The interaction between carbamazepine and erythromycin

Erythromycin has been reported to interact with the anticonvulsant, carbamazepine, in both children and adults. Toxic serum levels of carbamazepine are observed within 24 h of antibiotic administration, suggesting a mechanism not previously described for other erythromycin-based drug interactions. In rats erythromycin significantly depressed the elimination of carbamazepine in animals induced with carbamazepine for 4 days but had no effect on carbamazepine elimination in noninduced animals. Although the in vitro metabolism of carbamazepine to its epoxide by hepatic microsomes prepared from noninduced rats was significantly inhibited by erythromycin, the inhibition of carbamazepine epoxidation was greatly enhanced in carbamazepine-induced rats. In the pig the sensitivity of carbamazepine metabolism to erythromycin was much greater than in the rat, indicating the existence of a large species difference in this particular drug interaction. It is concluded that the interaction between erythromycin and carbamazepine is caused by a direct inhibition of carbamazepine oxidation by the antibiotic.     

Assessment of the efficacy of treating infections in hematopoietic proliferative diseases: Monotherapy with ceftazidime and tobramycin combined with amoxycillin/ampicillin

Efficacy of the ceftazidime monotherapy in 120 febrile children with neoplastic diseases and granulocytopenia was compared with that of tobramycin combined with amoxycillin/ampicillin. The obtained results were similar in both types of antibiotic therapy. However, granulocytopenia was higher and septicemia was more frequent in children treated with ceftazidime. Isolated bacteria were more sensitive to ceftazidime than to tobramycin with amoxycillin/ampicillin. Both regimens were tolerated well. Despite a low number of patients in both groups, one may conclude that ceftazidime is more efficient in patients with granulocytopenia. Less adverse reactions, lower number of infections, less frequent medical procedures, elimination of the potentially toxic aminoglycosides and lower cost of therapy advocate the use of ceftazidime monotherapy.     

Infectious plasmid resistance and efflux pump mediated resistance

Various bacterial plasmids can be eliminated from bacterial species cultured as pure or mixed bacterial cultures by non-mutagenic heterocyclic compounds at subinhibitory concentrations. For plasmid curing, the replication should be inhibited at three different levels simultaneously: the intracellular replication of plasmid DNA, partition and intercellular transconjugal transfer. The antiplasmid action of the compounds depends on the chemical structure. The targets for antiplasmid compounds were analysed in detail. It was found that amplified extrachromosomal DNA in the superhelical state binds more drug molecules than does the linear or open-circular form of the plasmid or the chromosome, without stereospecificity which leads to functional inactivation of the extrachromosomal genetic code. Plasmid elimination also occurs in ecosystems containing numerous bacterial species simultaneously, but the elimination of antibiotic resistance-encoding plasmids from all individual cells of the population is never complete. The medical significance of plasmid elimination in vitro is, it provides a method to isolate plasmid-free bacteria for biotechnology without any risk of mutations, and it opens up a new perspective in rational drug design against bacterial plasmids. Hypothetically, the combination of antiplasmid drugs and antibiotics may improve the effectivity of antibiotics against resistant bacteria; therefore, the results cannot be exploited until the curing efficiency reaches 100%. Inhibition of the conjugational transfer of antibiotic resistance plasmids can be exploited to reduce the spreading of these plasmids in ecosystems.     

Impact of cancer therapy on the reproductive axis

Cancer therapy includes surgery, chemotherapy and irradiation. Depending on the diagnosis, the location of the neoplasm and the age of the patient, these treatment modalities may be given alone or in combination. All forms of cancer therapy can affect the hypothalamic-pituitary-gonadal axis. The long-term consequences for reproductive function depend on several aspects. The sex of the patient is important, since ovarian and testicular function differ significantly. Sex hormone production in the female is dependent on the presence of germ cells, whereas this is not the case in the male. The sensitivity of germ cells to cancer therapy also differs between the sexes. Moreover, the sensitivity of both the hypothalamic-pituitary axis and the gonads is highly age dependent. With regard to chemotherapy, the possible damage to the gonads is dependent on the total dose and type of agent given. According to current knowledge, the hypothalamic-pituitary axis is not affected by conventional doses of chemotherapy. Radiotherapy has by far the most damaging effect on the reproductive axis, having serious adverse effects on both the hypothalamic-pituitary area as well as on the gonads themselves. The harmful effect of irradiation depends on the total dose of irradiation, the radiation field, as well as the number and size of fractions given. The long-term consequences of recently introduced radiotherapeutic methods such as stereotactic irradiation are not yet known. The present review will focus on the late effects of cancer therapy in children and young adults with acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, brain tumour, Hodgkin's lymphoma or Wilms' tumour, including the adverse effects of bone marrow transplantation.     

Effect of 1-(chloromethyl)silatrane on the alteration of the blood elements during extracorporeal circulation

The damaging effect of cardiopulmonary bypass on blood elements and the possibility of its correction with 1-(chloromethyl) silatrane have been investigated. Cardiopulmonary bypass is a powerful damaging factor producing a wide range of effects including the activation of lipid peroxidation, reduction of erythrocyte membrane resistance to ultra-sound, destruction of blood elements and appearance of hemoglobin in the plasma (hemolysis). A possible mechanism of cardiopulmonary bypass damaging effect on blood elements is suggested. The use of 1-(chloromethyl)silatrane drastically increases the resistance of blood element membranes to injury, which seems promising for the drug application during cardiopulmonary bypass.     

Listeria Monocytogenes Infections in Metropolitan Toronto: A Clinicopathological Study

The clinical and laboratory findings in 21 patients with listeriosis are described and the subject is reviewed. Eleven of the infections were septicemias of newborns, eight were meningitis in infants or adults, and two other children had unusual manifestations.Neonatal septicemia was rapidly fatal; one of 11 infants survived. The disease often seemed traceable to mild maternal infection during the third trimester usually leading to premature delivery of critically ill babies. Only awareness of the possible presence of listeriosis and early antibiotic therapy seem capable of reducing this high mortality.Tissues from autopsies showed characteristic microscopic necrotic foci with mononuclear infiltration progressing to microabscesses containing small Gram-positive rods. Lesions were found in the one placenta examined.Five infants with meningitis recovered, and one of three affected adults. Specific diagnosis depends on demonstrating Listeria monocytogenes; differentiation from other forms of acute meningitis cannot be made clinically.One older child had septicemia and another had listerial pharyngitis. Both recovered.     

Various methods of using lincomycin for treating acute and chronic hematogenic osteomyelitis in children]

Comparative data on the treatment of 209 children with acute and chronic hematogenic osteomyelitis are presented; 128 patients hospitalized before 1974 were treated with antibiotics, mainly penicillin and streptomycin without sensitivity testing. From 1974 81 children were treated with lincomycin; 80 per cent of the isolates were sensitive to this antibiotic. In lincomycin therapy the method of electrophoresis on the disease focus, intrabone administration of the drug and administration of the drug into the bone cavity together with the blood clot during surgical interventions in cases with chronic hematogenic osteomyelitis were used. A marked decrease in the rate of the chronic forms of the disease was registered (from 77.2 to 8.8 per cent).     

Combined antibacterial therapy of infectious complications in oncological patients

Rational antibacterial therapy of infections in oncological patients in relation to the polyetiological nature of the infections and polyresistance of their causative agents contemplates the use of drug combinations. The necessity of long-term antibacterial therapy in many oncological patients also predisposes to it. The choice of drugs for every patient should stem from bacteriological findings: isolation of the pathogen, its identification and assay of its antibiotic sensitivity. When isolation of the causative agent is not possible or could not be done immediately the drug should be chosen according to the general data on the etiological structure of infectious complications in the particular department and particular pathological process as well as antibiotic sensitivity of the bacteria isolated under such conditions.     

Identification of membrane associated drug targets in Borrelia burgdorferi ZS7- subtractive genomics approach

Lyme disease is an infectious disease caused by a spirochete Borrelia burgdorferi ZS7. This spirochete is most often spread by ticks. Single antibiotic therapy is sufficient for containment of the early stage progression of the disease but combinational therapy is more preferred in later stages. Research is in progress for the development of drugs against the pathogen, but till date no vaccines have been developed to effect the late stage infections. There is a rapid rise in the cases of antibiotic-resistant population which is more than 10% of the total infected individuals. In such condition vaccine becomes the sole alternative for prevention. Therefore effective treatment includes antibiotic combination and combination of antigenic surfaces (for vaccine preparation). Thus, a comprehensive list of drug targets unique to the microorganisms is often necessary. Availability of Borrelia burgdorferi ZS7 proteome has enabled insilico analysis of protein sequences for the identification of drug targets and vaccine targets. In this study, 272 essential proteins were identified out of which 42 proteins were unique to the microorganism. The study identified 15 membrane localized drug targets. Amongst these 15, molecular modeling and structure validation of the five membrane localized drug target proteins could only be achieved because of the low sequence identity of the remaining proteins with RCSB structures. These 3D structures can be further characterized by invitro and invivo studies for the development of novel vaccine epitopes and novel antibiotic therapy against Borrelia burgdorferi.     

铜绿假单胞菌感染的非抗生素治疗研究进展

铜绿假单胞菌是引起多种人体感染的常见致病菌,目前主要采用抗生素治疗铜绿假单胞菌感染.由于铜绿假单胞菌能对多种抗生素产生抗性,导致传统的抗生素治疗面临非常大的挑战.因而铜绿假单胞菌感染的非抗生素治疗方法受到了广泛重视,并取得了可喜的研究进展.本文从抗原抗体免疫疗法、噬菌体疗法、抗毒力因子疗法三个方面就铜绿假单胞菌的非抗生...     

Genotoxic effects of radiation and hyperthermia in linear mice with different radiation sensitivity

The features of the repair processes of DNA damage and their implementation at the chromosome level in marrow cells of experimental animals (mices of the CBA and C3H lines) with different radiation sensitivity were studied. It is shown that the radiomodifying efficiency of moderate hyperthermia (HT) is higher for animals of the radioresyst line. At the same time, it was possible to observe intensive elimination of chromosomal damages, the level of which in later observations almost was not distinguished from the control values. For mices of more radiosensitive lines, a long-term potentiation damaging action of irradiation at the chromosomal level was observed as an additional HT effect.     

Effect of anticonvulsant drugs on plasma total cholesterol, high-density lipoprotein cholesterol, and apolipoproteins A and B in children with epilepsy

The effect of long-term anticonvulsant drug therapy with phenobarbital, phenytoin, carbamazepine, primidone, and valproic acid in epileptic children on plasma total cholesterol and high-density lipoprotein cholesterol (HDLC) was studied. Except valproic acid, all the drugs significantly increased the total cholesterol and HDLC, but the effect was more pronounced with HDLC. Among the subfractions of HDLC, almost all the increase due to drug therapy were in the HDLC-2 fraction. Treatment with antiepileptic drugs had no effect on HDLC-3. Apolipoprotein-A levels were significantly higher with drug therapy, but no effect was seen in the apolipoprotein-B levels. Plasma concentration of total cholesterol, HDLC, or its components was unaffected with valproic acid therapy.     

Comparison of the Action of Ampicillin and Benzylpenicillin on Enterococci In Vitro

The bactericidal activity of benzylpenicillin and ampicillin on 21 strains of enterococci was evaluated and compared to the activity of these drugs in combination with streptomycin (20 mug/ml). On a weight basis, ampicillin was about twice as effective as benzylpenicillin. Neither of the drugs was rapidly and completely bactericidal for any of the 21 strains of enterococci when used alone. The addition of streptomycin greatly enhanced the early bactericidal rate achieved with any given amount of either penicillin and permitted the elimination of viable organisms in vitro. These results suggest that, for the time being, combined antibiotic therapy might be desirable in enterococcus endocarditis and that ampicillin, although more effective than benzylpenicillin, should not be relied upon as a single drug in that disease.     

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.     

The Effect of Polymeric Nanoparticles on Biocompatibility of Carrier Red Blood Cells

Red blood cells (RBCs) can be used for vascular delivery of encapsulated or surface-bound drugs and carriers. Coupling to RBC prolongs circulation of nanoparticles (NP, 200 nm spheres, a conventional model of polymeric drug delivery carrier) enabling their transfer to the pulmonary vasculature without provoking overt RBC elimination. However, little is known about more subtle and potentially harmful effects of drugs and drug carriers on RBCs. Here we devised high-throughput in vitro assays to determine the sensitivity of loaded RBCs to osmotic stress and other damaging insults that they may encounter in vivo (e.g. mechanical, oxidative and complement insults). Sensitivity of these tests is inversely proportional to RBC concentration in suspension and our results suggest that mouse RBCs are more sensitive to damaging factors than human RBCs. Loading RBCs by NP at 1:50 ratio did not affect RBCs, while 10–50 fold higher NP load accentuated RBC damage by mechanical, osmotic and oxidative stress. This extensive loading of RBC by NP also leads to RBCs agglutination in buffer; however, addition of albumin diminished this effect. These results provide a template for analyses of the effects of diverse cargoes loaded on carrier RBCs and indicate that: i) RBCs can tolerate carriage of NP at doses providing loading of millions of nanoparticles per microliter of blood; ii) tests using protein-free buffers and mouse RBCs may overestimate adversity that may be encountered in humans.     

Suppression of the damaging effect of amphotericin B on dog kidney lysosomes by amigluracyl

The effect of amphotericin B and its combination with amigluracyl on the dog kidney lyzosomes was studied in vitro. It was found that on incubation of the lyzosomes with the antibiotic in a concentration of 1 gamma/ml the latter stimulated liberation of proteases from them. At the same time, when the lyzosomes were exposed to amphotericin B in combination with amigluracyl, a significant decrease in the rise of the proteolytic activity in the incubation medium due to the antibiotic was observed. It was found that the combined use of amphotericin B with amigluracyl resulted in an intensive inhibition of the enzyme activity; The data are indicative of the fact that amigluracyl decreases the damaging effect of the antibiotic on the dog kidney lyzosomes.     

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.     

Complications from antibiotic therapy]

Analysis of 302 side effects of antibiotic theraphy is presented. The side effects were studied comparatively as dependent on the antibiotic group. Dependence of the toxic and toxicoallergic reactions to the antibiotics on the antibiotic blood levels were noted. Previous sensitization resulted in more frequent and earlier side effects. The analysis and clinical observations showed that antibiotic therapy should take into account the results of the laboratory tests, i.e. examination of the kidney functional state, antibiotic levels in the blood and urine, tolerance of the drug by the patient.     

Pharmacokinetic characteristics and the effectiveness of using carbenicillin on newborn premature infants with infectious and inflammatory diseases]

The results of the study on the pharmacokinetics peculiar properties of carbenicillin premature infants treated with the drug administered intravenously or intramuscularly are presented. The maximum antibiotic blood levels after intravenous administration exceeded the MIC for most of the causative agents isolated from the children. The schemes for the antibiotic use in treatment of purulent septic processes of children are recommended.     

Challenges: Selective compartments for resistant microorganisms in antibiotic gradients

The development of bacterial resistance to antibiotics is one of the best documented examples of contemporary biological evolution. Variability in the mechanisms of resistance depends on the diversity of genotypes in the huge bacterial populations, and also on the diversity of selective pressures that are produced along the antibiotic concentration gradients formed in the highly compartmentalized human body during therapy. These antibiotic gradients can be conceived as comprising selective compartments, each one of them defined as the concentration able to select a particular genetic variant. In vitro experimental models confirm that some antibiotic resistant variants are selected only at certain selective concentrations of antibiotics. The correspondence between selective compartments and selectable variants could offer a way of describing more accurately the antibiotic selective landscapes and for taking measures to prevent the development of a major threat to the future of modern medicine.