekhanizmu gipotenii, vyzyvaemoi rifampitsinom pri vnutrivennom vvedenii.

In vivo and in vitro experiments showed that the mechanism of hypotension induced by rifampicin was not associated with its effect on peripheral m- and n-cholinoreactive and adrenoreactive systems. It was due to the direct action of the drug on the vessel muscular wall and its mediated effect on the histaminergic systems participating in vascular tension control.

[General toxic and organotropic properties of azlocillin in acute and chronic experiments]. / Izuchenie obshchetoksicheskikh i organotropnykh svoistv azlotsillina v ostrom i khronicheskom éksperimente.

The general toxic and organotropic properties of azlocillin were studied in acute and chronic experiments with various animal species. By the body surface area the doses of azlocillin were equivalent to the drug average and maximum course doses for humans. The aim of the study was to determine the drug dose inducing certain side effects. It was found that only in a dose equivalent to the maximum course dose for humans i. e. 300 g the drug induced a transient increase in the blood levels of aspartate aminotransferase and alkaline phosphatase and some increase in the coagulation time. The allergenic properties of the drug were slightly pronounced. Within the tested doses azlocillin did not affect the peripheral blood indices and showed no immunomodulating embryotoxic, teratogenic or mutagenic effect. The experimental data indicated that the range between the drug therapeutic course doses and the doses inducing certain side effects was significant. This is evidence of a sufficiently high level of azlocillin safety.

[Pharmacokinetics of amikacin in the perilymph and blood serum. An approach to the comparative evaluation of the potential ototoxicity of aminoglycoside antibiotics]. / Farmakonietika amikatsina v perilimfe i syvorotke krovi. Podkhod k sravnitel'noi otsenke potentsial'noi ototoksichnosti antibiotikov-aminoglikozidov.

The pharmacokinetics of amikacin in serum and perilymph was studied on guinea pigs treated with its single subcutaneous administrations in doses of 100, 200, 400 and 800 mg/kg. Proportional relation between the values of the areas under the concentration against time curves of the antibiotic in serum and perilymph was shown. It suggested that the level of the antibiotic penetration into the internal ear might be predicted by the area under the concentration against time curve of the aminoglycoside. It was demonstrated that in equitherapeutic doses when D/Deq = 1 aminoglycosides had different areas under the concentration against time curve. Thus, the area under the curve of amikacin was 2.2 times higher than that of sisomicin. It was also demonstrated that the angle coefficient characterizing the relationship between the area under the concentration against time curve in perilymph and the dose standardized with respect to the equitherapeutic value was markedly higher for amikacin than for sisomicin.

[Sisomycin pharmacokinetics in the perilymph and blood serum--an approach to predicting its ototoxic effect]. / Izuchenie farmakokinetiki sizomitsina v perilimfe i syvorotke krovi--podkhod k prognozirovaniiu ototoksicheskogo éffekta.

To elucidate the possibility of predicting the level of aminoglycoside antibiotic penetration into the fluids of the internal ear by the antibiotic blood levels, the pharmacokinetics of sisomicin in the perilymph and blood serum was studied on guinea pigs. The antibiotic was administered to the animals subcutaneously in doses of 50, 100 and 200 mg/kg. On the basis of the comparison of the sisomicin concentrations in the perilymph normalized against the dose it was concluded that the pharmacokinetics of sisomicin in the perilymph and blood serum of the animals was linear. Comparison of the areas under the curves of the antibiotic concentration versus time in the perilymph (AUCp) and blood serum (AUCs) showed that the tissue availability of the antibiotic in this study characterized by its penetration into the perilymph and defined by the ratio of the AUCp to AUCs amounted to 55 per cent. In a two-compartment model it was not possible to predict the antibiotic levels in the perilymph by concentrations in the blood. However, by the antibiotic blood levels it was possible to characterize in a complex the pharmacokinetic behaviour of the antibiotic in the perilymph by predicting the areas under the respective curves of the antibiotic concentration versus time. The proportional relation between the values of the AUCp and AUCs suggested that the level of the antibiotic penetration into the internal ear and consequently the intensity of the potential ototoxic effect could be more reliably predicted not by separate values of the antibiotic concentration but by the areas under curves of aminoglycoside concentrations versus time.

[Experimental study of the pharmacological properties of amikacin]. / Izuchenie farmakologicheskikh svoistv amikatsina v éksperimente.

The general toxic and organotropic properties of amikacin were studied in acute and chronic experiments. The antibiotic was administered to the experimental animals in the doses equivalent to the therapeutic ones for humans or exceeding them 2-3 times. No unfavourable effect of amikacin in the above doses on hearing was observed. A certain increase in the level of urea nitrogen in the blood serum and leukopenia were registered only after administration of the highest drug dose exceeding 2 times the equivalent treatment dose of amikacin for humans (15 g). After the use of this dose separate microfocal necrotic lesions were detected morphologically in the proximal tubules of the kidneys. The lesions were of a transitory nature. It is concluded that amikacin has a wide range of therapeutic doses and the level of its safety is rather high.

[Experimental study of lincomycin ointment and gel]. / Eksperimental'noe izuchenie mazi i gelia linkomitsina.

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.

[General toxic and organotropic properties of sisomicin sulfate in chronic experiments on animals]. / IZuchenie obshchetoksicheskikh i organotropnykh svoistv sizomitsina sul'fata v khronicheskikh opytakh na zhivotnykh.

General toxic and organotropic properties of sisomicin sulfate were studied in chronic experiments on different animal species with the use of doses equivalent to therapeutic ones in humans or exceeding them by several times. When sisomicin was injected intramuscularly for 4 weeks in a dose equivalent by the body surface to the average daily dose for humans, no significant effect on the macroorganism was observed. When the dose was 2--4 times higher, a significant increase in the blood serum levels of the urea nitrogen, creatinine, bilirubin and aspartate aminotransferase was shown. Histological examinations revealed focal adiposis of epithelial cells of the convoluted tubules of the kidney and small areas of parenchymal necrosis. Impairment of vestibular and auditory functions was detected in some animals.

[Effect of sisomicin i on elements of the peripheral nervous system]. / O vliianii sizomitsina na nekotorye élementy perifericheskoi nervnoi sistemy.

In long-term experiments with anesthetized cats and albino mice sisomicin and gentamicin were found to impair the impulse conduction in the skeletal muscle synapses and in the ganglia of the sympathetic and parasympathetic nervous systems. Comparison of the drug doses inducing the above effects in experimental animals showed that the neuroblocking activity of sisomicin was almost 3 times higher than that of gentamicin. Since the therapeutic doses of sisomicin used in the treatment of patients are 2.5-3 times lower than the respective doses of gentamicin, it must be considered that both the drugs had the same ranges of the therapeutic activity from the standpoint of their side effects.