Treatment of infectious complications of experimental acute radiation injury with combined antibiotic sulacillin

An anti-infectious effect of sulacillin (ampicillin/sulbactam) is higher than that of ampicillin in treatment of irradiated mice infected with a beta-lactamaseproducing strain of Kl. pneumoniae. Involving of sulacillin as a principal antibiotic into the therapeutic scheme for acute radiation sickness results in 67% dogs survival at LD90/45.     

Experimental rationale for the feasibility of using sulacillin for the prevention of infectious complications of combined radiation and thermal injuries]

Concurrent radiation and thermal injury (IRTI) was simulated in Wistar rats. For prevention of the autoinfectious complications sulacillin, a combination of ampicillin and sulbactam, was used. The use of sulacillin was started on the onset of IRTI and continued for 7 days. The drug was administered intramuscularly twice a day. It was observed that the 8-day survival of the animals increased by more than 40 per cent and the statistical levels of bacteremia and bacterial endotoxemia significantly decreased. The experiments showed that sulacillin had no side immunodepressive effect and did not aggravate the affection of the blood system. The drug was recommended for further studies to provide evidence for rational schemes of antibacterial therapy in IRTI.     

Biologic activity and tolerance of a preparation of polyunsaturated fatty acids, obtained by a microbiological route ["biopolyene"]]

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 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.     

Kinetics of the antibacterial effect of ampicillin and sulbactam combinations in dynamic and static conditions

Kinetics of antimicrobial effect (AME) of ampicillin/sulbactam combinations (ratios of 4:1 to 1:2) on ampicillin resistant bacterial strains producing beta-lactamases of types II, III, IV and V according to Richmond classification was studied with using the computerized system MS-2 (turbidimetric recording) and an in vitro dynamic model (microcalorimetric recording). The concentrations of the drugs in system MS-2 (static conditions) corresponded to the maximum ones observed in serum of humans after bolus intravenous administration of ampicillin in a dose of 0.5 g and sulbactam in doses of 0.125 to 0.5 g. The pharmacokinetic profiles of the drugs observed in the human serum after their oral and intravenous administration and in the tissue-chamber fluid after intravenous administration of ampicillin (0.5 g) and sulbactam (0.125 g) were simulated in the dynamic model. The combination efficacy was estimated with using the parameter of AME duration (TE) reflecting shifts in the curves of the microbial regrowth in the presence of the drugs against the curve of the control growth (in the absence of the drugs) and the parameter of the AME intensity (IE) evaluated by the area between the curves. It was noted that increasing of the ampicillin/sulbactam ratio from 1:4 to 1:1 was accompanied by an increase in the AME. Further increasing of the sulbactam content in the combination did not result in higher AME. For combined ampicillin/sulbactam dosage forms the ratios of 1:1 to 2:1 should be recommended.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Experimental study of the organotropic side-effect properties of polymyxin B]

Toxicity of Soviet polymyxin B and its effect on the central peripheral nervous system, blood circulation, respiration, smooth muscles, functional liver and kidney state, growth and development of young animals, the picture of the peripheral blood were studied in acute and chronic experiments on various species of animals. It was found that polymyxin B had a suppressing effect on the peripheral n-cholinoreactive systems of the neuromuscle synapses of the skeletal muscles and ganglia of the sympathic and parasympathic innervation and deprimizing effect on the central nervous system. Caffeine, adrenaline and calcium chloride proved to be the antagonists of the neurotoxic effects of polymyxin B. The chronic experiments revealed that polymyxin B induced disorders in the kidney function and morphological changes in the glomeruli after its repeated administration. No significant effect of polymyxin B on the growth and development of the young animals, the functional state of the liver and the picture of the peripheral blood was observed when the drug was used in doses corresponding to the therapeutic ones in clinics.     

Experimental study of the organotropic properties of dactinomycin

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.     

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.     

Use of a semisynthetic broad-spectrum penicillin (ampicillin) in surgical practice]

Parenterally ampicillin was used for the treatment of 87 patients with lung and abdominal diseases, liver abscesses, extremity phlegmonas, osteomyelitis and other diseases. The antibiotic was administered intravenously and intramuscularly. High efficacy of the treatment was observed in all the cases with ampicillin sensitive microflora. In some cases a satisfactory therapeutic effect was observed only with the use of ampicillin in combination with other antibiotics and aminoglycosides in particular. No side effects of the antibiotic were registered.     

The use of ampicillin/sulbactam (Unasyn) in treating inflammatory urological diseases

Unasyn is a combination of ampicillin, a bactericidal antibiotic, and sulbactam, an inhibitor of beta-lactamases. It was used in treatment of 36 patients with urogenital infections. The combination was administered intravenously and in the main intramuscularly. The treatment course amounted to 7-10 days. The average daily dose was 6 to 9 g. 22 patients with acute nonocclusive pyelonephritis were treated with the combination and its clinical and bacteriological efficacy was stated in 95 per cent of the cases. An excellent clinical effect of the combination was observed in 6 patients with acute epididymitis. A clinical improvement was also observed in the treatment of the patients with acute prostatitis and chronic renal infections. Unasyn proved to be a highly efficient antibacterial combination with regard to gram-positive flora and colon bacilli as representatives of gram-negative organisms. Satisfactory results were also stated in the treatment of infections caused by Proteus spp. Complete elimination of the pathogen was achieved in 57.7 per cent of the cases. No adverse reactions to Unasyn except pain in the site of the injection were recorded.     

Study of the pharmacological properties and safety of a solution of levomycetin in hexamethylene tetramine for intravenous administration]

Pharmacological properties of 2 per cent levomycetin solution in 40 percent hexamethylentetramine solution, as a new pharmaceutical form of levomycetin for intravenous administration prepared at drug-stores were studied. The maximum tolerating doses of the drug for mice, rabbits, and dogs were 26-47 times higher than the therapeutic ones with respect to the content of levomycetin and hexamethylentetramine. No increase in the toxicity of levomycetin and hexamethylentetramine in the preparation was observed. The drug in the doses 16 times higher than the therapeutic ones by the content of levomycetin did not almost change the arterial pressure and the drug in the doses 3.7 times higher than the therapeutic ones did not affect the blood coagulation either in acute experiments, or on its prolong intravenous infusion. Repeated administrations of the drug to rats and rabbits for 15-18 days in doses 3.7-4.8 times higher than the therapeutic ones by the content of levomycetin were innocuous for the animals. Absorption, circulation in the blood, distribution in the tissues and excretion with the urine of levomycetin used in the above pharmaceutical form did not differ from circulation of the antibiotic on its intravenous and oral administration. The drug is recommended for use in medical practice.     

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.     

Overcoming resistance to beta-lactamase inhibitors: comparing sulbactam to novel inhibitors against clavulanate resistant SHV enzymes with substitutions at Ambler position 244

Amino acid changes at Ambler position R244 in class A TEM and SHV beta-lactamases confer resistance to ampicillin/clavulanate, a beta-lactam/beta-lactamase inhibitor combination used to treat serious infections. To gain a deeper understanding of this resistance phenotype, we investigated the activities of sulbactam and two novel penem beta-lactamase inhibitors with sp2 hybridized C3 carboxylates and bicyclic R1 side chains against a library of SHV beta-lactamase variants at the 244 position. Compared to SHV-1 expressed in Escherichia coli, all 19 R244 variants exhibited increased susceptibility to ampicillin/sulbactam, an important difference compared to ampicillin/clavulanate. Kinetic analyses of SHV-1 and three SHV R244 (-S, -Q, and -L) variants revealed the Ki for sulbactam was significantly elevated for the R244 variants, but the partition ratios, kcat/kinact, were markedly reduced (13 000 --> 相似文献   

Study of metabolic mechanisms of the isolated and combined effect of a chemical allergen]

Biochemical study of the activity of the enzyme systems of different localization in the cell connected with the subcellular structures - lysosomes (hyaluronidase, N-acetyl-beta-D-glucosaminidase, beta-glucosidase) and hyaloplasm-soluble (aldolase of neuraminic acid), and also a study of the state of the enzyme-substrate groups, belonging to the immunoreactive biopolymeres containing a carbohydrate (glucoproteins, glycosaminoglycanes) was carried out in the tissues of different organs (the liver, kidneys, small intestine, skin) and in the blood serum of albino rats exposed to the isolated and joint (in combination with various doses of ultraviolet irradiation) action of the chemical allergen (dinitrochlorbenzene). General and specific regularities of metabolic reactions, the appearance of which could presumably be connected with the development of delayed allergy were revealed.     

Stability of the pBR322 plasmid derivative pBB210 in Escherichia coli TG1 under non-selective and selective conditions

The stability behaviour of the pBR322 plasmid derivative pBB210 with β-lactamase gene and human interferon-α1 gene in Escherichia coli TG1 was studied in chemostat cultures under non-selective (medium without antibiotics), selective (medium with β-lactam antibiotic ampicillin) and modified selective (medium with ampicillin and the β-lactamase inhibitor sulbactam) conditions. Under non-selective conditions, a behaviour typical of unstable systems was found. Under selective conditions, the behaviour predicted by the models was obtained – the fraction of plasmid-bearing cells in the population approached a constant value which was dependent on the ampicillin concentration in the feeding and on the cell concentration in the chemostat. Under modified selective conditions, the higher the concentration of sulbactam in the medium was, the higher the fraction of plasmid-bearing cells was in steady state conditions.     

Combined action of antiblastoma preparations on lysozyme activity in animal organs]

The lysozyme activity in the spleen, kidneys and lungs of the mice treated with neocid, sarcolysine or Tio-Fef in therapeutic doses increased or remained at the control level by the 5th or 10th day after the drug administration. The use of sarcolysine per se or in combination with neocid increased the activity of lysozyme in the spleen, kidneys and lungs during the whole period of the experiment as compared to the control. The values of the lysozyme activity in the spleen and lungs of the animals treated with neocid in combination with sarcolysine were higher for 5 days, and in all organs examined were higher by the 10the day as compared to the animals treated with neocid alone. Increased lysozyme activity in the spleen, kidneys and lungs was observed under the effect of neocid in combination with sarcolysine as compared to the lysozyme activity in mice treated with sarcolysine per se (assay on the 10th day). Decreased lysozyme activity was determined in the spleen, kidneys and lungs by the 5th day and in the kidneys by the 10th day in the mice treated with sarcolysine in combination with Tio-Tel and in the spleen and lungs by the 5th and 10th days in the animals treated with neocid in combination with sarcolysine or Tio-Tef as compared to the animals treated with sarcolysine. The lysozyme activity in the kidneys under the effect of sarcolysine combination with Tio-Tef was lower by the 5th days and higher by the 10th day as compared to that under the effect of Tio-Tef.     

Postantibiotic effect of ampicillin/sulbactam against mycobacteria.

The postantibiotic effect (PAE) is an important pharmacodynamic property of antibiotics. Most drugs continue to exert a suppressive effect on the growth of bacteria, both in vitro and in vivo, even after the drug concentrations have fallen below detectable levels. Only limited information is available on the PAE of slow-growing organisms like mycobacteria. The PAE of ampicillin/sulbactam (Unasyn) was investigated against six species of mycobacteria, viz Mycobacterium avium, M. africanum, M. bovis BCG, M. simiae, M. scrofulaceum and M. tuberculosis H37Ra, by spectrophotometry. The cell counter method was also used in one set of experiments. The bacteria were exposed to ampicillin/sulbactam for 2 h, 24 h, 72 h or 7-10 days. Five concentrations, 5, 10, 50 or 100 micrograms/ml, of the drug were tested. Afterwards, the bacteria were washed free of Unasyn and allowed to multiply. Treatment of the mycobacteria for 2 h did not produce any PAE, although 100 micrograms/ml of the drug caused slower growth. Exposure to 50, 60, or 100 micrograms/ml, resulted in a prolonged PAE of approximately 3 days. The data on the PAE of Unasyn may be of clinical relevance in determining dosage regimens of the drug.     

Modelling the stability of the pBR322 plasmid derivative pBB210 in Escherichia coli TG1 under non-selective and selective conditions

A mathematical model has been developed to describe the stability behaviour of the pBR322 plasmid derivative pBB210 with the β-lactamase gene and the human interferon-α1 gene in Escherichia coli TG1 under non-selective, selective and modified selective conditions in a chemostat. The model was formulated on the basis of experimental investigations. It includes the interaction between β-lactam antibiotics (ampicillin and sulbactam) and cells (with and without plasmids), in particular the correlation between the growth rate of plasmid-free cells and ampicillin concentration in the medium; ampicillin transport into the periplasm of the plasmid-bearing cells; ampicillin degradation in the periplasm by by plasmid-encoded β-lactamase and the inhibition of the latter by sulbactam. The results obtained by the simulation of chemostat cultivations under various conditions and by steady state analyses are closely related to the results of experiments. Under non-selective conditions, the fraction of plasmid-bearing cells was approaching zero. Under selective and modified selective conditions, a coexistence between plasmid-free and plasmid-bearing cells was reached at steady state. Under these conditions, the steady state fraction of plasmid-bearing cells was proportional to the ampicillin concentration in the feed and inversely proportional to the cell concentration in the chemostat. During high-density cultivation, a large amount of ampicillin is necessary to suppress plasmid-free cells. Even small concentrations of the β-lactamase inhibitor sulbactam in the feed increased the steady state fraction of plasmid-bearing cells (from 17.2% to 99.6% at sulbactam-Na concentrations of 0 to 5 mg/l).