[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.

[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.

[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.

[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.

[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.

[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.

[Toxicity of anti-tumor preparations after intracranial, subarachnoid and suboccipital administration (experimental study)]. / Toksichnost' protivoopukholevykh preparatov pri vnutrimozgovom, subarakhnoidal'nom i suboktsipital'nom vvedenii (éksperimental'noe issledovanie.

Experiments were conducted on animals to study intrathecal injection of agents differing in the mechanism of action: variamycin, mitramycin, reumycin, proxyphein, and prospidin. Their acute toxicity in a single intracerebral injection and chronic toxicity in repeated suboccipital injection were studied. The brains of animals who died or were killed were studied pathomorphologically in different periods. Intracerebrally and suboccipitally injected variamycin and mitramycin induced marked toxic reactions, even the death of animals, and cannot be recommended for the neurooncological clinic. The antineoplastic reumycin, proxyphein, and prospidin cause no toxic reactions of the brain and meninges on injection by the above mentioned methods; they are recommended for approbation in the neurooncological clinic for the treatment of patients with malignant tumors of the brain by injection into the system of the cerebrospinal fluid.

[Pharmacokinetic analysis of the nephrotoxic effect of sisomycin]. / Farmakokineticheskii analiz nefrotoksicheskogo éffekta sizomitsina.

The kinetics of the urea nitrogen in serum was studied on anesthetized cats with constant concentrations of sisomycin in the blood. A correlation between the nephrotoxic effect of sisomycin and its concentration in the blood serum was found. High nephrotoxicity of sisomycin as compared to that of gentamicin, kanamycin or streptomycin under conditions of their equal levels in the blood was revealed on the basis of the above correlation. Still, when the antibiotic concentrations in the blood serum were maintained at the respective therapeutic levels, the nephrotoxic effects of sisomycin and gentamicin were almost equal. The above correlation was used for calculation of the maximum value of the sisomycin safe concentration in blood serum. The safe concentration of gentamicin in blood serum is 8 micrograms/ml, while that of sisomycin in 6 micrograms/ml. This approach may be used in estimation of safe concentrations for new aminoglycosides.

[Parameters of the toxic action of antibiotic derivatives of aureolic acid in acute and subchronic experiments]. / Parametry toksicheskogo deistviia antibiotikor--proizvodnykh aureolovoi kisloty v ostrom i subkhronicheskom opytakh

The parameters of the lethal effect of aureolic acid derivatives, such as mithramycin, variamycin and olivomycin were studied on mice, rats and rabbits. As for the most of the administration routes the first two drugs were characterized by irregular distribution of resistance to thier lethal effect, which was mathematically expressed by polymodality of the dose-response curve. The above drugs were characterized by cumulative properties. The toxicity parameters depended on the animal species and administration route.

[Dependence of the nephrotoxic effect of kanamycin on its concentration in the blood (an experimental study)]. / Zavisimost' nefrotoksicheskogo éffekta kanamitsina ot ego kontsentratsii v krovi (éksperimental'noe issledovanie).

The kinetics of changes in the urea nitrogen level of the serum was studied experimentally on narcotized cats with constant blood levels of kanamycin. A relationship between the intensity of the nephrotoxic effect of kanamycin and its blood level was found. On the basis of this relationship lower nephrotoxicity of kanamycin as compared to that of gentamicin and streptomycin under conditions of their constant blood levels was shown. However, the concentrations of gentamicin and kanamycin provided in the blood by their use in therapeutic doses differeing 3--4 times allow a conclusion that the nephrotoxic effect of kanamycin and gentamicin to be practically the same.

[Experimental study of the organotropic properties of dactinomycin]. / Eksperimental'noe izuchenie organotropnykh svoistv daktinomitsina.

Dactinomycin was studied pharmacologically on experimental animals. When dactinomycin was administered to the test-animals in doses close to the therapeutic ones for humans, suppression of the bone marrow blood formation was registered in spite of some increase in the number of the reticulocytes and thrombocytes in the peripheral blood and acceleration of the process of blood coagulation. In addition, the urea nitrogen blood levels increased. When the drug was administered in higher doses, suppression of the bone marrow blood formation was pronounced and the number of the leucocytes, reticulocytes and thrombocytes in the peripheral blood decreased. The rate of the blood coagulation decreased, while the biochemical values of the blood were indicative of impairement of the liver and kidney functions.

[Pharmacokinetic validation of the nephrotoxic action of sisomycin. The relationship between nephrotoxicity and sisomycin concentration in the blood serum of rats]. / Farmakokineticheskoe obosnovanie nefrotoksicheskogo deistviia sizomitsina. Sviaz' mezhdu nefrotoksichnost'iu i kontsentratsiei sizomitsina v syvorotke krovi krys.

The kinetics of urine nitrogen in the blood serum and morphological changes in the kidneys after a single and repeated intramuscular administrations of the antibiotic in doses of 12.5 and 25 mg/kg a day were studied in Wistar rats. When sisomycin was administered in a dose of 12.5 mg/kg, the increase in the urine nitrogen level after 1--30 injections was reversible, whereas at a dose of 25 mg/kg it became irreversible already after the 5th injection. Maximum deviations in the urine nitrogen level observed within 3--6 hours after each injection of sisomicin were recorded after the 5th injection of the drug in a dose of 12.5 mg/kg and even after the 1st injection of the drug in a dose of 25 mg/kg. The deviations increased up to the 5th and 16th injection of sisomycin in doses of 12.5 and 25 mg/kg respectively. Later the deviations were less pronounced. Regardless of the dose, adipose degeneration in renal tubules was registered after 8--16 injections of the drug. By the 30th and 16th days of the drug administration in doses of 12.5 and 25 mg/kg respectively, the above changes also decreased. On the whole, pronounced functional and morphological changes in the kidneys correlated with the antibiotic dose. Relationship between the time from the beginning of sisomycin administration and the moment when the average integral concentration of the urine nitrogen increased to the upper limit of normal and the logarithm of the average integral concentration of the antibiotic in the serum was found. The safety of the clinical schemes for the use of sisomicin was estimated with the help of this relationship with respect to its nephrotoxic effect.

[Effect of carfecillin on the body of animals in single and multiple administrations]. / Izuchenie vliianiia karfetsillina na organizm zhivotnykh pri odno- i mnogokdratnom vvedenii.

The effect of carfecillin on blood circulation, respiration, hepatic and renal functions, peripheral blood picture, growth and development of young animals was studied in acute and chronic experiments. The allergizating properties of the drug were also investigated. Carfecillin is low toxic. LD50 for albino mice on intravenous and oral administration of the drug is 782.5 and 3924 mg/kg respectively. When used repeatedly for treatment of rats in oral doses of 180 and 275 mg/kg corresponding to the daily doses for humans calculated for the body surface, carfecillin had no adverse effect on hepatic or renal function, cell composition of the blood, augmentation of the weight and relative weight of the organs of the growing animals. No detectable effect of carfecillin on arterial pressure, respiration, rhythm and amplitude of the systole was observed in acute experiments with anesthetized cats treated with the antibiotic intravenously in doses of 320 mg/kg. Histological examination of the internal organs of the rats treated with oral carfecillin during 2 months showed that the drug had an irritating effect on the gastrointestinal mucosa only in a dose of 540 mg/kg, which is 2 times higher than the equivalent daily dose for humans. Carfecillin possesses the allergizating properties and induces development of cross allergy to benzylpenicillin. The above properties were less pronounced in carfecillin than in benzylpenicillin.

[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.

[Pharmacology of gentamicin sulfate]. / K farmakologii gentamitsina sul'fata

Pharmacology of gentamicin sulfate prepared at the All-Union Research Institute of Antibiotics was studied. By the paramaters of acute toxicity the drug did not differ from a Bulgarian sample of gentamicin sulfate. Under the conditions of the acute experiment on animals it was found that only high doses of gentamicin significantly exceeding the therapeutic ones induced some decrease in the arterial pressure, respiration suppression, blocking of the neuromuscle transmission in the synapses of the skeletal muscles. The latter may be eliminated by the use of calcium chloride. Under conditions of the chronic experiment with intramuscular administration of gentamicin sulfate to the animals for 4 weeks in doses equivalent to the theraputic ones for humans, impairement of the vestibular function and albuminuria often accompanied by pronounced distrophic changes in the kidney canaliculi were observed in some animals. An increase in the drug dose resulted in more pronounced distrophic changes in the kidney tissue.

[Experimental study of the antitumor anthracycline antibiotic aclarubicin (aclacinomycin A)]. / Eksperimental'noe izuchenie protivoopukholevogo antratsiklinovogo antibiotika aklarubitsina (aklatsinomitsina A).

Aclarubicin (ACR) has a selective inhibitory effect on the synthesis of RNA in the cells. The time of the antibiotic contact with the cells is an important factor in realization of its cytotoxic activity. As compared to adriamycin, ACR has a low specific activity in lymphoid leukemia P388, melanoma B16 and lung cancer LL. The therapeutic efficacy of ACR depended on the scheme of its use: in treatment of rapidly proliferating tumors such as P388 the highest effect is attained with the daily use of the antibiotic for 9 days, in treatment of slowly developing melanoma B16 the results were more satisfactory with intermittent use of the drug on days 1, 5 and 9 after the strain transplantation. The new antibiotic was highly effective on its use either intravenously or orally.

[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.

[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.