Tolerance of gentacycol--a local dosage form of gentamicin based on collagen--animal experiments

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 gentamicin aerosol]

The study of gentamicin aerosol showed its relative innocuousness: it did not inhibit the growth and development of young animals, did not induce pathological changes in the upper respiratory tract, kidneys, liver, heart and spleen on its prolonged use. Pathohistological examination revealed slight irritating effect of the gentamicin aerosol in the lungs after its use in a dose of 8 or 25 mg/kg for 6 weeks. A procedure for investigating the effect of the aerosol on the activity of the trachea ciliated epithelium of warm blooded animals was developed. The gentamicin aerosols prepared from solutions of different concentrations (1 to 50 mg/ml) induced ingibition of the ciliated epithelium function at average from 15 to 35 per cent which was associated with the solution acidity (pH 4.54 to 4.82). Such a decrease in the function of the ciliated epithelium due to the antibiotic aerosol use was a factor prolonging the antibiotic retention time in the respiratory organs. It was found that aqueous solutions of drugs used for inhalation, such as ephedrin, euphelin, dimedrol, N-acetyl-L-cystein and others had no effect on the activity of gentamicin and may be used with it in a form of aerosols.     

Pharmacokinetic study of implantable gentamycin preparations. I. Antibiotic pharmacokinetics in the implantation area and an evaluation of the prolonged effect of the preparations

Gentamicin pharmacokinetics was studied in the zone of subcutaneous implantation to rats of Septopal, a dosage form based on polymethylmethacrylate stable in vivo (4.5 mg of the antibiotic) and of preparations based on biodegradable polymers such as monocarboxycellulose, alginic acid, nonmodified and modified collagens (1 and 5 mg of the antibiotic). A three-phase pattern of gentamicin level changing in the implantation zone was observed: (1) rapid increasing and decreasing of the antibiotic concentration, (2) stabilization of the gentamicin content at a practically constant level and (3) slow lowering of the antibiotic level in the tissue. Comparison of the areas under the concentration/time curves showed that the modified collagen, alginic acid and monocarboxycellulose had the highest prolongation effect among the biodegradable polymers. Their use in the compositions provided during the first hours after the implantation the antibiotic concentrations in the administration site equal to tens micrograms per 1 g of the tissue. After that during 14 days the concentration of gentamicin in the implantation zone maintained at the level higher than its MIC for the main pathogens of wound infections.     

Study of the immunotropic activity of aminoglycoside antibiotics

The action of some aminoglycoside antibiotics on the immune system was studied on both intact mice and the animals with immune deficiency caused by administration of cyclophosphamide. The following tests were used: local hemolysis (the Herne test), lymphocyte transformation (LT), delayed hypersensitivity to sheep red blood cells and the local graft versus host reaction (GVHR). Amikacin was shown to have no significant action on the activity of lymphocytes in the intact mice and stimulated both cellular (LT and GVHR) and humoral (the Herne test) immunity in the animals with lowered immunological reactivity. Sisomicin had no significant action on the immune system of the animals. Gentamicin suppressed the immune response only in the intact mice. Kanamycin and streptomycin induced inhibition of humoral and cellular immunity in both the intact mice and animals with immune deficiency. On the basis of the results it was concluded that gentamicin, amikacin and sisomicin may be used in the treatment of diseases developing in the presence of immune deficiency whereas streptomycin and kanamycin should be recommended when inhibition of the immunity is needed.     

Growth of Anopheles mosquito larvae on dietary microbiota in aquatic surface microlayers

Abstract. Hydrophobic organic matter accumulates under the surface film of water bodies to form the surface microlayers. Heterotrophic microorganisms use this organic matter for growth, and they, in turn, are fed upon by Anopheles mosquito larvae and other animals. From laboratory experiments we show that two species of mosquito larvae, Anopheles gambiae and An.quadrimaculatus , grew most rapidly where surface micro-layers were present and, especially, where labile dissolved organic matter was added to promote growth of microorganisms. The importance of microorganisms was confirmed by the addition of gentamicin antibiotic, which suppressed the microbiota and reduced the growth of larvae feeding on surface microlayers. Anopheles larvae grew well on a suspension of finely ground fish food to which the antibiotic had been added, showing that reduced growth was not due to gentamicin itself. Because sub-surface microorganisms are the components of the larval diet that most affect growth, we discuss their relevance to strategies for larval control of Anopheles mosquitoes.     

Immunocorrective effect of proteolytic enzymes on antibody genesis in mice subjected to infectious burn trauma and treatment with antibiotics

As revealed in this study, massive burn trauma manifestly suppresses the genesis of antibodies to T-dependent antigen (sheep red blood cells). The administration of ampicillin to the burned animals enhances immunosuppression, while gentamicin produces no essential impact on immune processes under these conditions. Proteolytic enzymes, terrilytin and terridecase, have corrective influence on disturbances in immune response in animals with burns. Enzyme in the immobilized form (terridecase) has a more pronounced immunotropic activity in this type of pathology.     

Gentamicin level in the prostate and its pharmacokinetics in patients with benign prostatic hypertrophy]

The study involved 15 male patients with periurethral prostatic adenoma without complete anuresis. The patients were given 80 mg of gentamicin intramuscularly one day before surgery and 80 mg in a one-hour infusion immediately before an operation. Gentamicin blood concentrations were measured. Pharmacokinetic parameters were calculated and dosage schemes for each patient basing on the antibiotic blood levels. Gentamicin levels in removed adenomas were also determined. Adenomas weighed between 18.0 and 45.8 grams while gentamicin concentration ranged from 1.31 to 3.8 micrograms/mL. It was found that gentamicin concentration in adenomas depend upon their weight. Moreover, pharmacokinetic parameters of this antibiotic exert negligible effect on its levels in adenoma.     

On the interaction between heparin and some aminoglycoside antibiotics

An interaction between the aminoglycoside antibiotics and heparin wherein charge transfer complexes are formed has been investigated to determine the degree of inhibition of antibacterial function of the antibiotic in the complexed form.Minimum inhibitory concentration (MIC) values have been obtained for the action of the aminoclycoside antibiotics tobramycin, gentamicin, amikacin, kanamycin, and streptomycin, on a sensitive strain ofE. coli. Growth curves ofE. coli determined at concentrations of these antibiotics just below the MIC demonstrated significant lengthening of the lag phase relative to control growth curves generated in the absence of antibiotic. Heparin (1 U ml^–1 and 10 U ml^–1) had no effect on control growth curves; however, particularly at the higher concentration, it reduced the effect on the lag phase produced by the aminoglycoside antibiotics. Thus kanamycin, gentamicin, and tobramycin were most affected, while amikacin and streptomycin were least affected. The rank order of inhibition of antibiotic activity by interaction with heparin was in qualitative agreement with previously published figures for the degree of complexation between antibiotics and heparin.     

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.     

Immunocorrecting and protective effect of proteolytic enzymes on antibody formation in mice in staphylococcal infection and antibiotic treatment

The impact of proteolytic enzymes on the humoral immune response, survival rate and mean survival time of mice, infected with S. aureus culture and receiving antibiotics was studied. Infection with staphylococcal suppressed the formation of antibodies to sheep red blood cells. Ampicillin made this immunosuppression even more pronounced, while gentamicin produced practically no effect on the degree of immunosuppression in the infected animals. Proteolytic enzymes terrilytin and terridecase exhibited immunocorrecting properties when used in combination with antibiotics. Terridecase, the immobilized form of the enzyme proved to have the highest activity. In experimental generalized staphylococcal infection all preparations under study produced a protective effect. The maximum effect was noted after the use of ampicillin in combination with terridecase.     

Experimental data on the penetration of gentamicin into the media of the eye]

Penetration of Soviet gentamicin into the humor of the anterior chamber and vitreous body of the eye with aseptic inflammation was studied after the antibiotic administration by various routed, i.e. instillations of 8 per cent antibiotic solution and 8 per cent antibiotic solution methylcellulose into the conjunctival sac, injections of 20 mg of gentamicin subconjunctivally and retrobulbarly, injections of gentamicin intramuscularly in doses of 0.6 mg/kg. The studies showed that gentamicin penetrated into the humor of the anterior chamber and vitreous body of the eye after all the administration routes mentioned above in concentrations sufficient for the antibiotic antimicrobial effect and persisted in the eye media for prolong periods of time (24--48 hours). The highest concentrations of the antibiotic in the tumor of the anterior chamber were achieved after its administration subconjunctivally or after instillation of its 8 per cent on methylcellulose, while in the vitreous body its highest concentrations were achieved after injections subconjunctively, retrobulbarly or intramuscularly. Instillations of gentamicin solution on methylcellulose provided higher and more persistant concentrations of the antibiotic in the humor as compared to instillations of its aqueous solutions. Retrobulbar injections of gentamicin had no advantages as compared to subconjunctival administration with respect to providing higher concentrations of the antibiotic in the eye media.     

Microbial biosynthesis and applications of gentamicin: a critical appraisal

Gentamicin is an aminoglycoside antibiotic produced by various species of the genus Micromonospora and has received much attention in the recent years as a broad-spectrum antibiotic for treatment of various infections. It exists as a complex of closely related aminoglycoside structures and the clinically significant one is the gentamicin C complex. This review article focuses attention on the present status of knowledge and the main advancements achieved in the last few decades on the subject of gentamicin with regard to its production, biosynthetic pathway, mode of action, and uses. The various nutritional and environmental parameters affecting gentamicin production and the factors affecting the release of bound gentamicin are discussed. Further, strain improvement using UV and/or chemical mutagenesis can be applied to augment the efficiency of the producer strain and a number of case studies are presented. Different detection and quantitative methods for gentamicin estimation and the mode of action of gentamicin are discussed in detail. This antibiotic finds extensive use in combination chemotherapy and as a drug for different delivery agents for treatment of osteomyelitis and other recent applications in gene therapy.     

Experimental study of a novel formulation for local application based on gentamicin, erythromycin and protease 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.     

Optimal Combination and Concentration of Antibiotics in Media for Isolation of Pathogenic Fungi and Nocardia asteroides

Strains of Blastomyces dermatitidis, Sporothrix schenckii, Histoplasma capsulatum, Cryptococcus neoformans, Nocardia asteroides, and Coccidioides immitis were tested for in vitro susceptibility to polymyxin, gentamicin, kanamycin, chloramphenicol, and neomycin at concentrations of 1, 2, 4, 8, and 16 mug/ml. Polymyxin was the most inhibitory and gentamicin was the least inhibitory of the five antibiotics. Two Histoplasma mycelial strains were partially inhibited by 2 and 8 mug of gentamicin per ml and showed at least a 2+ growth at the higher antibiotic concentration. Kanamycin and neomycin produced significant inhibition of N. asteroides but otherwise were noninhibitory. A combination of chloramphenicol and kanamycin, each at 16 mug/ml, and gentamicin, at 4 mug/ml, was noninhibitory to the strains tested except for N. asteroides. Chloramphenicol at 16 mug/ml was not inhibitory for N. asteroides. The results suggest that the optimal antibiotic combination to use in the isolation of fungi and higher bacteria is chloramphenicol, 16 mug/ml, and gentamicin, 4 mug/ml. Addition of sheep blood (5%) had no effect on antibiotic susceptibility of the organisms studied.     

Fiber entrapment of naringinase from Penicillium sp. and application to fruit juice debittering

Naringinase from Penicillium sp. was immobilized on cellulose triacetate by the fiber entrapment method. Although the optimum pH (3.7) and optimum temperature (55°C) of the fiber-entrapped enzyme were similar to those of the native form, the immobilized enzyme had better heat stability. Kinetic studies showed that the immobilized enzyme had higher K_m values than its native form. When this immobilized naringinase was successively used in a column reactor for the hydrolysis of ρ-nitrophenyl-α-l-rhamnoside or naringin in a simulated fruit juice system or grapefruit juice, the enzyme column could be operated with satisfactory stability. In addition, when the natural grapefruit juice was recycled through the column reactor, no column blocking or filtering action of the catalyst bed was observed.     

Gentamicin-Induced Chronotoxicity: Use of Body Temperature as a Orcadian Marker Rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induxed ototoxicity. Two groups of 3 male Sprague-Dawley rats (250–400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16kHz, 24kHz and 32kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80–90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.     

Gentamicin-Induced Chronotoxicity: Use of Body Temperature as a Orcadian Marker Rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induxed ototoxicity. Two groups of 3 male Sprague-Dawley rats (250-400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16kHz, 24kHz and 32kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80-90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.     

Gentamicin-induced chronotoxicity: use of body temperature as a circadian marker rhythm

Aminoglycoside antibiotics produce varying degrees of ototoxicity, dependent on dosage time, in animals synchronized for rhythm study. Herein, we illustrate the use of an economical and reliable system to telemeter body temperature of laboratory animals as an endogenous marker rhythm for gentamicin-induced ototoxicity. Two groups of 3 male Sprague-Dawley rats (250-400 gm) were housed in separate cages in a temperature-controlled room programmed with a 12:12 LD schedule and monitored for hearing thresholds at the frequencies of 8kHz, 16 kHz, 24 kHz and 32 kHz at 2-week intervals. Each rat was dosed with 100 mg/kg/day gentamicin subcutaneously for a duration of 28 days. The animals from one group were dosed at their daily temperature maximum, while the animals of the other group were dosed at their daily temperature minimum. Both after 14 and 28 days of gentamicin treatment there was no important changes in auditory thresholds from baseline values when treatment was timed daily to the circadian peak of body temperature. Animals dosed daily at the trough of the circadian temperature rhythm evidenced an auditory threshold shift of between 5 and 25 dB after 14 days of treatment and a total hearing loss (80-90 dB) after 28 days of such treatment. These results document a dramatically greater level of hearing loss induced in those animals dosed with gentamicin at the body temperature trough (diurnal rest span) as compared to those dosed at the acrophase (nocturnal activity span). The findings indicate that the peak and trough of the circadian pattern of body temperature serve as meaningful markers of the resistance and susceptibility, respectively, of gentamicin-induced ototoxicity in rodent models.     

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.     

Clinico-experimental study of the possibility of the use of immobilized enzymes for local thrombolysis and thromboformation

Fibrinolysin immobilized by a solid polysaccharide carrier capable of controllable biodegradation is shown to exert a local effective thrombolyzing action. Certain results of clinical studies of immobilized streptase (streptodecase) are presented. They show essential advantages of the new preparation over the known native enzymes. Experiments with animals show that the immobilized thrombin may be applied in therapeutic embolization for the hemorrhage cessation.