Toxicity of tobramycin in single and multiple administrations to laboratory animals]

The LD50 of tobramycin sulphate administered intravenously, intraperitoneally, subcutaneously and orally to albino mice was 77 (73--82), 262 (234--294), 560 (500--627) and greater than 10500 mg/kg respectively. With an increase in the rate of intravenous administration tobramycin toxicity increased. When tobramycin sulphate was administered subcutaneously daily in multiple doses equivalent to the daily therapeutic doses from humans (calculated for the body surface) and in the doses 2--3 times higher than the above therapeutic ones, the function of the kidneys, liver and the Preier's reflex did not significantly change. When the doses were 8--10 times higher than the therapeutic ones, an increase in the urea level in the blood serum, disappearance and a decrease in the Preier's reflex were observed. The impairment of the kidney function was accompanied by degenerative changes in the convoluted tubules of the kidneys, ischemia of the renal glomeruli and appearance of protein secretion in their capsule cavities. The picture of the peripheral blood did not suffer significant changes. The studies on the acute and chronic toxicity of tobramycin sulphate prepared at the Institute of New Antibiotics showed that the drug did not differ from the import tobramycin samples.     

Use of sodium nucleinate and its combinations with bacterial polysaccharides for preventing the nephrotoxic action of aminoglycoside antibiotics

Possible prevention of the nephrotoxic effect of different doses of aminoglycoside antibiotics, such as monomycin, kanamycin and gentamicin was studied experimentally on chinchilla rabbits. Substances increasing the cell resistance (sodium nucleinate, prodigiosan and pyrogenal alone and sodium nucleinate combinations with the bacterial polysaccharides) were used. It was shown that sodium nucleinate prevented nephrotoxicity of the aminoglycosides in the doses 2.5 times higher than the therapeutic ones. The combined use of sodium nucleinate with pyrogenal or prodigiosan was most effective. It prevented the nephrotoxic effect of the antibiotics in the doses 5 times higher than the therapeutic ones.     

Coamide stimulation of immunogenesis during experimental levomycetin therapy]

The effect of various doses of levomycetin on immunogenesis and capacity of coamide for stimulation of immunogenesis in levomycetin therapy was studied. It was found that massive five-fold doses of levomycetin sodium succinate (I and 0.5 g/kg) administered parenterally or orally inhibited immunogenesis, the inhibition being more pronounced on administration of the antibiotic per os. When levomycetin sodium succinate was used in massive doses (1 g/kg) in combination with coamide (0.5 mg/kg) the inhibition of the immune response to the antigenic stimulation was less pronounced.     

Water and sodium intake of wild and New Zealand Rabbits following angiotensin

Two rabbit strains, New Zealand (laboratory) rabbits and Australian wild rabbits, both members of the Oryctolagus cuniculus genus were studied. New Zealand rabbits under control conditions consumed 2-5 times more water and 8-30 times more 0.5 M NaCl/kg body weight than wild rabbits. Single injections of angiotensin II or III administered ICV did not induce water drinking in either strain. Acute ICV infusion of angiotensin II also did not influence water intake, but after several days of administration, induced increased sodium intake. Intravenous infusion of graded doses of angiotensin II induced diuresis only at the higher doses in both strains. In New Zealand rabbits, this was accompanied by a commensurate and concurrent increase in water intake. Intravenous infusion of angiotensin II also induced urinary sodium loss that was either accompanied or followed by increased sodium intake. The development of salt appetite in both strains was preceded by sodium loss.     

Pharmacokinetics of poly(hydroxyethyl-l-asparagine)-coated liposomes is superior over that of PEG-coated liposomes at low lipid dose and upon repeated administration

'Stealth' liposomes with a poly(ethylene glycol) (PEG) coating are frequently studied for drug delivery and diagnostic purposes because of their prolonged blood circulation kinetics. However, several recent reports have demonstrated that PEG-liposomes are rapidly cleared at single low lipid doses (<1 micromol/kg) and upon repeated administration (time interval between the injections 5 days-4 weeks). Recently, poly(amino acid)-based stealth liposome coatings have been developed as alternative to the PEG-coating. In this study, the pharmacokinetic behavior of liposomes coated with the poly(amino acid) poly(hydroxyethyl-l-asparagine) (PHEA) was evaluated at low lipid doses and upon repeated administration in rats. Blood circulation times and hepatosplenic localization of PHEA-liposomes were assessed after intravenous injection. When administered at a dose of 0.25 micromol/kg or less, PHEA-liposomes showed significantly longer blood circulation times than PEG-liposomes. A second dose of PHEA-liposomes 1 week after the first injection was less rapidly cleared from the circulation than a second dose of PEG-liposomes. Although the mechanisms behind these observations are still not clear yet, the use of PHEA-liposomes appears beneficial when single low lipid doses and/or repeated dosing schedules are being applied.     

A HPLC method for the analysis of germacrone in rabbit plasma and its application to a pharmacokinetic study of germacrone after administration of zedoary turmeric oil

A validated new, simple and highly sensitive reversed-phase HPLC method is developed for studying the pharmacokinetics of germacrone after intravenous administration of zedoary turmeric oil (ZTO) oil-in-water microemulsion. The method did not require a complex and expensive equipment. A high extraction recovery (>80%) of germacrone was obtained. Linear calibration curves obtained with the peak-area ratio (y) of germacrone to internal standard (tanshinoneIIA) versus drug concentration (x) were found to be linear between 8.08 and 808 ng/ml. The limit of quantitation was 8.08 ng/ml.The monitored compounds were completely separated from others in ZTO and from endogenous species in plasma by HPLC. Pharmacokinetic investigations were performed on 18 male rabbits after intravenous administration of ZTO microemulsion via the ear vein at germacrone doses of 3.2, 6.4 and 9.6 mg/kg. The plasma concentration-time data fit to a two-compartment intravenous model with a weight of 1/C(2) (C: germacrone concentration in plasma). Germacrone exhibited linear pharmacokinetics after intravenous administration of ZTO microemulsion to rabbits over the germacrone dose range 3.2-9.6 mg/ml.     

Pharmacokinetics of penicillins in the blood of dogs administered the combination preparation, ampiox, internally]

The pharmacokinetics of penicillins in the blood of dogs treated with ampiox, a combination of ampicillin and oxacillin at a ratio of 1 : 1 was studied. The drug was administered orally in single or repeated doses of 25, 50 and 100 mg/kg. The maximum levels of ampicillin in the blood serum were observed 1 hour after a single administration of the drug. The therapeutic concentrations of the antibiotic were preserved for 6 hours, its value being depended on the dose used. The maximum concentration of oxacillin was detected 1 hour after the drug administration in various doses and it was preserved in the blood at the therapeutic levels for 3 hours. The dynamics of circulation of ampicillin and oxacillin administered separately did not differ from that established for the use of ampiox. The regularities of the pharmacokinetics of ampiox on its repeated use remained practically unchanged.     

Plasma concentrations of 9-deoxo-16,16-dimethyl-9-methylene-PGE2 in Rhesus monkeys after administration by various routes

A method is described for the estimation of 9-deoxo-16,16-dimethyl-9-methylene-PGE₂ by double antibody radioimmunoassay. Plasma samples obtained from animals treated with 9-methylene-16,16-dimethyl-PGE₂,1-adamantanamine salt were extracted with diethyl ether to recover the prostaglandin. The validation of sample preparation and assay procedure are presented. Rhesus females were treated by several routes of administration and the samples assayed for drug content. Maximum blood levels were probably reached 30 minutes following subcutaneous injection and within 30 seconds of an intravenous injection. Results of the acute intravenous injection indicate an initial half-life of approximately one minute in peripheral circulation. Continuous intravenous infusion at 3 increasing doses of this compound resulted in a stepwise increase in plasma drug concentrations. Vaginal administration of 9-methylene-16,16-dimethyl-PGE₂,1-adamantanamine salt in suppositories produced a dose dependent increase in plasma drug concentration. Higher plasma drug concentrations were produced when the prostaglandin was delivered in H-15 base suppositories than in E-76 base suppositories.     

Effect of rifampicin on the synthesis of antibodies to fraction I of vaccine EV]

Multifactorial analysis was used to study the influence of rifampicin on the dynamics of synthesis of antibodies belonging to IgM and IgG classes in mice immunized by fraction I of the vaccinal strain EV. Equations and quadric surfaces describing individual dynamics of antibody formation within a wide range of antibiotic doses and time of antibody content determination were developed by the experimental data. It was shown that within the range of the doses corresponding to the therapeutic ones in man rifampicin stimulated antibody formation. It had an inhibitory effect on antibody genesis only when used in the doses many times higher than the therapeutic ones.     

Acute toxicity of carminomycin administered perorally to laboratory animals

Rather high species sensitivity to carminomycin was found in the experiment with albino mice, rats, guinea pigs, rabbits and dogs. The highest difference in the antibiotic toxicity for various species of the laboratory animals was shown on oral administration of the drug which was due to the differences in the antibiotic absorption from the gastro-intestinal tract. On single oral administration to the dogs in toxic or lethal doses the antibiotic suppressed the blood formation up to aplasia of the bone marrow. The equitoxic doses of carminomycin on its single oral and intravenous administration differed approximately by 3 times. Carminomycin had no effect on the smooth muscles of the isolated rabbit ear vessels and cat intestine in situ. The antibiotic had an irritating effect on the rabbit eye mucosa. Carminomycin had no skin-irritating effect.     

Effect of prodigiozan and pyrimidine derivatives on the effectiveness of the antibiotic therapy of experimental infections]

The effect of prodigiozan and pyrimidine derivatives, such as methyluracyl, oxymetacyl and 2-methyl-4-amino-6-hydroxypyrimidine on the efficiency of antibiotic therapy of experimental infections caused by Staph. aures and E. Coli under conditions of immune depression due to levomycetin, prednisolone, 6-mercaptopurine and ionizing radiation was studied. The effect of prodigiozan on the efficiency of the antibiotic treatment of staphylococcal infection in the presence of the immune depression due to 6-mercatopurine, levomycetin and prednisolone was higher than that of pyrimidines. The combined use of prodigiozan and pyrimidines usually was not more effective than the use of every drug alone. The efficiency of the drugs in radiation disease was the same. After prednisolone administration prodigiozan increased the host resistance to the infection without the antibiotic use.     

Cephazolin and cephapirin circulation in the blood of rabbits

Circulation of 2 semi-synthetic cephalosporins, i. e. cephazoline and cephapyrine in the blood of rabbits after their intramuscular administration in single doses of 5 and 20 mg/kg was studied. It was found that the antibiotics were well adsorbed into the blood. Their maximum blood levels were achieved 15--30 minutes after administration. Cephazoline provided a higher blood level persisting for longer periods of time as compared to cephapyrine. The value of the time of the two-fold decrease in the cephazoline blood level was higher. A four-fold increase in the dose of the cephalosporines resulted in an increase in their blood levels but did not induce any significant increase in the time of their circulation.     

Amphotericin B fever in rabbits

The slow intravenous infusion of amphotericin B (amB) induced a moderate, partially dose-dependent fever in male adult rabbits, whereas the iv bolus injection of the drug was less pyrogenic and only at higher doses. Higher, more sustained fevers occured with doses of 2.5 and 5.0 mg of amB. The threshold pyrogenic dose of amB in the rabbits tested approached 0.16 mg per Kg (ΔT greater than 0.4°C). Endotoxin-tolerant rabbits had a lower increase in rectal temperature when challenged with amB. No fever occured in mice treated with amB.     

Relationship of bispectral index values, haemodynamic changes and recovery times during sevoflurane or propofol anaesthesia in rabbits

The aim of this study was to determine and compare the degree of hypnosis achieved during propofol or sevoflurane anaesthesia in rabbits using bispectral index (BIS), and to evaluate its usefulness as a predictor of both haemodynamic changes during anaesthesia and recovery times. Twenty adult male New Zealand White rabbits, average weight 4.4 +/- 0.4 kg, were used for this study. Animals were randomly allocated to one of two groups with 10 rabbits/group. An electroencephalographic recording was obtained from each conscious rabbit prior to drug administration. All animals received buprenorphine as a preanaesthetic medication (0.05 mg/kg, intravenous [i.v.]). Anaesthesia was induced with propofol (8 mg/kg, i.v.) in all animals; 10 rabbits were maintained with sevoflurane via inhalation (1 minimum alveolar concentration--end-tidal sevoflurane concentration of 3.7%--at a fresh gas flow rate of 3 L/min; group I), and 10 were maintained with i.v. propofol (0.6 mg/kg/min; group II). The rabbits were orotracheally intubated and spontaneous ventilation was maintained throughout the study (100% oxygen). After abdominal surgery through a ventral midline laparotomy, rabbits were allowed to recover from anaesthesia. Cardiovascular variables and BIS values were recorded at intervals throughout the procedure, as was the duration of recovery from anaesthesia. In both groups, mean BIS values were significantly decreased immediately after induction, compared with baseline values obtained during consciousness. Anaesthetic depth (evaluated by clinical observation) was similar in both groups; however, group II rabbits had significantly higher (P<0.001) BIS values from 30 s before incision until anaesthesia was discontinued. There was no significant difference in BIS recorded 1 and 5 min after incision as compared with values obtained 30 s before incision in either group. During sevoflurane or propofol administration, correlations were found between BIS values and mean arterial blood pressure (MABP), and between BIS values and heart rate (HR). Mean BIS values at discontinuation of administration of the anaesthetic agent were greater in group II (69.1 +/- 6.0) than in group I (49.3 +/- 2.2). However, recovery from anaesthesia was significantly longer in group II (38.4 +/- 7.2 min) than in group I (11.5 +/- 2.5 min). In conclusion, BIS can be used to differentiate between conscious and unconscious states during anaesthesia in rabbits. BIS values derived from an electroencephalogram at the end of anaesthesia were not useful for predicting the speed of anaesthetic recovery in sevoflurane or propofol-anaesthetized rabbits undergoing abdominal surgery. Despite the correlation found between BIS and haemodynamic parameters, its usefulness as a predictor of clinically important changes in arterial blood pressure and HR in anaesthetized rabbits was limited.     

Pharmacology of gentamicin sulfate]

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.     

General toxic and organotropic properties of cefotaxime in acute and chronic experiments

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.     

Slow intravenous administration of low dose aspirin inhibits both vascular and platelet cyclooxygenase activity: an experimental study in the rat

Aspirin irreversibly inhibits cyclooxygenase, thus preventing thromboxane (Tx)A2 production in platelets and prostacyclin in vascular cells. While it is generally accepted that the inhibitory effect of low dose aspirin is cumulative on platelet cyclooxygenase, it is still a matter of debate whether a similar phenomenon also occurs on vascular cyclooxygenase. We have measured in anesthetized rats the inhibitory effect of two doses of aspirin (2.5 and 5.0 mg/kg), given intravenously either as a bolus or as a continuous infusion (for 30 min), on platelet TxB2 and 6-ketoprostaglandin F1 alpha generation by different vascular segments. Aspirin significantly inhibited both platelet and vascular cyclooxygenase independently of the rate of drug administration. The aspirin peak plasma levels at the end of bolus injection was about 170 times higher than the average level measured during the slow infusion (1.21 +/- 0.15 micrograms/ml). At this concentration aspirin did not affect in vitro either platelet or vascular cyclooxygenase activity. Thus the inhibitory effect of aspirin on both platelet and vascular cyclooxygenase seems to be related to total exposure of the enzyme to the drug rather than to the maximal drug concentration attainable in the systemic circulation. These findings may be relevant to the current debate on optimal conditions for the biochemical selectivity of aspirin as an antithrombotic drug.     

Age peculiarities in the effect of M- and N-cholinolytics on the activity of the epileptogenic zone in the rabbit hippocampus]

In experiments on 6-10, 16-20-day and adult rabbits, electrochimiotrodes were chronically implanted into the dorsal hippocamp. Direct application of a M-cholinolytic, metamizyl, or N-cholinolytic, gangleron, to penicillin-induced epileptogenic zone in the hippocamp inhibited seizures in rabbits of all age groups. The intensity of interseizure epileptiform discharges in the EEG did not change under the action of cholinolytics in adult and 6-10-day rabbits, and decreased in 16-20-day ones. Parenteral administration of gangleron caused the same effect on the activity of epileptogenic zone, as its direct application to the hippocamp. Parenteral administration of metamizyl inhibited seizures in young animals (similarly to its direct application to the hippocamp), but increased the seizures and interseizure discharges in adult rabbits. Therefore, already to the 6th day of postnatal life of rabbits, blocking of the cholinoreactive system of the hippocamp may inhibit circulation of seizural discharges along closed neuronal circuits, which is necessary for the formation of the seizure.     

Antitumor activity of doxorubicin in the treatment of hemocytoblastosis La and various ascites tumors in mice

Antitumor activity of doxorubicin made in the USSR was studied on mice in respect to three transplantable tumors (lymphadenosis NK/LI, sarcoma 37 and Ehrlich's carcinoma) and hemocytoblastosis La. Doxorubicin injected intravenously 4 times was shown to be highly active against the above ascites tumors. The highest inhibitory effect of doxorubicin was observed in respect to the development of Ehrlich's carcinoma. By the selectivity of the therapeutic effect on this tumor it was superior to rubomycin and carminomycin. A high antileukemic activity of doxorubicin in respect to hemocytoblastosis La was shown. In experiments with this leukemia, intravenous injection of doxorubicin provided a higher efficacy than intraperitoneal injection. When used intravenously in the doses equivalent by their toxicity doxorubicin was inferior to rubomycin in terms of the therapeutic effect on leukemia La. However, on intraperitoneal injection of the drugs rubomycin showed no such advantage. Doxorubicin made in the USSR did not differ by its antitumor activity from the analogous foreign drug.     

Pharmacokinetics of poly(hydroxyethyl-l-asparagine)-coated liposomes is superior over that of PEG-coated liposomes at low lipid dose and upon repeated administration

‘Stealth’ liposomes with a poly(ethylene glycol) (PEG) coating are frequently studied for drug delivery and diagnostic purposes because of their prolonged blood circulation kinetics. However, several recent reports have demonstrated that PEG-liposomes are rapidly cleared at single low lipid doses (< 1 μmol/kg) and upon repeated administration (time interval between the injections 5 days-4 weeks). Recently, poly(amino acid)-based stealth liposome coatings have been developed as alternative to the PEG-coating. In this study, the pharmacokinetic behavior of liposomes coated with the poly(amino acid) poly(hydroxyethyl-l-asparagine) (PHEA) was evaluated at low lipid doses and upon repeated administration in rats. Blood circulation times and hepatosplenic localization of PHEA-liposomes were assessed after intravenous injection. When administered at a dose of 0.25 μmol/kg or less, PHEA-liposomes showed significantly longer blood circulation times than PEG-liposomes. A second dose of PHEA-liposomes 1 week after the first injection was less rapidly cleared from the circulation than a second dose of PEG-liposomes. Although the mechanisms behind these observations are still not clear yet, the use of PHEA-liposomes appears beneficial when single low lipid doses and/or repeated dosing schedules are being applied.