[Organic solvents for determination of bacterial endotoxin index in water-insoluble pharmaceutical substances].

Substances for manufacture of parenteral drugs require control by the "Bacterial Endotoxin" (BE) index with the LAL-test. The aim of the study was to show possible applicability of organic solvents in BE determination by the gel-thromb test in case of water-insoluble pharmaceutical substances. The results confirmed that ethyl alcohol practically had no effect on the endotoxin activity. In the routine assays it is advisable to test solutions of the substances at the alcohol concentration of 6% below.

[Pharmacokinetics of n-(5-oxynicotinoyl)-L-glutamic acid calcium salt upon bolus administration in rats and rabbits: interspecies extrapolation].

The pharmacokinetics of N-(5-oxynicotinoyl)-L-glutamate (ONG) was studied in rats (doses, 20, 100 and 500 mg/kg) and rabbits (50 mg/kg) after bolus administration of calcium salt of N-(5-oxynicotinoyl)-L-glutamic acid (Ampasse preparation). The ONG concentration in the blood serum was determined by HPLC assay with fluorimetric detection. The lower limit of accurate detection for ONG was 100 ng/ml. The ONG pharmacokinetics in rats was linear at relatively small doses (20-100 mg/kg) but nonlinear at a large dose (500 mg/kg). The ONG concentration decay had a two-phase character in both rats and rabbits, so that the pharmacokinetic profiles were fitted to a biexponential equation of the two-compartment model. Systemic pharmacokinetic parameters determined in rats and rabbits, respectively, were as follows: total clearance, 18 and 15 ml/(min kg); steady state distribution volume, 330 and 880 ml/kg; mean retention time, 0.3 and 1.0 h; half-life, 0.73 and 2.3 h. Using the allometric approach to the interspecies extrapolation of the pharmacokinetic data, the half-life of ONG in humans is predicted to be 4 h.

[Estimation of the efficacy of screened natural hypolipidemic compounds in a model of rabbit hypercholesterolemia]. / Otsenka éffektivnosti otobrannykh prirodnykh gipolipidemicheskikh veshchestv na modeli giperkholesterinemii u krolikov.

Thirteen strains producing hydrophobic compounds with high hypolipidemic activity were screened among 657 tested strains of fungi, actinomycetes and bacteria with the use of 2 models. The further aim of the study was to estimate the efficacy of the compounds with respect to their ability to inhibit cholesterol synthesis in vivo. For that purpose a model of hyperlipidemia in rabbits was used. The model provided screening of 9 new compounds that showed satisfactory hypolipidemic effect evident from a significant decrease of the lipid levels in the rabbit serum. The study of the serum lipid profile revealed that the inhibitory effect of compounds No. 16 and No. 281 was similar to that of lovastatin whereas the serum level of general cholesterol remained decreased for a longer period. Compound No. 25 was of interest because of its possible use in low doses and significant effect on the serum triglyceride fraction.

[Aprotinin antiviral aerosol: study of the local irritating and allergenic action after inhalation]. / Antivirusnyi aérozol' aprotinina: izuchenie mestnorazdrazhaiushchego i allergiziruiushchego deistviia pri ingaliatsionnom vvedenii.

The aerosol of aprotinin, a natural low molecular weight polypeptide (m.w. about 160 kD) inhibiting a wide range of serine proteases may be used as an antiviral drug. The animal studies showed that it had no local irritating action on the mucosa. A long-term use of aprotinin in the form of a fine aerosol practically induced no allergenic side effects. The results of the study indicative of the absence of the allergic complications made it possible to recommend the aprotinin inhalations as a safe means in the treatment and prophylaxis of viral infections of the respiratory tract.

[The antiviral aerosol aprotinin. General effect on the body after inhalation administration]. / Antivirusnyi aérozol' aprotinina. Obshchee vozdeistvie na organizm pri ingaliatsionnom vvedenii.

A new medicine for the treatment of respiratory viral infections is described. It contains aprotinin, a natural inhibitor of proteases, and is used in the form of a fine aerosol for inhalation or intra-respiratory instillation. To estimate its innocuousness, the inhalation effect of the aerosol was studied on animals of two species. The experiments included examination of the functional state of the central nervous and cardiovascular systems, determination of the blood cell composition and biochemical blood count, morphological and histological investigation of the internal organs. The toxicological studies showed that aprotinin inhalation induced no adverse reactions which made it possible to recommend the aprotinin inhalation for the use in the treatment and prophylaxis of infections caused by a wide variety of respiratory viruses in humans.

[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.