Antibiotic penetration through the blood-brain barrier in rats and the effect on this process of proteolytic enzymes]

Penetration of penicillin, ampicillin, oxacillin, tetracycline, streptomycin and gentamycin through the hemato-encephalic barrier in rats and effect of proteolytic enzymes on the above process were studied comparatively. The levels of penetration to the brain were highest for ampicillin, then followed penicillin, tetracycline, oxacillin, streptomycin and gentamycin. Preliminary intramuscular administration of trypsin and chimotrypsin (10 mg/kg) to the animals had no effect on permeability of the hemato-encephalic barrier for the antibiotics tested, except penicillin. Higher levels of the antibiotics in the brain tissue may be explained by higher antibiotic blood levels under the effect of proteolytic enzymes.     

Results of an experimental study of the pharmacokinetics of polymyxin B sulfate]

Pharmacokinetics of polymyxin B sulfate of Soviet production was studied in various species of animals with the use of different administration routes and dosage. After a single intramuscular administration of the drug to dogs in doses of 1.1 and 2.2 mg/kg the antibiotic was detected within 5 hours at the maximum level during the 1st hour. A two-fold increase of the dose was accompanied by 1.5 times increase in the antibiotic level. Repeated administrations of polymyxin B sulfate in a dose of 4.5 mg/kg did not result in an increase in the blood level as compared to a single use of the drug. When polymyxin B sulfate was administered intravenously, the concentration peak was observed in 15 minutes independent of the dosage. Later the antibiotic level decreased. The maximum level of the drug in the mice was observed 1 hour after its intramuscular administration in a dose of 8 mg/kg, the highest levels being registered in the kidney tissues and urine.     

An evaluation of ampicillin pharmacokinetics and toxicity in guinea pigs

Sodium ampicillin was administered subcutaneously to 350-550 g male Dunkin Hartley guinea pigs at doses of 6, 8 and 10 mg/kg tid for 5 days. Over a period of 12 days, the lowest ampicillin dose appeared to be tolerated well. However, significant body weight reduction and mortality occurred with the two higher dosage regimens. Cecal cultures of dead animals confirmed the presence of Clostridium difficile, an organism associated with antibiotic-induced enterotoxemia. Assay of serum collected from ampicillin-treated animals revealed ampicillin concentrations of approximately 10 micrograms/ml at 5 minutes post-dosing which fell precipitously to less than 0.2 micrograms/ml at 60 minutes. Determination of biliary ampicillin levels during the 60 minutes after administration of a single 10 mg/kg SQ dose revealed concentrations ranging from 18 micrograms/ml to 90 micrograms/ml. Estimates of total urinary ampicillin content after a single 10 mg/kg SQ dose were less than 500 micrograms/animal at 7.5 minutes, but increased to greater than 2000 micrograms/animal at 60 minutes after dosing. Results of this study indicated that due to its short serum half-life, sodium ampicillin probably has little systemic therapeutic efficacy in guinea pigs. Because high concentrations of ampicillin accumulated in the urine and bile, the antibiotic probably would have therapeutic efficacy for urinary and intestinal infections. However, its associated toxicity at large doses probably precludes its use. In view of the rapid clearance of ampicillin in guinea pigs in comparison to other species, the pharmacokinetics of other antibiotics, especially those reported to be less toxic for guinea pigs, should be considered.     

Effect of a modified terrilytin on ampicillin pharmacokinetics in experimental peritonitis

The effect of modified terrilytin, a new enzyme of the microbial origin on the pharmacokinetics of ampicillin in experimental peritonitis was studied on 16 pubertal rabbits. Peritonitis was caused by laparotomy and administration of a 15 per cent fecal suspension into the abdominal cavity. The drugs were injected intramuscularly: the enzyme in a dose of 5 PU/kg and the antibiotic in a dose of 10 mg/kg. The ampicillin levels in the blood and peritoneal exudate were determined with the agar-diffusion method. The specimens were collected 30 minutes, 1, 1.5 and 2 hours after administration of the drugs. The animals were divided into 2 groups: control (not treated with the enzyme) and experimental. An increase in the antibiotic levels in the blood and peritoneal exudate by 50--54 per cent was observed. The maximum increase was recorded 30 minutes after simultaneous administration of the drugs.     

Effect of furosemide on the pharmacokinetics of benzylpenicillin and its penetration through the hematoencephalic barrier in experimental and clinical meningococcic meningitis]

Pharmacokinetics of sodium benzylpenicillin after intramuscular administration in a dose of 250 000 gamma/kg and simultaneous intramuscular injection of furosemid (lazix) in doses of 0.5--1--2 mg/kg was studied in experiments on a model of meningococcal meningitis of rabbits and in clinics on patients with meningococcal meningitis. A pronounced effect of furosemid on pharmacokinetics of benzylpenicillin as dependent on a number of factors was found. Furosemid and meningococcal endotoxin had a synergic effect and decreased benzylpenicillin excretion with urine resulting in prolongation of the antibiotic effect in the blood. An increase in benzylpenicillin blood levels and inflammation of the soft brain membranes increased permeability of the hemato-encephalic barrier for the antibiotic.     

Experimental protective action of kanamycin, ampicillin and their combination with methyluracil and pyrogenal]

Efficacy of kanamycin, ampicillin and their combinations with methyluracyl and pyrogenal in experimental Coli infections was studied. The antibiotics were administered an hour after the infection. Methyluracyl and pyrogenal were used according to 2 schemes. Scheme No. I: the drug is used daily for 7 days in increasing doses, the last dose is administered 24 hours before the infection. Scheme No. 2: the drug is used once at the moment of the infection. The methyluracyl doses were: 0.5, 1.0, 2.5 mg and 5 mg and 5 mg per a mouse during the following 4 days. The pyrrogenal doses were: 5, 10, 15, 25, 30 and 35 minimum pyrogenic doses. 5 mg of methyluracyl and 35 minimum pyrogenic doses of pyrogenal were used according to scheme No. 2. The most pronounced increase in the efficacy of kanamycin, ampicillin and their combination was observed in the animals treated simultaneously with methyluracyl and pyrogenal according to scheme No. 1. The efficacy of kanamycin and ampicillin increased 3 and 2.68 times respectively. ED50 of kanamycin and ampicillin used in combination in the animals treated with methyluracyl and pyrogenal was lowered 4 and 2.9 times respectively as compared to that in the animal groups treated only with the antibiotic combination and 21 and 15.2 times respectively when the antibiotics were used alone. Sanation of the animal organs was also rather successful. A single administration of methyluracyl and pyrogenal simultaneously with the infection (scheme No. 2) had a lower effect on the efficacy.     

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.     

Efficient use of a combination of ampicillin and chymotrypsin]

The effect of chimotripsin on the level and duration of the ampicillin concentration increase in rats, as well as the effect of the enzyme on the in vitro antibiotic detection in the blood serum and organ homogenates of the animals was studied. It was found that rational combined use of ampicillin and chimotripsin required the enzyme administration not later than 1 hour before the antibiotic injection. Chimotripsin provided increased ampicillin levels in the blood serum and liver of the rats for at least 5 hours and in the kidneys and lungs for at least 4 hours. The enzyme present in the rats for 2 hours had no effect on determination of ampicillin activity in vitro in the presence of the blood serum and organ homogenates of the animals.     

Changes in the microbial ecology and morphology of large intestine biofilm in albino rats under the influence of rifampicin

After oral administration in single doses of 40 and 160 mg/kg to Wistar rats rifampicin was detected in 3 hours in the contents of the large intestine The maximum rifampicin concentrations in the feces (120 and 300 micrograms/g) were detected in 24 hours. The antibiotic was present in the animal feces for 6-7 days. The antibiotic administration led to marked changes in microbiocenosis of the large intestine: disappearance of coccal flora, lower quantities of Escherichia and Lactobacillus and lower total quantities of anaerobic bacteria. It was also accompanied by changes in the structure of the typhlon biofilm. By the 28th day after discontinuation of the antibiotic administration (the end of the observation period) the large intestine microflora did not recover completely.     

Acute toxicity and the cumulative properties of carfecillin

Acute toxicity of oral and intraperitoneal carfecillin was studied on different species of laboratory animals, such as albino mice, rats and guinea pigs. The average lethal doses equal to 3040 (2393.7-3860.8) and 1325 (1104.2-1590) mg/kg for oral and intraperitoneal administration respectively allowed the authors to consider the antibiotic as a low toxic substance under conditions of a single administration. Higher toxicity of carfecillin as compared to carbenicillin may be due to production of free phenol on carfecillin hydrolysin in the animal organism. The different laboratory animals of both sexes had almost the same sensitivity to the antibiotic. On repeated administration of carfecillin to the albino mouse stomach (in portions of LD50) no cumulative properties of the antibiotic were observed.     

Chlorlincocin kinetics in animals with a disordered hormonal balance]

Distribution of chlorlincomycin in intact rats and animals with an impaired hormonal balance was studied. Estradiol or hydrocortizon acetate were administered repeatedly to the animals in large doses with a purpose of inducing pathological conditions. Chlorlincomycin was administered intravenously for 11 days in a dose of 15 mg/kg. The antibiotic levels in the blood serum and organs of the rats were determined at various intervals after the drug administration. The hormones induced changes in the sexual cycle. Hydrocortizon acetate markedly changed the animal weight and the weight coefficient of the internal organs. The kinetics of chlorlincomycin in the animals with hormonal impairments induced by estradiol or hydrocortizon acetate changed insufficiently as compared to that in the intact rats. Individual fluctuations in the antibiotic distribution was observed in the animals treated with hydrocortizon acetate. The levels of chlorlincomycin in the blood of the weakest animals were higher. No cumulation of the drug was noted.     

Preclinical toxicological study of the new antibiotic eremomycin. Chronic toxicity and effect on intrauterine development of rats

Toxicity of eremomycin was studied after its multiple parenteral administration to albino rats, guinea pigs and dogs in doses equivalent by the body surface to the daily doses for humans i. e. 1 and 3 g. The antibiotic was administered for 1 to 6 months. Tolerance of the antibiotic by the dogs after intravenous and intramuscular administration was satisfactory. In some animals there were observed an insignificant increase in the activity of alanine aminotransferase and a rise in the level of urea in blood serum. Pathomorphological examination of the internal organs of the albino rats and dogs showed that in high doses the antibiotic could have a damaging effect on the kidneys and epithelium of the gastrointestinal tract. The level of the damages depended on the dose of the antibiotic and duration of its use. The damages induced by eremomycin were reversible. It had no marked effect on the peripheral blood count, coagulation system and erythrocyte resistance. In the tested doses the antibiotic had no unfavourable effect on the hearing function in the experiments with guinea pigs. Studies with rats revealed that eremomycin had no teratogenic effect. A slightly pronounced embryotoxic action was observed only after using the antibiotic in doses exceeding more than 12 times the approximate therapeutic dose.     

Accumulation of gentamicin in biological fluids, organs and tissues during regional lymphotropic therapy with antibiotics

Gentamicin distribution in biological fluids, organs and tissues, lymph nodes was studied on 70 dogs. Three administration routes were compared: lymphotropic, intramuscular and regional subcutaneous. The lymphotropic route for the drug administration was recommended not long ago. It was shown that the lymphotropic route provided the antibiotic accumulation mainly in some of the abdominal organs as compared to intramuscular administration. Regional lymphotropic administration of the antibiotic to the experimental animals resulted in higher gentamicin levels in the regional lymph nodes and regional organs as compared to the levels observed after the antibiotic regional subcutaneous administration in the same doses.     

Effects of naloxone on plasma corticosterone in the opiate-naive rat

Naloxone HCl (NX) has long been considered to be a pure narcotic antagonist, having an effect only subsequent to pretreatment with a narcotic. Characteristically, low doses of NX have been used to antagonize the effects of analgesic doses of narcotics and to precipitate withdrawal in chronically treated animals. In this study, the effects of high doses of NX (2.0–20.0 mg/kg) on changes in plasma corticosterone were examined in the opiate-naive animal. Using male rats with chronic intravenous catheters and one-way vision boxes, injections were made and serial blood samples were obtained in the conscious, unrestrained animal. The acute administration of NX to the opiate-naive animal produced a dose-related increase in plasma corticosterone with respect to both amplitude and duration. NX (10.0 mg/kg i.v.) produced a significant elevation in hormone level at 15 and 30 minutes. With NX (20.0 mg/kg i.v.) the duration of the response was extended to 60 minutes. To examine whether short-term tolerance to this effect could be produced, animals were given a single pretreatment with either NX (10.0 mg/kg) or saline i.v. Two hours later NX produced a similar elevation in hormone level in both groups. The effect of chronic injection of NX was also studied. Animals pretreated with either NX (10.0 mg/kg) or saline s.c. once daily for 7 days did not show a significant difference following the subsequent administration of NX. In both cases, a significant elevation of plasma corticosterone resulted. The results suggest that NX may have a direct effect on opiate receptors resulting in an elevation of plasma hormone levels or NX may be disrupting an endogenous opiate-receptor interaction producing a stress response.     

Effect of tobramycin and gentamicin on the activity of some glycosidases in rat serum and urine

beta-Galactosidase, alpha-D-mannosidase, alpha-L-fucosidase and N-acetyl-beta-D-glucosaminidase activities were assayed in serum and urine from rats treated with three different doses of the nephrotoxic antibiotic tobramycin (100 mg/kg/day for 5 days, 10 mg/kg/day for 10 days and 5 mg/kg/day for 20 days) and gentamicin (100 mg/kg/day for 5 days). A significant increase of beta-galactosidase, N-acetyl-beta-D-glucosaminidase and alpha-L-fucosidase activities occurred in urine following the administration of high doses of antibiotic. The enzyme activity was dependent on the dose level used. The excretion of alpha-D-mannosidase was atypical and elevated activities were observed on some days but no pattern of excretion of this enzyme was established. No change in any of the four glycosidase activities was found in serum of treated rats. The results obtained when high doses of gentamicin were employed are similar to those obtained with a similar dose of tobramycin. These results indicate that the assay of urinary glycosidase activities provides a useful method for monitoring the nephrotoxicity of antibiotics.     

Variation of the level of mercury and metallothionein in the kidneys and liver of rats with time of exposure to sodium selenite

Sodium selenite was administered to rats before, after, and simultaneously with mercuric chloride. In all animal groups, mercury was administered intravenously in doses of 0.5 mg/kg every other day for two weeks. Selenium was given intragastrically either in a single dose of 7.0 mg Se/kg or in repeated doses of 0.1 mg Se/kg every day for weeks. It was demonstrated that, depending on the administration schedule, selenium induced significant changes in the binding of mercury by soluble fraction proteins both in the kidneys and in the liver. In every exposure, the mercury content decreased mainly in the low-molecular weight proteins, and the level of metallothionein-like proteins was diminished in the both organs. In the kidneys, the mercury content showed a correlation with the level of metallothionein (r=0.78). Amounts of mercury below 10 μg/g kidney do not stimulate metallothionein biosynthesis in this organ. A distinct interaction effect was observed in the case of a simultaneous administration of equimolar amounts of both the metals in question.     

Comparative study of the circulation of semisynthetic cephalosporins in the blood of rabbits]

Circulation of 4 semisynthetic cephalosporins, such as cephaloridin, cephalotin, cephradin and cephacetryl in the blood of rabbits after their intramuscular administration in single doses of 5 or 20 mg/kg was studied. The above antibiotics were satisfactorily absorbed into the blood reaching the maximum level within 15 to 30 minutes. The blood levels of cephalotin were the lowest and the rate of its elimination from the blood was higher than that of the other drugs. A four-fold increase in the doses of cephalosporins was not accompanied by a proportional increase in their levels in the rabbit blood, the time of the antibiotic circulation in the blood being not significantly changed.     

The Effects of Caffeine on <Emphasis Type="SmallCaps">l</Emphasis>-Arginine Metabolism in the Brain of Rats

In our study, the short-term effects of caffeine on L- arginine metabolism in the brains of rats were investigated. Caffeine was given orally at two different doses: 30 mg/kg and 100 mg/kg (a high non-toxic dose). Brain tissue arginase activity in rats from the caffeine-treated groups decreased significantly compared with the control group. Malondialdehyde (MDA) levels in the brain tissue and serum of animals in the caffeine groups also decreased significantly. Brain tissue and serum nitric oxide (NO) levels increased significantly after caffeine administration. Tumor necrosis factor-α (TNF-α) levels were also investigated in rat serum, but there was no statistically significant difference between the TNF-α levels of the caffeine-treated rats groups and the control rats. Our study indicates that brain arginase activity decreases after caffeine administration at doses of 30 mg/kg and 100 mg/kg. As a result, we can say that arginine induces production of NO in the organism.     

Study of trans-placental transport of methylamphotericin B in albino rats after intravenous administration]

Transplacental penetration of amphotericin B, an methyl derivative, was studied on rats after its intravenous administration. Microbiological and radioisotopic methods were used. When the microbiological method was applied the drug was administered on days 16 to 20 or on day 20 of pregnancy in a dose of 4 mg/kg. For extraction of the antibiotic dimethylformamide was added to the substrates. The labeled antibiotic was administered in a dose of 3.3 mg/kg on days 6 to 16 and on day 20 of pregnancy. It was noted that the antibiotic accumulated in the placenta. The accumulation was more pronounced after antibiotic use in the course doses. A significant part of the antibiotic was in the placenta in the bound state. The methyl derivative amphotericin B was not detected microbiologically in the umbilical cord serum, fetal organs and amniotic fluid. Neither was it detected by extraction with ++dimethylformamide. The labeled antibiotic was neither detected in the amniotic fluid and fetal organs during the whole observation period. Therefore, the methyl derivative amphotericin B did not penetrate through the placental barrier either in the free or bound state. The direct teratogenic action of amphotericin B, a methyl derivative, after its intravenous administration to female rats is likely possible.