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Sample records for antibiotic antitumour agent

  1. Structural effects of nogalamycin, an antibiotic antitumour agent, on DNA

    SciTech Connect

    Banerjee, T.; Mukhopadhyay, R.

    2008-09-19

    The structural changes of DNA, induced by the antitumour antibiotic nogalamycin, have been studied by atomic force microscopy (AFM). The transformation in the tertiary structure of 4361 bp long plasmid pBR322 DNA, after incubation with nogalamycin at 37 deg. C, has been monitored at the single molecule level. The AFM topographs of free DNA and the DNA-nogalamycin complex, incubated for 6, 12, 24, 36 and 48 h, reveal a gradual change from the circular supercoiled form having strand crossovers to the more compact plectonemic superhelix. With increasing incubation time, the extent of plectonemic coiling increases, indicating increasing level of drug binding via intercalative mode. Supportive evidences are obtained from the CD and UV-vis spectroscopic studies. To our knowledge, this is the first report on an AFM imaging study of the effects of nogalamycin, an anthracyclin intercalator, on DNA.

  2. Antibiotic Agents

    MedlinePlus

    ... Work Contact Us ABOUT THE ISSUE What is Antibiotic Resistance? General Background Science of Resistance Glossary References POLICY ... for Adaptation Genetics and Drug Resistance Reservoirs of Antibiotic Resistance Project (ROAR) INTERNATIONAL CHAPTERS APUA Chapter Network Africa ...

  3. Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase.

    PubMed

    Pantouris, Georgios; Mowat, Christopher G

    2014-01-01

    The involvement of tryptophan 2,3-dioxygenase (TDO) in cancer biology has recently been described, with the enzyme playing an immunomodulatory role, suppressing antitumour immune responses and promoting tumour cell survival and proliferation. This finding reinforces the need for specific inhibitors of TDO that may potentially be developed for therapeutic use. In this work we have screened ~2800 compounds from the library of the National Cancer Institute USA and identified seven potent inhibitors of TDO with inhibition constants in the nanomolar or low micromolar range. All seven have antitumour properties, killing various cancer cell lines. For comparison, the inhibition potencies of these compounds were tested against IDO and their inhibition constants are reported. Interestingly, this work reveals that NSC 36398 (dihydroquercetin, taxifolin), with an in vitro inhibition constant of ~16 μM, is the first TDO-selective inhibitor reported. PMID:24269239

  4. Antitumour agents as inhibitors of tryptophan 2,3-dioxygenase

    SciTech Connect

    Pantouris, Georgios; Mowat, Christopher G.

    2014-01-03

    Highlights: •∼2800 National Cancer Institute USA compounds have been screened as potential inhibitors of TDO and/or IDO. •Seven compounds with anti-tumour properties have been identified as potent inhibitors. •NSC 36398 (taxifolin, dihydroquercetin) is selective for TDO with a K{sub i} of 16 M. •This may help further our understanding of the role of TDO in cancer. -- Abstract: The involvement of tryptophan 2,3-dioxygenase (TDO) in cancer biology has recently been described, with the enzyme playing an immunomodulatory role, suppressing antitumour immune responses and promoting tumour cell survival and proliferation. This finding reinforces the need for specific inhibitors of TDO that may potentially be developed for therapeutic use. In this work we have screened ∼2800 compounds from the library of the National Cancer Institute USA and identified seven potent inhibitors of TDO with inhibition constants in the nanomolar or low micromolar range. All seven have antitumour properties, killing various cancer cell lines. For comparison, the inhibition potencies of these compounds were tested against IDO and their inhibition constants are reported. Interestingly, this work reveals that NSC 36398 (dihydroquercetin, taxifolin), with an in vitro inhibition constant of ∼16 μM, is the first TDO-selective inhibitor reported.

  5. Phase I trials of antitumour agents: fundamental concepts

    PubMed Central

    Toloi, Diego de Araujo; Jardim, Denis Leonardo Fontes; Hoff, Paulo Marcelo Gehm; Riechelmann, Rachel Simões Pimenta

    2015-01-01

    Phase I trials are an important step in the development of new drugs. Because of the advancing knowledge of cancer’s molecular biology, these trials offer an important platform for the development of new agents and also for patient treatment. Therefore, comprehension of their peculiar terminology and methodology are increasingly important. Our objectives were to review the fundamental concepts of phase I designs and to critically contextualise this type of study as a therapeutic option for patients with refractory cancer. PMID:25729414

  6. Organometallic Antitumour Agents with Alternative Modes of Action

    NASA Astrophysics Data System (ADS)

    Casini, Angela; Hartinger, Christian G.; Nazarov, Alexey A.; Dyson, Paul J.

    The therapeutic index of drugs that target DNA, a ubiquitous target present in nearly all cells, is low. Nevertheless, DNA has remained the primary target for medicinal chemists developing metal-based anticancer drugs, although DNA has been essentially abandoned in favour of non-genomic targets by medicinal chemists developing organic drugs. A number of organometallic drugs that target proteins/enzymes have been developed and these compounds, based on ruthenium, osmium and gold, are described in this chapter. Targets include cathepsin B, thioredoxin reductases, multidrug resistance protein (Pgp), glutathione S-transferases and kinases. It is found that compounds that inhibit these various targets are active against metastatic tumours, or tumours that are resistant to classical DNA damaging agents such as cisplatin, and therefore offer considerable potential in clinical applications.

  7. Induction of DT-diaphorase by 1,2-dithiole-3-thione and increase of antitumour activity of bioreductive agents.

    PubMed Central

    Begleiter, A.; Leith, M. K.; Curphey, T. J.

    1996-01-01

    Bioreductive antitumour agents are an important new class of anticancer drugs that require activation by reduction. The two-electron reducing enzyme, DT-diaphorase, has been shown to be an important activating enzyme for the bioreductive agents, mitomycin C (MMC) and EO9. Incubation of L5178Y murine lymphoma cells in vitro with 1,2-dithiole-3-thione (D3T) increased the level of DT-diaphorase activity in these cells 22-fold. In contrast, D3T had no effect on the DT-diaphorase level in normal mouse bone marrow cells. Combination therapy with D3T and MMC or EO9, produced a 2- or 7-fold enhancement, respectively, of the cytotoxic activity of these antitumour agents in L5178Y cells. By comparison, D3T did not enhance the activity of MMC in marrow cells and produced only a small increase in EO9 cytotoxicity in these cells. The DT-diaphorase inhibitor, dicoumarol, inhibited the effect of D3T on the antitumour activity of the bioreductive agents, supporting the proposal that the enhanced anticancer activity was due to the elevated enzyme level. These findings suggest that D3T, or other inducers of DT-diaphorase, could be used to enhance the antitumour efficacy of bioreductive antitumour agents. PMID:8763837

  8. Interaction of thalidomide, phthalimide analogues of thalidomide and pentoxifylline with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid: concomitant reduction of serum tumour necrosis factor-alpha and enhancement of anti-tumour activity.

    PubMed Central

    Ching, L. M.; Browne, W. L.; Tchernegovski, R.; Gregory, T.; Baguley, B. C.; Palmer, B. D.

    1998-01-01

    DMXAA (5,6-dimethylxanthenone-4-acetic acid), a novel anti-tumour agent currently undergoing clinical evaluation, appears to mediate its anti-tumour effects through immune modulation and the production of the cytokine tumour necrosis factor-alpha (TNF). Our previous studies have shown that thalidomide, a potent inhibitor of TNF biosynthesis that has numerous biological effects, including inhibition of tumour angiogenesis, unexpectedly augments the anti-tumour response in mice to DMXAA. We show here that thalidomide (100 mg kg(-1)) has no effect when administered with inactive doses of DMXAA, and that it must be given simultaneously with an active dose of DMXAA to have its maximum potentiating effect on the growth of the murine Colon 38 adenocarcinoma. To address the issue of whether inhibition of serum TNF production is important for potentiation of anti-tumour activity, we have tested three potent analogues of thalidomide. All three analogues, when co-administered with DMXAA to mice at doses lower than those used with thalidomide, inhibited TNF production and were effective in potentiating the anti-tumour activity of DMXAA against transplanted Colon 38 tumours. One of the analogues, N-phenethyltetrafluorophthalimide, was 1000-fold more potent than thalidomide and at a dose of 0.1 mg kg(-1) in combination with DMXAA (30 mg kg(-1)) cured 100% of mice, compared with 67% for the group treated with DMXAA alone. We also tested pentoxifylline and found it to suppress TNF production in response to DMXAA and to potentiate the anti-tumour effect of DMXAA. The results are compatible with the hypothesis that pharmacological reduction of serum TNF levels might benefit the anti-tumour effects of DMXAA and suggest new strategies for therapy using this agent. PMID:9703279

  9. New antibiotic agents for bloodstream infections.

    PubMed

    Vergidis, Paschalis I; Falagas, Matthew E

    2008-11-01

    Infections due to multidrug-resistant pathogens have shown a dramatic worldwide increase in prevalence. Bloodstream infections (BSIs) represent an important cause of morbidity and mortality in hospitalised patients. Research in the field led to the introduction of several novel antibiotic agents in the fight against bacterial pathogens. New antibiotics used against Gram-positive bacteria, mainly meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, include daptomycin, linezolid, quinupristin/dalfopristin and semisynthetic lipoglycopeptides. Among the Gram-negative bacteria, extended-spectrum beta-lactamase-producing Enterobacteriaceae as well as highly resistant Pseudomonas and Acinetobacter isolates are of particular concern. Doripenem is a recently approved carbapenem. Polymyxins are reconsidered as valuable therapeutic options for Gram-negative infections. Tigecycline, a glycylcycline, and ceftobiprole, a novel cephalosporin under investigation, have activity both against Gram-positive and Gram-negative organisms. In addition to the above agents, alternative treatment approaches that require further investigation have also been introduced into clinical practice. These include antibiotic lock therapy and continuous intravenous administration of antibiotics. In this article, we review the above treatment options for BSIs based on current clinical evidence. Comparative trials specifically focusing on patients with bacteraemia were generally not performed; however, a proportion of patients from the reported studies did have bacteraemia. PMID:18723329

  10. Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents.

    PubMed

    Wu, Lin-tao; Jiang, Zhi; Shen, Jia-jia; Yi, Hong; Zhan, Yue-chen; Sha, Ming-quan; Wang, Zhen; Xue, Si-tu; Li, Zhuo-rong

    2016-05-23

    A series of novel benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives were designed and synthesized. The biological activities of these derivatives were then evaluated as potential antitumour agents. These compounds were assayed for growth-inhibitory activity against HCT116, MCF-7 and HepG2 cell lines in vitro. The IC50 values of compounds A1 and A7 against the cancer cells were 0.06-3.64 μM and 0.04-9.80 μM, respectively. Their antiproliferative activities were significantly better than that of 5-Fluorouracil (IC50: 56.96-174.50 μM) and were close to that of Paclitaxel (IC50: 0.026-1.53 μM). The activity of these derivatives was over 100 times more effective than other reported structures of chalcone analogues (licochalcone A). A preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding. Compounds A1, A7 and A9 effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compound A7 showed a 74.6% tumour growth inhibition with no signs of toxicity at high doses that was similar to the inhibition achieved with the 12.5 mg/kg irinotecan positive control (70.2%). Therefore, this class of benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives represents a promising lead structure for the development of possible p53-MDM2 inhibitors as new antitumour agents. PMID:27017265

  11. Differential inhibition of restriction enzyme cleavage by chromophore-modified analogues of the antitumour antibiotics mithramycin and chromomycin reveals structure-activity relationships.

    PubMed

    Mansilla, Sylvia; Garcia-Ferrer, Irene; Méndez, Carmen; Salas, José A; Portugal, José

    2010-05-15

    Differential cleavage at three restriction enzyme sites was used to determine the specific binding to DNA of the antitumour antibiotics mithramycin A (MTA), chromomycin A(3) (CRO) and six chromophore-modified analogues bearing shorter side chains attached at C-3, instead of the pentyl chain. All these antibiotics were obtained through combinatorial biosynthesis in the producer organisms. MTA, CRO and their six analogues showed differences in their capacity for inhibiting the rate of cleavage by restriction enzymes that recognize C/G-rich tracts. Changes in DNA melting temperature produced by these molecules were also analyzed, as well as their antiproliferative activities against a panel of colon, ovarian and prostate human carcinoma cell lines. Moreover, the cellular uptake of several analogues was examined to identify whether intracellular retention was related to cytotoxicity. These experimental approaches provided mutually consistent evidence of a seeming correlation between the strength of binding to DNA and the antiproliferative activity of the chromophore-modified molecules. Four of the analogues (mithramycin SK, mithramycin SDK, chromomycin SK and chromomycin SDK) showed promising biological profiles. PMID:20093108

  12. Synthesis, analysis and biological evaluation of novel indolquinonecryptolepine analogues as potential anti-tumour agents.

    PubMed

    Le Gresley, A; Gudivaka, V; Carrington, S; Sinclair, A; Brown, J E

    2016-03-21

    A small library of cryptolepine analogues were synthesised incorporating halogens and/or nitrogen containing side chains to optimise their interaction with the sugar-phosphate backbone of DNA to give improved binding, interfering with topoisomerase II hence enhancing cytotoxicity. Cell viability, DNA binding and Topoisomerase II inhibition is discussed for these compounds. Fluorescence microscopy was used to investigate the uptake of the synthesised cryptolepines into the nucleus. We report the synthesis and anti-cancer biological evaluation of nine novel cryptolepine analogues, which have greater cytotoxicity than the parent compound and are important lead compounds in the development of novel potent and selective indoloquinone anti-neoplastic agents. PMID:26893255

  13. Coping with antibiotic resistance: combining nanoparticles with antibiotics and other antimicrobial agents.

    PubMed

    Allahverdiyev, Adil M; Kon, Kateryna Volodymyrivna; Abamor, Emrah Sefik; Bagirova, Malahat; Rafailovich, Miriam

    2011-11-01

    The worldwide escalation of bacterial resistance to conventional medical antibiotics is a serious concern for modern medicine. High prevalence of multidrug-resistant bacteria among bacteria-based infections decreases effectiveness of current treatments and causes thousands of deaths. New improvements in present methods and novel strategies are urgently needed to cope with this problem. Owing to their antibacterial activities, metallic nanoparticles represent an effective solution for overcoming bacterial resistance. However, metallic nanoparticles are toxic, which causes restrictions in their use. Recent studies have shown that combining nanoparticles with antibiotics not only reduces the toxicity of both agents towards human cells by decreasing the requirement for high dosages but also enhances their bactericidal properties. Combining antibiotics with nanoparticles also restores their ability to destroy bacteria that have acquired resistance to them. Furthermore, nanoparticles tagged with antibiotics have been shown to increase the concentration of antibiotics at the site of bacterium-antibiotic interaction, and to facilitate binding of antibiotics to bacteria. Likewise, combining nanoparticles with antimicrobial peptides and essential oils generates genuine synergy against bacterial resistance. In this article, we aim to summarize recent studies on interactions between nanoparticles and antibiotics, as well as other antibacterial agents to formulate new prospects for future studies. Based on the promising data that demonstrated the synergistic effects of antimicrobial agents with nanoparticles, we believe that this combination is a potential candidate for more research into treatments for antibiotic-resistant bacteria. PMID:22029522

  14. Anti-tumour necrosis factor agent and liver injury: Literature review, recommendations for management

    PubMed Central

    Rossi, Roberta Elisa; Parisi, Ioanna; Despott, Edward John; Burroughs, Andrew Kenneth; O'Beirne, James; Conte, Dario; Hamilton, Mark Ian; Murray, Charles Daniel

    2014-01-01

    Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF-related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti-TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self-limiting and drug withdrawal seems to be an exception. PMID:25516646

  15. Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents.

    PubMed Central

    Doherty, G. P.; Leith, M. K.; Wang, X.; Curphey, T. J.; Begleiter, A.

    1998-01-01

    DT-diaphorase is a two-electron-reducing enzyme that is an important activator of bioreductive anti-tumour agents, such as mitomycin C (MMC) and EO9, and is inducible by many compounds, including 1,2-dithiole-3-thiones (D3Ts). We showed previously that D3T selectively increased DT-diaphorase activity in mouse lymphoma cells compared with normal mouse marrow cells, and also increased MMC or EO9 cytotoxic activity in the lymphoma cells with only minor effects in the marrow cells. In this study, we found that D3T significantly increased DT-diaphorase activity in 28 of 38 human tumour cell lines representing ten tissue types with no obvious relationships between the tumour type, or the base level of DT-diaphorase activity, and the ability of D3T to increase the enzyme activity. Induction of DT-diaphorase activity in human tumour cell lines by 12 D3T analogues varied markedly with the D3T structure. D3T also increased DT-diaphorase activity in normal human bone marrow and kidney cells but the increases were small in these cells. In addition, D3T increased the level of enzyme activity in normal human lung cells. Pretreatment of human tumour cells with D3T analogues significantly increased the cytotoxic activity of MMC or EO9 in these cells, and the level of enhancement of anti-tumour activity paralleled the level of DT-diaphorase induction. In contrast, D3T did not effect the toxicity of EO9 in normal kidney cells. These results demonstrate that D3T analogues can increase DT-diaphorase activity in a wide variety of human tumour cells and that this effect can enhance the anti-tumour activity of the bioreductive agents MMC and EO9. PMID:9579829

  16. Interaction of the antitumour antibiotic luzopeptin with the hexanucleotide duplex d(5'-GCATGC)2. One-dimensional and two-dimensional n.m.r. studies.

    PubMed Central

    Searle, M S; Hall, J G; Denny, W A; Wakelin, L P

    1989-01-01

    1H- and 31P-n.m.r. spectroscopy were used to characterize the solution structure of the 1:1 complex formed between the antitumour antibiotic luzopeptin and the self-complementary hexanucleotide d(5'-GCATGC)2. Eighteen nuclear Overhauser effects between antibiotic and nucleotide protons, together with ring-current-induced perturbations to base-pair and quinoline 1H resonances, define the position and orientation of the bound drug molecule. Luzopeptin binds in the minor groove of the DNA with full retention of dyad symmetry, its quinoline chromophores intercalating at the 5'-CpA and 5'-TpG steps and its depsipeptide ring spanning the central two A.T base-pairs. The chromophores stack principally on the adenine base with their carbocyclic rings pointing towards the deoxyribose of the cytosine. There is no evidence for Hoogsteen base-pairing in the complex, all glycosidic bond angles and sugar puckers being typical of B-DNA as found for the free hexanucleotide. The 'breathing' motions of the A.T and internal G.C base-pairs are substantially slowed in the complex compared with the free DNA, and the observation that two phosphate resonances are shifted downfield by at least 0.5 p.p.m. in the 31P-n.m.r. spectrum of the complex suggests pronounced local helix unwinding at the intercalation sites. The data are consistent with a model of the complex in which luzopeptin bisintercalates with its depsipeptide essentially in the conformation found in the crystal of the free antibiotic [Arnold & Clardy (1981) J. Am. Chem. Soc. 103, 1243-1244]. We postulate only one conformational change within the peptide ring, which involves rotation of the pyridazine-glycine amide group linkage by 90 degrees towards the DNA surface. This manoeuvre breaks the glycine-to-glycine transannular hydrogen bonds and enables the glycine NH groups to bond to the thymine O-2 atoms of the sandwiched A.T base-pairs. It also shortens the major axis of the depsipeptide so that the interchromophore distance is

  17. Ecology of Anti-Biofilm Agents I: Antibiotics versus Bacteriophages.

    PubMed

    Abedon, Stephen T

    2015-01-01

    Bacteriophages, the viruses that infect bacteria, have for decades been successfully used to combat antibiotic-resistant, chronic bacterial infections, many of which are likely biofilm associated. Antibiotics as anti-biofilm agents can, by contrast, be inefficacious against even genetically sensitive targets. Such deficiencies in usefulness may result from antibiotics, as naturally occurring compounds, not serving their producers, in nature, as stand-alone disruptors of mature biofilms. Anti-biofilm effectiveness by phages, by contrast, may result from a combination of inherent abilities to concentrate lytic antibacterial activity intracellularly via bacterial infection and extracellularly via localized population growth. Considered here is the anti-biofilm activity of microorganisms, with a case presented for why, ecologically, bacteriophages can be more efficacious than traditional antibiotics as medically or environmentally applied biofilm-disrupting agents. Four criteria, it can be argued, generally must be met, in combination, for microorganisms to eradicate biofilms: (1) Furnishing of sufficiently effective antibacterial factors, (2) intimate interaction with biofilm bacteria over extended periods, (3) associated ability to concentrate antibacterial factors in or around targets, and, ultimately, (4) a means of physically disrupting or displacing target bacteria. In nature, lytic predators of bacteria likely can meet these criteria whereas antibiotic production, in and of itself, largely may not. PMID:26371010

  18. Ecology of Anti-Biofilm Agents I: Antibiotics versus Bacteriophages

    PubMed Central

    Abedon, Stephen T.

    2015-01-01

    Bacteriophages, the viruses that infect bacteria, have for decades been successfully used to combat antibiotic-resistant, chronic bacterial infections, many of which are likely biofilm associated. Antibiotics as anti-biofilm agents can, by contrast, be inefficacious against even genetically sensitive targets. Such deficiencies in usefulness may result from antibiotics, as naturally occurring compounds, not serving their producers, in nature, as stand-alone disruptors of mature biofilms. Anti-biofilm effectiveness by phages, by contrast, may result from a combination of inherent abilities to concentrate lytic antibacterial activity intracellularly via bacterial infection and extracellularly via localized population growth. Considered here is the anti-biofilm activity of microorganisms, with a case presented for why, ecologically, bacteriophages can be more efficacious than traditional antibiotics as medically or environmentally applied biofilm-disrupting agents. Four criteria, it can be argued, generally must be met, in combination, for microorganisms to eradicate biofilms: (1) Furnishing of sufficiently effective antibacterial factors, (2) intimate interaction with biofilm bacteria over extended periods, (3) associated ability to concentrate antibacterial factors in or around targets, and, ultimately, (4) a means of physically disrupting or displacing target bacteria. In nature, lytic predators of bacteria likely can meet these criteria whereas antibiotic production, in and of itself, largely may not. PMID:26371010

  19. The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters.

    PubMed

    Nancolas, Bethany; Guo, Lili; Zhou, Rong; Nath, Kavindra; Nelson, David S; Leeper, Dennis B; Blair, Ian A; Glickson, Jerry D; Halestrap, Andrew P

    2016-04-01

    Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitizing tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, whereas indirect evidence suggests it may also inhibitL-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). In the present study, we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki2.5 μM) and co-operatively inhibitsL-lactate transport by MCT1, MCT2 and MCT4 expressed inXenopus laevisoocytes withK0.5and Hill coefficient values of 36-40 μM and 1.65-1.85 respectively. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50∼ 7 μM) than other substrates including glutamate (IC50∼ 20 μM). In isolated DB-1 melanoma cells 1-10 μM LND increasedL-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreasedL-lactate output whereas increasing intracellular [L-lactate] > 5-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediatedL-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND onL-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate (CHC). PMID:26831515

  20. The anti-tumour agent lonidamine is a potent inhibitor of the mitochondrial pyruvate carrier and plasma membrane monocarboxylate transporters

    PubMed Central

    Nancolas, Bethany; Guo, Lili; Zhou, Rong; Nath, Kavindra; Nelson, David S.; Leeper, Dennis B.; Blair, Ian A.; Glickson, Jerry D.; Halestrap, Andrew P.

    2016-01-01

    Lonidamine (LND) is an anti-tumour drug particularly effective at selectively sensitising tumours to chemotherapy, hyperthermia and radiotherapy, although its precise mode of action remains unclear. It has been reported to perturb the bioenergetics of cells by inhibiting glycolysis and mitochondrial respiration, while indirect evidence suggests it may also inhibit L-lactic acid efflux from cells mediated by members of the proton-linked monocarboxylate transporter (MCT) family and also pyruvate uptake into the mitochondria by the mitochondrial pyruvate carrier (MPC). Here we test these possibilities directly. We demonstrate that LND potently inhibits MPC activity in isolated rat liver mitochondria (Ki 2.5 μM) and cooperatively inhibits L-lactate transport by MCT1, MCT2 and MCT4 expressed in Xenopus laevis oocytes with K0.5 and Hill Coefficient values of 36–40 μM and 1.65–1.85. In rat heart mitochondria LND inhibited the MPC with similar potency and uncoupled oxidation of pyruvate was inhibited more effectively (IC50 ~7 μM) than other substrates including glutamate (IC50 ~20 μM). In isolated DB-1 melanoma cells 1–10 μM LND increased L-lactate output, consistent with MPC inhibition, but higher concentrations (150 μM) decreased L-lactate output while increasing intracellular [L-lactate] > five-fold, consistent with MCT inhibition. We conclude that MPC inhibition is the most sensitive anti-tumour target for LND, with additional inhibitory effects on MCT-mediated L-lactic acid efflux and glutamine/glutamate oxidation. Together these actions can account for published data on the selective tumour effects of LND on L-lactate, intracellular pH (pHi) and ATP levels that can be partially mimicked by the established MPC and MCT inhibitor α-cyano-4-hydroxycinnamate. PMID:26831515

  1. Overview on the Current Antibiotic Containing Agents Used in Endodontics

    PubMed Central

    Bansal, Ramta; Jain, Aditya

    2014-01-01

    Antibiotics are systemically and locally used extensively in endodontics. However, local antibiotic application mode is considered more effective than systemic administration. The local mode enables the dentist to target bacteria in every nook and corner of root canal system, which is otherwise beyond reach if targeted by instrumentation or conventional root canal treatment protocols. Therefore, they are an important adjunct to conventional treatment of root canal. The present study reviews the various antibiotic containing dental agents used in endodontics. A web-based research on MedLine was performed with terms Review Articles published in the last 10 year's dental journals in English for literature researching, extracting, and synthesizing data. Relevant articles were shortlisted. Important cross-reference articles were also reviewed. PMID:25210667

  2. Recruitment of trimeric proliferating cell nuclear antigen by G1-phase cyclin-dependent kinases following DNA damage with platinum-based antitumour agents

    PubMed Central

    He, G; Kuang, J; Koomen, J; Kobayashi, R; Khokhar, A R; Siddik, Z H

    2013-01-01

    Background: In cycling tumour cells, the binary cyclin-dependent kinase Cdk4/cyclin D or Cdk2/cyclin E complex is inhibited by p21 following DNA damage to induce G1 cell-cycle arrest. However, it is not known whether other proteins are also recruited within Cdk complexes, or their role, and this was investigated. Methods: Ovarian A2780 tumour cells were exposed to the platinum-based antitumour agent 1R,2R-diaminocyclohexane(trans-diacetato)(dichloro)platinum(IV) (DAP), which preferentially induces G1 arrest in a p21-dependent manner. The Cdk complexes were analysed by gel filtration chromatography, immunoblot and mass spectrometry. Results: The active forms of Cdk4 and Cdk2 complexes in control tumour cells have a molecular size of ∼140 kDa, which increased to ∼290 kDa when inhibited following G1 checkpoint activation by DAP. Proteomic analysis identified Cdk, cyclin, p21 and proliferating cell nuclear antigen (PCNA) in the inhibited complex, and biochemical studies provided unequivocal evidence that the increase in ∼150 kDa of the inhibited complex is consistent with p21-dependent recruitment of PCNA as a trimer, likely bound to three molecules of p21. Although p21 alone was sufficient to inhibit the Cdk complex, PCNA was critical for stabilising p21. Conclusion: G1 Cdk complexes inhibited by p21 also recruit PCNA, which inhibits degradation and, thereby, prolongs activity of p21 within the complex. PMID:24104967

  3. A new arylbenzofuran derivative functions as an anti-tumour agent by inducing DNA damage and inhibiting PARP activity

    PubMed Central

    Chen, Hongbo; Zeng, Xiaobin; Gao, Chunmei; Ming, Pinghong; Zhang, Jianping; Guo, Caiping; Zhou, Lanzhen; Lu, Yin; Wang, Lijun; Huang, Laiqiang; He, Xiangjiu; Mei, Lin

    2015-01-01

    We previously reported that 7-hydroxy-5, 4’-dimethoxy-2-arylbenzofuran (HDAB) purified from Livistona chinensis is a key active agent. The present study investigated the function and molecular mechanism of HDAB. HDAB treatment of cervical cancer cells resulted in S phase arrest and apoptosis, together with cyclin A2 and CDK2 upregulation. Cyclin A2 siRNA and a CDK inhibitor efficiently relieved S phase arrest but increased the apoptosis rate. Mechanistic studies revealed that HDAB treatment significantly increased DNA strand breaks in an alkaline comet assay and induced ATM, CHK1, CHK2 and H2A.X phosphorylation. Wortmannin (a broad inhibitor of PIKKs) and CGK733 (a specific ATM inhibitor), but not LY294002 (a phosphatidylinositol 3-kinase inhibitor) or NU7026 (a DNA-PK specific inhibitor), prevented H2A.X phosphorylation and γH2A.X-positive foci formation in the nuclei, reversed S phase arrest and promoted the HDAB-induced apoptosis, suggesting that HDAB is a DNA damaging agent that can activate the ATM-dependent DNA repair response, thereby contributing to cell cycle arrest. In addition, molecular docking and in vitro activity assays revealed that HDAB can correctly dock into the hydrophobic pocket of PARP-1 and suppress PARP-1 ADP-ribosylation activity. Thus, the results indicated that HDAB can function as an anti-cancer agent by inducing DNA damage and inhibiting PARP activity. PMID:26041102

  4. NIR and visible investigation of some potential SERS-active substrates for studying antitumour agent all- trans retinoic acid

    NASA Astrophysics Data System (ADS)

    Beljebbar, A.; Sockalingum, G. D.; Morjani, H.; Angiboust, J. F.; Manfait, M.

    1997-01-01

    Red and near-infrared excited Fourier transform surface-enhanced Raman spectra of an anticancer agent, all- trans retinoic acid (ATRA), adsorbed on gold island films are reported. Best results have been obtained with plates 80 Å and 40 Å thick respectively in the red and near-infrared and at concentrations of 10 -5 and 5 × 10 -6 M with a spinning system. The use of near-infrared laser excitation with low photon energy, allows us to overcome the problems of isomerisation when the sample is exposed for a long time to the laser radiation. Comparison between the Raman and SERS spectra in the visible shows that the adsorption on the surface does not perturb the structure of ATRA and confirms the long range enhancement of the island films with this type of molecule. Spectral data show that while gold island films and colloids are appropriate substrates for use with red excitation, silver and gold colloids as well as gold island films exhibit satisfactory enhancement levels in the near-infrared. This study will in the future allow us to choose the appropriate system that will serve to investigate the interaction of ATRA with its target in vitro and the effect of this differentiating agent in human leukaemia cell lines such as K562 and HL60.

  5. Clinically Relevant Growth Conditions Alter Acinetobacter baumannii Antibiotic Susceptibility and Promote Identification of Novel Antibacterial Agents

    PubMed Central

    Colquhoun, Jennifer M.; Wozniak, Rachel A. F.; Dunman, Paul M.

    2015-01-01

    Biological processes that govern bacterial proliferation and survival in the host-environment(s) are likely to be vastly different from those that are required for viability in nutrient-rich laboratory media. Consequently, growth-based antimicrobial screens performed in conditions modeling aspects of bacterial disease states have the potential to identify new classes of antimicrobials that would be missed by screens performed in conventional laboratory media. Accordingly, we performed screens of the Selleck library of 853 FDA approved drugs for agents that exhibit antimicrobial activity toward the Gram-negative bacterial pathogen Acinetobacter baumannii during growth in human serum, lung surfactant, and/or the organism in the biofilm state and compared those results to that of conventional laboratory medium. Results revealed that a total of 90 compounds representing 73 antibiotics and 17 agents that were developed for alternative therapeutic indications displayed antimicrobial properties toward the test strain in at least one screening condition. Of the active library antibiotics only four agents, rifampin, rifaximin, ciprofloxacin and tetracycline, exhibited antimicrobial activity toward the organism during all screening conditions, whereas the remainder were inactive in ≥ 1 condition; 56 antibiotics were inactive during serum growth, 25 and 38 were inactive toward lung surfactant grown and biofilm-associated cells, respectively, suggesting that subsets of antibiotics may outperform others in differing infection settings. Moreover, 9 antibiotics that are predominantly used for the treatment Gram-positive pathogens and 10 non-antibiotics lacked detectable antimicrobial activity toward A. baumannii grown in conventional medium but were active during ≥ 1 alternative growth condition(s). Such agents may represent promising anti-Acinetobacter agents that would have likely been overlooked by antimicrobial whole cell screening assays performed in traditional

  6. Successful use of oral linezolid as a single active agent in endocarditis unresponsive to conventional antibiotic therapy.

    PubMed

    Ravindran, V; John, J; Kaye, G C; Meigh, R E

    2003-08-01

    Treatment of resistant gram-positive endocarditis is difficult. We report a case of resistant Staphylococcus epidermidis endocarditis that failed to respond to conventional antibiotic therapy but was treated successfully with an oral regimen of a new antibiotic, linezolid as a single active agent. This case report demonstrates the use of linezolid as an effective alternative to conventional antibiotics in such cases. PMID:12860152

  7. Modeling the Population Dynamics of Antibiotic-Resistant Bacteria:. AN Agent-Based Approach

    NASA Astrophysics Data System (ADS)

    Murphy, James T.; Walshe, Ray; Devocelle, Marc

    The response of bacterial populations to antibiotic treatment is often a function of a diverse range of interacting factors. In order to develop strategies to minimize the spread of antibiotic resistance in pathogenic bacteria, a sound theoretical understanding of the systems of interactions taking place within a colony must be developed. The agent-based approach to modeling bacterial populations is a useful tool for relating data obtained at the molecular and cellular level with the overall population dynamics. Here we demonstrate an agent-based model, called Micro-Gen, which has been developed to simulate the growth and development of bacterial colonies in culture. The model also incorporates biochemical rules and parameters describing the kinetic interactions of bacterial cells with antibiotic molecules. Simulations were carried out to replicate the development of methicillin-resistant S. aureus (MRSA) colonies growing in the presence of antibiotics. The model was explored to see how the properties of the system emerge from the interactions of the individual bacterial agents in order to achieve a better mechanistic understanding of the population dynamics taking place. Micro-Gen provides a good theoretical framework for investigating the effects of local environmental conditions and cellular properties on the response of bacterial populations to antibiotic exposure in the context of a simulated environment.

  8. Increased antibiotic release and equivalent biomechanics of a spacer cement without hard radio contrast agents.

    PubMed

    Bitsch, R G; Kretzer, J P; Vogt, S; Büchner, H; Thomsen, M N; Lehner, B

    2015-10-01

    We compared a novel calcium carbonate spacer cement (Copal® spacem) to well-established bone cements. Electron microscopic structure and elution properties of the antibiotics ofloxacin, vancomycin, clindamycin, and gentamicin were examined. A knee wear simulator model for articulating cement spacers was established. Mechanical tests for bending strength, flexural modulus, and compressive and fatigue strength were performed. The electron microscopic analysis showed a microporous structure of the spacer cement, and this promoted a significantly higher and longer antibiotic elution. All spacer cement specimens released the antibiotics for a period of up to 50days with the exception of the vancomycin loading. The spacer cement showed significantly less wear scars and fulfilled the ISO 5833 requirements. The newly developed spacer cement is a hydrophilic antibiotic carrier with an increased release. Cement without hard radio contrast agents can improve tribological behaviour of spacers, and this may reduce reactive wear particles and abrasive bone defects. PMID:26219491

  9. Selective advantage of resistant strains at trace levels of antibiotics: a simple and ultrasensitive color test for detection of antibiotics and genotoxic agents.

    PubMed

    Liu, Anne; Fong, Amie; Becket, Elinne; Yuan, Jessica; Tamae, Cindy; Medrano, Leah; Maiz, Maria; Wahba, Christine; Lee, Catherine; Lee, Kim; Tran, Katherine P; Yang, Hanjing; Hoffman, Robert M; Salih, Anya; Miller, Jeffrey H

    2011-03-01

    Many studies have examined the evolution of bacterial mutants that are resistant to specific antibiotics, and many of these focus on concentrations at and above the MIC. Here we ask for the minimum concentration at which existing resistant mutants can outgrow sensitive wild-type strains in competition experiments at antibiotic levels significantly below the MIC, and we define a minimum selective concentration (MSC) in Escherichia coli for two antibiotics, which is near 1/5 of the MIC for ciprofloxacin and 1/20 of the MIC for tetracycline. Because of the prevalence of resistant mutants already in the human microbiome, allowable levels of antibiotics to which we are exposed should be below the MSC. Since this concentration often corresponds to low or trace levels of antibiotics, it is helpful to have simple tests to detect such trace levels. We describe a simple ultrasensitive test for detecting the presence of antibiotics and genotoxic agents. The test is based on the use of chromogenic proteins as color markers and the use of single and multiple mutants of Escherichia coli that have greatly increased sensitivity to either a wide range of antibiotics or specific antibiotics, antibiotic families, and genotoxic agents. This test can detect ciprofloxacin at 1/75 of the MIC. PMID:21199928

  10. The anti-tumour effects of zoledronic acid

    PubMed Central

    Zekri, Jamal; Mansour, Maged; Karim, Syed Mustafa

    2014-01-01

    Bone is the most common site for metastasis in patients with solid tumours. Bisphosphonates are an effective treatment for preventing skeletal related events and preserving quality of life in these patients. Zoledronic acid (ZA) is the most potent osteoclast inhibitor and is licensed for the treatment of bone metastases. Clodronate and pamidronate are also licensed for this indication. In addition, ZA has been demonstrated to exhibit antitumour effect. Direct and indirect mechanisms of anti-tumour effect have been postulated and at many times proven. Evidence exists that ZA antitumour effect is mediated through inhibition of tumour cells proliferation, induction of apoptosis, synergistic/additive to inhibitory effect of cytotoxic agents, inhibition of angiogenesis, decrease tumour cells adhesion to bone, decrease tumour cells invasion and migration, disorganization of cell cytoskeleton and activation of specific cellular antitumour immune response. There is also clinical evidence from clinical trials that ZA improved long term survival outcome in cancer patients with and without bone metastases. In this review we highlight the preclinical and clinical studies investigating the antitumour effect of bisphosphonates with particular reference to ZA. PMID:26909294

  11. Antibiotics

    MedlinePlus

    ... or not using them properly, can add to antibiotic resistance. This happens when bacteria change and become able ... survive and re-infect you. Do not save antibiotics for later or use someone else's prescription. Centers for Disease Control and Prevention

  12. Formation of complexes of antimicrobial agent norfloxacin with antitumor antibiotics of anthracycline series

    NASA Astrophysics Data System (ADS)

    Evstigneev, M. P.; Rybakova, K. A.; Davies, D. B.

    2007-05-01

    The formation of complexes in solutions of the norfloxacin antimicrobial agent (NOR) with daunomycin (DAU) and nogalamycin (NOG), antitumor anthracycline antibiotics, was studied using 1H NMR spectroscopy. Based on the concentration and temperature dependences of the chemical shifts of the protons of interacting molecules, the equilibrium constants and thermodynamic parameters (enthalpy and entropy) of heteroassociation of the antibiotics were calculated. It was shown that NOR interacts with DAU (NOG) in aqueous solutions forming stacked heterocomplexes with parallel orientation of the molecular chromophores. The conclusion was drawn that such interactions should be taken into account when anthracyclines and quinolones are jointly administered during combined chemotherapy, since they can contribute to the medico-biological synergistic effect of these antibiotics.

  13. Marine Pharmacology in 2005-6: Antitumour and Cytotoxic Compounds

    PubMed Central

    Mayer, Alejandro M.S.; Gustafson, Kirk R.

    2009-01-01

    During 2005 and 2006, marine pharmacology research directed towards the discovery and development of novel antitumour agents was reported in 171 peer-reviewed articles. The purpose of this article is to present a structured review of the antitumour and cytotoxic properties of 136 marine natural products, many of which are novel compounds that belong to diverse structural classes, including polyketides, terpenes, steroids, and peptides. The organisms yielding these bioactive marine compounds included invertebrate animals, algae, fungi and bacteria. Antitumour pharmacological studies were conducted with 42 structurally defined marine natural products in a number of experimental and clinical models which further defined their mechanisms of action. Particularly potent in vitro cytotoxicity data generated with murine and human tumour cell lines was reported for 94 novel marine chemicals with as yet undetermined mechanisms of action. Noteworthy is the fact that marine anticancer research was sustained by a global collaborative effort, involving researchers from Australia, Belgium, Benin, Brazil, Canada, China, Egypt, France, Germany, India, Indonesia, Italy, Japan, Mexico, the Netherlands, New Zealand, Panama, the Philippines, Slovenia, South Korea, Spain, Sweden, Taiwan, Thailand, United Kingdom, and the United States. Finally, this 2005-6 overview of the marine pharmacology literature highlights the fact that the discovery of novel marine antitumour agents continued at the same active pace as during 1998-2004. PMID:18701274

  14. Effective Phages as Green Antimicrobial Agents Against Antibiotic-Resistant Hospital Escherichia coli

    PubMed Central

    Rahmani, Rana; Zarrini, Gholamreza; Sheikhzadeh, Farzam; Aghamohammadzadeh, Naser

    2015-01-01

    Background: Bacteriophages are viruses that attack bacteria and lead to their lysis in an efficient and highly specific manner. These natural enemies of bacteria were used as therapeutic agents before the advent of antibiotics. Currently, with the rapid spread of multi-drug resistant bacteria, phage therapy can be an effective alternative treatment for antibiotic resistant bacteria. Objectives: This study evaluated the effectiveness of bacteriophages in removing antibiotic-resistant clinical Escherichia coli strains in vitro and in vivo. Patients and Methods: Different samples were taken from bed sore and foot ulcers of patients with diabetes. E. coli strains were isolated and identified by standard methods. The antibiogram was ascertained using the Kirby Bauer disc diffusion method for ten antibiotics. The bacteriophages were isolated from environmental water samples. They were exposed to the host bacteria by the double-layer agar technique (DLA) to observe plaques. Cross reaction of the phages on test E. coli strains was performed to determine broader-spectrum phages. Phage TPR7 was selected for animal trials. Five groups of mice including a control group, bacterial group, phage group, antibiotic therapy group and phage therapy group, were examined. Results: Ten E. coli strains were isolated from hospital samples. They showed high resistance to the used antibiotics. An effective bacteriophage was isolated for each strain. The cross-reaction showed phages which affect more than six E. coli strains. They can be a good choice for clinical therapeutic use. In animal trials the group challenged with phages after being infected showed similar results as the group treated with gentamicin after being infected. In both groups infection was removed after 48 hours. Conclusions: According to the results, six strains were resistant to six or seven antibiotics and all strains were at least resistant to two antibiotics. However, for each of these resistant bacteria one

  15. G9a inhibition potentiates the anti-tumour activity of DNA double-strand break inducing agents by impairing DNA repair independent of p53 status.

    PubMed

    Agarwal, Pallavi; Jackson, Stephen P

    2016-10-01

    Cancer cells often exhibit altered epigenetic signatures that can misregulate genes involved in processes such as transcription, proliferation, apoptosis and DNA repair. As regulation of chromatin structure is crucial for DNA repair processes, and both DNA repair and epigenetic controls are deregulated in many cancers, we speculated that simultaneously targeting both might provide new opportunities for cancer therapy. Here, we describe a focused screen that profiled small-molecule inhibitors targeting epigenetic regulators in combination with DNA double-strand break (DSB) inducing agents. We identify UNC0638, a catalytic inhibitor of histone lysine N-methyl-transferase G9a, as hypersensitising tumour cells to low doses of DSB-inducing agents without affecting the growth of the non-tumorigenic cells tested. Similar effects are also observed with another, structurally distinct, G9a inhibitor A-366. We also show that small-molecule inhibition of G9a or siRNA-mediated G9a depletion induces tumour cell death under low DNA damage conditions by impairing DSB repair in a p53 independent manner. Furthermore, we establish that G9a promotes DNA non-homologous end-joining in response to DSB-inducing genotoxic stress. This study thus highlights the potential for using G9a inhibitors as anti-cancer therapeutic agents in combination with DSB-inducing chemotherapeutic drugs such as etoposide. PMID:27431310

  16. Binding of the potential antitumour agent indirubin-5-sulphonate at the inhibitor site of rabbit muscle glycogen phosphorylase b. Comparison with ligand binding to pCDK2-cyclin A complex.

    PubMed

    Kosmopoulou, Magda N; Leonidas, Demetres D; Chrysina, Evangelia D; Bischler, Nicolas; Eisenbrand, Gerhard; Sakarellos, Constantinos E; Pauptit, Richard; Oikonomakos, Nikos G

    2004-06-01

    The binding of indirubin-5-sulphonate (E226), a potential anti-tumour agent and a potent inhibitor (IC(50) = 35 nm) of cyclin-dependent kinase 2 (CDK2) and glycogen phosphorylase (GP) has been studied by kinetic and crystallographic methods. Kinetic analysis revealed that E226 is a moderate inhibitor of GPb (K(i) = 13.8 +/- 0.2 micro m) and GPa (K(i) = 57.8 +/- 7.1 micro m) and acts synergistically with glucose. To explore the molecular basis of E226 binding we have determined the crystal structure of the GPb/E226 complex at 2.3 A resolution. Structure analysis shows clearly that E226 binds at the purine inhibitor site, where caffeine and flavopiridol also bind [Oikonomakos, N.G., Schnier, J.B., Zographos, S.E., Skamnaki, V.T., Tsitsanou, K.E. & Johnson, L.N. (2000) J. Biol. Chem.275, 34566-34573], by intercalating between the two aromatic rings of Phe285 and Tyr613. The mode of binding of E226 to GPb is similar, but not identical, to that of caffeine and flavopiridol. Comparative structural analyses of the GPb-E226, GPb-caffeine and GPb-flavopiridol complex structures reveal the structural basis of the differences in the potencies of the three inhibitors and indicate binding residues in the inhibitor site that can be exploited to obtain more potent inhibitors. Structural comparison of the GPb-E226 complex structure with the active pCDK2-cyclin A-E226 complex structure clearly shows the different binding modes of the ligand to GPb and CDK2; the more extensive interactions of E226 with the active site of CDK2 may explain its higher affinity towards the latter enzyme. PMID:15153119

  17. Lack of new antiinfective agents: Passing into the pre-antibiotic age?

    PubMed Central

    Brandenburg, Klaus; Schürholz, Tobias

    2015-01-01

    The lack of newly developed antibiotics, together with the increase in multi-resistance of relevant pathogenic bacteria in the last decades, represents an alarming signal for human health care worldwide. The number of severely infected persons increases not only in developing but also in highly industrialized countries. This relates in first line to the most severe form of a bacterial infection, sepsis and the septic shock syndrome, with high mortality on critical care units. No particular anti-sepsis drug is available, and the therapy with conventional antibiotics more and more fails to provide a survival benefit. Due to the fact that the pharmaceutical industry has withdrawn to a high degree from the development of anti-infectious agents, a huge challenge for health care is approaching in the 21st century. In this article, these problems are outlined and possible alternatives are presented which may be helpful to solve the problem. PMID:26322166

  18. Molecular modelling, synthesis, cytotoxicity and anti-tumour mechanisms of 2-aryl-6-substituted quinazolinones as dual-targeted anti-cancer agents

    PubMed Central

    Hour, M J; Lee, K H; Chen, T L; Lee, K T; Zhao, Yu; Lee, H Z

    2013-01-01

    Background and Purpose Our previous study demonstrated that 6-(pyrrolidin-1-yl)-2-(3-methoxyphenyl)quinazolin-4-one (HMJ38) was a potent anti-tubulin agent. Here, HMJ38 was used as a lead compound to develop more potent anti-cancer agents and to examine the anti-cancer mechanisms. Experimental Approach Using computer-aided drug design, 2-aryl-6-substituted quinazolinones (MJ compounds) were designed and synthesized by introducing substituents at C-2 and C-6 positions of HMJ38. The cytotoxicity of MJ compounds towards human cancer cells was examined by Trypan blue exclusion assay. Microtubule distribution was visualized using TubulinTracker™ Green reagent. Protein expression of cell cycle regulators and JNK was assessed by Western blot analysis. Key Results Compounds MJ65–70 exhibited strong anti-proliferative effects towards melanoma M21, lung squamous carcinoma CH27, lung non-small carcinoma H460, hepatoma Hep3B and oral cancer HSC-3 cells, with one compund MJ66 (6-(pyrrolidin-1-yl)-2-(naphthalen-1-yl)quinazolin-4-one) highly active against M21 cells (IC50 about 0.033 μM). Treatment of CH27 or HSC-3 cells with MJ65–70 resulted in significant mitotic arrest accompanied by increasing multiple asters of microtubules. JNK protein expression was involved in the MJ65–70-induced CH27 and M21 cell death. Consistent with the cell cycle arrest at G2/M phase, marked increases in cyclin B1 and Bcl-2 phosphorylation were also observed, after treatment with MJ65–70. Conclusions and Implication MJ65–70 are dual-targeted, tubulin- and JNK-binding, anti-cancer agents and induce cancer cell death through up-regulation of JNK and interfering in the dynamics of tubulin. Our work provides a new strategy and mechanism for developing dual-targeted anti-cancer drugs, contributing to clinical anti-cancer drug discovery and application. PMID:23638624

  19. CO-releasing Metal Carbonyl Compounds as Antimicrobial Agents in the Post-antibiotic Era*

    PubMed Central

    Wareham, Lauren K.; Poole, Robert K.; Tinajero-Trejo, Mariana

    2015-01-01

    The possibility of a “post-antibiotic era” in the 21st century, in which common infections may kill, has prompted research into radically new antimicrobials. CO-releasing molecules (CORMs), mostly metal carbonyl compounds, originally developed for therapeutic CO delivery in animals, are potent antimicrobial agents. Certain CORMs inhibit growth and respiration, reduce viability, and release CO to intracellular hemes, as predicted, but their actions are more complex, as revealed by transcriptomic datasets and modeling. Progress is hindered by difficulties in detecting CO release intracellularly, limited understanding of the biological chemistry of CO reactions with non-heme targets, and the cytotoxicity of some CORMs to mammalian cells. PMID:26055702

  20. Preclinical emergence of vandetanib as a potent antitumour agent in mesothelioma: molecular mechanisms underlying its synergistic interaction with pemetrexed and carboplatin

    PubMed Central

    Giovannetti, E; Zucali, P A; Assaraf, Y G; Leon, L G; Smid, K; Alecci, C; Giancola, F; Destro, A; Gianoncelli, L; Lorenzi, E; Roncalli, M; Santoro, A; Peters, G J

    2011-01-01

    Background: Although pemetrexed, a potent thymidylate synthase (TS) inhibitor, enhances the cytoytoxic effect of platinum compounds against malignant pleural mesothelioma (MPM), novel combinations with effective targeted therapies are warranted. To this end, the current study evaluates new targeted agents and their pharmacological interaction with carboplatin–pemetrexed in human MPM cell lines. Methods: We treated H2052, H2452, H28 and MSTO-211H cells with carboplatin, pemetrexed and targeted compounds (gefitinib, erlotinib, sorafenib, vandetanib, enzastaurin and ZM447439) and evaluated the modulation of pivotal pathways in drug activity and cancer cell proliferation. Results: Vandetanib emerged as the compound with the most potent cytotoxic activity, which interacted synergistically with carboplatin and pemetrexed. Drug combinations blocked Akt phosphorylation and increased apoptosis. Vandetanib significantly downregulated epidermal growth factor receptor (EGFR)/Erk/Akt phosphorylation as well as E2F-1 mRNA and TS mRNA/protein levels. Moreover, pemetrexed decreased Akt phosphorylation and expression of DNA repair genes. Finally, most MPM samples displayed detectable levels of EGFR and TS, the variability of which could be used for patients' stratification in future trials with vandetanib–pemetrexed–carboplatin combination. Conclusion: Vandetanib markedly enhances pemetrexed–carboplatin activity against human MPM cells. Induction of apoptosis, modulation of EGFR/Akt/Erk phosphorylation and expression of key determinants for pemetrexed and carboplatin activity contribute to this synergistic interaction, and, together with the expression of these determinants in MPM samples, warrant further clinical investigation. PMID:21970874

  1. Non-antibiotic selection systems for soybean somatic embryos: the lysine analog aminoethyl-cysteine as a selection agent

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In soybean somatic embryo transformation, the standard selection agent currently used is hygromycin. However, hygromycin being an antibiotic is not ideal in the final product. When tested against different alternate selection agents our studies show that 0.16 µg/ mL glufosinate, 40 mg/L isopropylam...

  2. Antibiotics.

    PubMed

    Hariprasad, Seenu M; Mieler, William F

    2016-01-01

    The Endophthalmitis Vitrectomy Study (EVS) provided ophthalmologists with evidence-based management strategies to deal with endophthalmitis for the first time. However, since the completion of the EVS, numerous unresolved issues remain. The use of oral antibiotics has important implications for the ophthalmologist, particularly in the prophylaxis and/or management of postoperative, posttraumatic, or bleb-associated bacterial endophthalmitis. One can reasonably conclude that significant intraocular penetration of an antibiotic after oral administration may be a property unique to the newer-generation fluoroquinolones. Prophylactic use of mupirocin nasal ointment resulted in significant reduction of conjunctival flora with or without preoperative topical 5% povidone-iodine preparation. Ocular fungal infections have traditionally been very difficult to treat due to limited therapeutic options both systemically and intravitreally. Because of its broad spectrum of coverage, low MIC90 levels for the organisms of concern, good tolerability, and excellent bioavailability, voriconazole through various routes of administration may be useful to the ophthalmologist in the primary treatment of or as an adjunct to the current management of ocular fungal infections. PMID:26501865

  3. Influence of Mycotoxins and a Mycotoxin Adsorbing Agent on the Oral Bioavailability of Commonly Used Antibiotics in Pigs

    PubMed Central

    Goossens, Joline; Vandenbroucke, Virginie; Pasmans, Frank; De Baere, Siegrid; Devreese, Mathias; Osselaere, Ann; Verbrugghe, Elin; Haesebrouck, Freddy; De Saeger, Sarah; Eeckhout, Mia; Audenaert, Kris; Haesaert, Geert; De Backer, Patrick; Croubels, Siska

    2012-01-01

    It is recognized that mycotoxins can cause a variety of adverse health effects in animals, including altered gastrointestinal barrier function. It is the aim of the present study to determine whether mycotoxin-contaminated diets can alter the oral bioavailability of the antibiotics doxycycline and paromomycin in pigs, and whether a mycotoxin adsorbing agent included into diets interacts with those antibiotics. Experiments were conducted with pigs utilizing diets that contained blank feed, mycotoxin-contaminated feed (T-2 toxin or deoxynivalenol), mycotoxin-contaminated feed supplemented with a glucomannan mycotoxin binder, or blank feed supplemented with mycotoxin binder. Diets with T-2 toxin and binder or deoxynivalenol and binder induced increased plasma concentrations of doxycycline administered as single bolus in pigs compared to diets containing blank feed. These results suggest that complex interactions may occur between mycotoxins, mycotoxin binders, and antibiotics which could alter antibiotic bioavailability. This could have consequences for animal toxicity, withdrawal time for oral antibiotics, or public health. PMID:22606377

  4. Five-year assessment of causative agents and antibiotic resistances in urinary tract infections

    PubMed Central

    Çoban, Bayram; Ülkü, Nesrin; Kaplan, Halit; Topal, Burhan; Erdoğan, Haluk; Baskın, Esra

    2014-01-01

    Aim: To show the distribution and changes of causative agents of urinary tract infections in children and resistance rates by years and select the most appropriate antibiotics. Material and Methods: In this study, the Başkent University Alanya Research and Application Hospital automation system microbiology recording book was screened retrospectively. Growth of a single microorganism above 105 colonies (cfu/mL) was included in the assessment. Throughout the study, 10 691 urinary cultures were studies and growth was found in 392 (3.7%). Results: Three hundred and nine (78.8%) of the samples with growth belonged to girls. Growth was found in the neonatal period in 32 patients (8.2%). The most commonly isolated microorganism was Escherichia coli (E. coli) which was found in 68.4% of the patients. Klebsiella spp. were found with a rate of 12.0%; Enterobacter spp. were found with a rate of 10.7% and proteus spp. were found with a rate of 5.1%. Resistance to cefalotin (62.1%), trimethoprim-sulfamethoxasole (43.1%), amoxycillin-clavulanate (34.8%), ampicillin (30.4%), cefixim (26.3%) and nitrofurantoin (3.6%) was found in E. coli species. The antibiotic which had the highest resistance rate was ampicillin with a rate of 93.2% for klebsiella and 83.4% for enterobacter. Klebsiella spp. were the most commonly grown pathogens in newborns (40.6%). In a follow-up period of 5 years, the resistance of E. coli to amoxycillin-clavulanate regressed from 40.3% to 31.3%, while the resistance to trimethoprim-sulfamethoxasole (TMP-SMX) regressed from 45.6% to 34.7%. Conclusions: A high resistance against first-generation cephalosporins, ampicillin, amoxycillin-clavulanate and TMP-SMX which are the first-line antibiotics in childhood urinary tract infections was found. Carbapenem (meropenem, imipenem) resistance was not found in our center. Nitrofurantoin, aminoglycosides and cefixime can be recommended for empirical treatment in our hospital because of low resistance. Antibiotic

  5. Rewiring macrophages for anti-tumour immunity.

    PubMed

    Lee, Yunqin; Biswas, Subhra K

    2016-06-28

    Tumour-associated macrophages facilitate cancer progression, but whether they can be reprogrammed to elicit an anti-tumour response remains unclear. Deletion of the microRNA-processing enzyme Dicer is now shown to rewire macrophages to an anti-tumour mode, leading to an enhanced response to immunotherapy and inhibition of tumour progression. PMID:27350442

  6. Effects of nandrolone decanoate on the toxicity and anti-tumour action of CCNU and FU in murine tumours.

    PubMed Central

    Bibby, M. C.; Double, J. A.; Mughal, M. A.

    1981-01-01

    Pre-treatment with the anabolic steroid nandrolone decanoate (ND) increases the LD50 of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and 5-Fluorouracil (FU) in NMRI mice. Administration of ND did not affect the anti-tumour action of CCNU against a transplantable mouse adenocarcinoma of the colon (MAC 13) or the anti-tumour action of FU against MAC 26. In both tumour lines ND had no significant effect on tumour growth. These data suggest that an increase in the anti-tumour selectivity of these agents may be produced by pre-treatment with ND. PMID:7295514

  7. Indications and Types of Antibiotic Agents Used in 6 Acute Care Hospitals, 2009-2010: A Pragmatic Retrospective Observational Study.

    PubMed

    Kelesidis, Theodoros; Braykov, Nikolay; Uslan, Daniel Z; Morgan, Daniel J; Gandra, Sumanth; Johannsson, Birgir; Schweizer, Marin L; Weisenberg, Scott A; Young, Heather; Cantey, Joseph; Perencevich, Eli; Septimus, Edward; Srinivasan, Arjun; Laxminarayan, Ramanan

    2016-01-01

    BACKGROUND To design better antimicrobial stewardship programs, detailed data on the primary drivers and patterns of antibiotic use are needed. OBJECTIVE To characterize the indications for antibiotic therapy, agents used, duration, combinations, and microbiological justification in 6 acute-care US facilities with varied location, size, and type of antimicrobial stewardship programs. DESIGN, PARTICIPANTS, AND SETTING Retrospective medical chart review was performed on a random cross-sectional sample of 1,200 adult inpatients, hospitalized (>24 hrs) in 6 hospitals, and receiving at least 1 antibiotic dose on 4 index dates chosen at equal intervals through a 1-year study period (October 1, 2009-September 30, 2010). METHODS Infectious disease specialists recorded patient demographic characteristics, comorbidities, microbiological and radiological testing, and agents used, dose, duration, and indication for antibiotic prescriptions. RESULTS On the index dates 4,119 (60.5%) of 6,812 inpatients were receiving antibiotics. The random sample of 1,200 case patients was receiving 2,527 antibiotics (average: 2.1 per patient); 540 (21.4%) were prophylactic and 1,987 (78.6%) were therapeutic, of which 372 (18.7%) were pathogen-directed at start. Of the 1,615 empirical starts, 382 (23.7%) were subsequently pathogen-directed and 1,231 (76.2%) remained empirical. Use was primarily for respiratory (27.6% of prescriptions) followed by gastrointestinal (13.1%) infections. Fluoroquinolones, vancomycin, and antipseudomonal penicillins together accounted for 47.1% of therapy-days. CONCLUSIONS Use of broad-spectrum empirical therapy was prevalent in 6 US acute care facilities and in most instances was not subsequently pathogen directed. Fluoroquinolones, vancomycin, and antipseudomonal penicillins were the most frequently used antibiotics, particularly for respiratory indications. Infect. Control Hosp. Epidemiol. 2015;37(1):70-79. PMID:26456803

  8. [Comparative analysis of the antibiotic sensitivity determination methods of conventionally pathogenic bacteria--agents of human opportunistic infections].

    PubMed

    Kulia, A F; Sabo, Iu; Koval', H M; Boĭko, N V

    2011-01-01

    Investigation of biological properties of pathogenic bacteria and, first of all, their sensitivity to antibiotics is the key to successful treatment of human opportunistic infections and to selection of appropriate tactics of their prevention. This paper is devoted to the comparative characteristic of modem and classical approaches to determination of sensitivities to antibiotics of conventionally pathogenic bacteria: methods applied in Ukraine and recommendations proposed by European Committee aimed to unify all the methods of testing sensitivity to antimicrobial agents (EUCAST). The major differences of the above-mentioned methods of testing sensitivity of clinical and non-clinical isolates of potentially pathogenic bacteria to antibiotics have been examined in order to confirm the feasibility of usage and permanent updating the EUCAST database and to promote creation of the appropriate unifield national electronic resource. PMID:22164699

  9. Synthesis and antitumour activity of 4-aminoquinazoline derivatives

    NASA Astrophysics Data System (ADS)

    Lipunova, G. N.; Nosova, E. V.; Charushin, V. N.; Chupakhin, O. N.

    2016-07-01

    Pieces of data on the synthesis and antitumour activity of 4-aminoquinazolines are summarized and analyzed. Key methods for the synthesis of these compounds are considered, primarily cyclocondensation of carboxylic acid derivatives, as well as the oxidation of quinazolines and the cyclization of disubstituted thioureas. Improvements of synthetic schemes for erlotinib, gefitinib and lapatinib, which are the best-known pharmaceuticals based on compounds of the title class, are also considered. Synthetic strategies and biological activities for new 4-aminoquinazoline derivatives that are EGFR-tyrosine kinase inhibitors, multiactive compounds, and labelled compounds for use as positron emission tomography (PET) imaging agents are discussed. The bibliography includes 263 references.

  10. Non-antibiotic selection systems for soybean somatic embryos: the lysine analog aminoethyl-cysteine as a selection agent

    PubMed Central

    2009-01-01

    Background In soybean somatic embryo transformation, the standard selection agent currently used is hygromycin. It may be preferable to avoid use of antibiotic resistance genes in foods. The objective of these experiments was to develop a selection system for producing transgenic soybean somatic embryos without the use of antibiotics such as hygromycin. Results When tested against different alternate selection agents our studies show that 0.16 μg/mL glufosinate, 40 mg/L isopropylamine-glyphosate, 0.5 mg/mL (S-(2 aminoethyl)-L-cysteine) (AEC) and the acetolactate synthase (ALS) inhibitors Exceed® and Synchrony® both at 150 μg/mL inhibited soybean somatic embryo growth. Even at the concentration of 2 mg/mL, lysine+threonine (LT) were poor selection agents. The use of AEC may be preferable since it is a natural compound. Unlike the plant enzyme, dihydrodipicolinate synthase (DHPS) from E. coli is not feed-back inhibited by physiological concentrations of lysine. The dapA gene which codes for E. coli DHPS was expressed in soybean somatic embryos under the control of the CaMV 35S promoter. Following introduction of the construct into embryogenic tissue of soybean, transgenic events were recovered by incubating the tissue in liquid medium containing AEC at a concentration of 5 mM. Only transgenic soybeans were able to grow at this concentration of AEC; no escapes were observed. Conclusion Genetically engineered soybeans expressing a lysine insensitive DHPS gene can be selected with the non-antibiotic selection agent AEC. We also report here the inhibitory effects of glufosinate, (isopropylamine-glyphosate) (Roundup®), AEC and the ALS inhibitors Exceed® and Synchrony® against different tissues of soybean PMID:19922622

  11. New antibiotic agents in the pipeline and how they can help overcome microbial resistance

    PubMed Central

    Gould, Ian M.; Bal, Abhijit M.

    2013-01-01

    Bacterial resistance is a growing threat and yet few new antibiotics active against multi-resistant bacteria are being explored. A combination of falling profits, regulatory mechanisms and irrational and injudicious use of antibiotics has led to an alarming situation where some infections have no cure. In this article, we summarize the new developments that have been suggested to incentivize the pharmaceutical industries toward the field of infections. We also briefly mention the new compounds on the horizon and some newly approved compounds that might help us tide over this crisis. PMID:23302792

  12. Novel Quorum-Quenching Agents Promote Methicillin-Resistant Staphylococcus aureus (MRSA) Wound Healing and Sensitize MRSA to β-Lactam Antibiotics

    PubMed Central

    Kuo, David; Yu, Guanping; Hoch, Wyatt; Gabay, Dean; Long, Lisa; Ghannoum, Mahmoud; Nagy, Nancy; Harding, Clifford V.; Viswanathan, Rajesh

    2014-01-01

    The dwindling repertoire of antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA) calls for novel treatment options. Quorum-quenching agents offer an alternative or an adjuvant to antibiotic therapy. Three biaryl hydroxyketone compounds discovered previously (F1, F12, and F19; G. Yu, D. Kuo, M. Shoham, and R. Viswanathan, ACS Comb Sci 16:85–91, 2014) were tested for efficacy in MRSA-infected animal models. Topical therapy of compounds F1 and F12 in a MRSA murine wound infection model promotes wound healing compared to the untreated control. Compounds F1, F12, and F19 afford significant survival benefits in a MRSA insect larva model. Combination therapy of these quorum-quenching agents with cephalothin or nafcillin, antibiotics to which MRSA is resistant in monotherapy, revealed additional survival benefits. The quorum-quenching agents sensitize MRSA to the antibiotic by a synergistic mode of action that also is observed in vitro. An adjuvant of 1 μg/ml F1, F12, or F19 reduces the MIC of nafcillin and cephalothin about 50-fold to values comparable to those for vancomycin, the antibiotic often prescribed for MRSA infections. These findings suggest that it is possible to resurrect obsolete antibiotic therapies in combination with these novel quorum-quenching agents. PMID:25534736

  13. Development of antimicrobial agents in the era of new and reemerging infectious diseases and increasing antibiotic resistance.

    PubMed

    Cassell, G H; Mekalanos, J

    2001-02-01

    During the past 2 decades, new infectious diseases have appeared and old ones previously thought to be controlled have reemerged. New and reemerging infectious agents will continue to pose serious threats well into the 21st century. The prediction that the threat of infectious disease may not diminish is supported by evidence that infectious agents cause many chronic diseases and cancer of previous unknown etiology. Moreover, the utility of existing antimicrobial agents is rapidly eroding, tipping the balance in favor of multidrug-resistant pathogens, and there appear to be few, if any, new classes of drugs currently in clinical development. The need for research directed toward development of new antibiotics has never been greater. Advances in research technologies and microbial genome sequencing in the past decade have led to identification of a large number of new targets. Functional genomics and integrative biology should validate these targets and provide the best opportunity for developing effective new therapies, improved diagnostic techniques, and better tools to understand host-pathogen interactions. PMID:11176866

  14. The frequency of antibiotic-resistant bacteria in homes differing in their use of surface antibacterial agents.

    PubMed

    Marshall, Bonnie M; Robleto, Eduardo; Dumont, Theresa; Levy, Stuart B

    2012-10-01

    Antibacterial agents are common in household cleaning and personal care products, but their long-range impacts on commensal and pathogenic household bacteria are largely unknown. In a one-time survey of 38 households from Boston, MA [19] and Cincinnati, OH [18], 13 kitchen and bathroom sites were sampled for total aerobic bacteria and screened for gram phenotype and susceptibility to six antibiotic drug families. The overall bacterial titers of both user (2 or more antibacterial cleaning or personal care products) and non-user (0 or 1 product) rooms were similar with sponges and sink drains consistently showing the highest overall titers and relatively high titers of antibiotic-resistant bacteria. The mean frequency of resistant bacteria ranged from ≤20 % to as high as 45 % and multi-drug resistance was common. However, no significant differences were noted between biocide users and non-users. The frequency of pathogen recovery was similar in both user and non-user groups. PMID:22752336

  15. New Approaches to Antibiotic Use and Review of Recently Approved Antimicrobial Agents.

    PubMed

    Hahn, Andrew W; Jain, Rupali; Spach, David H

    2016-07-01

    Antimicrobial drug-resistance continues to force adaptation in our clinical practice. We explore new evidence regarding adjunctive antibiotic therapy for skin and soft tissue abscesses as well as duration of therapy for intra-abdominal abscesses. As new evidence refines optimal practice, it is essential to support clinicians in adopting practice patterns concordant with evidence-based guidelines. We review a simple approach that can 'nudge' clinicians towards concordant practices. Finally, the use of novel antimicrobials will play an increasingly important role in contemporary therapy. We review five new antimicrobials recently FDA-approved for use in drug-resistant infections: dalbavancin, oritavancin, ceftaroline, ceftolozane-tazobactam, and ceftazidime-avibactam. PMID:27235621

  16. Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (III)

    PubMed Central

    Liu, Yan; Haste, Nina M.; Thienphrapa, Wdee; Li, Jerry; Nizet, Victor; Hensler, Mary; Li, Rongshi

    2014-01-01

    The marine natural product, marinopyrrole A (1), was previously shown to have significant antibiotic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Although compound (1) exhibits a significant reduction in MRSA activity in the presence of human serum, we have identified key modifications that partially restore activity. We previously reported our discovery of a chloro-derivative of marinopyrrole A (1a) featuring a 2–4 fold improved minimum inhibitory concentration (MIC) against MRSA, significantly less susceptibility to serum inhibition and rapid and concentration-dependent killing of MRSA. Here, we report a novel fluoro-derivative of marinopyrrole A (1e) showing an improved profile of potency, less susceptibility to serum inhibition, as well as rapid and concentration-dependent killing of MRSA. PMID:24796304

  17. Antibiotics and Resistance: Glossary

    MedlinePlus

    ... induced by natural or human activity on the ecology and living organisms. Ecology The study of the relationships and interactions between ... antibiotics The Cost of Resistance Science of Resistance Ecology Antibiotics in Agriculture Antibacterial Agents Glossary References Web ...

  18. Effect of hairpin loop structure on reactivity, sequence preference and adduct orientation of a DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepine (PBD) antitumour agent.

    PubMed

    Thurston, David E; Vassoler, Higia; Jackson, Paul J M; James, Colin H; Rahman, Khondaker M

    2015-04-01

    The pyrrolobenzodiazepines (PBDs) are a family of covalent-binding DNA-interactive minor-groove binding agents with a thermodynamic preference for binding to 5'-Pu-G-Pu-3' sequences (Pu = Purine) but a kinetic preference for 5'-Py-G-Py-3' (Py = Pyrimidine). Using HPLC/MS methodology and a range of designed hairpin-forming oligonucleotides, the kinetics of reaction of a C8-bis-pyrrole pyrrolobenzodiazepine (PBD) conjugate (GWL-78, 2) with sixteen isomeric oligonucleotides has been evaluated, each containing a single PBD binding site in one of two locations. The PBD-binding base-pair triplets were designed to include every possible combination of A and T bases adjacent to the covalently-reacting guanine, with the set of hairpins consisting of isomeric pairs containing the same sequence in the hairpin stem but with either hexaethylene glycol (HEG) or TTT loops. The PBD 2 reacted most rapidly with TGT and TGA sequences, with the possibility that adducts might form in both the 3'- and 5'-directions with some sequences according to modelling studies. A faster reaction rate was observed for all hairpins containing the HEG loop except one (Seq 10) when the PBD binding triplets were located either near the loop or adjacent to the 5'-end. Modelling studies have suggested that this difference in reactivity could be due to the structural flexibility of the HEG loop allowing both A-ring-3' and A-ring-5' adducts to form, while a TTT loop should favour only A-ring-5' adducts due to steric considerations. These findings contrast with the results reported by Nguyen and Wilson for the interaction of non-covalent DNA-binding molecules with DNA hairpins, where the loop structure was found to have little effect on interaction in the main stem of the hairpin. PMID:25733051

  19. Salmonella enterica serovar Typhimurium immunotherapy for B-cell lymphoma induces broad anti-tumour immunity with therapeutic effect

    PubMed Central

    Grille, Sofía; Moreno, María; Bascuas, Thais; Marqués, Juan M; Muñoz, Natalia; Lens, Daniela; Chabalgoity, Jose A

    2014-01-01

    Despite the efficacy of current immune-chemotherapy for treatment of B-cell non-Hodgkin lymphoma, a substantial proportion of patients relapse, highlighting the need for new therapeutic modalities. The use of live microorganisms to develop anti-tumoural therapies has evolved since Coley's toxin and is now receiving renewed attention. Salmonella Typhimurium has been shown to be highly effective as an anti-tumour agent in many solid cancer models, but it has not been used in haemato-oncology. Here, we report that intra-tumoural administration of LVR01 (attenuated S. Typhimurium strain with safety profile) elicits local and systemic anti-tumour immunity, resulting in extended survival in a lymphoma model. LVR01 induces intra-tumoural recruitment of neutrophils and activated CD8+ T cells, as well as increasing the natural killer cell activation status. Furthermore, a systemic specific anti-tumour response with a clear T helper type 1 profile was observed. This approach is an alternative therapeutic strategy for lymphoma patients that could be easily moved into clinical trials. PMID:24834964

  20. Se-methylselenocysteine offers selective protection against toxicity and potentiates the antitumour activity of anticancer drugs in preclinical animal models

    PubMed Central

    Cao, S; Durrani, F A; Tóth, K; Rustum, Y M

    2014-01-01

    Background: Identification and development of drugs that can effectively modulate the therapeutic efficacy and toxicity of chemotherapy remain an unmet challenge. We evaluated the effects of Se-methylselenocysteine (MSC) on the toxicity and antitumour activity of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan in animal models. Methods: Cyclophosphamide, cisplatin, and oxaliplatin were administered by a single i.v. injection and irinotecan by i.v. weekly × 4 schedules. For the combination, MSC was administered daily via the oral route for 7 days in mice and daily for 14 days in rats before and concurrent with drug administration. Results: Se-methylselenocysteine significantly protected against organ-specific toxicity induced by lethal doses of cyclophosphamide, cisplatin, oxaliplatin, and irinotecan. These include diarrhoea, stomatitis, alopecia, bladder, kidney, and bone marrow toxicities. Protection from lethal toxicity by MSC was associated with enhanced antitumour activity in rats bearing advanced Ward colorectal carcinoma and in nude mice bearing human squamous cell carcinoma of the head and neck, FaDu, and A253 xenografts. Conclusions: Se-methylselenocysteine offers selective protection against organ-specific toxicity induced by clinically active agents and enhances further antitumour activity, resulting in improved therapeutic index. These data provided the rationale for the need to clinically evaluate MSC as selective modulator of the antitumour activity and selectivity of anticancer drugs. PMID:24619073

  1. Antibiotic resistant in microorganisms

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Antimicrobial agents are necessary for use in veterinary medicine including the production of food producing animals. Antibiotic use is indicated for the treatment of bacterial target organisms and/or disease for which the antibiotic was developed. However, an unintended consequence of antibiotic ...

  2. Anti-tumour promoting activity of diphenylmethyl selenocyanate against two-stage mouse skin carcinogenesis.

    PubMed

    Das, Rajat Kumar; Bhattacharya, Sudin

    2005-01-01

    Epidemiological, clinical and experimental evidence collectively suggests that Se in different inorganic and organic forms provides a potential cancer chemopreventive agent, active against several types of cancer. It can exert preventive activity in all the three stages of cancer: initiation, promotion and progression. Literature reports revealed that organoselenocyanates have more potential as chemopreventive agents than inorganic forms due to their lower toxicity. In our previous report we showed chemopreventive efficacy of diphenylmethyl selenocyanate during the initiation and pre- plus post-initiation phases of skin and colon carcinogenesis process. The present study was undertaken to explore the anti-tumour promoting activity of diphenylmethyl selenocyanate in a 7,12-dimethylbenz (a) anthracene (DMBA)-croton oil two-stage skin carcinogenesis model. The results obtained showed significant (p<0.01) reduction of the incidence and number of skin papillomas, precancerous skin lesions, along with significant (p<0.01) elevation of phase II detoxifying enzymes (GST, Catalase and SOD) and inhibition of lipid peroxidation in liver and skin. Thus, the present data strongly suggest that diphenylmethyl selenocyanate also has the potential to act as anti-tumour promoter agent in a two-stage skin carcinogenesis mouse model, pointing to possible general efficacy. PMID:16101330

  3. Molecular insights on the biosynthesis of antitumour compounds by actinomycetes

    PubMed Central

    Olano, Carlos; Méndez, Carmen; Salas, José A.

    2011-01-01

    Summary Natural products are traditionally the main source of drug leads. In particular, many antitumour compounds are either natural products or derived from them. However, the search for novel antitumour drugs active against untreatable tumours, with fewer side‐effects or with enhanced therapeutic efficiency, is a priority goal in cancer chemotherapy. Microorganisms, particularly actinomycetes, are prolific producers of bioactive compounds, including antitumour drugs, produced as secondary metabolites. Structural genes involved in the biosynthesis of such compounds are normally clustered together with resistance and regulatory genes, which facilitates the isolation of the gene cluster. The characterization of these clusters has represented, during the last 25 years, a great source of genes for the generation of novel derivatives by using combinatorial biosynthesis approaches: gene inactivation, gene expression, heterologous expression of the clusters or mutasynthesis. In addition, these techniques have been also applied to improve the production yields of natural and novel antitumour compounds. In this review we focus on some representative antitumour compounds produced by actinomycetes covering the genetic approaches used to isolate and validate their biosynthesis gene clusters, which finally led to generating novel derivatives and to improving the production yields. PMID:21342461

  4. Antitumour activity of the novel flavonoid Oncamex in preclinical breast cancer models

    PubMed Central

    Martínez-Pérez, Carlos; Ward, Carol; Turnbull, Arran K; Mullen, Peter; Cook, Graeme; Meehan, James; Jarman, Edward J; Thomson, Patrick IT; Campbell, Colin J; McPhail, Donald; Harrison, David J; Langdon, Simon P

    2016-01-01

    Background: The natural polyphenol myricetin induces cell cycle arrest and apoptosis in preclinical cancer models. We hypothesised that myricetin-derived flavonoids with enhanced redox properties, improved cell uptake and mitochondrial targeting might have increased potential as antitumour agents. Methods: We studied the effect of a second-generation flavonoid analogue Oncamex in a panel of seven breast cancer cell lines, applying western blotting, gene expression analysis, fluorescence microscopy and immunohistochemistry of xenograft tissue to investigate its mechanism of action. Results: Proliferation assays showed that Oncamex treatment for 8 h reduced cell viability and induced cytotoxicity and apoptosis, concomitant with increased caspase activation. Microarray analysis showed that Oncamex was associated with changes in the expression of genes controlling cell cycle and apoptosis. Fluorescence microscopy showed the compound's mitochondrial targeting and reactive oxygen species-modulating properties, inducing superoxide production at concentrations associated with antiproliferative effects. A preliminary in vivo study in mice implanted with the MDA-MB-231 breast cancer xenograft showed that Oncamex inhibited tumour growth, reducing tissue viability and Ki-67 proliferation, with no signs of untoward effects on the animals. Conclusions: Oncamex is a novel flavonoid capable of specific mitochondrial delivery and redox modulation. It has shown antitumour activity in preclinical models of breast cancer, supporting the potential of this prototypic candidate for its continued development as an anticancer agent. PMID:27031849

  5. Antibiotic-loaded, silver core-embedded mesoporous silica nanovehicles as a synergistic antibacterial agent for the treatment of drug-resistant infections.

    PubMed

    Wang, Yao; Ding, Xiali; Chen, Yuan; Guo, Mingquan; Zhang, Yan; Guo, Xiaokui; Gu, Hongchen

    2016-09-01

    Drug-resistant bacterial infections have become one of the most serious risks in public health as they make the conventional antibiotics less efficient. There is an urgent need for developing new generations of antibacterial agents in this field. In this work, a nanoplatform of LEVO-loaded and silver core-embedded mesoporous silica nanovehicles (Ag@MSNs@LEVO) is demonstrated as a synergistic antibacterial agent for the treatment of drug-resistant infections both in vitro and in vivo. The combination of the inner Ag core and the loaded antibiotic drug in mesopores endows the single-particle nanoplatform with a synergistic effect on killing the drug-resistant bacteria. The nanoplatform of Ag@MSNs@LEVO exhibits superior antibacterial activity to LEVO-loaded MSNs (MSNs@LEVO) and silver core-embedded MSNs (Ag@MSNs) in vitro. In the in vivo acute peritonitis model, the infected drug-resistant Escherichia coli GN102 in peritoneal cavity of the mice is reduced by nearly three orders of magnitude and the aberrant pathological feature of spleen and peritoneum disappears after treatment with Ag@MSNs@LEVO. Importantly, this nanopaltform renders no obvious toxic side effect to the mice during the tested time. There is no doubt that this study strongly indicates a promising potential of Ag@MSNs@LEVO as a synergistic and safety therapy tool for the clinical drug-resistant infections. PMID:27294538

  6. In vitro susceptibility of e.faecalis and c.albicans isolates from apical periodontitis to common antimicrobial agents, antibiotics and antifungal medicaments

    PubMed Central

    Yoldas, Oguz; Yilmaz, Sehnaz; Akcimen, Beril; Seydaoglu, Gulsah; Kipalev, Arzu; Koksal, Fatih

    2012-01-01

    The aim of this study was to evaluate in vitro antimicrobial activity of 4 antibiotic agents (for E.faecalis) and 4 antifungal agents (for C.albicans) by agar dilution method. Additionally, modified strip diffusion method was used for detection of in vitro antimicrobial activities of 5% NaOCl, 2.5% NaOCl, 17% EDTA and 2% CHX and agar diffusion method for detection of in vitro susceptibilities of three intracanal medicaments for 18 E.faecalis and 18 C.albicans isolates from primary and secondary root canal infection. Isolates were recovered from 231 endodontic samples of patients, with the need of root canal treatment and retreatment. All tested E.faecalis isolates showed resistance to antibiotics. For irrigation solutions, 2% CHX was more effective in eliminating E.faecalis but 5% NaOCl showed larger inhibition zone than 2.5% NaOCl, 17% EDTA and 2% CHX. For intracanal medication, Ca(OH)2-CHX worked efficiently in killing E.faecalis isolates compared to Ca(OH)2-Steril saline solution, Ca(OH)2-Glycerin. For C.albicans, 18 isolates were susceptible to amphotericin B, nistatin, fluconazole but showed resistance to ketoconazole. 5% NaOCl was more effective in eliminating and produced larger inhibition zone compared to 2.5% NaOCl, 17% EDTA and 2% CHX. Ca(OH)2-Glycerin intracanal medication was better in eliminating C.albicans isolates and produced larger inhibition zone compared to other Ca(OH)2 medicaments. Key words:E.faecalis, C.albicans, antimicrobial, antibiotic, antifungal. PMID:24558517

  7. The membrane protein PrsS mimics σS in protecting Staphylococcus aureus against cell wall-targeting antibiotics and DNA-damaging agents

    PubMed Central

    Krute, Christina N.; Bell-Temin, Harris; Miller, Halie K.; Rivera, Frances E.; Weiss, Andy; Stevens, Stanley M.

    2015-01-01

    Staphylococcus aureus possesses a lone extracytoplasmic function (ECF) sigma factor, σS. In Bacillus subtilis, the ECF sigma factor, σW, is activated through a proteolytic cascade that begins with cleavage of the RsiW anti-sigma factor by a site-1 protease (S1P), PrsW. We have identified a PrsW homologue in S. aureus (termed PrsS) and explored its role in σS regulation. Herein, we demonstrate that although a cognate σS anti-sigma factor currently remains elusive, prsS phenocopies sigS in a wealth of regards. Specifically, prsS expression mimics the upregulation observed for sigS in response to DNA-damaging agents, cell wall-targeting antibiotics and during ex vivo growth in human serum and murine macrophages. prsS mutants also display the same sensitivities of sigS mutants to the DNA-damaging agents methyl methane sulfonate (MMS) and hydrogen peroxide, and the cell wall-targeting antibiotics ampicillin, bacitracin and penicillin-G. These phenotypes appear to be explained by alterations in abundance of proteins involved in drug resistance (Pbp2a, FemB, HmrA) and the response to DNA damage (BmrA, Hpt, Tag). Our findings seem to be mediated by putative proteolytic activity of PrsS, as site-directed mutagenesis of predicted catalytic residues fails to rescue the sensitivity of the mutant to H2O2 and MMS. Finally, a role for PrsS in S. aureus virulence was identified using human and murine models of infection. Collectively, our data indicate that PrsS and σS function in a similar manner, and perhaps mediate virulence and resistance to DNA damage and cell wall-targeting antibiotics, via a common pathway. PMID:25741016

  8. Antibiotic-induced diarrhea.

    PubMed

    Vogel, L C

    1995-01-01

    Diarrhea is a common complication of antibiotic therapy and can range from mild soiling of a cast to severe and life-threatening pseudomembranous colitis. Although clindamycin is the most notorious, almost all antibiotics, particularly penicillins and cephalosporins, may also be responsible (Bartlett, 1992; Kelly, Pothoulakis, & LaMont, 1994). Because of the frequent use of these antibiotics in orthopaedic patients, antibiotic-associated enteric disease is a common problem in this population. About 15% to 25% of cases of antibiotic-associated diarrhea are caused by Clostridium difficile (Bartlett, 1992; George, 1984; Kelly et al., 1994). The majority of patients with antibiotic-associated diarrhea have no identifiable etiologic agent. Salmonella, enterotoxin-producing Clostridium perfringens (Borriello et al., 1984) and Candida albicans (Danna et al., 1991) have rarely been identified as causative agents. This article describes the role of C. difficile as an enteric pathogen and its spectrum of clinical disease, including diagnosis, treatment, and prevention of nosocomial transmission. PMID:7761131

  9. Antibiotic Resistance

    MedlinePlus

    ... lives. But there is a growing problem of antibiotic resistance. It happens when bacteria change and become able ... resistant to several common antibiotics. To help prevent antibiotic resistance Don't use antibiotics for viruses like colds ...

  10. Complete genome sequence of antibiotic and anticancer agent violacein producing Massilia sp. strain NR 4-1.

    PubMed

    Myeong, Nu Ri; Seong, Hoon Je; Kim, Hye-Jin; Sul, Woo Jun

    2016-04-10

    Massilia sp. NR 4-1 was a violacein producing strain newly isolated from topsoil under nutmeg tree, Torreya nucifera in Korean national monument Bijarim Forest. Violacein is a novel class of drug exhibiting anticancer and antibiotic activities originated from l-tryptophan. Here, we present the complete genome of Massilia sp. strain NR 4-1 of 6,361,416bp and total 5285 coding sequences (CDSs) including a complete violacein biosynthesis pathway, vioABCDE. The genome sequence of Massilia sp. NR 4-1 will provide stable and efficient biotechnological applications of violacein production. PMID:26916415

  11. Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

    PubMed Central

    Wirth, Marius; Niro, Giuliana; Leyerer, Kristin

    2016-01-01

    Summary Muraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field. PMID:27340469

  12. Elevation of serum KL-6 in patients with psoriasis treated with anti-tumour necrosis factor-α therapy.

    PubMed

    Higashi, Y; Tada, K; Shimokawa, M; Kawai, K; Kanekura, T

    2016-01-01

    We report three patients with psoriasis whose serum level of Krebs Von Den Lungen (KL)-6 increased during therapy with anti-tumour necrosis factor (TNF)-α. A diagnosis of early-phase or subclinical interstitial pneumonia was made in two patients, and their KL-6 level decreased after anti-TNF-α discontinuation. The rise in KL-6 in the other patient was attributed to methotrexate. We propose that serum KL-6 should be monitored routinely in patients treated with anti-TNF agents. PMID:25557847

  13. Antibiotic Conjugated Fluorescent Carbon Dots as a Theranostic Agent for Controlled Drug Release, Bioimaging, and Enhanced Antimicrobial Activity

    PubMed Central

    Patil, Vaibhav; Khade, Monika; Goshi, Ekta; Sharon, Madhuri

    2014-01-01

    A novel report on microwave assisted synthesis of bright carbon dots (C-dots) using gum arabic (GA) and its use as molecular vehicle to ferry ciprofloxacin hydrochloride, a broad spectrum antibiotic, is reported in the present work. Density gradient centrifugation (DGC) was used to separate different types of C-dots. After careful analysis of the fractions obtained after centrifugation, ciprofloxacin was attached to synthesize ciprofloxacin conjugated with C-dots (Cipro@C-dots conjugate). Release of ciprofloxacin was found to be extremely regulated under physiological conditions. Cipro@C-dots were found to be biocompatible on Vero cells as compared to free ciprofloxacin (1.2 mM) even at very high concentrations. Bare C-dots (∼13 mg mL−1) were used for microbial imaging of the simplest eukaryotic model—Saccharomyces cerevisiae (yeast). Bright green fluorescent was obtained when live imaging was performed to view yeast cells under fluorescent microscope suggesting C-dots incorporation inside the cells. Cipro@C-dots conjugate also showed enhanced antimicrobial activity against both model gram positive and gram negative microorganisms. Thus, the Cipro@C-dots conjugate paves not only a way for bioimaging but also an efficient new nanocarrier for controlled drug release with high antimicrobial activity, thereby serving potential tool for theranostics. PMID:24744921

  14. Antitumour-Promoting and Cytotoxic Constituents of Etlingera Elatior

    PubMed Central

    Habsah, M; Ali, AM; Lajis, NH; Sukari, MA; Yap, YH; Kikuzaki, H; Nakatani, N

    2005-01-01

    Phytochemical studies on rhizome of Etlingera elatior have resulted in the isolation of 1,7-bis(4-hydroxyphenyl)-2,4,6-heptatrienone (1), demethoxycurcumin (2), 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (3), 16-hydroxylabda-8(17),11,13-trien-16,15-olide (4), stigmast-4-en-3-one (5), stigmast-4-ene-3,6-dione (6), stigmast-4-en-6b-ol-3-one (7), 5α,8α-epidioxyergosta-6,22-dien-3β-ol (8). 1 and 4 were new compounds. Compounds 5 and 7 displayed high antitumour-promoting activity. Ethyl acetate extract showed a very significant cytotoxic activity against CEM-SS and MCF-7 cell lines (4 μg/ml and 6.25 μg/ml respectively). The antitumour-promoting activity was determined by EBV-EA assay and cytotoxic activity was determined by MTT assay. PMID:22605941

  15. Antitumour-promoting and cytotoxic constituents of etlingera elatior.

    PubMed

    Habsah, M; Ali, Am; Lajis, Nh; Sukari, Ma; Yap, Yh; Kikuzaki, H; Nakatani, N

    2005-01-01

    Phytochemical studies on rhizome of Etlingera elatior have resulted in the isolation of 1,7-bis(4-hydroxyphenyl)-2,4,6-heptatrienone (1), demethoxycurcumin (2), 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (3), 16-hydroxylabda-8(17),11,13-trien-16,15-olide (4), stigmast-4-en-3-one (5), stigmast-4-ene-3,6-dione (6), stigmast-4-en-6b-ol-3-one (7), 5α,8α-epidioxyergosta-6,22-dien-3β-ol (8). 1 and 4 were new compounds. Compounds 5 and 7 displayed high antitumour-promoting activity. Ethyl acetate extract showed a very significant cytotoxic activity against CEM-SS and MCF-7 cell lines (4 μg/ml and 6.25 μg/ml respectively). The antitumour-promoting activity was determined by EBV-EA assay and cytotoxic activity was determined by MTT assay. PMID:22605941

  16. Etiologic Agents of Bacterial Sepsis and Their Antibiotic Susceptibility Patterns among Patients Living with Human Immunodeficiency Virus at Gondar University Teaching Hospital, Northwest Ethiopia

    PubMed Central

    Alebachew, Gelila; Teka, Brhanu; Endris, Mengistu; Shiferaw, Yitayal; Tessema, Belay

    2016-01-01

    Background. Bacterial sepsis is a major cause of illness in human immunodeficiency virus infected patients. There is scarce evidence about sepsis among HIV patients in Ethiopia. This study aimed to determine the etiologic agents of bacterial sepsis and their antibiotic susceptibility patterns among HIV infected patients. Methods. A cross-sectional study was carried out from March 1 to May 2, 2013. One hundred patients infected with HIV and suspected of having sepsis were included. Sociodemographic data were collected by interview and blood sample was aseptically collected from study participants. All blood cultures were incubated aerobically at 35°C and inspected daily for 7 days. The positive blood cultures were identified following the standard procedures and antimicrobial susceptibility testing was performed using disk diffusion technique. Data was entered by Epi-info version 3.5.1 and analysis was done using SPSS version 20. Results. Of the study participants, 31 (31%) confirmed bacterial sepsis. The major isolates were 13 (13%) Staphylococcus aureus, 8 (8%) coagulates negative staphylococci, and 3 (3%) viridans streptococci. Majority of the isolates, 25 (80.6%), were multidrug resistant to two or more antimicrobial agents. Conclusions. Bacterial sepsis was a major cause of admission for HIV infected patients predominated by Staphylococcus aureus and coagulase negative staphylococci species and most of the isolates were multidrug resistant. PMID:27314025

  17. Antibacterial and antitumour activities of some plants grown in Turkey

    PubMed Central

    Usta, Canan; Yildirim, Arzu Birinci; Turker, Arzu Ucar

    2014-01-01

    Screening of antibacterial and antitumour activities of 33 different extracts prepared with three types of solvents (water, ethanol and methanol) was conducted. The extracts were obtained from 11 different plant species grown in Turkey: Eryngium campestre L., Alchemilla mollis (Buser) Rothm., Dorycnium pentaphyllum Scop., Coronilla varia L., Onobrychis oxyodonta Boiss., Fritillaria pontica Wahlenb., Asarum europaeum L., Rhinanthus angustifolius C. C. Gmelin, Doronicum orientale Hoffm., Campanula glomerata L. and Campanula olympica Boiss. Antibacterial activity against six bacteria was evaluated: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Staphylococcus epidermidis by using disc diffusion and well diffusion methods. S. aureus and S. epidermidis were most sensitive to the methanolic extract from A. europaeum. S. pyogenes was vulnerable to all used extracts of D. orientale. In addition, ethanolic or methanolic extracts of E. campestre, A. mollis, D. pentaphyllum, C. varia, R. angustifolius, C. glomerata and C. olympica displayed strong antibacterial activity against at least one of the tested gram-negative bacteria. The methanolic extract from R. angustifolius showed a broad-spectrum activity against both gram-positive and gram-negative bacteria. Antitumour activity was evaluated with Agrobacterium-tumefaciens-induced potato disc tumour assay. Best antitumour activity was obtained with the aqueous extract from A. europaeum and methanolic extract from E. campestre (100% and 86% tumour inhibition, respectively). PMID:26740759

  18. Antibiotic Resistance

    MedlinePlus

    ... For Consumers Consumer Information by Audience For Women Antibiotic Resistance Share Tweet Linkedin Pin it More sharing options ... these products really help. To Learn More about Antibiotic Resistance Get Smart About Antibiotics (Video) Fact Sheets and ...

  19. Pseudomonas aeruginosa cells adapted to benzalkonium chloride show resistance to other membrane-active agents but not to clinically relevant antibiotics.

    PubMed

    Loughlin, M F; Jones, M V; Lambert, P A

    2002-04-01

    Our objective was to determine whether strains of Pseudomonas aeruginosa can adapt to growth in increasing concentrations of the disinfectant benzalkonium chloride (BKC), and whether co-resistance to clinically relevant antimicrobial agents occurs. Attempts were made to determine what phenotypic alterations accompanied resistance and whether these explained the mechanism of resistance. Strains were serially passaged in increasing concentrations of BKC in static nutrient broth cultures. Serotyping and genotyping were used to determine purity of the cultures. Two strains were examined for cross-resistance to other disinfectants and antibiotics by broth dilution MIC determination. Alterations in outer membrane proteins and lipopolysaccharide (LPS) expressed were examined by SDS-PAGE. Cell surface hydrophobicity and charge, uptake of disinfectant and proportion of specific fatty acid content of outer and cytoplasmic membranes were determined. Two P. aeruginosa strains showed a stable increase in resistance to BKC. Co-resistance to other quaternary ammonium compounds was observed in both strains; chloramphenicol and polymyxin B resistance were observed in one and a reduction in resistance to tobramycin observed in the other. However, no increased resistance to other biocides (chlorhexidine, triclosan, thymol) or antibiotics (ceftazidime, imipenem, ciprofloxacin, tobramycin) was detected. Characteristics accompanying resistance included alterations in outer membrane proteins, uptake of BKC, cell surface charge and hydrophobicity, and fatty acid content of the cytoplasmic membrane, although no evidence was found for alterations in LPS. Each of the two strains had different alterations in phenotype, indicating that such adaptation is unique to each strain of P. aeruginosa and does not result from a single mechanism shared by the whole species. PMID:11909837

  20. Enediyne antibiotics and their models: new potential of acetylene chemistry

    NASA Astrophysics Data System (ADS)

    Maretina, Irina A.; Trofimov, Boris A.

    2006-09-01

    Structures and chemical properties of enediynes, viz., compounds comprising a system of conjugated double and triple bonds, are surveyed. The presence of this system in the molecules of enediyne antitumour antibiotics ensures their high activity. The mechanism of biological action of enediynes is discussed based on cycloaromatisation of the enediyne chromophore resulting in highly active benzenoid 1,4-diradicals, which selectively cleave DNA. The key strategies of enediyne synthesis are analysed.

  1. Bortezomib-induced pro-inflammatory macrophages as a potential factor limiting anti-tumour efficacy.

    PubMed

    Beyar-Katz, Ofrat; Magidey, Ksenia; Ben-Tsedek, Neta; Alishekevitz, Dror; Timaner, Michael; Miller, Valeria; Lindzen, Moshit; Yarden, Yosef; Avivi, Irit; Shaked, Yuval

    2016-07-01

    Multiple myeloma (MM) is a chronic progressive malignancy of plasma cells. Although treatment with the novel proteasome inhibitor, bortezomib, significantly improves patient survival, some patients fail to respond due to the development of de novo resistance. We have previously shown that cytotoxic drugs can induce pro-tumorigenic host-mediated effects which contribute to tumour re-growth and metastasis, and thus limit anti-tumour efficacy. However, such effects and their impact on tumour cell aggressiveness have not been investigated using cytostatic agents such as bortezomib. Here we show that plasma from bortezomib-treated mice significantly increases migration, viability and proliferation of MM cells in vitro, compared to plasma from vehicle treated mice. In vivo, bortezomib induces the mobilization of pro-angiogenic bone marrow cells. Furthermore, mice treated with bortezomib and subsequently were used as recipients for an injection of MM cells succumb to MM earlier than mice treated with the vehicle. We show that bortezomib promotes pro-inflammatory macrophages which account for MM cell aggressiveness, an effect which is partially mediated by interleukin-16. Accordingly, co-inoculation of MM cells with pro-inflammatory macrophages from bortezomib-treated mice accelerates MM disease progression. Taken together, our results suggest that, in addition to the known effective anti-tumour activity of bortezomib, host-driven pro-tumorigenic effects generated in response to treatment can promote MM aggressiveness, and thus may contribute to the overall limited efficacy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27037906

  2. Triazene drug metabolites. Part 17: Synthesis and plasma hydrolysis of acyloxymethyl carbamate derivatives of antitumour triazenes.

    PubMed

    Carvalho, E; Francisco, A P; Iley, J; Rosa, E

    2000-07-01

    A series of 3-acyloxymethyloxycarbonyl-1-aryl-3-methyltriazenes 5 was synthesised by the sequential reaction of 1-aryl-3-methyltriazenes with (i) chloromethyl chloroformate, (ii) NaI in dry acetone, and (iii) either the silver carboxylate or the carboxylic acids in the presence of silver carbonate. The hydrolysis of these compounds was studied in pH 7.7 isotonic phosphate buffer and in human plasma. Triazene acyloxycarbamates demonstrated their ability to act as substrates for plasma enzymes. For compound 5f, a pH-rate profile was obtained which showed the hydrolysis to involve acid-base catalysis. The reaction is also buffer catalysed. Thus, at pH 7.7, pH-independent, base-catalysed and buffer-catalysed processes all contribute to the hydrolysis reaction. The sensitivity of the hydrolysis reaction to various structural parameters in the substrates indicates that hydrolysis occurs at the ester rather than the carbamate functionality. In plasma, the rates of hydrolysis correlate with partition coefficients, the most lipophilic compounds being the most stable. An aspirin derivative suffers two consecutive enzymatic reactions, the scission of the aspirin acetyl group being followed by the scission of the acyloxy ester group. These results indicate that triazene acyloxymethyl carbamates are prodrugs of the antitumour monomethyltriazenes. They combine chemical stability with a rapid enzymatic hydrolysis, and are consequently good candidates for further prodrug development. Moreover, this type of derivative allowed the synthesis of mutual prodrugs, associating the antitumour monomethyltriazenes with anti-inflammatory NSAIDs as well as with the anticancer agent butyric acid. PMID:10976519

  3. Antibiotic Resistance

    MedlinePlus

    Antibiotics are medicines that fight bacterial infections. Used properly, they can save lives. But there is a growing problem of antibiotic resistance. It happens when bacteria change and become able to resist the effects of an antibiotic. Using antibiotics can lead to resistance. ...

  4. Antibiotic Resistance in Staphylococcus aureus Strains Isolated from Cows with Mastitis in Eastern Poland and Analysis of Susceptibility of Resistant Strains to Alternative Nonantibiotic Agents: Lysostaphin, Nisin and Polymyxin B

    PubMed Central

    SZWEDA, Piotr; SCHIELMANN, Marta; FRANKOWSKA, Aneta; KOT, Barbara; ZALEWSKA, Magdalena

    2013-01-01

    ABSTRACT The aim of this study was to analyze the resistance of Staphylococcus aureus isolates from bovine mastitis in the eastern part of Poland to a set of 20 antibiotics and three alternative agents: lysostaphin, nisin and polymyxin B. Eighty-six out of 123 examined isolates were susceptible to all 20 tested antibiotics (70%). The highest percentage of resistance was observed in the case of β-lactam antibiotics: amoxicillin (n=22, 17.9%), ampicillin (n=28, 22.8%), penicillin (n=29, 23.6%) and streptomycin (n=13; 10.6%). Twenty-five of the penicillin-resistant strains were found to carry the blaZ gene coding for β-lactamases. Two strains were found to be mecA positive and a few strains were classified as multidrug resistant (MDR), one of them was simultaneously resistant to six antibiotics. All strains, resistant to at least one antibiotic (n=37) and two control strains, were susceptible to lysostaphin with MIC values of 0.008–0.5 µg/ml (susceptibility breakpoint 32 µg/ml). Twenty-one (54%) isolates were susceptible to nisin. The MIC value of this agent for 17 (44%) strains was 51.2 µg/ml and was not much higher than the susceptibility breakpoint value (32 µg/ml). Polymyxin B was able to inhibit the growth of the strains only at a high concentration (32–128 µg/ml). The presented results confirmed the observed worldwide problem of spreading antibiotic resistance among staphylococci isolated from bovine mastitis; on the other hand, we have indicated a high level of bactericidal activity of nisin and especially lysostaphin. PMID:24212507

  5. Antibiotic resistance in Staphylococcus aureus strains isolated from cows with mastitis in eastern Poland and analysis of susceptibility of resistant strains to alternative nonantibiotic agents: lysostaphin, nisin and polymyxin B.

    PubMed

    Szweda, Piotr; Schielmann, Marta; Frankowska, Aneta; Kot, Barbara; Zalewska, Magdalena

    2014-03-01

    The aim of this study was to analyze the resistance of Staphylococcus aureus isolates from bovine mastitis in the eastern part of Poland to a set of 20 antibiotics and three alternative agents: lysostaphin, nisin and polymyxin B. Eighty-six out of 123 examined isolates were susceptible to all 20 tested antibiotics (70%). The highest percentage of resistance was observed in the case of β-lactam antibiotics: amoxicillin (n=22, 17.9%), ampicillin (n=28, 22.8%), penicillin (n=29, 23.6%) and streptomycin (n=13; 10.6%). Twenty-five of the penicillin-resistant strains were found to carry the blaZ gene coding for β-lactamases. Two strains were found to be mecA positive and a few strains were classified as multidrug resistant (MDR), one of them was simultaneously resistant to six antibiotics. All strains, resistant to at least one antibiotic (n=37) and two control strains, were susceptible to lysostaphin with MIC values of 0.008-0.5 µg/ml (susceptibility breakpoint 32 µg/ml). Twenty-one (54%) isolates were susceptible to nisin. The MIC value of this agent for 17 (44%) strains was 51.2 µg/ml and was not much higher than the susceptibility breakpoint value (32 µg/ml). Polymyxin B was able to inhibit the growth of the strains only at a high concentration (32-128 µg/ml). The presented results confirmed the observed worldwide problem of spreading antibiotic resistance among staphylococci isolated from bovine mastitis; on the other hand, we have indicated a high level of bactericidal activity of nisin and especially lysostaphin. PMID:24212507

  6. The multifaceted roles of antibiotics and antibiotic resistance in nature

    PubMed Central

    Sengupta, Saswati; Chattopadhyay, Madhab K.; Grossart, Hans-Peter

    2013-01-01

    Antibiotics are chemotherapeutic agents, which have been a very powerful tool in the clinical management of bacterial diseases since the 1940s. However, benefits offered by these magic bullets have been substantially lost in subsequent days following the widespread emergence and dissemination of antibiotic-resistant strains. While it is obvious that excessive and imprudent use of antibiotics significantly contributes to the emergence of resistant strains, antibiotic resistance is also observed in natural bacteria of remote places unlikely to be impacted by human intervention. Both antibiotic biosynthetic genes and resistance-conferring genes have been known to evolve billions of years ago, long before clinical use of antibiotics. Hence it appears that antibiotics and antibiotics resistance determinants have some other roles in nature, which often elude our attention because of overemphasis on the therapeutic importance of antibiotics and the crisis imposed by the antibiotic resistance in pathogens. In the natural milieu, antibiotics are often found to be present in sub-inhibitory concentrations acting as signaling molecules supporting the process of quorum sensing and biofilm formation. They also play an important role in the production of virulence factors and influence host–parasite interactions (e.g., phagocytosis, adherence to the target cell, and so on). The evolutionary and ecological aspects of antibiotics and antibiotic resistance in the naturally occurring microbial community are little understood. Therefore, the actual role of antibiotics in nature warrants in-depth investigations. Studies on such an intriguing behavior of the microorganisms promise insight into the intricacies of the microbial physiology and are likely to provide some lead in controlling the emergence and subsequent dissemination of antibiotic resistance. This article highlights some of the recent findings on the role of antibiotics and the genes that confer resistance to antibiotics

  7. MicroRNAs Involved in Anti-Tumour Immunity

    PubMed Central

    Yu, Hong W. H.; Sze, Daniel M. Y.; Cho, William C. S.

    2013-01-01

    MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a number of cancers. miRNAs have been found to participate in cell transformation and multiplication by acting as tumour oncogenes or suppressors; therefore, harnessing miRNAs may provide promising cancer therapeutics. Another major function of miRNAs is their activity as critical regulatory vehicles eliciting important regulatory processes in anti-tumour immunity through their influence on the development, differentiation and activation of various immune cells of both innate and adaptive immunity. This review aims to summarise recent findings focusing on the regulatory mechanisms of the development, differentiation, and proliferative aspects of the major immune populations by a diverse profile of miRNAs and may enrich our current understanding of the involvement of miRNAs in anti-tumour immunity. PMID:23478435

  8. An antitumour lectin from the edible mushroom Agrocybe aegerita.

    PubMed Central

    Zhao, Chenguang; Sun, Hui; Tong, Xin; Qi, Yipeng

    2003-01-01

    An antitumour lectin (named AAL) consisting of two identical subunits of 15.8 kDa was isolated from the fruiting bodies of the edible mushroom Agrocybe aegerita using a procedure which involved precipitating the extract by addition of (NH(4))(2)SO(4), ion exchange chromatography on DEAE-Sepharose Fast Flow, gel filtration chromatography on Sephacryl S-200 HR and finally purification on a GF-250 HPLC column. Amino acid analysis of the N-terminus and an internal fragment indicated that the sequences of the two fragments were QGVNIYNI and Q(K)PDGPWLVEK(Q)R respectively. AAL showed strong inhibition of the growth of human tumour cell lines HeLa, SW480, SGC-7901, MGC80-3, BGC-823, HL-60 and mouse sarcoma S-180. AAL also inhibited the viability of S-180 tumour cells in vivo. Analysis by Hoechst 33258 staining, MitoSensor Kit and flow cytometry showed that AAL induced apoptosis in HeLa cells. TUNEL (terminal transferase deoxytidyl uridine end labelling) analysis of slides of tumour tissues excised from BALB/c mice also demonstrated the apoptosis-induction activity of the lectin. Furthermore, AAL was shown to possess DNase activity in assays using plasmid pCDNA3 and salmon sperm DNA. Based on the results obtained in these assays, we conclude that AAL exerts its antitumour effects via apoptosis-inducing and DNase activities. PMID:12757412

  9. Antibiotic Safety

    MedlinePlus

    ... specific to women Antibiotics can lead to vaginal yeast infections. This happens because antibiotics kill the normal bacteria in the vagina and this causes yeast to grow rapidly. Symptoms of a yeast infection ...

  10. [Analysis of antibiotic usage].

    PubMed

    Balpataki, R; Balogh, J; Zelkó, R; Vincze, Z

    2001-01-01

    Economic analysis is founded on the assumption that resources are limited and that should be used in a way that maximizes the benefits gained. Pharmacoeconomics extends these assumptions to drug treatment. Therefore, a full pharmacoeconomic analysis must consider two or more alternative treatments and should be founded on measurement of incremental cost, incremental efficacy, and the value of successful outcome. Antibiotic policy based only on administrative restrictions is failed, instead of it disease formularies and infectologist consultation system are needed. Equally important are various programmes that encourage the cost-conscious use of the antibiotics chosen. Some of the methods evaluated in the literature include: streamlining from combination therapy to a single agent, early switching from parenteral to oral therapy, initiating treatment with oral agents, administering parenteral antibiotic at home from outset of therapy, and antibiotic streamlining programmes that are partnered with infectious disease physicians. The solution is the rational and adequate use of antibiotics, based on the modern theory and practice of antibiotic policy and infection control, that cannot be carried out without the activities of experts in this field. PMID:11769090

  11. Antibiotic alternatives: the substitution of antibiotics in animal husbandry?

    PubMed Central

    Cheng, Guyue; Hao, Haihong; Xie, Shuyu; Wang, Xu; Dai, Menghong; Huang, Lingli; Yuan, Zonghui

    2014-01-01

    It is a common practice for decades to use of sub-therapeutic dose of antibiotics in food-animal feeds to prevent animals from diseases and to improve production performance in modern animal husbandry. In the meantime, concerns over the increasing emergence of antibiotic-resistant bacteria due to the unreasonable use of antibiotics and an appearance of less novelty antibiotics have prompted efforts to develop so-called alternatives to antibiotics. Whether or not the alternatives could really replace antibiotics remains a controversial issue. This review summarizes recent development and perspectives of alternatives to antibiotics. The mechanism of actions, applications, and prospectives of the alternatives such as immunity modulating agents, bacteriophages and their lysins, antimicrobial peptides, pro-, pre-, and synbiotics, plant extracts, inhibitors targeting pathogenicity (bacterial quorum sensing, biofilm, and virulence), and feeding enzymes are thoroughly discussed. Lastly, the feasibility of alternatives to antibiotics is deeply analyzed. It is hard to conclude that the alternatives might substitute antibiotics in veterinary medicine in the foreseeable future. At the present time, prudent use of antibiotics and the establishment of scientific monitoring systems are the best and fastest way to limit the adverse effects of the abuse of antibiotics and to ensure the safety of animal-derived food and environment. PMID:24860564

  12. Cytotoxic and antitumour principles from Ixora coccinea flowers.

    PubMed

    Latha, P G; Panikkar, K R

    1998-08-14

    The antitumour activity of Ixora coccinea L. (Rubiaceae) flowers was studied in comparison to intraperitoneally transplanted Dalton's lymphoma (ascitic and solid tumours) and Ehrlich ascites carcinoma (EAC) tumours in mice. Intraperitoneal administration of 200 mg/kg of the active fraction (AF) of the I. coccinea flower increased the life-span of DLA and EAC ascitic tumour-bearing mice by 113 and 68%, respectively. The AF showed less activity against solid tumours (DLA) as compared to ascitic tumours. The same active fraction showed 50% cytotoxicity to DLA, EAC and Sarcoma-180 (S-180) cells in vitro at concentrations of 18, 60 and 25 microg/ml, respectively. It was not toxic to normal lymphocytes, whereas it was toxic to transformed lymphocytes from leukaemic patients, acute lymphoblastic leukaemia (ALL) and chronic myelogenous leukaemia (CML) and K-562 suspension cell cultures. The AF inhibited tritiated thymidine incorporation in cellular DNA. PMID:9751274

  13. Current status of carbapenem antibiotics.

    PubMed

    El-Gamal, Mohammed I; Oh, Chang-Hyun

    2010-01-01

    β-Lactam antibiotics are the most prescribed antibacterial agents. They comprise more than half of all antibiotics. They are considered as the cornerstone of the antibiotic armamentarium. By inhibiting bacterial cell wall biosynthesis, they are highly effective against Gram-positive and Gram-negative bacteria. Antibiotic resistance among Gram-negative pathogens in hospitals represents a dangerous threat to public health. Since many bacteria have developed resistance to older agents, new β-lactam antibiotics have been continuously developed. In the late 1970s, a new class of exceptionally broad-spectrum non-traditional β-lactams, carbapenems, was developed. This review article focuses on the new developments related to the field of carbapenems for treatment of bacterial infections, especially those caused by Gram-negative bacteria. The structural features, principal characteristics, and clinical implications of carbapenems including thienamycin, imipenem/cilastatin, panipenem/betamipron, biapenem, tebipenem, tebipenem pivoxil, meropenem, ertapenem, doripenem, lenapenem, and tomopenem are discussed herein. PMID:20615191

  14. Antibiotic drug discovery.

    PubMed

    Wohlleben, Wolfgang; Mast, Yvonne; Stegmann, Evi; Ziemert, Nadine

    2016-09-01

    Due to the threat posed by the increase of highly resistant pathogenic bacteria, there is an urgent need for new antibiotics; all the more so since in the last 20 years, the approval for new antibacterial agents had decreased. The field of natural product discovery has undergone a tremendous development over the past few years. This has been the consequence of several new and revolutionizing drug discovery and development techniques, which is initiating a 'New Age of Antibiotic Discovery'. In this review, we concentrate on the most significant discovery approaches during the last and present years and comment on the challenges facing the community in the coming years. PMID:27470984

  15. Adaptation of Mycoplasmas to Antimicrobial Agents: Acholeplasma laidlawii Extracellular Vesicles Mediate the Export of Ciprofloxacin and a Mutant Gene Related to the Antibiotic Target

    PubMed Central

    Medvedeva, Elena S.; Baranova, Natalia B.; Mouzykantov, Alexey A.; Grigorieva, Tatiana Yu.; Davydova, Marina N.; Trushin, Maxim V.; Chernova, Olga A.; Chernov, Vladislav M.

    2014-01-01

    This study demonstrated that extracellular membrane vesicles are involved with the development of resistance to fluoroquinolones by mycoplasmas (class Mollicutes). This study assessed the differences in susceptibility to ciprofloxacin among strains of Acholeplasma laidlawii PG8. The mechanisms of mycoplasma resistance to antibiotics may be associated with a mutation in a gene related to the target of quinolones, which could modulate the vesiculation level. A. laidlawii extracellular vesicles mediated the export of the nucleotide sequences of the antibiotic target gene as well as the traffic of ciprofloxacin. These results may facilitate the development of effective approaches to control mycoplasma infections, as well as the contamination of cell cultures and vaccine preparations. PMID:24605048

  16. Dissociation reactions of protonated anthracycline antibiotics following electrospray ionization-tandem mass spectrometry

    NASA Astrophysics Data System (ADS)

    Sleno, Lekha; Campagna-Slater, Valerie; Volmer, Dietrich A.

    2006-09-01

    Fragmentation pathways of doxorubicin, a common cancer therapy agent, and three closely related analogs (epirubicin, daunorubicin, idarubicin) were compared using electrospray ionization with tandem mass spectrometry. This class of antibiotics with anti-tumour activity has important structural features, with a tetracyclic aromatic, polyketide portion, which is glycosylated with an amino sugar in order to exhibit its biological activity. Collision-induced dissociation spectra revealed very similar product ions for each analog, however, important differences were seen in the relative abundances and the ease at which certain fragments were formed. Fragment ions observed included those from cleavage of the glycosidic bond, loss of the side chain from the aglycone moiety, water losses and loss of a methyl radical. Following cleavage of the glycosidic bond, the charge can either reside on the aglycone portion or the sugar moiety, and each of these primary fragments undergoes several secondary dissociation pathways, depending on the collision energy. By ramping the collision voltage, we were able to correlate the changes in fragmentation behavior with small alterations in the structure of the precursor ion. The detailed study of the fragmentation behavior of doxorubicin was supported by accurate mass measurements, using an electrospray-time of flight instrument, as well as MS3 data from a quadrupole-linear ion trap mass spectrometer. Computational studies were also performed to help explain the role of certain functional groups in the fragmentation reactions.

  17. Cardiac toxicities of antibiotics.

    PubMed Central

    Adams, H R; Parker, J L; Durrett, L R

    1978-01-01

    Isolated heart muscle preparations are useful in the study of cardiac toxicities of drugs and environmental chemicals: such tissues allow assessment of chemical effects on heart muscle that is free from indirect in vivo influences that can mask or even accentuate cardiac responses measured in the intact animal. In the present study, left atria of guinea pigs were used to demonstrate a direct cardiac depressant effect of greater-than-therapeutic concentrations of several aminoglycoside antibiotics. The toxic effect of these antibiotics seems to be a calcium-dependent event, and may prove useful to characterize contractile responses of the heart. Other antibiotic agents can also depress cardiovascular function, as summarized in this report, but mechanisms of action have not been clearly defined. PMID:720315

  18. Antitumour Activity of the Microencapsulation of Annona vepretorum Essential Oil.

    PubMed

    Bomfim, Larissa M; Menezes, Leociley R A; Rodrigues, Ana Carolina B C; Dias, Rosane B; Rocha, Clarissa A Gurgel; Soares, Milena B P; Neto, Albertino F S; Nascimento, Magaly P; Campos, Adriana F; Silva, Lidércia C R C E; Costa, Emmanoel V; Bezerra, Daniel P

    2016-03-01

    Annona vepretorum Mart. (Annonaceae), popularly known as 'bruteira', has nutritional and medicinal uses. This study investigated the chemical composition and antitumour potential of the essential oil of A. vepretorum leaf alone and complexed with β-cyclodextrin in a microencapsulation. The essential oil was obtained by hydrodistillation using a Clevenger-type apparatus and analysed using GC-MS and GC-FID. In vitro cytotoxicity of the essential oil and some of its major constituents in tumour cell lines from different histotypes was evaluated using the alamar blue assay. Furthermore, the in vivo efficacy of essential oil was demonstrated in mice inoculated with B16-F10 mouse melanoma. The essential oil included bicyclogermacrene (35.71%), spathulenol (18.89%), (E)-β-ocimene (12.46%), α-phellandrene (8.08%), o-cymene (6.24%), germacrene D (3.27%) and α-pinene (2.18%) as major constituents. The essential oil and spathulenol exhibited promising cytotoxicity. In vivo tumour growth was inhibited by the treatment with the essential oil (inhibition of 34.46%). Importantly, microencapsulation of the essential oil increased in vivo tumour growth inhibition (inhibition of 62.66%). PMID:26348780

  19. Bp44mT: an orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy

    PubMed Central

    Yu, Y; Rahmanto, Y Suryo; Richardson, DR

    2012-01-01

    BACKGROUND AND PURPOSE Our previous studies demonstrated that a thiosemicarbazone iron chelator (di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; Dp44mT) possesses potent and selective anti-cancer activity but led to cardiotoxicity at non-optimal doses. In this study, we examined the in vivo anti-tumour efficacy and tolerability of a new-generation 2-benzoylpyridine thiosemicarbazone iron chelator (2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone; Bp44mT) administered via the oral or i.v. routes. EXPERIMENTAL APPROACH BpT chelators were tested in vitro against human lung cancer cells (DMS-53) and in vivo in DMS-53 tumour xenografts in mice. The toxicity of Bp44mT in vivo and its effects on the expression of iron-regulated molecules involved in growth and cell cycle control were investigated. KEY RESULTS Administration of Bp44mT by either route resulted in marked dose-dependent inhibition of tumour growth. When administered at 50 mg·kg−1 via oral gavage three times per week for 23 days, the net xenograft growth was inhibited by 75%, compared with vehicle-treated mice. Toxicological examination showed reversible alterations including slight reduction of RBC count, with a decrease of liver and splenic iron levels, which confirmed iron chelation in vivo. Importantly, in contrast to Dp44mT, the chelator-treated mice did not show cardiac histological abnormalities. There was also no significant weight loss in mice, suggesting oral administration of Bp44mT was well tolerated. CONCLUSIONS AND IMPLICATIONS This is the first study to show that Bp44mT can be given orally with potent anti-tumour efficacy. Oral administration of a novel and effective chemotherapeutic agent provides the benefits of convenience for chronic dosing regimens. PMID:21658021

  20. Antibiotics Quiz

    MedlinePlus

    ... Viruses b) Bacteria c) Viruses and Bacteria 2. Bacteria are germs that cause colds and flu. a) ... The Flu c) Cold d) Strep Throat 4. Bacteria that cause infections can become resistant to antibiotics. ...

  1. [Antibiotic pharmacoeconomics].

    PubMed

    Jahnz-Rózyk, Karina

    2008-11-01

    Today more than ever, doctors in the ambulatory care and hospitals must effectively manage the use of antibiotics to control costs and preserve their usefulness. To achieve this goal, antibiotic management must evolve from simplistic antibiotic cost containment to more complex, appropriate use program that are founded on clinical outcomes-based pharmacoeconomic analyses. The successful application of pharmacoeconomic principles to antimicrobial therapy requires maximizing therapeutic effectiveness while minimizing costs, with the primary on pharmacokinetic considerations. This article reviews the various pharmacoeconomic factors that affect antibiotic costs in relation to patients and institutions. Cost-effectiveness studies of macrolides in pulmonary infections are presented in this study to illustrate the utility of these analyses. PMID:19177784

  2. Methylseleninic acid promotes antitumour effects via nuclear FOXO3a translocation through Akt inhibition

    PubMed Central

    Tarrado-Castellarnau, Míriam; Cortés, Roldán; Zanuy, Miriam; Tarragó-Celada, Josep; Polat, Ibrahim H.; Hill, Richard; Fan, Teresa W.; Link, Wolfgang; Cascante, Marta

    2016-01-01

    Selenium supplement has been shown in clinical trials to reduce the risk of different cancers including lung carcinoma. Previous studies reported that the antiproliferative and pro-apoptotic activities of methylseleninic acid (MSA) in cancer cells could be mediated by inhibition of the PI3K pathway. A better understanding of the downstream cellular targets of MSA will provide information on its mechanism of action and will help to optimise its use in combination therapies with PI3K inhibitors. For this study, the effects of MSA on viability, cell cycle, metabolism, apoptosis, protein and mRNA expression, and Reactive Oxygen Species production were analysed in A549 cells. FOXO3a subcellular localisation was examined in A549 cells and in stably transfected human osteosarcoma U2foxRELOC cells. Our results demonstrate that MSA induces FOXO3a nuclear translocation in A549 cells and in U2OS cells that stably express GFP-FOXO3a. Interestingly, sodium selenite, another selenium compound, did not induce any significant effects on FOXO3a translocation despite inducing apoptosis. Single strand break of DNA, disruption of tumour cell metabolic adaptations, decrease in ROS production, and cell cycle arrest in G1 accompanied by induction of apoptosis are late events occurring after 24 h of MSA treatment in A549 cells. Our findings suggest that FOXO3a is a relevant mediator of the antiproliferative effects of MSA. This new evidence on the mechanistic action of MSA can open new avenues in exploiting its antitumour properties and in the optimal design of novel combination therapies. We present MSA as a promising chemotherapeutic agent with synergistic antiproliferative effects with cisplatin. PMID:26375988

  3. Impact of Feed Supplementation with Antimicrobial Agents on Growth Performance of Broiler Chickens, Clostridium perfringens and Enterococcus Counts, and Antibiotic Resistance Phenotypes and Distribution of Antimicrobial Resistance Determinants in Escherichia coli Isolates▿

    PubMed Central

    Diarra, Moussa S.; Silversides, Fred G.; Diarrassouba, Fatoumata; Pritchard, Jane; Masson, Luke; Brousseau, Roland; Bonnet, Claudie; Delaquis, Pascal; Bach, Susan; Skura, Brent J.; Topp, Edward

    2007-01-01

    The effects of feed supplementation with the approved antimicrobial agents bambermycin, penicillin, salinomycin, and bacitracin or a combination of salinomycin plus bacitracin were evaluated for the incidence and distribution of antibiotic resistance in 197 commensal Escherichia coli isolates from broiler chickens over 35 days. All isolates showed some degree of multiple antibiotic resistance. Resistance to tetracycline (68.5%), amoxicillin (61.4%), ceftiofur (51.3%), spectinomycin (47.2%), and sulfonamides (42%) was most frequent. The levels of resistance to streptomycin, chloramphenicol, and gentamicin were 33.5, 35.5, and 25.3%, respectively. The overall resistance levels decreased from day 7 to day 35 (P < 0.001). Comparing treatments, the levels of resistance to ceftiofur, spectinomycin, and gentamicin (except for resistance to bacitracin treatment) were significantly higher in isolates from chickens receiving feed supplemented with salinomycin than from the other feeds (P < 0.001). Using a DNA microarray analysis capable of detecting commonly found antimicrobial resistance genes, we characterized 104 tetracycline-resistant E. coli isolates from 7- to 28-day-old chickens fed different growth promoters. Results showed a decrease in the incidence of isolates harboring tet(B), blaTEM, sulI, and aadA and class 1 integron from days 7 to 35 (P < 0.01). Of the 84 tetracycline-ceftiofur-resistant E. coli isolates, 76 (90.5%) were positive for blaCMY-2. The proportions of isolates positive for sulI, aadA, and integron class 1 were significantly higher in salinomycin-treated chickens than in the control or other treatment groups (P < 0.05). These data demonstrate that multiantibiotic-resistant E. coli isolates can be found in broiler chickens regardless of the antimicrobial growth promoters used. However, the phenotype and the distribution of resistance determinants in E. coli can be modulated by feed supplementation with some of the antimicrobial agents used in broiler

  4. Metabonomics applied in exploring the antitumour mechanism of physapubenolide on hepatocellular carcinoma cells by targeting glycolysis through the Akt-p53 pathway

    PubMed Central

    Ma, Ting; Fan, Bo-Yi; Zhang, Chao; Zhao, Hui-Jun; Han, Chao; Gao, Cai-Yun; Luo, Jian-Guang; Kong, Ling-Yi

    2016-01-01

    Metabolomics can be used to identify potential markers and discover new targets for future therapeutic interventions. Here, we developed a novel application of the metabonomics method based on gas chromatography-mass spectrometry (GC/MS) analysis and principal component analysis (PCA) for rapidly exploring the anticancer mechanism of physapubenolide (PB), a cytotoxic withanolide isolated from Physalis species. PB inhibited the proliferation of hepatocellular carcinoma cells in vitro and in vivo, accompanied by apoptosis-related biochemical events, including the cleavage of caspase-3/7/9 and PARP. Metabolic profiling analysis revealed that PB disturbed the metabolic pattern and significantly decreased lactate production. This suggests that the suppression of glycolysis plays an important role in the anti-tumour effects induced by PB, which is further supported by the decreased expression of glycolysis-related genes and proteins. Furthermore, the increased level of p53 and decreased expression of p-Akt were observed, and the attenuated glycolysis and enhanced apoptosis were reversed in the presence of Akt cDNA or p53 siRNA. These results confirm that PB exhibits anti-cancer activities through the Akt-p53 pathway. Our study not only reports for the first time the anti-tumour mechanism of PB, but also suggests that PB is a promising therapeutic agent for use in cancer treatments and that metabolomic approaches provide a new strategy to effectively explore the molecular mechanisms of promising anticancer compounds. PMID:27416811

  5. Goshajinkigan reduces oxaliplatin-induced peripheral neuropathy without affecting anti-tumour efficacy in rodents.

    PubMed

    Ushio, Soichiro; Egashira, Nobuaki; Sada, Hikaru; Kawashiri, Takehiro; Shirahama, Masafumi; Masuguchi, Ken; Oishi, Ryozo

    2012-06-01

    Oxaliplatin is a key drug in the treatment of colorectal cancer, but it causes acute and chronic neuropathies in patients. Goshajinkigan (GJG) is a Kampo medicine that is used for the treatments of several neurological symptoms including pain and numbness. More recently, GJG has been reported to prevent the oxaliplatin-induced peripheral neuropathy in clinical studies. No experimental study, however, has been conducted to date to determine the effect of GJG on pain behaviour in a rat model of oxaliplatin-induced neuropathy. Moreover, the impact on the anti-tumour effect of oxaliplatin remains unknown. In the present study, we examined the effects of GJG on the peripheral neuropathy and anti-tumour activity of oxaliplatin in rodents. Repeated administration of oxaliplatin caused cold hyperalgesia from days 3 to 37 and mechanical allodynia from days 21 to 28. Repeated administration of GJG prevented the oxaliplatin-induced cold hyperalgesia but not mechanical allodynia and axonal degeneration in rat sciatic nerve. Single administration of GJG reduced both cold hyperalgesia and mechanical allodynia after the development of neuropathy. In addition, GJG did not affect the anti-tumour effect of oxaliplatin in the tumour cells or tumour cells-implanted mice. These results suggest that GJG relieves the oxaliplatin-induced cold hyperalgesia and mechanical allodynia without affecting anti-tumour activity of oxaliplatin, and, therefore, may be useful for the oxaliplatin-induced neuropathy in clinical practice. PMID:21907570

  6. Resistance-induced antibiotic substitution.

    PubMed

    Howard, David H

    2004-06-01

    In many cases, physicians prescribe antibiotics without knowing whether an individual patient is infected with a susceptible or resistant pathogen. As the proportion of resistant organisms in a community increases, physicians substitute away from older-inexpensive drugs to newer, more expensive agents as first line therapy. This paper explores the implications of resistance-induced antibiotic substitution for epidemiological models to predict future resistance levels, efforts to measure the health care costs associated with resistance, and policies to improve physicians' antibiotic prescribing decisions. The extent of resistance-induced substitution in outpatient settings is documented using a data set consisting of observations on initial physician office visits for otitis media in the US controlling for new product introductions and price increases, per prescription antibiotic spending increased by 22% between 1980 and 1996, corresponding to a steep increase in resistance levels over the same period. PMID:15185388

  7. Generic antibiotics in Japan.

    PubMed

    Fujimura, Shigeru; Watanabe, Akira

    2012-08-01

    Generic drugs have been used extensively in many developed countries, although their use in Japan has been limited. Generic drugs reduce drug expenses and thereby national medical expenditure. Because generic drugs provide advantages for both public administration and consumers, it is expected that they will be more widely used in the future. However, the diffusion rate of generic drugs in Japan is quite low compared with that of other developed countries. An investigation on generic drugs conducted by the Ministry of Health, Labour and Welfare in Japan revealed that 17.2 % of doctors and 37.2 % of patients had not used generic drugs. The major reasons for this low use rate included distrust of off-patent products and lower drug price margin compared with the brand name drug. The generic drugs available in the market include external drugs such as wet packs, antihypertensive agents, analgesics, anticancer drugs, and antibiotics. Among them, antibiotics are frequently used in cases of acute infectious diseases. When the treatment of these infections is delayed, the infection might be aggravated rapidly. The pharmacokinetics-pharmacodynamics (PK-PD) theory has been adopted in recent chemotherapy, and in many cases, the most appropriate dosage and administration of antibiotics are determined for individual patients considering renal function; high-dosage antibiotics are used preferably for a short duration. Therefore, a highly detailed antimicrobial agent is necessary. However, some of the generic antibiotics have less antibacterial potency or solubility than the brand name products. We showed that the potency of the generic products of vancomycin and teicoplanin is lower than that of the branded drugs by 14.6 % and 17.3 %, respectively. Furthermore, we confirmed that a generic meropenem drug for injection required about 82 s to solubilize in saline, whereas the brand product required only about 21 s. It was thought that the cause may be the difference in size of bulk

  8. Raloxifene Inhibits NF-kB Pathway and Potentiates Anti-Tumour Activity of Cisplatin with Simultaneous Reduction in its Nephrotoxictiy.

    PubMed

    Jamdade, Vinayak Sudhir; Mundhe, Nitin A; Kumar, Parveen; Tadla, Venkatesh; Lahkar, Mangala

    2016-01-01

    Cisplatin induced nephrotoxicity is the chief obstacle in the use of cisplatin as chemotherapeutic agent. However, it remains as most widely employed anticancer agent to treat various solid tumours like head-neck, testicular, ovarian and mammary gland cancer. Raloxifene is claimed to be potent anti-inflammatory as well as anti-cancer agent. The present study was carried out to explore the effect of pre-treatment of raloxifene on cisplatin induced nephrotoxicity and its anti-tumour activity in 7, 12 dimethyl benz [a] anthracene induced mammary tumour in animal model. Renal damage was accessed by measuring serum level of creatinine, blood urea nitrogen and albumin whereas systemic inflammation was accessed by measuring level of pro-inflammatory cytokines like tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 10 (IL-10) and nuclear factor kappa B (NFκB). Moreover, assessment of tumour reduction was done by measuring tumour volume and percentage tumour reduction. A single dose of cisplatin (7.5 mg/kg) resulted in significant increase in serum creatinine, blood urea nitrogen, NF-kB, TNF-α and IL-6 levels along with decrease in albumin and IL-10 levels. However, there were no significant changes in raloxifene (8 mg/kg) treated group. Pre-treatment of raloxifene (8 mg/kg) caused marked decrease in serum creatinine, blood urea nitrogen, TNF-α and IL-6 levels whereas increase in albumin and IL-10 levels. However, pre-treatment of raloxifene showed maximum tumour reduction as compared to cisplatin and raloxifene treated groups. The present study demonstrates that raloxifene potentiates anti-tumour activity of cisplatin with simultaneous reduction in its nephrotoxicity, and this effect is attributed to its direct anti-inflammatory activity. PMID:26439246

  9. Treating appendicitis with antibiotics.

    PubMed

    Brook, Itzhak

    2016-03-01

    A nonsurgical approach using antimicrobial agents has been advocated as the initial treatment of uncomplicated appendicitis. Several studies and meta-analyses explored this approach. Because many of these studies included individuals with resolving appendicitis, their results were biased. Antimicrobials, however, are warranted and needed for the management of surgical high-risk patients with perforated appendicitis and those with localized abscess or phlegmon. Randomized placebo-controlled trials that focus on early identification of complicated acute appendicitis patients needing surgery and that prospectively evaluate the optimal use of antibiotic treatment in patients with uncomplicated acute appendicitis are warranted. PMID:26689849

  10. Chiral copper(II) complex based on natural product rosin derivative as promising antitumour agent.

    PubMed

    Fei, Bao-Li; Huang, Zhi-Xiang; Xu, Wu-Shuang; Li, Dong-Dong; Lu, Yang; Gao, Wei-Lin; Zhao, Yue; Zhang, Yu; Liu, Qing-Bo

    2016-07-01

    To evaluate the biological preference of chiral drug candidates for molecular target DNA, the synthesis and characterization of a chiral copper(II) complex (2) of a chiral ligand N,N'-(pyridin-2-ylmethylene) dehydroabietylamine (1) was carried out. The interactions of 1 and 2 with salmon sperm DNA were investigated by viscosity measurements, UV, fluorescence and circular dichroism (CD) spectroscopic techniques. Absorption spectral, emission spectral and viscosity analysis reveal that 1 and 2 interacted with DNA through intercalation and 2 exhibited a higher DNA binding ability. In the absence/presence of ascorbic acid, 1 and 2 cleaved supercoiled pBR322 DNA by single-strand and 2 displayed stronger DNA cleavage ability. In addition, in vitro cytotoxicity of 1 and 2 against HeLa, SiHa, HepG-2 and A431 cancer cell lines study show that they exhibited effective cytotoxicity against the tested cell lines, notably, 2 showed a superior cytotoxicity than the widely used drug cisplatin under identical conditions, indicating it has the potential to act as effective anticancer drug. Flow cytometry analysis indicates 2 produced death of HeLa cancer cells through an apoptotic pathway. Cell cycle analysis demonstrates that 2 mainly arrested HeLa cells at the S phase. The study represents the first step towards understanding the mode of the promising chiral rosin-derivative based copper complexes as chemotherapeutics. PMID:27088508

  11. Toxicity Profiles In Vivo in Mice and Antitumour Activity in Tumour-Bearing Mice of Di- and Triorganotin Compounds

    PubMed Central

    Willem, R.; Dalil, H.; de Vos, D.; Kuiper, C. M.; Peters, G. J.

    1998-01-01

    The in vivo toxicity profiles in mice and the antitumour activity in tumour bearing mice were screened for four di-n-butyltin and five triorganotin carboxylates, di-n-butyltin diterebate (5), bis(phenylacetate) (6), bis(deoxycholate) (7), bis(lithocholate) (8), tri-n-butyltin terebate (9), cinnamate (10), and triphenyltin terebate (11). At their maximum tolerated dosis (MTD), no antitumour effect (T/C ~1) was observed for the compounds 5, 7, 9, 10 and 11. The compounds 6 (T/C = 0.51) and 8 (T/C = 0.42) showed clear antitumour activity after single dose administration and might therefore be of interest for further antitumour activity studies. PMID:18475827

  12. Antitumoural activity of a cytotoxic peptide of Lactobacillus casei peptidoglycan and its interaction with mitochondrial-bound hexokinase.

    PubMed

    Fichera, Giuseppe A; Fichera, Marco; Milone, Giuseppe

    2016-08-01

    In a previous study, we reported the cytotoxic activity against various tumour cells of the peptidoglycan of Lactobacillus casei. To isolate the most active components, we performed column-chromatography separation of the peptidoglycan complex and tested the related fractions for their cytotoxic activity. The most active fractions were then lyophilized and the residue was analysed by gas chromatography for its amino acid content and composition. On the basis of the known chemical formula of the basic peptidic component of the peptidoglycan complex of L. casei, a peptide was then synthesized [Europ. (CH-DE-FR-GB) Patent number 1217005; IT number 01320177] and its cytotoxicity was tested against tumoural and normal cells. The synthetic peptide was found to impair the entire metabolism of cultured tumour cells and to restore the apoptotic process. By contrast, normal cells appeared to be stimulated rather than inhibited by the peptide, whereas primary mouse embryo fibroblasts behaved similarly to tumour cells. On the basis of these results, L. casei peptidoglycan fragments and their constituent basic peptide might be applicable as potent antitumour agents. PMID:27101258

  13. Antitumoural activity of a cytotoxic peptide of Lactobacillus casei peptidoglycan and its interaction with mitochondrial-bound hexokinase

    PubMed Central

    Fichera, Giuseppe A.; Milone, Giuseppe

    2016-01-01

    In a previous study, we reported the cytotoxic activity against various tumour cells of the peptidoglycan of Lactobacillus casei. To isolate the most active components, we performed column-chromatography separation of the peptidoglycan complex and tested the related fractions for their cytotoxic activity. The most active fractions were then lyophilized and the residue was analysed by gas chromatography for its amino acid content and composition. On the basis of the known chemical formula of the basic peptidic component of the peptidoglycan complex of L. casei, a peptide was then synthesized [Europ. (CH-DE-FR-GB) Patent number 1217005; IT number 01320177] and its cytotoxicity was tested against tumoural and normal cells. The synthetic peptide was found to impair the entire metabolism of cultured tumour cells and to restore the apoptotic process. By contrast, normal cells appeared to be stimulated rather than inhibited by the peptide, whereas primary mouse embryo fibroblasts behaved similarly to tumour cells. On the basis of these results, L. casei peptidoglycan fragments and their constituent basic peptide might be applicable as potent antitumour agents. PMID:27101258

  14. Facts about Antibiotic Resistance

    MedlinePlus

    ... Trends and Cost Español: Datos breves Facts about Antibiotic Resistance Antibiotic resistance has been called one of the world’s most ... antibiotic use is a key strategy to control antibiotic resistance. Antibiotic resistance in children is of particular concern ...

  15. Enhanced immunogenicity of multivalent MUC1 glycopeptide antitumour vaccines based on hyperbranched polymers.

    PubMed

    Glaffig, M; Palitzsch, B; Stergiou, N; Schüll, C; Strassburger, D; Schmitt, E; Frey, H; Kunz, H

    2015-10-28

    Enhancing the immunogenicity of an antitumour vaccine still poses a major challenge. It depends upon the selected antigen and the mode of its presentation. We here describe a fully synthetic antitumour vaccine, which addresses both aspects. For the antigen, a tumour-associated MUC1 glycopeptide as B-cell epitope was synthesised and linked to the immunostimulating T-cell epitope P2 derived from tetanus toxoid. The MUC1-P2 conjugate is presented multivalently on a hyperbranched polyglycerol to the immune system. In comparison to a related vaccine of lower multivalency, this vaccine exposing more antigen structures on the hyperbranched polymer induced significantly stronger immune responses in mice and elicited IgG antibodies of distinctly higher affinity to epithelial tumour cells. PMID:26299280

  16. Interactions between rnacrophage cytokines and eicosanoids in expression of antitumour activity

    PubMed Central

    Ben-Efraim, Shlomo

    1992-01-01

    Cytokines and eicosanoid products of macrophages play an essential role in expression of antitumour activity of macrophages either in a cell-to-cell contact system between the effector and the target cell or as cell-free soluble products. In this review the relationship between three main monokines, namely TNF-α, IL-1 and IL-6 and the interrelationship between these monokines and eicosanoids (PGE2, PGI2, LTB4, LTC4) in their production and in expression of antitumour activity is discussed. Emphasis is given to the effect of tumour burden on production of the monokines and of the eicosanoids and on the production of these compounds by the tumour cells. Finally, the therapeutic implications drawn from animal studies and clinical trials is discussed. PMID:18475475

  17. Enhanced anti-tumour effects of Vinca alkaloids given separately from cytostatic therapies

    PubMed Central

    Ehrhardt, H; Pannert, L; Pfeiffer, S; Wachter, F; Amtmann, E; Jeremias, I

    2013-01-01

    Background and Purpose In polychemotherapy protocols, that is for treatment of neuroblastoma and Ewing sarcoma, Vinca alkaloids and cell cycle-arresting drugs are usually administered on the same day. Here we studied whether this combination enables the optimal antitumour effects of Vinca alkaloids to be manifested. Experimental Approach Vinca alkaloids were tested in a preclinical mouse model in vivo and in vitro in combination with cell cycle-arresting drugs. Signalling pathways were characterized using RNA interference. Key Results In vitro, knockdown of cyclins significantly inhibited vincristine-induced cell death indicating, in accordance with previous findings, Vinca alkaloids require active cell cycling and M-phase transition for induction of cell death. In contrast, anthracyclines, irradiation and dexamethasone arrested the cell cycle and acted like cytostatic drugs. The combination of Vinca alkaloids with cytostatic therapeutics resulted in diminished cell death in 31 of 36 (86%) tumour cell lines. In a preclinical tumour model, anthracyclines significantly inhibited the antitumour effect of Vinca alkaloids in vivo. Antitumour effects of Vinca alkaloids in the presence of cytostatic drugs were restored by caffeine, which maintained active cell cycling, or by knockdown of p53, which prevented drug-induced cell cycle arrest. Therapeutically most important, optimal antitumour effects were obtained in vivo upon separating the application of Vinca alkaloids from cytostatic therapeutics. Conclusion and Implications Clinical trials are required to prove whether Vinca alkaloids act more efficiently in cancer patients if they are applied uncoupled from cytostatic therapies. On a conceptual level, our data suggest the implementation of polychemotherapy protocols based on molecular mechanisms of drug–drug interactions. Linked Article This article is commented on by Solary, pp 1555–1557 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph

  18. Anti-tumour immunity in malignant melanoma assay by tube leucocyte adherence inhibition.

    PubMed Central

    Marti, J. H.; Thomson, D. M.

    1976-01-01

    Tumour antigen-induced inhibition of leucocyte adherence was modified for use in glass test tubes (Tube LAI assay) for the study of cell-mediated anti-tumour immunity to human malignant melanoma. Peripheral blood leucocytes (PBL) of 20 out of 25 patients (80%) with active malignant melanoma responded to an extract of malignant melanoma with LAI, whereas only 4-5% of 475 control subjects showed a response. The malignant melanoma patients reacted to both allogeneic and autologous extracts of malignant melanoma which indicates a common cross-reacting antigen. Malignant melanoma patients did not respond to unrelated tumour extracts. The LAI was mediated by PBL (monocytes) "armed" with cytophilic anti-tumour antibody specific for the sensitizing tumour antigen. The anti-tumour response of the malignant melanoma patients was dependent on the stage of the cancer, and 11 out of 13 Stage I patients had a positive NAI, whereas patients with disseminated cancer had decreased response. The diminished LAI in patients with large tumour burdens appeared to be the result of release of tumour antigen systemically. Also, surgery and chemotherapy depressed LAI. Although LAI was depressed after surgical excision of the cutaneous melanoma, most patients showed LAI 1-3 months later. Tumour-free melanoma patients monitored for one year by the Tube LAI assay showed a decline in their anti-tumour immunity 5-6 months after surgery. The NAI was low or negative after the 8th post-surgical month in tumour-free patients. Patients with residual malignant melanoma showed persistent or recurrent LAI after the 8th post-surgical month. LAI reactivity monitored after "curative" surgery for malignant melanoma may assist in determining whether the patient is tumour-free or has a recurrence. PMID:962991

  19. Evaluation of the purified fraction of Wilbrandia (c.f.) verticillata for antitumour activity.

    PubMed

    Rao, V S; Almeida, F R; Moraes, A P; Silva, J V; Nascimento, S C; Moraes, M O

    1991-01-01

    Cucurbitacins are known to produce cytotoxic and anticancer activities. Two novel norcucurbitacin glucosides (Wv1 and Wv2) have recently been isolated from a purified fraction obtained from the rhizome of Wilbrandia verticillata. The present study evaluates the cytotoxic and antitumour activities of these norcucurbitacins. We have found a regular cytotoxicity in KB cells (Cy50 = 12 micrograms/ml) as well as a significant inhibition in the Walker 256 carcinosarcoma growth (approximately 75%). PMID:1842011

  20. Which alkylglycerols from shark liver oil have anti-tumour activities?

    PubMed

    Deniau, Anne-Laure; Mosset, Paul; Le Bot, Damien; Legrand, Alain B

    2011-01-01

    Alkylglycerols (alkyl-Gro) are ether lipids abundant in shark liver oil (SLO), and oral SLO or alkyl-Gro mix from this source have several in vivo biological activities including stimulation of haematopoiesis an immunological defences, or anti-tumour and anti-metastasis activities in vivo. Composition of natural alkyl-Gro mix contains several alkyl-Gro varying by chain length and unsaturation, and individual anti-tumour activity of each molecule present in natural mix remained unknown. We synthesized six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0 16:0, 18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro. Using an in vivo model of grafted tumour in mice (3LL cells), we studied and compared the oral anti-tumour and anti-metastasis activities of each of these 6 alkyl-Gro. 16:1 and 18:1 alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl-Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Spleen weights at day 20 after graft were also measured and showed tremendous variations depending on the treatment. Tumour graft resulted in a raise in spleen weight in control group, this raise was nearly abolished in 16:1 and 18:1 alkyl-Gro-treated mice, and was reduced in 14:0 and 16:0 alkyl-Gro-treated mice. Conversely, 18:0 alkyl-Gro-treated mice showed spleen weigh raise as compared with untreated grafted mice. These new data demonstrate a prominent role of unsaturation in the anti-tumour activities of alkyl-Gro. PMID:20036307

  1. Biodegradation of the X-ray contrast agent iopromide and the fluoroquinolone antibiotic ofloxacin by the white rot fungus Trametes versicolor in hospital wastewaters and identification of degradation products.

    PubMed

    Gros, Meritxell; Cruz-Morato, Carles; Marco-Urrea, Ernest; Longrée, Philipp; Singer, Heinz; Sarrà, Montserrat; Hollender, Juliane; Vicent, Teresa; Rodriguez-Mozaz, Sara; Barceló, Damià

    2014-09-01

    This paper describes the degradation of the X-ray contrast agent iopromide (IOP) and the antibiotic ofloxacin (OFLOX) by the white-rot-fungus Trametes versicolor. Batch studies in synthetic medium revealed that between 60 and 80% of IOP and OFLOX were removed when spiked at approximately 12 mg L(-1) and 10 mg L(-1), respectively. A significant number of transformation products (TPs) were identified for both pharmaceuticals, confirming their degradation. IOP TPs were attributed to two principal reactions: (i) sequential deiodination of the aromatic ring and (ii) N-dealkylation of the amide at the hydroxylated side chain of the molecule. On the other hand, OFLOX transformation products were attributed mainly to the oxidation, hydroxylation and cleavage of the piperazine ring. Experiments in 10 L-bioreactor with fungal biomass fluidized by air pulses operated in batch achieved high percentage of degradation of IOP and OFLOX when load with sterile (87% IOP, 98.5% OFLOX) and unsterile (65.4% IOP, 99% OFLOX) hospital wastewater (HWW) at their real concentration (μg L(-1) level). Some of the most relevant IOP and OFLOX TPs identified in synthetic medium were also detected in bioreactor samples. Acute toxicity tests indicated a reduction of the toxicity in the final culture broth from both experiments in synthetic medium and in batch bioreactor. PMID:24867600

  2. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism.

    PubMed

    Yang, Wei; Bai, Yibing; Xiong, Ying; Zhang, Jin; Chen, Shuokai; Zheng, Xiaojun; Meng, Xiangbo; Li, Lunyi; Wang, Jing; Xu, Chenguang; Yan, Chengsong; Wang, Lijuan; Chang, Catharine C Y; Chang, Ta-Yuan; Zhang, Ti; Zhou, Penghui; Song, Bao-Liang; Liu, Wanli; Sun, Shao-cong; Liu, Xiaolong; Li, Bo-liang; Xu, Chenqi

    2016-03-31

    CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy. PMID:26982734

  3. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells.

    PubMed

    Zhao, Yinghua; Chu, Xiao; Chen, Jintong; Wang, Ying; Gao, Sujun; Jiang, Yuxue; Zhu, Xiaoqing; Tan, Guangyun; Zhao, Wenjie; Yi, Huanfa; Xu, Honglin; Ma, Xingzhe; Lu, Yong; Yi, Qing; Wang, Siqing

    2016-01-01

    Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4(+) T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF-κB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications. PMID:27492902

  4. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism

    PubMed Central

    Yang, Wei; Bai, Yibing; Xiong, Ying; Zhang, Jin; Chen, Shuokai; Zheng, Xiaojun; Meng, Xiangbo; Li, Lunyi; Wang, Jing; Xu, Chenguang; Yan, Chengsong; Wang, Lijuan; Chang, Catharine C. Y.; Chang, Ta-Yuan; Zhang, Ti; Zhou, Penghui; Song, Bao-Liang; Liu, Wanli; Sun, Shao-cong; Liu, Xiaolong; Li, Bo-liang; Xu, Chenqi

    2016-01-01

    CD8+ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment1–4. Reactivating the cytotoxicity of CD8+ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8+ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme5, led to potentiated effector function and enhanced proliferation of CD8+ but not CD4+ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8+ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8+ T cells were better than wild-type CD8+ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile6,7, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy. PMID:26982734

  5. Dectin-1-activated dendritic cells trigger potent antitumour immunity through the induction of Th9 cells

    PubMed Central

    Zhao, Yinghua; Chu, Xiao; Chen, Jintong; Wang, Ying; Gao, Sujun; Jiang, Yuxue; Zhu, Xiaoqing; Tan, Guangyun; Zhao, Wenjie; Yi, Huanfa; Xu, Honglin; Ma, Xingzhe; Lu, Yong; Yi, Qing; Wang, Siqing

    2016-01-01

    Dectin-1 signalling in dendritic cells (DCs) has an important role in triggering protective antifungal Th17 responses. However, whether dectin-1 directs DCs to prime antitumour Th9 cells remains unclear. Here, we show that DCs activated by dectin-1 agonists potently promote naive CD4+ T cells to differentiate into Th9 cells. Abrogation of dectin-1 in DCs completely abolishes their Th9-polarizing capability in response to dectin-1 agonist curdlan. Notably, dectin-1 stimulation of DCs upregulates TNFSF15 and OX40L, which are essential for dectin-1-activated DC-induced Th9 cell priming. Mechanistically, dectin-1 activates Syk, Raf1 and NF-κB signalling pathways, resulting in increased p50 and RelB nuclear translocation and TNFSF15 and OX40L expression. Furthermore, immunization of tumour-bearing mice with dectin-1-activated DCs induces potent antitumour response that depends on Th9 cells and IL-9 induced by dectin-1-activated DCs in vivo. Our results identify dectin-1-activated DCs as a powerful inducer of Th9 cells and antitumour immunity and may have important clinical implications. PMID:27492902

  6. Galactosylated streptavidin for improved clearance of biotinylated intact and F(ab')2 fragments of an anti-tumour antibody.

    PubMed Central

    Marshall, D.; Pedley, R. B.; Melton, R. G.; Boden, J. A.; Boden, R.; Begent, R. H.

    1995-01-01

    Persistence of high levels of radiolabelled antibody in the circulation is a major limitation of radioimmunotherapy. Biotinylation of the radiolabelled anti-tumour antibody followed by administration of streptavidin is known to give much improved tumour to blood ratios as the radioantibody is complexed and subsequently cleared via the reticuloendothelial system, although prolonged splenic uptake is a problem. We have investigated the effect on the clearance pattern and tumour localisation of a 125I-labelled biotinylated anti-CEA antibody (A5B7) after administration of a galactosylated form of streptavidin (gal-streptavidin) in nude mice bearing a human colon carcinoma xenograft. Fifteen minutes to 1 h after gal-streptavidin administration the complexes were cleared via the liver alone (as opposed to liver and spleen after native streptavidin). Twenty-four hours after administration of gal-streptavidin, the tumour to blood ratio for biotinylated A5B7 IgG increased from 2.9 to 13.2 and for biotinylated F(ab')2 fragments an increase from 4.9 to 33.2 was achieved. The reduction in tumour accumulation of F(ab')2 24 h after injection of the clearing agent was less than that seen with intact antibody. Injection of asialofetuin inhibited clearance, confirming that removal of the gal-streptavidin-biotinylated antibody complexes from the blood was via the asialoglycoprotein receptor on liver hepatocytes. Therefore, galactosylation of the streptavidin clearing agent allows rapid removal of radiolabelled biotinylated antibodies via the liver asialoglycoprotein receptor, as opposed to the reticuloendothelial system. Images Figure 5 Figure 6 Figure 7 PMID:7529526

  7. Antibiotic research and development: business as usual?

    PubMed

    Harbarth, S; Theuretzbacher, U; Hackett, J

    2015-01-01

    The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a €9.4 million public-private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents. PMID:25673635

  8. Improved antiangiogenic and antitumour activity of the combination of the natural flavonoid fisetin and cyclophosphamide in Lewis lung carcinoma-bearing mice

    PubMed Central

    Touil, Yasmine S.; Seguin, Johanne; Scherman, Daniel; Chabot, Guy G.

    2011-01-01

    Purpose The natural flavonoid fisetin was recently identified as a lead compound that stabilizes endothelial cell microtubules. In this study we investigated the antiproliferative and antiangiogenic properties of fisetin in vitro and in vivo. Methods Fisetin cytotoxicity was evaluated using Lewis lung carcinoma cells (LLC), endothelial cells and NIH 3T3 cells. Endothelial cell (EC) migration and capillary-like structure formation were evaluated using EAhy 926 cells. In vivo tumour growth inhibition studies were performed using LLC bearing mice treated with fisetin and/or cyclophosphamide (CPA). Results The fisetin IC50 was 59 μM for LLC and 77 μM for EC cells, compared to 210 μM for normal NIH 3T3 cells (24 h). Fisetin inhibited EC migration and capillary-like structure formation at non-cytotoxic concentrations (22–44 μM). In mice, fisetin inhibited angiogenesis assessed using the Matrigel plug assay. In LLC bearing mice, fisetin produced a 67% tumour growth inhibition (223 mg/kg, intraperitoneal), similar to the 66% produced by low dose CPA (30 mg/kg, subcutaneous). When fisetin and CPA were combined, however, a marked improvement in antitumour activity was observed (92% tumour growth inhibition), with low systemic toxicity. Tumour histology showed decreased microvessel density with either fisetin or CPA alone, and a dramatic decrease after the fisetin/CPA combination. Conclusions We have shown that fisetin not only displays in vitro and in vivo antiangiogenic properties, but that it can also markedly improve the in vivo antitumour effect of CPA. We propose that this drug combination associating a non-toxic dietary flavonoid with a cytotoxic agent could advantageously be used in the treatment of solid tumours. PMID:21069336

  9. Impact of antibiotic restrictions: the pharmaceutical perspective.

    PubMed

    Power, E

    2006-08-01

    The development of new antibiotics is dependent on their performance in economic models that favour products with large markets, high levels of potential sales and low development risks. There is a trend toward more severe and more widespread market restrictions for the use of antibiotics, ostensibly to control resistance, though they may be enacted through the control of drug budgets. The restrictions reduce the potential earnings of new antibiotics. In addition, more stringent regulatory procedures increase development costs and risk. As a consequence, compared with drugs for other diseases, particularly chronic diseases, antibiotics perform poorly in economic decision models and are therefore less likely to be selected by pharmaceutical companies for continued development. Overall, this creates a conflict between the twin objectives of controlling resistance through antibiotic restriction and addressing resistance clinically through the introduction of new agents. Ultimately, this may lead to the accelerated loss of efficacy for currently available agents, as we become more dependent on them. Moreover, the new agents that we need to maintain our current levels of health will be lacking in pharmaceutical pipelines. Antibiotic resistance is inevitable; the development of new antibiotics is, however, under threat. Unless the market conditions can be economically rebalanced to encourage innovation and investment, or new models of pharmaceutical development can be applied to this area, the number of companies with active antibiotic research programmes will continue to fall. Just as we should not be complacent regarding the development of resistance, we should not be complacent in assuming that the antibiotics of tomorrow will be there when we need them. PMID:16827822

  10. Antibiotic resistance: from Darwin to Lederberg to Keynes.

    PubMed

    Amábile-Cuevas, Carlos F

    2013-04-01

    The emergence and spread of antibiotic-resistant bacteria reflects both, a gradual, completely Darwinian evolution, which mostly yields slight decreases in antibiotic susceptibility, along with phenotypes that are not precisely characterized as "resistance"; and sudden changes, from full susceptibility to full resistance, which are driven by a vast array of horizontal gene transfer mechanisms. Antibiotics select for more than just antibiotic resistance (i.e., increased virulence and enhanced gene exchange abilities); and many non-antibiotic agents or conditions select for or maintain antibiotic resistance traits as a result of a complex network of underlying and often overlapping mechanisms. Thus, the development of new antibiotics and thoughtful, integrated anti-infective strategies is needed to address the immediate and long-term threat of antibiotic resistance. Since the biology of resistance is complex, these new drugs and strategies will not come from free-market forces, or from "incentives" for pharmaceutical companies. PMID:23046150

  11. Mecillinam: a new antibiotic for enteric fever.

    PubMed Central

    Clarke, P D; Geddes, A M; McGhie, D; Wall, J C

    1976-01-01

    Mecillinam is a new antibiotic related to the penicillins but more active than ampicillin against salmonellae, including Salmonella typhi. Mecillinam must be administered parenterally, but the ester, pivmecillinam, is absorbed from the gut. Eight patients suffering from typhoid fever and one suffering from paratyphoid fever were treated with the antibiotic, and seven responded satisfactorily. One patient could not tolerate pivmecillinam because of vomiting but there were no other adverse reactions. Serum and bile levels of mecillinam were many times the minimum inhibitory concentrations for most salmonellae. The antibiotic is a promising addition to the agents available for treating typhoid. PMID:820402

  12. Fractionated Radiotherapy with 3 x 8 Gy Induces Systemic Anti-Tumour Responses and Abscopal Tumour Inhibition without Modulating the Humoral Anti-Tumour Response

    PubMed Central

    Habets, Thomas H. P. M.; Oth, Tammy; Houben, Ans W.; Huijskens, Mirelle J. A. J.; Senden-Gijsbers, Birgit L. M. G.; Schnijderberg, Melanie C. A.; Brans, Boudewijn; Dubois, Ludwig J.; Lambin, Philippe; De Saint-Hubert, Marijke; Germeraad, Wilfred T. V.; Tilanus, Marcel G. J.; Mottaghy, Felix M.

    2016-01-01

    Accumulating evidence indicates that fractionated radiotherapy (RT) can result in distant non-irradiated (abscopal) tumour regression. Although preclinical studies indicate the importance of T cells in this infrequent phenomenon, these studies do not preclude that other immune mechanisms exhibit an addition role in the abscopal effect. We therefore addressed the question whether in addition to T cell mediated responses also humoral anti-tumour responses are modulated after fractionated RT and whether systemic dendritic cell (DC) stimulation can enhance tumour-specific antibody production. We selected the 67NR mammary carcinoma model since this tumour showed spontaneous antibody production in all tumour-bearing mice. Fractionated RT to the primary tumour was associated with a survival benefit and a delayed growth of a non-irradiated (contralateral) secondary tumour. Notably, fractionated RT did not affect anti-tumour antibody titers and the composition of the immunoglobulin (Ig) isotypes. Likewise, we demonstrated that treatment of tumour-bearing Balb/C mice with DC stimulating growth factor Flt3-L did neither modulate the magnitude nor the composition of the humoral immune response. Finally, we evaluated the immune infiltrate and Ig isotype content of the tumour tissue using flow cytometry and found no differences between treatment groups that were indicative for local antibody production. In conclusion, we demonstrate that the 67NR mammary carcinoma in Balb/C mice is associated with a pre-existing antibody response. And, we show that in tumour-bearing Balb/C mice with abscopal tumour regression such pre-existing antibody responses are not altered upon fractionated RT and/or DC stimulation with Flt3-L. Our research indicates that evaluating the humoral immune response in the setting of abscopal tumour regression is not invariably associated with therapeutic effects. PMID:27427766

  13. Bacteriocins – Exploring Alternatives to Antibiotics in Mastitis Treatment

    PubMed Central

    Pieterse, Reneé; Todorov, Svetoslav D.

    2010-01-01

    Mastitis is considered to be the most costly disease affecting the dairy industry. Management strategies involve the extensive use of antibiotics to treat and prevent this disease. Prophylactic dosages of antibiotics used in mastitis control programmes could select for strains with resistance to antibiotics. In addition, a strong drive towards reducing antibiotic residues in animal food products has lead to research in finding alternative antimicrobial agents. In this review we have focus on the pathogenesis of the mastitis in dairy cows, existing antibiotic treatments and possible alternative for application of bacteriocins from lactic acid bacteria in the treatment and prevention of this disease. PMID:24031528

  14. Anti-tumour effect of metformin in canine mammary gland tumour cells.

    PubMed

    Saeki, K; Watanabe, M; Tsuboi, M; Sugano, S; Yoshitake, R; Tanaka, Y; Ong, S M; Saito, T; Matsumoto, K; Fujita, N; Nishimura, R; Nakagawa, T

    2015-08-01

    Metformin is an oral hypoglycaemic drug used in type 2 diabetes. Its pharmacological activity reportedly involves mitochondrial respiratory complex I, and mitochondrial respiratory complex inhibitors have a strong inhibitory effect on the growth of metastatic canine mammary gland tumour (CMGT) cell lines. It is hypothesised that metformin has selective anti-tumour effects on metastatic CMGT cells. The aim of this study was to investigate the in vitro effect of metformin on cell growth, production of ATP and reactive oxygen species (ROS), and the AMP-activated protein kinase (AMPK) mammalian target of rapamycin (mTOR) pathway in two CMGT clonal cell lines with different metastatic potential. In addition, transcriptome analysis was used to determine cellular processes disrupted by metformin and in vivo anti-tumour effects were examined in a mouse xenograft model. Metformin inhibited CMGT cell growth in vitro, with the metastatic clone (CHMp-5b) displaying greater sensitivity. ATP depletion and ROS elevation were observed to a similar extent in the metastatic and non-metastatic (CHMp-13a) cell lines after metformin exposure. However, subsequent AMPK activation and mTOR pathway inhibition were prominent only in metformin-insensitive non-metastatic cells. Microarray analysis revealed inhibition of cell cycle progression by metformin treatment in CHMp-5b cells, which was further confirmed by Western blotting and cell cycle analysis. Additionally, metformin significantly suppressed tumour growth in xenografted metastatic CMGT cells. In conclusion, metformin exhibited an anti-tumour effect in metastatic CMGT cells through AMPK-independent cell cycle arrest. Its mechanism of action differed in the non-metastatic clone, where AMPK activation and mTOR inhibition were observed. PMID:25981932

  15. Naphthylnitrobutadienes as pharmacologically active molecules: evaluation of the in vivo antitumour activity.

    PubMed

    Petrillo, Giovanni; Fenoglio, Carla; Ognio, Emanuela; Aiello, Cinzia; Spinelli, Domenico; Mariggiò, Maria A; Maccagno, Massimo; Morganti, Stefano; Cordazzo, Cinzia; Viale, Maurizio

    2007-12-01

    On the basis of our previous interesting results in vitro on the antiproliferative activity of (1E,3E)-1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (1-Naph-DNB) we have designed and synthesized the new molecule methyl (2Z,4E)-2-methylsulphanyl-5-(1-naphthyl)-4-nitro-2,4-pentadienoate (1-Naph-NMCB) characterized by the same naphthylnitrobutadiene array but with a different functional group at one end of the diene system. This new molecule showed an in vitro antiproliferative activity more significant than that found for the original 1-Naph-DNB. In order to verify in vivo our in vitro results we have tested the antitumour activity of 1-Naph-DNB and 1-Naph-NMCB in several murine tumour models, namely the myelomonocytic P388 and the Lewis lung carcinoma 3LL in BDF1 mice, the melanoma B16 in C57Bl mice, the fibrosarcoma WEHI 164 in nude mice and, finally, the C51 colon cancer in Balb/c mice. In the case of 1-Naph-NMCB the analysis of the antitumour activity has been preceded by toxicological experiments on CD-1 mice, in order to determine the lethal (LD) and the maximal tolerated (MTD) doses together with the spectrum of histological alterations caused by its iv administration. The results obtained show that the modification of the original structure of 1-Naph-DNB according to the molecular-simplification strategy has led to an asymmetric nitrobutadiene array, i.e. that of 1-Naph-NMCB, endowed with an antitumour activity which is in some cases even better than that showed by the parental compound itself, together with differences in tumour selectivity and negligible histological toxic effects.A promising, versatile route to new, more active and/or safe nitrobutadiene derivatives has thus been positively tested. PMID:17572851

  16. Stimulation of anti-tumour immunity in guinea-pigs by methanol extraction residue of BCG.

    PubMed Central

    Wainberg, M. A.; Deutsch, V.; Weiss, D. W.

    1976-01-01

    The immunoprophylactic effects of the methanol extraction residue (MER) of BCG were investigated in Strain 2 guinea-pigs injected with cells of the transplantable, diethylnitrosamine-induced, Line 10 hepatocarcinoma. Pretreatment with MER at times ranging from 18 to 182 days prior to tumour implantation protected approximately 40% of guinea-pigs from progressive neoplastic disease. In addition, MER-treated animals developed specific cell-mediated anti-tumour immunity both more rapidly and at higher levels than did non-MER-treated tumour-bearing controls. It was not possible, however, to prognosticate from the results of such laboratory studies to the outcome of immunoprophylaxis. PMID:187207

  17. Bacteria subsisting on antibiotics.

    PubMed

    Dantas, Gautam; Sommer, Morten O A; Oluwasegun, Rantimi D; Church, George M

    2008-04-01

    Antibiotics are a crucial line of defense against bacterial infections. Nevertheless, several antibiotics are natural products of microorganisms that have as yet poorly appreciated ecological roles in the wider environment. We isolated hundreds of soil bacteria with the capacity to grow on antibiotics as a sole carbon source. Of 18 antibiotics tested, representing eight major classes of natural and synthetic origin, 13 to 17 supported the growth of clonal bacteria from each of 11 diverse soils. Bacteria subsisting on antibiotics are surprisingly phylogenetically diverse, and many are closely related to human pathogens. Furthermore, each antibiotic-consuming isolate was resistant to multiple antibiotics at clinically relevant concentrations. This phenomenon suggests that this unappreciated reservoir of antibiotic-resistance determinants can contribute to the increasing levels of multiple antibiotic resistance in pathogenic bacteria. PMID:18388292

  18. Antibiotic Application and Emergence of Multiple Antibiotic Resistance (MAR) in Global Catfish Aquaculture.

    PubMed

    Chuah, Li-Oon; Effarizah, M E; Goni, Abatcha Mustapha; Rusul, Gulam

    2016-06-01

    Catfish is one of the most cultivated species worldwide. Antibiotics are usually used in catfish farming as therapeutic and prophylactic agents. In the USA, only oxytetracycline, a combination of sulfadimethoxine and ormetoprim, and florfenicol are approved by the Food Drug Administration for specific fish species (e.g., catfish and salmonids) and their specific diseases. Misuse of antibiotics as prophylactic agents in disease prevention, however, is common and contributes in the development of antibiotic resistance. Various studies had reported on antibiotic residues and/or resistance in farmed species, feral fish, water column, sediments, and, in a lesser content, among farm workers. Ninety percent of the world aquaculture production is carried out in developing countries, which lack regulations and enforcement on the use of antibiotics. Hence, efforts are needed to promote the development and enforcement of such a regulatory structure. Alternatives to antibiotics such as antibacterial vaccines, bacteriophages and their lysins, and probiotics have been applied to curtail the increasing emergence of antibiotic-resistant bacteria due to the imprudent application of antibiotics in aquaculture. PMID:27038482

  19. Antibodies: an alternative for antibiotics?

    PubMed

    Berghman, L R; Abi-Ghanem, D; Waghela, S D; Ricke, S C

    2005-04-01

    In 1967, the success of vaccination programs, combined with the seemingly unstoppable triumph of antibiotics, prompted the US Surgeon General to declare that "it was time to close the books on infectious diseases." We now know that the prediction was overly optimistic and that the fight against infectious diseases is here to stay. During the last 20 yr, infectious diseases have indeed made a staggering comeback for a variety of reasons, including resistance against existing antibiotics. As a consequence, several alternatives to antibiotics are currently being considered or reconsidered. Passive immunization (i.e., the administration of more or less pathogen-specific antibodies to the patient) prior to or after exposure to the disease-causing agent is one of those alternative strategies that was almost entirely abandoned with the introduction of chemical antibiotics but that is now gaining interest again. This review will discuss the early successes and limitations of passive immunization, formerly referred to as "serum therapy," the current use of antibody administration for prophylaxis or treatment of infectious diseases in agriculture, and, finally, recent developments in the field of antibody engineering and "molecular farming" of antibodies in various expression systems. Especially the potential of producing therapeutic antibodies in crops that are routine dietary components of farm animals, such as corn and soy beans, seems to hold promise for future application in the fight against infectious diseases. PMID:15844826

  20. Optimizing antibiotic therapy in the intensive care unit setting

    PubMed Central

    Kollef, Marin H

    2001-01-01

    Antibiotics are one of the most common therapies administered in the intensive care unit setting. In addition to treating infections, antibiotic use contributes to the emergence of resistance among pathogenic microorganisms. Therefore, avoiding unnecessary antibiotic use and optimizing the administration of antimicrobial agents will help to improve patient outcomes while minimizing further pressures for resistance. This review will present several strategies aimed at achieving optimal use of antimicrobial agents. It is important to note that each intensive care unit should have a program in place which monitors antibiotic utilization and its effectiveness. Only in this way can the impact of interventions aimed at improving antibiotic use (e.g. antibiotic rotation, de-escalation therapy) be evaluated at the local level. PMID:11511331

  1. Metal–5-Fluorouracil–Histamine Complexes: Solution, Structural, and Antitumour Studies

    PubMed Central

    Tyagi, Sadhna; Singh, Sukh Mahendra; Gencaslan, Sujan; Sheldrick, W. S.

    2002-01-01

    Solution studies were performed pH-metrically to study the interaction of Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) metal ions with 5-fluorouracil (5FU) and histamine (Hm) separately (binary) and in the presence of each other (ternary) at 25±0.1 °C temperature and a constant ionic strength of 0.1 M NaNO3 in aqueous solution. The ternary complexes have been found to be more stable than the corresponding binary complexes as shown by the positive value of ΔlogK. The species distribution curves have been obtained using the computer programme BEST. On the basis of species distribution results, efforts were also made to prepare some mixed complexes of Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) ions by performing the reaction of their metal nitrates, 5FU and Hm in aqueous ethanol medium at suitable pH. The isolated solid complexes were characterized by different physico-chemical method in order to suggest the possible binding site of the ligands and the structure of the resultant complexes. All these complexes were checked for their antitumour activity by injecting in Dalton's lymphoma (DL) and Sarcoma-180 (S-180) bearing C3H/He mice. The results indicate that some complexes have good antitumour activity both in vivo and in vitro. PMID:18476016

  2. Cytotoxicity and antitumour activity of 5-fluorouracil-loaded polyhydroxybutyrate and cellulose acetate phthalate blend microspheres.

    PubMed

    Chaturvedi, Kiran; Tripathi, Santosh Kumar; Kulkarni, Anandrao R; Aminabhavi, Tejraj M

    2013-01-01

    Pharmacokinetics, biodistribution and antitumour activity of 5-fluorouracil (5-FU)-loaded polyhydroxybutyrate (PHB) and cellulose acetate phthalate (CAP) blend microspheres were investigated in chemically induced colorectal cancer in albino male Wistar rats and compared with pristine 5-FU given as a suspension. The microspheres were characterised for particle size, encapsulation efficiency, in vitro release and in vitro cytotoxicity on human HT-29 colon cancer cell line. Spherical particles with a mean size of 44 ± 11 µm were obtained that showed sustained release of 5-FU. A high concentration of 5-FU was achieved in colonic tissues and significant reduction in tumour volume and multiplicity were observed in animals treated with 5-FU-loaded microspheres. The decreased levels of plasma albumin, creatinine, leucocytopenia and thrombocytopenia were observed in animals for 5-FU microspheres compared to the standard 5-FU formulation. The results suggest the extended release of 5-FU from the PHB-CAP blend microspheres in colonic region to enhance the antitumour efficacy. PMID:23078151

  3. Antitumour properties of the leaf essential oil of Xylopia frutescens Aubl. (Annonaceae).

    PubMed

    Ferraz, Rosana P C; Cardoso, Gabriella M B; da Silva, Thanany B; Fontes, José Eraldo do N; Prata, Ana Paula do N; Carvalho, Adriana A; Moraes, Manoel O; Pessoa, Claudia; Costa, Emmanoel V; Bezerra, Daniel P

    2013-11-01

    The aim of this study was to investigate the chemical composition and anticancer effect of the leaf essential oil of Xylopia frutescens in experimental models. The chemical composition of the essential oil was analysed by GC/FID and GC/MS. In vitro cytotoxic activity of the essential oil was determined on cultured tumour cells. In vivo antitumour activity was assessed in Sarcoma 180-bearing mice. The major compounds identified were (E)-caryophyllene (31.48%), bicyclogermacrene (15.13%), germacrene D (9.66%), δ-cadinene (5.44%), viridiflorene (5.09%) and α-copaene (4.35%). In vitro study of the essential oil displayed cytotoxicity on tumour cell lines and showed IC50 values ranging from 24.6 to 40.0 μg/ml for the NCI-H358M and PC-3M cell lines, respectively. In the in vivo antitumour study, tumour growth inhibition rates were 31.0-37.5%. In summary, the essential oil was dominated by sesquiterpene constituents and has some interesting anticancer activity. PMID:23768347

  4. CD169 identifies an anti-tumour macrophage subpopulation in human hepatocellular carcinoma.

    PubMed

    Zhang, Yi; Li, Jin-Qing; Jiang, Ze-Zhou; Li, Lian; Wu, Yan; Zheng, Limin

    2016-06-01

    Macrophages are a major component of most solid tumours and can exert both anti- and pro-tumourigenic functions. Although the immunosuppressive/pro-tumour roles of macrophages have been widely examined, significantly less is known about macrophage subpopulations that have potential anti-tumour properties in humans. In the present study, a population of CD169(+) macrophages with relatively high expression levels of HLA-DR and CD86 was identified in human hepatocellular carcinoma tissues. The frequency of CD169-expressing macrophages within cancer nests was significantly lower than that found in paired non-tumour areas. In vitro experiments revealed that in the presence of anti-CD3 stimulation, CD169(+) macrophages could significantly enhance the proliferation, cytotoxicity, and cytokine production capacity of CD8(+) T cells in a CD169 molecule-dependent manner. Autocrine TGF-β produced by tumour-stimulated macrophages was involved in the down-regulation of CD169 expression on these cells. Moreover, the accumulation of CD169(+) macrophages in tumour tissues was negatively associated with disease progression and predicted favourable survival in hepatocellular carcinoma patients, which was in contrast to the trend observed for total CD68(+) macrophages. Therefore, CD169 might act as a co-stimulatory molecule for cytotoxic T-cell activation, and could define a population of tumour-infiltrating macrophages with potential anti-tumour properties in human hepatocellular carcinoma tissues. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID:27174787

  5. Antitumour effect of Diospyros cordifolia bark on Ehrlich ascites carcinoma-bearing Swiss albino mice.

    PubMed

    Das, Sudipta; Bhattacharya, Sanjib; Pramanik, Goutam; Haldar, Pallab Kanti

    2012-01-01

    Diospyros cordifolia Roxb. (Ebenaceae), commonly known as Indian ebony, is used traditionally for several medicinal purposes. In this study, the methanol extract of D. cordifolia bark (MEDC) was evaluated for its antitumour effect against Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. Twenty-four hours after intraperitoneal inoculation of tumour (EAC) cells in mice, MEDC was administered intraperitoneally at 25 and 50 mg kg⁻¹ bodyweight for 9 consecutive days. On the 10th day, half of the mice were sacrificed to determine the tumour volume, viable and non-viable tumour cell counts, and rest were kept alive for the assessment of median survival time and increase in life span. Haematological profiles were also determined. MEDC exhibited a marked decrease in tumour growth parameters and increased the survival rate of EAC-bearing animals. MEDC normalised the haematological parameters as compared with the EAC control mice. Therefore, this study demonstrated that D. cordifolia bark possessed remarkable antitumour efficacy. PMID:21985607

  6. Polyphenolic compounds with anti-tumour potential from Corchorus olitorius (L.) Tiliaceae, a Nigerian leaf vegetable.

    PubMed

    Taiwo, Bamigboye J; Taiwo, Grace O; Olubiyi, Olujide O; Fatokun, Amos A

    2016-08-01

    Chromatographic fractionation of the methanolic extract of Corchorus olitorius (L.) (Tiliaceae), on silica gel yielded two polyphenolic compounds. The structures of the compounds were elucidated as Methyl-1,4,5-tri-O-caffeoyl quinate and trans-3-(4-Hydroxy-3-methoxyphenyl)acrylic anhydride, based on extensive use of spectroscopic techniques such as (1)H and (13)C NMR, DEPT and 2D NMR experiments (COSY, HSQC, HMBC), IR and MS. To establish an initial proof-of-concept for the biological relevance of these compounds, their cytotoxicity against the cancer cell lines HeLa, HL460 and PC3, which might indicate their anti-tumour potential, was assessed. The compounds when tested at a range of concentrations up to 1.6mM were found to possess mild cytotoxic activity which was significant against HeLa cells at ⩾800μM. The trans-3-(4-Hydroxy-3-methoxyl phenyl)acrylic anhydride was found to be related to curcumin, a compound known to have anti-cancer activity. Docking of each of the two compounds and also of curcumin into some molecular targets implicated in tumourigenesis revealed that the three compounds had binding affinities that were superior to those obtained for the co-crystallized inhibitors of metalloproteinase-9, fibroblast growth factor receptor 2 (FGFR2) and epidermal growth factor receptor (EGFR). The plant Corchorus olitorius therefore represents a potential source of natural 'lead' compounds with anti-tumour potential. PMID:27381082

  7. Antibiotic-associated encephalopathy.

    PubMed

    Bhattacharyya, Shamik; Darby, R Ryan; Raibagkar, Pooja; Gonzalez Castro, L Nicolas; Berkowitz, Aaron L

    2016-03-01

    Delirium is a common and costly complication of hospitalization. Although medications are a known cause of delirium, antibiotics are an underrecognized class of medications associated with delirium. In this article, we comprehensively review the clinical, radiologic, and electrophysiologic features of antibiotic-associated encephalopathy (AAE). AAE can be divided into 3 unique clinical phenotypes: encephalopathy commonly accompanied by seizures or myoclonus arising within days after antibiotic administration (caused by cephalosporins and penicillin); encephalopathy characterized by psychosis arising within days of antibiotic administration (caused by quinolones, macrolides, and procaine penicillin); and encephalopathy accompanied by cerebellar signs and MRI abnormalities emerging weeks after initiation of antibiotics (caused by metronidazole). We correlate these 3 clinical phenotypes with underlying pathophysiologic mechanisms of antibiotic neurotoxicity. Familiarity with these types of antibiotic toxicity can improve timely diagnosis of AAE and prompt antibiotic discontinuation, reducing the time patients spend in the delirious state. PMID:26888997

  8. Combating Antibiotic Resistance

    MedlinePlus

    ... for infectious diseases. back to top Antibiotics Fight Bacteria, Not Viruses Antibiotics are meant to be used ... treat strep throat, which is caused by streptococcal bacteria, and skin infections caused by staphylococcal bacteria. Although ...

  9. MedlinePlus: Antibiotics

    MedlinePlus

    ... or not using them properly, can add to antibiotic resistance . This happens when bacteria change and become able ... ports Pseudomembranous colitis Sensitivity analysis Related Health Topics Antibiotic Resistance Bacterial Infections Medicines National Institutes of Health The ...

  10. Generic antibiotic drugs: is effectiveness guaranteed?

    PubMed

    Gauzit, R; Lakdhari, M

    2012-04-01

    There are recently published arguments suggesting all generic antibiotic drugs do not present the full reliability needed to claim therapeutic equivalence with branded drugs. The problem is especially crucial for generic intravenous drugs, which do not need any bioequivalence study before they can be marketed. The evaluation of generic antibiotic drug effectiveness yields an important dispersion of results according to antibiotic agents and for the same antibiotic agent all generic drugs are not equivalent. There are differences at all levels: drug components, levels of impurity, pharmacokinetics, pharmacokinetic/pharmacodynamic relationship, in vitro effectiveness, therapeutic effectiveness in experimental models, etc. So that finally, the specifications approved in the initial submission file of a brand name drugs are not always respected by a generic drug. There is also a specific problem of taste and treatment acceptability for pediatric oral antibiotic drugs. Available data on clinical effectiveness is excessively rare. The marketing of a great number of generic drugs of the same specialty is followed by a sometimes very important increase of their use, even in countries where consumption is low. The corollary of this increase in consumption is an increase of resistance, and this is especially true for oral fluoroquinolones. Even if most of this information needs to be verified, it seems necessary to review regulations for marketing authorization of generic antibiotic drugs. PMID:22480963

  11. Squalamine: an aminosterol antibiotic from the shark.

    PubMed

    Moore, K S; Wehrli, S; Roder, H; Rogers, M; Forrest, J N; McCrimmon, D; Zasloff, M

    1993-02-15

    In recent years, a variety of low molecular weight antibiotics have been isolated from diverse animal species. These agents, which include peptides, lipids, and alkaloids, exhibit antibiotic activity against environmental microbes and are thought to play a role in innate immunity. We report here the discovery of a broad-spectrum steroidal antibiotic isolated from tissues of the dogfish shark Squalus acanthias. This water-soluble antibiotic, which we have named squalamine, exhibits potent bactericidal activity against both Gram-negative and Gram-positive bacteria. In addition, squalamine is fungicidal and induces osmotic lysis of protozoa. The chemical structure of the antibiotic 3 beta-N-1-(N-[3-(4-aminobutyl)]- 1,3-diaminopropane)-7 alpha,24 zeta-dihydroxy-5 alpha-cholestane 24-sulfate has been determined by fast atom bombardment mass spectroscopy and NMR. Squalamine is a cationic steroid characterized by a condensation of an anionic bile salt intermediate with spermidine. The discovery of squalamine in the shark implicates a steroid as a potential host-defense agent in vertebrates and provides insights into the chemical design of a family of broad-spectrum antibiotics. PMID:8433993

  12. Antibiotics, Bacteria, and Antibiotic Resistance Genes: Aerial Transport from Cattle Feed Yards via Particulate Matter

    PubMed Central

    McEachran, Andrew D.; Blackwell, Brett R.; Hanson, J. Delton; Wooten, Kimberly J.; Mayer, Gregory D.; Cox, Stephen B.

    2015-01-01

    Background: Emergence and spread of antibiotic resistance has become a global health threat and is often linked with overuse and misuse of clinical and veterinary chemotherapeutic agents. Modern industrial-scale animal feeding operations rely extensively on veterinary pharmaceuticals, including antibiotics, to augment animal growth. Following excretion, antibiotics are transported through the environment via runoff, leaching, and land application of manure; however, airborne transport from feed yards has not been characterized. Objectives: The goal of this study was to determine the extent to which antibiotics, antibiotic resistance genes (ARG), and ruminant-associated microbes are aerially dispersed via particulate matter (PM) derived from large-scale beef cattle feed yards. Methods: PM was collected downwind and upwind of 10 beef cattle feed yards. After extraction from PM, five veterinary antibiotics were quantified via high-performance liquid chromatography with tandem mass spectrometry, ARG were quantified via targeted quantitative polymerase chain reaction, and microbial community diversity was analyzed via 16S rRNA amplification and sequencing. Results: Airborne PM derived from feed yards facilitated dispersal of several veterinary antibiotics, as well as microbial communities containing ARG. Concentrations of several antibiotics in airborne PM immediately downwind of feed yards ranged from 0.5 to 4.6 μg/g of PM. Microbial communities of PM collected downwind of feed yards were enriched with ruminant-associated taxa and were distinct when compared to upwind PM assemblages. Furthermore, genes encoding resistance to tetracycline antibiotics were significantly more abundant in PM collected downwind of feed yards as compared to upwind. Conclusions: Wind-dispersed PM from feed yards harbors antibiotics, bacteria, and ARGs. Citation: McEachran AD, Blackwell BR, Hanson JD, Wooten KJ, Mayer GD, Cox SB, Smith PN. 2015. Antibiotics, bacteria, and antibiotic

  13. Nonmedical Uses of Antibiotics: Time to Restrict Their Use?

    PubMed Central

    Meek, Richard William; Vyas, Hrushi; Piddock, Laura Jane Violet

    2015-01-01

    The global crisis of antibiotic resistance has reached a point where, if action is not taken, human medicine will enter a postantibiotic world and simple injuries could once again be life threatening. New antibiotics are needed urgently, but better use of existing agents is just as important. More appropriate use of antibiotics in medicine is vital, but the extensive use of antibiotics outside medical settings is often overlooked. Antibiotics are commonly used in animal husbandry, bee-keeping, fish farming and other forms of aquaculture, ethanol production, horticulture, antifouling paints, food preservation, and domestically. This provides multiple opportunities for the selection and spread of antibiotic-resistant bacteria. Given the current crisis, it is vital that the nonmedical use of antibiotics is critically examined and that any nonessential use halted. PMID:26444324

  14. Nonmedical Uses of Antibiotics: Time to Restrict Their Use?

    PubMed

    Meek, Richard William; Vyas, Hrushi; Piddock, Laura Jane Violet

    2015-10-01

    The global crisis of antibiotic resistance has reached a point where, if action is not taken, human medicine will enter a postantibiotic world and simple injuries could once again be life threatening. New antibiotics are needed urgently, but better use of existing agents is just as important. More appropriate use of antibiotics in medicine is vital, but the extensive use of antibiotics outside medical settings is often overlooked. Antibiotics are commonly used in animal husbandry, bee-keeping, fish farming and other forms of aquaculture, ethanol production, horticulture, antifouling paints, food preservation, and domestically. This provides multiple opportunities for the selection and spread of antibiotic-resistant bacteria. Given the current crisis, it is vital that the nonmedical use of antibiotics is critically examined and that any nonessential use halted. PMID:26444324

  15. Finding alternatives to antibiotics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The spread of antibiotic-resistant pathogens requires new treatments. The availability of new antibiotics has severely declined, and so alternatives to antibiotics need to be considered in both animal agriculture and human medicine. Products for disease prevention are different than products for d...

  16. Antibiotic Resistance Questions and Answers

    MedlinePlus

    ... on the Farm Get Smart About Antibiotics Week Antibiotic Resistance Questions and Answers Language: English Español (Spanish) Recommend ... Many ear infections Top of Page Questions about Antibiotic Resistance Examples of How Antibiotic Resistance Spreads Click for ...

  17. Elimination of bacteria from dogs with antibiotics*

    PubMed Central

    Hayes, Norman R.; van der Waaij, D.; Cohen, Bennett J.

    1974-01-01

    The effect of oral administration of neomycin cephalothin or kanamycin cephalothin on the aerobic intestinal bacterial flora, was studied in dogs maintained under isolation conditions in a conventional animal room. The dogs were successfully freed of aerobic bacteria with both combinations within two to seven days after the start of antibiotic treatment, and were maintained bacteria free for up to 21 days. Decontamination was attained more rapidly in dogs that were bathed in hexachlorophene surgical soap before and during the first and third days of antibiotic treatment. There was no evidence of toxicity from either of the antibiotic combinations. These results indicate that, as with mice and monkeys, decontamination of dogs with oral antibiotics is feasible. The technique is of potential value in preventing endogenous bacterial infections in canine experimental studies involving use of immunosuppressive agents. PMID:4529233

  18. Do antibiotics decrease effectiveness of oral contraceptives?

    PubMed

    Cottet, C

    1996-09-01

    The number of accidental pregnancies occurring in oral contraceptive (OC) users who are concurrently taking certain antibiotics and antifungal agents exceeds the 1% failure rate associated with OCs, suggesting some form of drug interaction. Two mechanisms of action have been proposed to explain this phenomenon. First, drugs such as rifampin and griseofulvin induce liver enzymes that break down the estrogen and progestin contained in OCs, reducing plasma hormone levels. Second, changes in the intestinal bacterial flora induced by penicillin and tetracycline may reduce the gut's absorption of hormones, also compromising efficacy. Since rifampin and griseofulvin are the medications most frequently implicated in accidental pregnancies in OC users, the induction of liver enzymes is the more probable, potent cause of failure. Although the risk of pregnancy due to OC-antibiotic interactions is extremely small, OC users prescribed antibiotics should be warned to use condoms or spermicides until the antibiotics are discontinued. PMID:9006212

  19. Mechanisms of antibiotic resistance in enterococci

    PubMed Central

    Miller, William R; Munita, Jose M; Arias, Cesar A

    2015-01-01

    Multidrug-resistant (MDR) enterococci are important nosocomial pathogens and a growing clinical challenge. These organisms have developed resistance to virtually all antimicrobials currently used in clinical practice using a diverse number of genetic strategies. Due to this ability to recruit antibiotic resistance determinants, MDR enterococci display a wide repertoire of antibiotic resistance mechanisms including modification of drug targets, inactivation of therapeutic agents, overexpression of efflux pumps and a sophisticated cell envelope adaptive response that promotes survival in the human host and the nosocomial environment. MDR enterococci are well adapted to survive in the gastrointestinal tract and can become the dominant flora under antibiotic pressure, predisposing the severely ill and immunocompromised patient to invasive infections. A thorough understanding of the mechanisms underlying antibiotic resistance in enterococci is the first step for devising strategies to control the spread of these organisms and potentially establish novel therapeutic approaches. PMID:25199988

  20. Empiric Antibiotic Therapy of Nosocomial Bacterial Infections.

    PubMed

    Reddy, Pramod

    2016-01-01

    Broad-spectrum antibiotics are commonly used by physicians to treat various infections. The source of infection and causative organisms are not always apparent during the initial evaluation of the patient, and antibiotics are often given empirically to patients with suspected sepsis. Fear of attempting cephalosporins and carbapenems in penicillin-allergic septic patients may result in significant decrease in the spectrum of antimicrobial coverage. Empiric antibiotic therapy should sufficiently cover all the suspected pathogens, guided by the bacteriologic susceptibilities of the medical center. It is important to understand the major pharmacokinetic properties of antibacterial agents for proper use and to minimize the development of resistance. In several septic patients, negative cultures do not exclude active infection and positive cultures may not represent the actual infection. This article will review the important differences in the spectrum of commonly used antibiotics for nosocomial bacterial infections with a particular emphasis on culture-negative sepsis and colonization. PMID:24413366

  1. A Supramolecular Antibiotic Switch for Antibacterial Regulation.

    PubMed

    Bai, Haotian; Yuan, Huanxiang; Nie, Chenyao; Wang, Bing; Lv, Fengting; Liu, Libing; Wang, Shu

    2015-11-01

    A supramolecular antibiotic switch is described that can reversibly "turn-on" and "turn-off" its antibacterial activity on demand, providing a proof-of-concept for a way to regulate antibacterial activity of biotics. The switch relies on supramolecular assembly and disassembly of cationic poly(phenylene vinylene) derivative (PPV) with cucurbit[7]uril (CB[7]) to regulate their different interactions with bacteria. This simple but efficient strategy does not require any chemical modification on the active sites of the antibacterial agent, and could also regulate the antibacterial activity of classical antibiotics or photosensitizers in photodynamic therapy. This supramolecular antibiotic switch may be a successful strategy to fight bacterial infections and decrease the emergence of bacterial resistance to antibiotics from a long-term point of view. PMID:26307170

  2. Tolerance of staphylococci to bactericidal antibiotics.

    PubMed

    Vaudaux, Pierre; Lew, Daniel P

    2006-05-01

    Antibiotic therapy for deep-seated staphylococcal infections, especially when they are associated with artificial devices used for orthopedic surgery is often associated with failure. Standard anti-staphylococcal bactericidal antibiotics, such as semi-synthetic penicillins, cephalosporins, or glycopeptides, are effective when given prophylactically in clinical conditions or experimental trials of implant-related infections. However, the efficacy of all anti-staphylococcal agents is seriously diminished on already established implant-related deep-seated infections, which then frequently require surgical implant removal to obtain a cure. The failure of antibiotic therapy to cure established staphylococcal foreign-body infections may arise in part from a broad-spectrum phenotypic tolerance expressed in vivo to different classes of antimicrobial agents. The molecular and physiological mechanisms of this in vivo tolerance remain poorly understood. PMID:16651066

  3. Trends in hospital antibiotic prescribing after introduction of an antibiotic policy.

    PubMed

    Gould, I M; Jappy, B

    1996-11-01

    Trends in antibiotic prescribing in Grampian were monitored prospectively for seven years from 1986 using computerised ward stock lists and laboratory data relating to all in-patient and out-patient treatments in all Grampian hospitals serving a population of 500,000. The main outcome measures were the number of antibiotics available for routine and restricted uses, annual expenditure and defined daily doses (DDDs) of high expenditure antimicrobial agents. An antibiotic committee introduced a policy and formulary in the third year of the study which had only limited success in controlling prescribing. During the period of the study 30 new antibiotics were considered for inclusion in the hospital formulary, but only seven were incorporated, and all for restricted use only. Despite this, expenditure on antibiotics has more than doubled since 1986, two thirds of the increase being due to the use of new drugs. There was also an increased use of older antibiotics (DDDs increased by 33%), often for no clear reasons, and an overall increase of 46% in DDDs. Antibiotics have increased from 11.9-18.7% as a proportion of the drug budget. These findings highlight the current difficulty in controlling prescribing budgets, the increasing use of antibiotics and the consequent spread of resistance. PMID:8961062

  4. [Development of an accelerated method of determining the antibiotic sensitivity of Cl. perfringens type A].

    PubMed

    Zemlianitskaia, E P; Kurbanova, I Z; Sergeeva, T I

    1979-02-01

    An express method for determination of antibiotic sensitivity in the strains of Cl. perfringens of type A using Soviet dry nutrient media and antibiotics is proposed. The criteria for estimation of the level of the antibiotic sensitivity of the causative agent of gas gangrene in short periods on the basis of comparison of the data of the antibiotic agar diffusion procedure and the antibiotic MIC were worked out. Twelve antibiotics and 45 collection strains of Cl. perfringens of type A were used in the experiment. The antibiotic agar diffusion method with the use of the nutrient media, microbial load and cultivation conditions developed by the authors is recommended for tentative determination of the antibiotic sensitivity in Cl. perfringens of type A for 4 hours. The use of the agar diffusion method and determination of the antibiotic MIC provided complete estimation of tha antibiotic sensitivity of Cl. perfringens of type A within not more than 24 hours. PMID:219770

  5. Metal-based antitumour drugs in the post-genomic era: what comes next?

    PubMed

    Sava, Gianni; Bergamo, Alberta; Dyson, Paul J

    2011-09-28

    In our Dalton Transactions Perspective article entitled, 'Metal-based antitumour drugs in the post genomic era', (Dalton Trans., 2006, 1929-1933) we discussed metal-based drugs in light of past decades of research. We concluded that the post-genomic era would dictate a change in the direction of the field with knowledge of the genome increasingly allowing protein targets to be identified and not simply assuming that DNA is the only relevant target of metal-based drugs. Since our article was published new insights into the mode of action of metal-based drugs have emerged making some older findings increasingly relevant to current drug design. In this article we discuss these developments in terms of what we believe should be the future direction for the field. PMID:21725573

  6. [Hybrid nanocarriers for controlled delivery of antitumour and retroviral drugs delivery].

    PubMed

    Horcajada, Patricia; Serre, Christian; Férey, Gérard; Couvreur, Patrick; Gref, Ruxandra

    2010-01-01

    The efficient delivery of drugs in the body requires the use of non-toxic nanocarriers. Most of the existing materials show poor drug loading and/or rapid release of the proportion of the drug that is simply adsorbed (or anchored) at the external surface of the nanocarrier. The new porous hybrid solids, with the ability to tune their structures and porosities are well suited to serve as nanocarriers for delivery and imaging applications. Here we show that specific non-toxic porous iron(III) - based metal - organic frameworks with engineered cores and surfaces, as well as imaging properties, function as superior nanocarriers for efficient controlled delivery of antitumour and retroviral drugs against cancer and AIDS. They also potentially associate therapeutics and diagnostics, and open the way for theranostics, or -personalized patient treatments. double dagger. PMID:20819715

  7. Antitumour and antioxidant activity of some Red Sea seaweeds in Ehrlich ascites carcinoma in vivo.

    PubMed

    Ahmed, Hanaa H; Hegazi, Muhammad M; Abd-Alla, Howaida I; Eskander, Emad F; Ellithey, Mona S

    2011-01-01

    The antitumour activities of extracts from the Red Sea seaweeds Jania rubens, Sargassum subrepandum, and Ulva lactuca were investigated in an in vivo mice model based on intramuscular injection of Ehrlich ascites tumour cells. In parallel, antioxidant activities were measured. Tumour marker levels, liver biochemical parameters, and hepatic oxidant/antioxidant status were measured to prove the anticancer and antioxidant nature of the algal extracts. Significant decreases in carcinoembryonic antigen (CEA) and a-fetoprotein (AFP) levels, activities of liver enzymes, levels of nitric oxide (NO) and malondialdehyde (MDA), and an increase in total antioxidant capacity (TAC) were recorded in groups treated with the algal extracts. Jania rubens was selected for phytochemical screening of its phytoconstituents. In addition, carotenoids, halides, minerals, lipoidal matters, proteins, and carbohydrates were studied. Furthermore, 7-oxo-cholest-5(6)-en-3-ol (1) and cholesterol (2) were isolated from the dichloromethane fraction. PMID:21950161

  8. Supramolecular Antibiotic Switches: A Potential Strategy for Combating Drug Resistance.

    PubMed

    Bai, Haotian; Lv, Fengting; Liu, Libing; Wang, Shu

    2016-08-01

    Bacterial infectious disease is a serious public health concern throughout the world. Pathogen drug resistance, arising from both rational use and abuse/misuse of germicides, complicates the situation. Aside from developing novel antibiotics and antimicrobial agents, molecular approaches have become another significant method to overcome the problem of pathogen drug resistance. Established supramolecular systems, the antibiotic properties of which can be switched "on" and "off" through host-guest interactions, show great potential in combating issues regarding antibiotic resistance in the long term, as indicated by several recent studies. In this Concept, recently developed strategies for antibacterial regulation are summarized and further directions for research into antibiotic switches are proposed. PMID:27312106

  9. Antitumour and anti-inflammatory effects of palladium(II) complexes on Ehrlich tumour.

    PubMed

    Quilles, Marcela B; Carli, Camila B A; Ananias, Sandra R; Ferreira, Lucas S; Ribeiro, Livia C A; Maia, Danielle C G; Resende, Flávia A; Moro, Antônio C; Varanda, Eliana A; Placeres, Marisa Campos Polesi; Mauro, Antonio E; Carlos, Iracilda Z

    2013-01-01

    Palladium(II) complexes are an important class of cyclopalladated compounds that play a pivotal role in various pharmaceutical applications. Here, we investigated the antitumour, anti-inflammatory, and mutagenic effects of two complexes: [Pd(dmba)(Cl)tu] (1) and [Pd(dmba)(N3)tu] (2) (dmba = N,N-dimethylbenzylamine and tu = thiourea), on Ehrlich ascites tumour (EAT) cells and peritoneal exudate cells (PECs) from mice bearing solid Ehrlich tumour. The cytotoxic effects of the complexes on EAT cells and PECs were assessed using the 3-(4,5-dimethylthiazol-3-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay. The effects of the complexes on the immune system were assessed based on the production of nitric oxide (NO) (Griess assay) and tumour necrosis factor-alpha (TNF-alpha), interleukin-12 (IL-12), and interleukin-10 (IL-10) (ELISA). Finally the mutagenic activity was assessed by the Ames test using the Salmonella typhimurium strain TA 98. Cisplatin was used as a standard. The IC50 ranges for the growth inhibition of EAT cells and PECs were found to be (72.8 +/- 3.23) microM and (137.65 +/- 0.22) microM for 1 and (39.7 +/- 0.30) microM and (146.51 +/- 2.67) microM for 2, respectively. The production of NO, IL-12, and TNF-alpha, but not IL-10, was induced by both complexes and cisplatin. The complexes showed no mutagenicity in vitro, unlike cisplatin, which was mutagenic in the strain. These results indicate that the complexes are not mutagenic and have potential immunological and antitumour activities. These properties make them promising alternatives to cisplatin. PMID:24066514

  10. Collective antibiotic treatment of trachoma

    PubMed Central

    Reinhards, J.; Weber, A.; Maxwell-Lyons, F.

    1959-01-01

    By the early 1950's, it was clear from numerous independent reports that certain of the broad-spectrum antibiotics were effective against the agent of trachoma. It seemed, however, that treatment had to be continued over long periods to effect a cure of the average case. With the assistance of WHO, comparative trials on a scale hitherto unprecedented in the disease—involving more than 9000 schoolchildren with active trachoma—have been conducted in Morocco since 1953 in order to assess the value of local treatment of trachoma with chlortetracycline and to develop simple and economic methods of treatment, for which there was a pressing need. Local application of 1% chlortetracycline ointment two or three times daily for 60 days gave almost 80% cures under reasonably favourable conditions and nearly 100% cures after re-treatment of cases not cured by the first course. Equally good results followed intermittent short-term treatment over longer periods. Relapse and reinfection rates were low. Collective mass treatment with antibiotics is clearly a valuable method of trachoma control. The use of intermittent treatment allows for a great economy both in antibiotics and in staff and other campaign expenses and makes possible the wide expansion of mass treatment programmes. PMID:14437176

  11. Biotic acts of antibiotics

    PubMed Central

    Aminov, Rustam I.

    2013-01-01

    Biological functions of antibiotics are not limited to killing. The most likely function of antibiotics in natural microbial ecosystems is signaling. Does this signaling function of antibiotics also extend to the eukaryotic – in particular mammalian – cells? In this review, the host modulating properties of three classes of antibiotics (macrolides, tetracyclines, and β-lactams) will be briefly discussed. Antibiotics can be effective in treatment of a broad spectrum of diseases and pathological conditions other than those of infectious etiology and, in this capacity, may find widespread applications beyond the intended antimicrobial use. This use, however, should not compromise the primary function antibiotics are used for. The biological background for this inter-kingdom signaling is also discussed. PMID:23966991

  12. [Rational use of antibiotics].

    PubMed

    Walger, P

    2016-06-01

    International and national campaigns draw attention worldwide to the rational use of the available antibiotics. This has been stimulated by the high prevalence rates of drug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), a threatening spread of development of resistance in Gram-negative rod-shaped bacteria and the selection of Clostridium difficile with a simultaneous clear reduction in the development of new antibiotics. The implementation of antibiotic stewardship programs aims to maintain their effectiveness by a rational use of the available antibiotics. The essential target of therapy with antibiotics is successful treatment of individual patients with bacterial infections. The optimal clinical treatment results can only be achieved when the toxicity, selection of pathogens and development of resistance are minimized. This article presents the principles of a rational antibiotic therapy. PMID:27246321

  13. Frontline antibiotic therapy.

    PubMed

    MacGowan, Alasdair; Albur, Maha

    2013-06-01

    The need to use front-line antibiotics wisely has never been greater. Antibiotic resistance and multi-drug resistant infection, driven by antibiotic use, remain major public health and professional concerns. To overcome these infection problems, use of older antibiotics active against multi drug-resistant pathogens is increasing - for example, colistin, fosfomycin, pivmecillinam, pristinamycin, temocillin and oral tetracyclines. The number of new antibacterials reaching clinical practice has reduced significantly in the last 20 years, most being focused on therapy of Gram-positive infection - eg linezolid, daptomycin, telavancin and ceftaroline. Recent guidance on antibiotic stewardship in NHS trusts in England is likely to provide a backdrop to antibiotic use in hospitals in the next 5 years. PMID:23760700

  14. New antimicrobial molecules and new antibiotic strategies.

    PubMed

    Rodríguez de Castro, Felipe; Naranjo, Olga Rajas; Marco, Javier Aspa; Violán, Jordi Solé

    2009-04-01

    Drug options for treatment of infections are increasingly limited. The pharmaceutical industry has found it difficult to discover new antimicrobial agents, and only two novel classes of antibiotics, the oxazolidinones and the cyclic lipopeptides, have entered the market since the late 1960s. Few new agents have reached the market in the last decade with potential interest for community-acquired pneumonia (CAP) treatment, including linezolid (the first oxazolidinone in clinical use), new fluoroquinolones, cefditoren, ertapenem, and telithromycin. Agents currently in clinical development include other novel quinolones and ketolides, broad-spectrum cephalosporin derivatives, faropenem, several glycopeptides, and iclaprim. Other molecules are considered to be promising candidates for the future. In addition to the foregoing agents, alternative treatment approaches have also been introduced into clinical practice, which include the administration of the appropriate antimicrobials in a timely manner and the consideration of the pharmacokinetic-pharmacodynamic properties of the agent(s). PMID:19296416

  15. Ataxia telangiectasia mutated- and Rad3-related kinase drives both the early and the late DNA-damage response to the monofunctional antitumour alkylator S23906.

    PubMed

    Soares, Daniele G; Battistella, Aude; Rocca, Céline J; Matuo, Renata; Henriques, João A P; Larsen, Annette K; Escargueil, Alexandre E

    2011-07-01

    Numerous anticancer agents and environmental mutagens target DNA. Although all such compounds interfere with the progression of the replication fork and inhibit DNA synthesis, there are marked differences in the DNA-damage response pathways they trigger, and the relative impact of the proximal or the distal signal transducers on cell survival is mainly lesion-specific. Accordingly, checkpoint kinase inhibitors in current clinical development show synergistic activity with some DNA-targeting agents, but not with others. In the present study, we characterize the DNA-damage response to the antitumour acronycine derivative S23906, which forms monofunctional adducts with guanine residues in the minor groove of DNA. S23906 exposure is accompanied by specific recruitment of RPA (replication protein A) at replication sites and rapid Chk1 activation. In contrast, neither MRN (Mre11-Rad50-Nbs1) nor ATM (ataxia-telangiectasia mutated), contributes to the initial response to S23906. Interestingly, genetic attenuation of ATR (ATM- and Ras3-related) activity inhibits not only the early phosphorylation of histone H2AX and Chk1, but also interferes with the late phosphorylation of Chk2. Moreover, loss of ATR function or pharmacological inhibition of the checkpoint kinases by AZD7762 is accompanied by abrogation of the S-phase arrest and increased sensitivity towards S23906. These findings identify ATR as a central co-ordinator of the DNA-damage response to S23906, and provide a mechanistic rationale for combinations of S23906 and similar agents with checkpoint abrogators. PMID:21470188

  16. Update on antibiotics in ocular infections.

    PubMed

    Leopold, I H

    1985-07-15

    Each year, new antimicrobials are found or synthesized in an effort to improve the chance of overcoming infections. In the early 1950s, the only antibiotic available for ocular use was penicillin. Today, ophthalmologists can make a choice from a large selection of antibiotics for ocular infections. The majority of antibiotics have been literally unearthed, since worldwide soil surveys may have been the means of their discovery. In addition, synthetic derivatives of penicillin, cephalosporins, aminoglycosides, and tetracyclines, as well as drugs against tuberculosis and fungi, have become available, and new names have been added to the already bewildering list of less frequently used sulfonamides. However, it takes several years to appreciate the impact of new agents and the continued contribution of older ones. Constant reevaluation is mandatory. The real benefits as well as the untoward effects of a new antimicrobial agent may not be known until several years after the clinical introduction. In addition to approaching infection from the viewpoint of the offending organism and a specific antibiotic to address this organism, one may also approach this problem from the host's immunity. Until now, we have relied largely on the corticosteroids, but one must also consider various nonsteroidal anti-inflammatory agents and, even more importantly, the development of drugs to enhance the host's natural immunity. PMID:3925785

  17. Selectable markers: antibiotic and herbicide resistance.

    PubMed

    Goodwin, Julia L; Pastori, Gabriela M; Davey, Michael R; Jones, Huw D

    2005-01-01

    The low efficiencies of most plant transformation methods necessitate the use of selectable marker genes to identify those cells that successfully integrate and express transferred DNA. Genes conferring resistance to various antibiotics or herbicides are commonly used in laboratory transformation research. They encode proteins that detoxify corresponding selection agents and allow the preferential growth of transformed cells. This chapter describes the application of two selection systems on the transformation of wheat. One is based on the nptII gene and corresponding aminoglycoside antibiotics, the other is based on the bar gene and corresponding glufosinate ammonium herbicides. PMID:15310922

  18. Ecological Application of Antibiotics as Respiratory Inhibitors of Bacterial Populations1

    PubMed Central

    Yetka, J. E.; Wiebe, W. J.

    1974-01-01

    Two terregenous and four marine bacterial isolates were treated with six antibiotics and antibiotic combinations. Comparisons made between responses of cells in early and late logarithmic and stationary growth phases indicated variable sensitivity to the agents. Bacteria in stationary and late log-phase cultures exhibited the greatest resistance, whereas the early log-phase cells exhibited greatest antibiotic susceptibility. We conclude that the tested antibiotics cannot be used for ecological purposes to delineate bacterial respiration in mixed microbial communities. PMID:4217588

  19. Antibiotic-Resistant Bacteria.

    ERIC Educational Resources Information Center

    Longenecker, Nevin E.; Oppenheimer, Dan

    1982-01-01

    A study conducted by high school advanced bacteriology students appears to confirm the hypothesis that the incremental administration of antibiotics on several species of bacteria (Escherichia coli, Staphylococcus epidermis, Bacillus sublitus, Bacillus megaterium) will allow for the development of antibiotic-resistant strains. (PEB)

  20. Setamycin, a new antibiotic.

    PubMed

    Omura, S; Otoguro, K; Nishikiori, T; Oiwa, R; Iwai, Y

    1981-10-01

    A new antibiotic, setamycin, was extracted from the mycelia of a rare actinomycete strain KM-6054. The antibiotic, the molecular formula of which was found to be C42H61NO12 (tentative), is a yellow powder showing activity against some fungi, trichomonads and weakly against Gram-positive bacteria. PMID:7309621

  1. The future of antibiotics.

    PubMed

    Spellberg, Brad

    2014-01-01

    Antibiotic resistance continues to spread even as society is experiencing a market failure of new antibiotic research and development (R&D). Scientific, economic, and regulatory barriers all contribute to the antibiotic market failure. Scientific solutions to rekindle R&D include finding new screening strategies to identify novel antibiotic scaffolds and transforming the way we think about treating infections, such that the goal is to disarm the pathogen without killing it or modulate the host response to the organism without targeting the organism for destruction. Future economic strategies are likely to focus on 'push' incentives offered by public-private partnerships as well as increasing pricing by focusing development on areas of high unmet need. Such strategies can also help protect new antibiotics from overuse after marketing. Regulatory reform is needed to re-establish feasible and meaningful traditional antibiotic pathways, to create novel limited-use pathways that focus on highly resistant infections, and to harmonize regulatory standards across nations. We need new antibiotics with which to treat our patients. But we also need to protect those new antibiotics from misuse when they become available. If we want to break the cycle of resistance and change the current landscape, disruptive approaches that challenge long-standing dogma will be needed. PMID:25043962

  2. Replacement for antibiotics: Lysozyme

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Antibiotics have been fed at subtherapeutic levels to swine as growth promoters for more than 60 years, and the majority of swine produced in the U.S. receive antibiotics in their feed at some point in their production cycle. These compounds benefit the producers by minimizing production losses by ...

  3. Aplyronine A, a potent antitumour macrolide of marine origin, and the congeners aplyronines B-H: chemistry and biology.

    PubMed

    Yamada, Kiyoyuki; Ojika, Makoto; Kigoshi, Hideo; Suenaga, Kiyotake

    2009-01-01

    Aplyronines A-H are cytotoxic macrolides isolated from the sea hare Aplysia kurodai. Aplyronine A is the major constituent among the aplyronines, and this review concentrates on the results of chemical and biological research into this natural product. The isolation, determination of stereostructure and enantioselective total synthesis of the aplyronines are covered, together with discussion of their antitumour activity and structure-activity relationships, and the three-dimensional X-ray structure of the actin-aplyronine A complex. PMID:19374121

  4. Antibiotic de-escalation.

    PubMed

    Masterton, Robert G

    2011-01-01

    Antibiotic de-escalation is a mechanism whereby the provision of effective initial antibiotic treatment is achieved while avoiding unnecessary antibiotic use that would promote the development of resistance. It is a key element within antimicrobial stewardship programs and treatment paradigms for serious sepsis. The embodiment of de-escalation is that based on microbiology results around the day 3 therapy point; the empiric antibiotic(s) that were started are stopped or reduced in number and/or narrowed in spectrum. Data are presented here which demonstrate that de-escalation is clinically effective and appropriate. However, the need for further studies, particularly in terms of realization of full benefits as well as implementation tools, is highlighted. De-escalation ought now to form a part of routine antimicrobial management, though how best to do it and the full breadth and scope of benefits remain to be identified. PMID:21144991

  5. Molecular design of hybrid tumour necrosis factor alpha with polyethylene glycol increases its anti-tumour potency.

    PubMed Central

    Tsutsumi, Y.; Kihira, T.; Tsunoda, S.; Kanamori, T.; Nakagawa, S.; Mayumi, T.

    1995-01-01

    This study was conducted to increase the anti-tumour potency and reduce the toxic side-effects of tumour necrosis factor alpha (TNF-alpha). Natural human TNF-alpha was chemically conjugated with monomethoxy polyethylene glycol (PEG) using succinimidyl coupling of lysine amino groups of TNF-alpha. The number-average molecular weight of PEG-modified TNF-alpha (PEG-TNF-alpha) increased with an increase in the reaction time and the initial molar ratio of PEG relative to TNF-alpha. The resulting modified TNF-alpha was separated into fractions of various molecular weights. The specific activity of separated PEG-TNF-alpha s relative to that of native TNF-alpha gradually decreased with an increase in the degree of PEG modification, but the plasma half-life was drastically increased with the increase in molecular weight of modified TNF-alpha. PEG-TNF-alpha s, in which 29% and 56% of lysine residues were coupled to PEG, had anti-tumour activity approximately 4 and 100 times greater than unmodified TNF-alpha in the murine Meth-A fibrosarcoma model. Extensive PEG modification did not increase its in vivo activity. A high dose of unmodified TNF-alpha induced toxic side-effects, but these were not observed with the modified TNF-alpha s. Optimal PEG modification of TNF-alpha markedly increased its bioavailability and may facilitate its potential anti-tumour therapeutic use. PMID:7734321

  6. Growth arrest vs direct cytotoxicity and the importance of molecular structure for the in vitro anti-tumour activity of ether lipids.

    PubMed Central

    Lohmeyer, M.; Workman, P.

    1995-01-01

    A panel of 25 different lipid agents was evaluated for in vitro activity against HT29 human colon carcinoma and HL60 promyelocytic leukaemia cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The structure-activity relationships seen with this series, including those for four sets of positional or stereoisomers, indicate that specific receptor proteins are unlikely as targets for anti-tumour lipid (ATL) action. Additional data confirm the lack of involvement of the platelet-activating factor receptor in particular and suggest that metabolic stability is a most important determinant of ATL activity. More detailed studies, with 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine (ET18-OCH3) and (+/-)-2-(Hydroxy[tetrahydro-2-(octadecyloxy)methylfuran-2- yl]methoxyphosphinyloxy)-N,N,N,-trimethylethaniminium hydroxide (SRI 62-834), suggest three different modes of activity, depending on drug concentration and exposure time. Low doses of up to 5 microM in standard serum-containing medium cause population growth arrest after prolonged exposure. Growth arrest was associated with a leaky G2/M block as determined by flow cytometry. These effects are reversible. Intermediate concentrations (5-40 microM) were cytotoxic, causing a net reduction in cell numbers after 2-3 days. At even higher concentrations, all lipids caused rapid, direct membrane lysis. When the clonogenic assay was used to assess the effects of ATLs, most agents reduced colony formation at concentrations above 5 microM. However, some compounds proved stimulatory at nanomolar concentrations, suggesting that they might possess mitogenic properties. These results, particularly those concerning the concentration and time dependence, may be relevant to current clinical trials with ether lipids. PMID:7640206

  7. Combination of essential oils and antibiotics reduce antibiotic resistance in plasmid-conferred multidrug resistant bacteria.

    PubMed

    Yap, Polly Soo Xi; Lim, Swee Hua Erin; Hu, Cai Ping; Yiap, Beow Chin

    2013-06-15

    In this study we investigated the relationship between several selected commercially available essential oils and beta-lactam antibiotics on their antibacterial effect against multidrug resistant bacteria. The antibacterial activity of essential oils and antibiotics was assessed using broth microdilution. The combined effects between essential oils of cinnamon bark, lavender, marjoram, tea tree, peppermint and ampicillin, piperacillin, cefazolin, cefuroxime, carbenicillin, ceftazidime, meropenem, were evaluated by means of the checkerboard method against beta-lactamase-producing Escherichia coli. In the latter assays, fractional inhibitory concentration (FIC) values were calculated to characterize interaction between the combinations. Substantial susceptibility of the bacteria toward natural antibiotics and a considerable reduction in the minimum inhibitory concentrations (MIC) of the antibiotics were noted in some paired combinations of antibiotics and essential oils. Out of 35 antibiotic-essential oil pairs tested, four of them showed synergistic effect (FIC≤0.5) and 31 pairs showed no interaction (FIC>0.5-4.0). The preliminary results obtained highlighted the occurrence of a pronounced synergistic relationship between piperacillin/cinnamon bark oil, piperacillin/lavender oil, piperacillin/peppermint oil as well as meropenem/peppermint oil against two of the three bacteria under study with a FIC index in the range 0.26-0.5. The finding highlighted the potential of peppermint, cinnamon bark and lavender essential oils being as antibiotic resistance modifying agent. Reduced usage of antibiotics could be employed as a treatment strategy to decrease the adverse effects and possibly to reverse the beta-lactam antibiotic resistance. PMID:23537749

  8. Solving the Antibiotic Crisis.

    PubMed

    Wright, Gerard D

    2015-02-13

    Antibiotics are essential for both treating and preventing infectious diseases. Paradoxically, despite their importance as pillars of modern medicine, we are in danger of losing antibiotics because of the evolution and dissemination of resistance mechanisms throughout all pathogenic microbes. This fact, coupled with an inability to bring new drugs to market at a pace that matches resistance, has resulted in a crisis of global proportion. Solving this crisis requires the actions of many stakeholders, but chemists, chemical biologists, and microbiologists must drive the scientific innovation that is required to maintain our antibiotic arsenal. This innovation requires (1) a deep understanding of the evolution and reservoirs of resistance; (2) full knowledge of the molecular mechanisms of antibiotic action and resistance; (3) the discovery of chemical and genetic probes of antibiotic action and resistance; (4) the integration of systems biology into antibiotic discovery; and (5) the discovery of new antimicrobial chemical matter. Addressing these pressing scientific gaps will ensure that we can meet the antibiotic crisis with creativity and purpose. PMID:27622298

  9. New antitumour agents with α,β-unsaturated δ-lactone scaffold: Synthesis and antiproliferative activity of (-)-cleistenolide and analogues.

    PubMed

    Benedeković, Goran; Kovačević, Ivana; Popsavin, Mirjana; Francuz, Jovana; Kojić, Vesna; Bogdanović, Gordana; Popsavin, Velimir

    2016-07-15

    A stereoselective total synthesis of (-)-cleistenolide (1) from d-glucose has been achieved. This new approach for the synthesis of (-)-cleistenolide and analogues involves a one-C-atom degradation of the chiral precursor, (Z)-selective Wittig olefination, followed by the final δ-lactonisation. Synthesized compounds showed potent growth inhibitory effects against selected human tumour cell lines, especially 2,4,6-trichlorobenzoyl derivative 12, which in the culture of MDA-MB 231 cells displayed the highest activity (IC50 0.02μM) of all compounds under evaluation. A preliminary SAR study reveals the structural features that are beneficial for antiproliferative activity of synthesized δ-lactones, such as presence of either electron-withdrawing or electron-donating substituents in the aromatic ring, as well as the presence of cinnamoyl functionality instead of benzoyl group at the O-7 position. PMID:27231128

  10. [Initial antibiotic therapy of neonatal sepsis].

    PubMed

    Jesić, Milos; Jesić, Maja; Maglajlić, Svjetlana; Lukac, Marija; Sindjić, Sanja; Vujović, Dragana; Grković, Slobodanka

    2004-10-01

    It is certain that in the past the types of bacterial agents responsible for neonatal sepsis and their sensitivity to antibiotics were not the same in all historical periods. However, the reports confirming the conclusion have been published only in the last three years. According to these facts, the bacterial causes of neonatal sepsis were analyzed in patients treated at the University children's hospital in Belgrade (S&M) as well as their sensitivity to antibiotics to determine the most effective initial therapy. Between January 2001 and June 2004, 35 neonates, aged from 1-30 days, with positive blood culture were treated. Gram-negative bacteria were the cause of sepsis in 57% of patients (Pseudomonas--20%, Klebsiella--20%, E. coli--8.5%, Acinetobacter--8.5%), gram-positive in 43% (coagulase-negative Staphylococci--14%, Staphylococcus epidermidis--14%, Staphylococcus aureus--9%, Streptococcus group B--3%, Listeria monocytogenes--3%). The bacteria were the most sensitive to carbapenems (85-89%), amikacin (68%), third-generation cephalosporins (47-50%), while the sensitivity to gentamicin was less than expected (48.5%). Sensitivity to ampicillin (8%) confirmed a high level of resistance to this antibiotic. All isolated Staphylococci were sensitive to vancomycin, and the overall methicillin resistance was 46%. Combined cefotaxime and amikacin therapy was the most effective of all suggested initial combinations of antibiotics (74%). The sensitivity to all other combinations of antibiotics was 51-71%. The most adequate initial combination of antibiotics for the treatment of neonatal sepsis is cefotaxime plus amikacin. The most adequate antibiotic for the treatment of nosocomial neonatal sepsis is carbapenem. PMID:15615466

  11. Antibiotics in development targeting protein synthesis.

    PubMed

    Sutcliffe, Joyce A

    2011-12-01

    The resolution of antibiotic-ribosomal subunit complexes and antibacterial-protein complexes at the atomic level has provided new insights into modifications of clinically relevant antimicrobials and provided new classes that target the protein cellular apparatus. New chemistry platforms that use fragment-based drug design or allow novel modifications in known structural classes are being used to design new antibiotics that overcome known resistance mechanisms and extend spectrum and potency by circumventing ubiquitous efflux pumps. This review provides details on seven antibiotics in development for treatment of moderate-to-severe community-acquired bacterial pneumonia and/or acute bacterial skin and skin structure infections: solithromycin, cethromycin, omadacycline, CEM-102, GSK1322322, radezolid, and tedizolid. Two antibiotics of the oxazolidinone class, PF-02341272 and AZD5847, are being developed as antituberculosis agents. Only three antibiotics that target the protein cellular machinery, TP-434, GSK2251052, and plazomicin, have a spectrum that encompasses multidrug-resistant Gram-negative pathogens. These compounds provide hope for treating key pathogens that cause serious disease in both the community and the hospital. PMID:22191530

  12. NIR-driven Smart Theranostic Nanomedicine for On-demand Drug Release and Synergistic Antitumour Therapy

    PubMed Central

    Zhao, Pengfei; Zheng, Mingbin; Luo, Zhenyu; Gong, Ping; Gao, Guanhui; Sheng, Zonghai; Zheng, Cuifang; Ma, Yifan; Cai, Lintao

    2015-01-01

    Smart nanoparticles (NPs) that respond to external and internal stimulations have been developing to achieve optimal drug release in tumour. However, applying these smart NPs to attain high antitumour performance is hampered by limited drug carriers and inefficient spatiotemporal control. Here we report a noninvasive NIR-driven, temperature-sensitive DI-TSL (DOX/ICG-loaded temperature sensitive liposomes) co-encapsulating doxorubicin (DOX) and indocyanine green (ICG). This theranostic system applies thermo-responsive lipid to controllably release drug, utilizes the fluorescence (FL) of DOX/ICG to real-time trace the distribution of NPs, and employs DOX/ICG to treat cancer by chemo/photothermal therapy. DI-TSL exhibits uniform size distribution, excellent FL/size stability, enhanced response to NIR-laser, and 3 times increased drug release through laser irradiation. After endocytosis by MCF-7 breast adenocarcinoma cells, DI-TSL in cellular endosomes can cause hyperthermia through laser irradiation, then endosomes are disrupted and DI-TSL ‘opens’ to release DOX simultaneously for increased cytotoxicity. Furthermore, DI-TSL shows laser-controlled release of DOX in tumour, enhanced ICG and DOX retention by 7 times and 4 times compared with free drugs. Thermo-sensitive DI-TSL manifests high efficiency to promote cell apoptosis, and completely eradicate tumour without side-effect. DI-TSL may provide a smart strategy to release drugs on demand for combinatorial cancer therapy. PMID:26400780

  13. Anti-tumour strategies aiming to target tumour-associated macrophages

    PubMed Central

    Tang, Xiaoqiang; Mo, Chunfen; Wang, Yongsheng; Wei, Dandan; Xiao, Hengyi

    2013-01-01

    Tumour-associated macrophages (TAMs) represent a predominant population of inflammatory cells that present in solid tumours. TAMs are mostly characterized as alternatively activated M2-like macrophages and are known to orchestrate nearly all stages of tumour progression. Experimental investigations indicate that TAMs contribute to drug-resistance and radio-protective effects, and clinical evidence shows that an elevated number of TAMs and their M2 profile are correlated with therapy failure and poor prognosis in cancer patients. Recently, many studies on TAM-targeted strategies have made significant progress and some pilot works have achieved encouraging results. Among these, connections between some anti-tumour drugs and their influence on TAMs have been suggested. In this review, we will summarize recent advances in TAM-targeted strategies for tumour therapy. Based on the proposed mechanisms, those strategies are grouped into four categories: (i) inhibiting macrophage recruitment; (ii) suppressing TAM survival; (iii) enhancing M1-like tumoricidal activity of TAMs; (iv) blocking M2-like tumour-promoting activity of TAMs. It is desired that further attention be drawn to this research field and more effort be made to promote TAM-targeted tumour therapy. PMID:23113570

  14. NIR-driven Smart Theranostic Nanomedicine for On-demand Drug Release and Synergistic Antitumour Therapy

    NASA Astrophysics Data System (ADS)

    Zhao, Pengfei; Zheng, Mingbin; Luo, Zhenyu; Gong, Ping; Gao, Guanhui; Sheng, Zonghai; Zheng, Cuifang; Ma, Yifan; Cai, Lintao

    2015-09-01

    Smart nanoparticles (NPs) that respond to external and internal stimulations have been developing to achieve optimal drug release in tumour. However, applying these smart NPs to attain high antitumour performance is hampered by limited drug carriers and inefficient spatiotemporal control. Here we report a noninvasive NIR-driven, temperature-sensitive DI-TSL (DOX/ICG-loaded temperature sensitive liposomes) co-encapsulating doxorubicin (DOX) and indocyanine green (ICG). This theranostic system applies thermo-responsive lipid to controllably release drug, utilizes the fluorescence (FL) of DOX/ICG to real-time trace the distribution of NPs, and employs DOX/ICG to treat cancer by chemo/photothermal therapy. DI-TSL exhibits uniform size distribution, excellent FL/size stability, enhanced response to NIR-laser, and 3 times increased drug release through laser irradiation. After endocytosis by MCF-7 breast adenocarcinoma cells, DI-TSL in cellular endosomes can cause hyperthermia through laser irradiation, then endosomes are disrupted and DI-TSL ‘opens’ to release DOX simultaneously for increased cytotoxicity. Furthermore, DI-TSL shows laser-controlled release of DOX in tumour, enhanced ICG and DOX retention by 7 times and 4 times compared with free drugs. Thermo-sensitive DI-TSL manifests high efficiency to promote cell apoptosis, and completely eradicate tumour without side-effect. DI-TSL may provide a smart strategy to release drugs on demand for combinatorial cancer therapy.

  15. Antitumour Effects of Isocurcumenol Isolated from Curcuma zedoaria Rhizomes on Human and Murine Cancer Cells

    PubMed Central

    Lakshmi, S.; Padmaja, G.; Remani, P.

    2011-01-01

    Curcuma zedoaria belonging to the family Zingiberaceae has been used in the traditional system of medicine in India and Southwest Asia in treating many human ailments and is found to possess many biological activities. The rationale of the present study was to isolate, identify, and characterize antitumour principles from the rhizomes of Curcuma zedoaria, to assess its cytotoxic effects on human and murine cancer cells, to determine its apoptosis inducing capacity in cancer cells, and to evaluate its tumour reducing properties in in vivo mice models. Isocurcumenol was characterized as the active compound by spectroscopy and was found to inhibit the proliferation of cancer cells without inducing significant toxicity to the normal cells. Fluorescent staining exhibited the morphological features of apoptosis in the compound-treated cancer cells. In vivo tumour reduction studies revealed that a dose of 35.7 mg/kg body weight significantly reduced the ascitic tumour in DLA-challenged mice and increased the lifespan with respect to untreated control mice.

  16. Pre-clinical antitumour evaluation of Biphosphinic Palladacycle Complex in human leukaemia cells.

    PubMed

    Oliveira, Carlos R; Barbosa, Christiano M V; Nascimento, Fábio D; Lanetzki, Camilla S; Meneghin, Marília B; Pereira, Flávia E G; Paredes-Gamero, Edgar J; Ferreira, Alice T; Rodrigues, Tiago; Queiroz, Mary L S; Caires, Antonio C F; Tersariol, Ivarne L S; Bincoletto, Claudia

    2009-02-12

    Previous studies reported by our group have introduced a new antitumoural drug called Biphosphinic Palladacycle Complex (BPC). In this paper we show that BPC causes apoptosis in leukaemia cells (HL60 and Jurkat), but not in normal human lymphocytes. IC(50) values obtained for both cell lines using the MTT and trypan blue exclusion assays 5h after BPC treatment were lower than 8.0 microM. Using metachromatic fluorophore, acridine orange, we observed that BPC elicited lysosomal rupture of leukaemic cells. Furthermore, BPC triggered caspase-3 and caspase-6 activation and apoptosis in cell lines, inducing chromatin condensation, apoptotic bodies, and DNA fragmentation. Interestingly, the lysosomal cathepsin B inhibitor CA074 markedly decreased BPC-induced caspase-3 and caspase-6 activation as well as cell death. Lysosomal BPC-induced membrane destabilisation was not dependent on reactive oxygen species generation, which was consistent with the absence of cellular HL60 and Jurkat membrane lipid peroxidation. We conclude that, following BPC treatment, lysosomal membrane rupture precedes cell death and the apoptotic signalling pathway is initiated by the release of cathepsin B in the cytoplasm of leukaemia cells. As no toxic effects for human lymphocytes were observed, we suggest that BPC is more selective for transformed cells, mainly due to their exacerbated lysosome expression. PMID:19026616

  17. Administration of DNA Encoding the Interleukin-27 Gene Augments Antitumour Responses through Non-adaptive Immunity.

    PubMed

    Li, Q; Sato, A; Shimozato, O; Shingyoji, M; Tada, Y; Tatsumi, K; Shimada, H; Hiroshima, K; Tagawa, M

    2015-10-01

    DNA-mediated immunization of a tumour antigen is a possible immunotherapy for cancer, and interleukin (IL)-27 has diverse functions in adaptive immunity. In this study, we examined whether IL-27 DNA administration enhanced antitumour effects in mice vaccinated with DNA encoding a putative tumour antigen, β-galactosidase (β-gal). An intramuscular injection of cardiotoxin before DNA administration facilitated the exogenous gene expression. In mice received β-gal and IL-27 DNA, growth of β-gal-positive P815 tumours was retarded and survival of the mice was prolonged. Development of β-gal-positive Colon 26 tumours was suppressed by vaccination of β-gal DNA and further inhibited by additional IL-27 DNA administration or IL-12 family cytokines. Nevertheless, a population of β-gal-specific CD8(+) T cells did not increase, and production of anti-β-gal antibody was not enhanced by IL-27 DNA administration. Spleen cells from mice bearing IL-27-expressing Colon 26 tumours showed greater YAC-1-targeted cytotoxicity although CD3(-)/DX5(+) natural killer (NK) cell numbers remained unchanged. Recombinant IL-27 enhanced YAC-1-targeted cytotoxicity of IL-2-primed splenic NK cells and augmented a phosphorylation of signal transducer and activator of transcription 3 and an expression of perforin. These data collectively indicate that IL-27 DNA administration activates NK cells and augments vaccination effects of DNA encoding a tumour antigen through non-adaptive immune responses. PMID:26095954

  18. The role of healthcare strategies in controlling antibiotic resistance.

    PubMed

    Aziz, Ann-Marie

    In an interview in March 2013, the Chief Medical Officer described antibiotic resistance as a 'ticking time bomb' and ranked it along with terrorism on a list of threats to the nation. Her report Infections and the Rise of Antimicrobial Resistance (Department of Health, 2011) highlighted that, while a new infectious disease has been discovered nearly every year over the past three decades, there have been very few new antibiotics developed, leaving our armoury nearly empty. Antibiotic resistance is a universal problem that needs to be tackled by a wide variety of strategies and players. Our approach to tackling resistance to antibiotic agents must therefore also be dynamic. As well as reducing environmental use, we also need to lower antibiotic use in the healthcare setting. Healthcare workers have a huge role to play in combating antibiotic resistance. This article focuses on several issues related to antibiotic resistance, including antibiotic modes of action and the properties that confer resistance on bacteria. It includes information on antibiotic usage and describes current healthcare strategies we can adopt to help reduce the development of resistance. PMID:24121851

  19. [Antibiotic resistance--bacteria fight back].

    PubMed

    Tambić Andrasević, Arjana

    2004-01-01

    Antibiotic resistance has become one of the leading problems in modern medicine. Resistance to antibiotics emerges in bacteria due to genetic mutations and consecutive selection of resistant mutants through selective pressure of antibiotics present in large amounts in soil, plants, animals and humans. Exchange of genetic material coding for resistance is possible even between unrelated organisms and further promotes the spread of resistance. Constantly evolving resistance mechanisms force experts to redefine breakpoint concentrations and interpretation of in vitro antibiotic sensitivity testing. Developing new antimicrobial agents does not seem to be enough to keep up pace with ever changing bacteria. Using antibiotics prudently and developing new approaches to the treatment of infections is vital for the future. The European Antimicrobial Resistance Surveillance System (EARSS) data clearly show that Scandinavian countries and The Netherlands have the lowest rates of resistance, while Southern and Eastern European countries have the highest prevalence of resistance. This is linked to the European Surveillance of Antimicrobial Consumption (ESAC) data that show very low consumption of antibiotics in Scandinavian countries and The Netherlands. Compliance with strict infection control policies related to multidrug resistant organisms is also high in these countries. Although it is important to be aware of the resistance problems worldwide, rational use of antibiotics should be based on the knowledge of local resistance patterns in common pathogens. Since 1996 there is a continuous surveillance of resistance in Croatia through the Croatian Committee for Antibiotic Resistance Surveillance. There is a particular concern about the rising penicillin and macrolide resistance in pneumococci. In Croatia, data for 2002 suggest that resistance to penicillin in pneumococci was 30% (low level) and 2% (high level). Among invasive isolates, 19% had reduced susceptibility to

  20. Handling Time-dependent Variables: Antibiotics and Antibiotic Resistance.

    PubMed

    Munoz-Price, L Silvia; Frencken, Jos F; Tarima, Sergey; Bonten, Marc

    2016-06-15

    Elucidating quantitative associations between antibiotic exposure and antibiotic resistance development is important. In the absence of randomized trials, observational studies are the next best alternative to derive such estimates. Yet, as antibiotics are prescribed for varying time periods, antibiotics constitute time-dependent exposures. Cox regression models are suited for determining such associations. After explaining the concepts of hazard, hazard ratio, and proportional hazards, the effects of treating antibiotic exposure as fixed or time-dependent variables are illustrated and discussed. Wider acceptance of these techniques will improve quantification of the effects of antibiotics on antibiotic resistance development and provide better evidence for guideline recommendations. PMID:27025824

  1. Targeting Antibiotic Resistance.

    PubMed

    Chellat, Mathieu F; Raguž, Luka; Riedl, Rainer

    2016-06-01

    Finding strategies against the development of antibiotic resistance is a major global challenge for the life sciences community and for public health. The past decades have seen a dramatic worldwide increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. More and more infections caused by resistant microorganisms fail to respond to conventional treatment, and in some cases, even last-resort antibiotics have lost their power. In addition, industry pipelines for the development of novel antibiotics have run dry over the past decades. A recent world health day by the World Health Organization titled "Combat drug resistance: no action today means no cure tomorrow" triggered an increase in research activity, and several promising strategies have been developed to restore treatment options against infections by resistant bacterial pathogens. PMID:27000559

  2. Colds and flus - antibiotics

    MedlinePlus

    Antibiotics - colds and flu ... treat infections that are caused by a virus. Colds and flu are caused by viruses. If you ... Hamilton A. Treatments for symptoms of the common cold. Am Fam Physician. 2013;88(12):Online. PMID: ...

  3. Antibiotic / Antimicrobial Resistance Glossary

    MedlinePlus

    ... on the Farm Get Smart About Antibiotics Week File Formats Help: How do I view different file formats (PDF, DOC, PPT, MPEG) on this site? Adobe PDF file Microsoft PowerPoint file Microsoft Word file Microsoft Excel ...

  4. [Prophylactic antibiotics in neurosurgery].

    PubMed

    Iacob, G; Iacob, Simona; Cojocaru, Inimioara

    2007-01-01

    Because of a low risk of infection (around 2-3%), prophylactic use of antibiotics in neurosurgery is a controversial issue. Some neurosurgeons consider that there are strong arguments against the use of antimicrobials (promotion of antibiotic-resistant strains of bacteria, superinfection and adverse drug reactions) and meticulous aseptic techniques could be more usefully than prophylactic antibiotics. On the other hand, despite of being rare, the consequences of a neurosurgical infection can be dramatic and may result in a rapid death, caused by meningitis, cerebritis, abscess formation or sepsis. Clinical studies emphasized that the most important factors influencing the choice of antibiotic prophylaxis in neurosurgery is the patient's immune status, virulence of the pathogens and the type of surgery ("clean contaminated"--procedure that crosses the cranial sinuses, "clean non-implant"--procedure that does not cross the cranial sinuses, CSF shunt surgery, skull fracture). Prophylaxis has become the standard of care for contaminated and clean-contaminated surgery, also for surgery involving insertion of artificial devices. The antibiotic (first/second generation of cephalosporins or vancomycin in allergic patients) should recover only the cutaneous possibly contaminating flora (S. aureus, S. epidermidis) and should be administrated 30' before the surgical incision, intravenously in a single dose. Most studies pointed that identification of the risk factors for infections, correct asepsis and minimal prophylactic antibiotic regimen, help neurosurgeons to improve patient care and to decrease mortality without selecting resistant bacteria. PMID:18293694

  5. [The history of antibiotics].

    PubMed

    Yazdankhah, Siamak; Lassen, Jørgen; Midtvedt, Tore; Solberg, Claus Ola

    2013-12-10

    The development of chemical compounds for the treatment of infectious diseases may be divided into three phases: a) the discovery in the 1600s in South America of alkaloid extracts from the bark of the cinchona tree and from the dried root of the ipecacuanha bush, which proved effective against, respectively, malaria (quinine) and amoebic dysentery (emetine); b) the development of synthetic drugs, which mostly took place in Germany, starting with Paul Ehrlich's (1854-1915) discovery of salvarsan (1909), and crowned with Gerhard Domagk's (1895-1964) discovery of the sulfonamides (1930s); and c) the discovery of antibiotics. The prime example of the latter is the development of penicillin in the late 1920s following a discovery by a solitary research scientist who never worked in a team and never as part of a research programme. It took another ten years or so before drug-quality penicillin was produced, with research now dependent on being conducted in large collaborative teams, frequently between universities and wealthy industrial companies. The search for new antibiotics began in earnest in the latter half of the 1940s and was mostly based on soil microorganisms. Many new antibiotics were discovered in this period, which may be termed «the golden age of antibiotics». Over the past three decades, the development of new antibiotics has largely stalled, while antibiotic resistance has increased. This situation may require new strategies for the treatment of infectious diseases. PMID:24326504

  6. Adverse antibiotic drug interactions.

    PubMed

    Bint, A J; Burtt, I

    1980-07-01

    There is enormous potential for drug interactions in patients who, today, often receive many drugs. Antibiotics are prominent amongst the groups of drugs commonly prescribed. Many interactions take place at the absorption stage. Antacids and antidiarrhoeal preparations, in particular, can delay and reduce the absorption of antibiotics such as tetracyclines and clindamycin, by combining with them in the gastrointestinal tract to form chelates or complexes. Other drugs can affect gastric motility, which in turn often controls the rate at which antibiotics are absorbed. Some broad spectrum antibiotics can alter the bacterial flora of the gut which may be related to malabsorption states. The potentiation of toxic side effects of one drug by another is a common type of interaction. Antibiotics which are implicated in this type of interaction are those which themselves possess some toxicity such as aminoglycosides, some cephalosporins, tetracyclines and colistin. Some of the most important adverse interactions with antibiotics are those which involve other drugs which have a low toxicity/efficacy ratio. These include anticoagulants such as warfarin, anticonvulsants such as phenytoin and phenobarbitone and oral antidiabetic drugs like tolbutamide. Risk of interaction arises when the metabolism of these drugs is inhibited by liver microsomal enzyme inhibitors such as some sulphonamides and chloramphenicol, or is enhanced by enzyme inducers such as rifampicin. PMID:6995091

  7. Biosynthesis of enediyne antitumor antibiotics.

    PubMed

    Van Lanen, Steven G; Shen, Ben

    2008-01-01

    The enediyne polyketides are secondary metabolites isolated from a variety of Actinomycetes. All members share very potent anticancer and antibiotic activity, and prospects for the clinical application of the enediynes has been validated with the recent marketing of two enediyne derivatives as anticancer agents. The biosynthesis of these compounds is of interest because of the numerous structural features that are unique to the enediyne family. The gene cluster for five enediynes has now been cloned and sequenced, providing the foundation to understand natures' means to biosynthesize such complex, exotic molecules. Presented here is a review of the current progress in delineating the biosynthesis of the enediynes with an emphasis on the model enediyne, C-1027. PMID:18397168

  8. Retapamulin: a newer topical antibiotic.

    PubMed

    Dhingra, D; Parakh, A; Ramachandran, S

    2013-01-01

    Impetigo is a common childhood skin infection. There are reports of increasing drug resistance to the currently used topical antibiotics including fusidic acid and mupirocin. Retapamulin is a newer topical agent of pleuromutilin class approved by the Food and Drug Administration for treatment of impetigo in children and has been recently made available in the Indian market. It has been demonstrated to have low potential for the development of antibacterial resistance and a high degree of potency against poly drug resistant Gram-positive bacteria found in skin infections including Staphylococcus aureus strains. The drug is safe owing to low systemic absorption and has only minimal side-effect of local irritation at the site of application. PMID:23793314

  9. Strategies to Minimize Antibiotic Resistance

    PubMed Central

    Lee, Chang-Ro; Cho, Ill Hwan; Jeong, Byeong Chul; Lee, Sang Hee

    2013-01-01

    Antibiotic resistance can be reduced by using antibiotics prudently based on guidelines of antimicrobial stewardship programs (ASPs) and various data such as pharmacokinetic (PK) and pharmacodynamic (PD) properties of antibiotics, diagnostic testing, antimicrobial susceptibility testing (AST), clinical response, and effects on the microbiota, as well as by new antibiotic developments. The controlled use of antibiotics in food animals is another cornerstone among efforts to reduce antibiotic resistance. All major resistance-control strategies recommend education for patients, children (e.g., through schools and day care), the public, and relevant healthcare professionals (e.g., primary-care physicians, pharmacists, and medical students) regarding unique features of bacterial infections and antibiotics, prudent antibiotic prescribing as a positive construct, and personal hygiene (e.g., handwashing). The problem of antibiotic resistance can be minimized only by concerted efforts of all members of society for ensuring the continued efficiency of antibiotics. PMID:24036486

  10. Antibiotic therapy for ocular infection.

    PubMed Central

    Snyder, R W; Glasser, D B

    1994-01-01

    Infections of the eye can rapidly damage important functional structures and lead to permanent vision loss or blindness. Broad-spectrum antibiotics should be administered to the appropriate site of infection as soon as a diagnosis is made. Topical drops are preferred for corneal and conjunctival infections. Intravitreal antibiotics, and possibly subconjunctival and parenteral antibiotics, are preferred for endophthalmitis. Parenteral antibiotics are recommended for infection in deep adnexal structures. We review specific aspects of antibiotic therapy for ocular and periocular infection. PMID:7856158

  11. Gold(I) chloride adducts of 1,3-bis(di-2-pyridylphosphino)propane: synthesis, structural studies and antitumour activity

    SciTech Connect

    Humphreys, Anthony S.; Filipovska, Aleksandra; Berners-Price, Susan J.; Koutsantonis, George A.; Skelton, Brian W.; White, Allan H.

    2008-06-30

    The novel water soluble bidentate phosphine ligand 1,3-bis(di-2-pyridylphosphino)propane (d2pypp) has been synthesized by a convenient route involving treatment of 2-pyridyllithium with Cl{sub 2}P(CH{sub 2}){sub 3}PCl{sub 2} and isolation in crystalline form as the hydrochloride salt. The synthesis of the precursor Cl{sub 2}P(CH{sub 2}){sub 3}PCl{sub 2} has been optimized by the use of triphosgene as the chlorinating agent. The 2:1 and 1:2 AuCl:d2pypp adducts have been synthesized and characterized by NMR spectroscopy and single crystal X-ray studies, and shown to be of the form (AuCl){sub 2}({mu}-d2pypp-P,P{prime}) and Au(d2pypp-P,P{prime}){sub 2}Cl(-3.75H{sub 2}O), respectively. The latter is more lipophilic than analogous 1:2 adducts of gold(I) chloride with the diphosphine ligands 1,2-bis(di-n-pyridylphosphino)ethane (dnpype) for n = 2, 3 and 4, based on measurement of the n-octanol-water partition coefficient (log P = -0.46). A single crystal structure determination of the 1:2 Au(I) complex of the 3-pyridyl ethane ligand shows it to be of the form [Au(d3pype-P,P{prime}){sub 2}]Cl {center_dot} 5H{sub 2}O. The in vitro cytotoxic activity of [Au(d2pypp){sub 2}]Cl was assessed in human normal and cancer breast cells and selective toxicity to the cancer cells found. The significance of these results to the antitumour properties of chelated 1:2 Au(I) diphosphine complexes is discussed.

  12. Pharmacokinetics, pharmacological and anti-tumour effects of the specific anti-oestrogen ICI 182780 in women with advanced breast cancer.

    PubMed Central

    Howell, A.; DeFriend, D. J.; Robertson, J. F.; Blamey, R. W.; Anderson, L.; Anderson, E.; Sutcliffe, F. A.; Walton, P.

    1996-01-01

    We have assessed the pharmacokinetics, pharmacological and anti-tumour effects of the specific steroidal anti-oestrogen ICI 182780 in 19 patients with advanced breast cancer resistant to tamoxifen. The agent was administered as a monthly depot intramuscular injection. Peak levels of ICI 182780 occurred a median of 8-9 days after dosing and then declined but were above the projected therapeutic threshold at day 28. Cmax during the first month was 10.5 ng/ml-1 and during the sixth month was 12.6 ng ml-1. The AUCs were 140.5 and 206.8 ng day ml-1 on the first and sixth month of dosing respectively, suggesting some drug accumulation. Luteinising hormone (LH) and follicle-stimulating hormone (FSH) levels rose after withdrawal of tamoxifen and then plateaued, suggesting no effect of ICI 182780 on the pituitary-hypothalamic axis. There were no significant changes in serum levels of prolactin, sex hormone-binding globulin (SHBG) or lipids. Side-effects were infrequent. Hot-flushes and sweats were not induced and there was no apparent effect of treatment upon the endometrium or vagina. Thirteen (69%) patients responded (seven had partial responses and six showed "no change' responses) to ICI 182780, after progression on tamoxifen, for a median duration of 25 months. Thus ICI 182780, given by monthly depot injection, and at the drug levels described, is an active second-line anti-oestrogen without apparent negative effects on the liver, brain or genital tract and warrants further evaluation in patients with advanced breast cancer. PMID:8688341

  13. Strategies for appropriate antibiotic use in intensive care unit

    PubMed Central

    da Silva, Camila Delfino Ribeiro; Silva, Moacyr

    2015-01-01

    The comsumption of antibiotics is high, mainly in intensive care units. Unfortunately, most are inappropriately used leading to increased multi-resistant bacteria. It is well known that initial empirical therapy with broad-spectrum antibiotics reduce mortality rates. However the prolonged and irrational use of antimicrobials may also increase the risk of toxicity, drug interactions and diarrhea due to Clostridium difficile. Some strategies to rational use of antimicrobial agents include avoiding colonization treatment, de-escalation, monitoring serum levels of the agents, appropriate duration of therapy and use of biological markers. This review discusses the effectiveness of these strategies, the importance of microbiology knowledge, considering there are agents resistant to Staphylococcus aureus and Klebsiella pneumoniae, and reducing antibiotic use and bacterial resistance, with no impact on mortality. PMID:26132360

  14. The Clinical Relevance of Antibiotic Resistance: Thirteen Principles That Every Dermatologist Needs to Consider When Prescribing Antibiotic Therapy.

    PubMed

    Del Rosso, James Q; Zeichner, Joshua A

    2016-04-01

    Antibiotics are commonly used by dermatologists in clinical practice, primarily because of the overall track record of favorable efficacy and safety with the most commonly used agents. During the past decade, increased attention has been given to the problems associated with antibiotic resistance. This article summarizes important principles gleaned from the continued efforts of the Scientific Panel on Antibiotic Use in Dermatology; other groups working diligently in this area, such as the Centers for Disease Control and Prevention and the Canadian Antimicrobial Resistance Alliance; and from the published literature. PMID:27015776

  15. Pharmacology and antitumour effects of intraportal pirarubicin on experimental liver metastases.

    PubMed Central

    Ramirez, L. H.; Munck, J. N.; Bognel, C.; Zhao, Z.; Ardouin, P.; Poupon, M. F.; Gouyette, A.; Rougier, P.

    1993-01-01

    Early liver metastases have a predominant portal blood supply. Intraportal (i.port.) vein administration of cytotoxics could theoretically achieve enhanced drug concentrations in tumour cells and be effective as adjuvant therapy after resection of colorectal carcinoma. Pirarubicin (which has a higher hepatic extraction than doxorubicin) was investigated on liver metastases of the VX2 rabbit tumour, which were of less than 2 mm in diameter 7 days after cells injection into the portal vein. To evaluate antitumour activity, 24 rabbits were randomised into three groups 7 days after implantation: (a) control, (b) i.v. pirarubicin, (c) i.port. pirarubicin at doses of 2 mg kg-1 in both groups. Portal infusions led to no hematological or hepatic toxicity. Pharmacokinetic parameters showed a significantly reduced systemic exposure after i.port. administration. Fourteen days after treatment, livers and lungs were analysed. The mean number (+/- s.d.) of tumour foci was (a) 8.62 (+/- 5.4), (b) 4.62 (+/- 3.2), (c) 2.25 (+/- 1.4) (P < 0.05 a vs c). The mean tumour area was (a) 6.31 (+/- 6.1), (b) 1.31 (+/- 2.2), (c) 0.43 (+/- 0.4 cm2) (P < 0.05 a vs c) and the percentage (95% C.I.) of rabbits with lung metastasis was: (a) 87.5% (47-99%), (b) 75% (35-97%), (c) 12.5% (3-52%) (P < 0.02 b vs c). Intraportal pirarubicin seems to be well tolerated and more efficient than i.v. administration, particularly in preventing extrahepatic dissemination. Images Figure 2 PMID:8347482

  16. Systemic anti-tumour effects of local thermally sensitive liposome therapy

    PubMed Central

    Viglianti, Benjamin L.; Dewhirst, Mark W.; Boruta, R.J.; Park, Ji-Young; Landon, Chelsea; Fontanella, Andrew N.; Guo, Jing; Manzoor, Ashley; Hofmann, Christina L.; Palmer, Gregory M.

    2015-01-01

    Purpose There were two primary objectives of this study: (1) to determine whether treatment of a tumour site with systemically administered thermally sensitive liposomes and local hyperthermia (HT) for triggered release would have dual anti-tumour effect on the primary heated tumour as well as an unheated secondary tumour in a distant site, and (2) to determine the ability of non-invasive optical spectroscopy to predict treatment outcome. The optical end points studied included drug levels, metabolic markers flavin adenine dinucleotide (FAD), nicotinamide adenine dinucleotide phosphate (NAD(P)H), and physiological markers (total haemoglobin (Hb) and Hb oxygen saturation) before and after treatment. Materials and methods Mice were inoculated with SKOV3 human ovarian carcinoma in both hind legs. One tumour was selected for local hyperthermia and subsequent systemic treatment. There were four treatment groups: control, DOXIL® (non-thermally sensitive liposomes containing doxorubicin), and two different thermally sensitive liposome formulations containing doxorubicin. Optical spectroscopy was performed prior to therapy, immediately after treatment, and 6, 12, and 24 h post therapy. Results Tumour growth delay was seen with DOXIL and the thermally sensitive liposomes in the tumours that were heated, similar to previous studies. Tumour growth delay was also seen in the opposing tumour in the thermally sensitive liposome-treated groups. Optical spectroscopy demonstrated correlation between growth delay, doxorubicin (DOX) levels, and changes of NAD(P)H from baseline levels. Hb and Hb saturation were not correlated with growth delay. Discussion The study demonstrated that thermally sensitive liposomes affect the primary heated tumour as well as systemic efficacy. Non-invasive optical spectroscopy methods were shown to be useful in predicting efficacy at early time points post-treatment. PMID:25164143

  17. Enhanced antitumour drug delivery to cholangiocarcinoma through the apical sodium-dependent bile acid transporter (ASBT).

    PubMed

    Lozano, Elisa; Monte, Maria J; Briz, Oscar; Hernández-Hernández, Angel; Banales, Jesus M; Marin, Jose J G; Macias, Rocio I R

    2015-10-28

    Novel antitumour drugs, such as cationic tyrosine kinase inhibitors, are useful in many types of cancer but not in others, such as cholangiocarcinoma (CCA), where their uptake through specific membrane transporters, such as OCT1, is very poor. Here we have investigated the usefulness of targeting cytostatic bile acid derivatives to enhance the delivery of chemotherapy to tumours expressing the bile acid transporter ASBT and whether this is the case for CCA. The analysis of paired samples of CCA and adjacent non-tumour tissue collected from human (n=15) and rat (n=29) CCA revealed that ASBT expression was preserved. Moreover, ASBT was expressed, although at different levels, in human and rat CCA cell lines. Both cells in vitro and rat tumours in vivo were able to carry out efficient uptake of bile acid derivatives. Using Bamet-UD2 (cisplatin-ursodeoxycholate conjugate) as a model ASBT-targeted drug, in vitro and in vivo antiproliferative activity was evaluated. ASBT expression enhanced the sensitivity to Bamet-UD2, but not to cisplatin, in vitro. In nude mice, Bamet-UD2 (more than cisplatin) inhibited the growth of human colon adenocarcinoma tumours with induced stable expression of ASBT. As compared with cisplatin, administration of Bamet-UD2 to rats with CCA resulted in an efficient liver and tumour uptake but low exposure of extrahepatic tissues to the drug. Consequently, signs of liver/renal toxicity were absent in animals treated with Bamet-UD2. In conclusion, endogenous or induced ASBT expression may be useful in pharmacological strategies to treat enterohepatic tumours based on the use of cytostatic bile acid derivatives. PMID:26278512

  18. Targeting ALCAM in the cryo-treated tumour microenvironment successfully induces systemic anti-tumour immunity.

    PubMed

    Kudo-Saito, Chie; Fuwa, Takafumi; Kawakami, Yutaka

    2016-07-01

    Cryoablative treatment has been widely used for treating cancer. However, the therapeutic efficacies are still controversial. The molecular mechanisms of the cryo-induced immune responses, particularly underlying the ineffectiveness, remain to be fully elucidated. In this study, we identified a new molecular mechanism involved in the cryo failure. We used cryo-ineffective metastatic tumour models that murine melanoma B16-F10 cells were subcutaneously and intravenously implanted into C57BL/6 mice. When the subcutaneous tumours were treated cryoablation on day 7 after tumour implantation, cells expressing activated leucocyte cell adhesion molecule (ALCAM/CD166) were significantly expanded not only locally in the treated tumours but also systemically in spleen and bone marrow of the mice. The cryo-induced ALCAM(+) cells including CD45(-) mesenchymal stem/stromal cells, CD11b(+)Gr1(+) myeloid-derived suppressor cells, and CD4(+)Foxp3(+) regulatory T cells significantly suppressed interferon γ production and cytotoxicity of tumour-specific CD8(+) T cells via ALCAM expressed in these cells. This suggests that systemic expansion of the ALCAM(+) cells negatively switches host-immune directivity to the tumour-supportive mode. Intratumoural injection with anti-ALCAM blocking monoclonal antibody (mAb) following the cryo treatment systemically induced tumour-specific CD8(+) T cells with higher cytotoxic activities, resulting in suppression of tumour growth and metastasis in the cryo-resistant tumour models. These suggest that expansion of ALCAM(+) cells is a determinant of limiting the cryo efficacy. Further combination with an immune checkpoint inhibitor anti-CTLA4 mAb optimized the anti-tumour efficacy of the dual-combination therapy. Targeting ALCAM may be a promising strategy for overcoming the cryo ineffectiveness leading to the better practical use of cryoablation in clinical treatment of cancer. PMID:27208904

  19. Antibiotic resistance of gram-negative enteric bacteria from pigs in three herds with different histories of antibiotic exposure.

    PubMed Central

    Gellin, G; Langlois, B E; Dawson, K A; Aaron, D K

    1989-01-01

    The antibiotic resistance patterns of gram-negative fecal bacteria from pigs in three herds with different histories of antibiotic exposure were examined. In general, smaller proportions of antibiotic-resistant or multiply resistant fecal isolates (P less than 0.05) were obtained from pigs in a herd not exposed to antimicrobial agents for 154 months than from pigs in a herd continuously exposed to antimicrobial agents at subtherapeutic doses or from pigs in a herd exposed only to therapeutic doses of antimicrobial agents. The proportions of antibiotic-resistant and multiply resistant strains were greater among isolates from pigs in the therapeutic herd than in the non-antibiotic-exposed herd (P less than 0.05). The proportion of antibiotic-resistant isolates in the non-lactose-fermenting population was greater than that in the lactose-fermenting population, regardless of herd. The results suggest that any form of antimicrobial exposure will increase the prevalence of antimicrobial resistance and multiple resistance of fecal bacteria. PMID:2802608

  20. Antibiotics, Acne, and Staphylococcus aureus Colonization

    PubMed Central

    Fanelli, Matthew; Kupperman, Eli; Lautenbach, Ebbing; Edelstein, Paul H.; Margolis, David J.

    2011-01-01

    Objectives To determine the frequency of Staphylococcus aureus colonization among patients with acne and to compare the susceptibility patterns between the patients who are using antibiotics and those who are not using antibiotics. Design Survey (cross-sectional) study of patients treated for acne. Setting Dermatology outpatient office practice Participants The study included 83 patients who were undergoing treatment and evaluation for acne. Main Outcome Measure Colonization of the nose or throat with S aureus. Results A total of 36 of the 83 participants (43%) were colonized with S aureus. Two of the 36 patients (6%) had methicillin-resistant S aureus; 20 (56%) had S aureus solely in their throat; 9 (25%) had S aureus solely in their nose; and 7 (19%) had S aureus in both their nose and their throat. When patients with acne who were antibiotic users were compared with nonusers, the prevalence odds ratio for the colonization of S aureus was 0.16 (95% confidence interval [CI], 0.08–1.37) after 1 to 2 months of exposure and increased to 0.52 (95% CI, 0.12–2.17) after 2 months of exposure (P =.31). Many of the S aureus isolates were resistant to treatment with clindamycin and erythromycin (40% and 44%, respectively), particularly the nasal isolates. Very few showed resistance rates (<10%) to treatment with tetracycline antibiotics. Conclusion Unlike current dogma about the long-term use of antimicrobial agents, the prolonged use of tetracycline antibiotics commonly used to treat acne lowered the prevalence of colonization by S aureus and did not increase resistance to the tetracycline antibiotics. PMID:21482860

  1. Ecological antibiotic policy.

    PubMed

    Høiby

    2000-08-01

    Development of resistance to antibiotics is a major problem worldwide. The normal oropharyngeal flora, the intestinal flora and the skin flora play important roles in this development. Within a few days after the onset of antibiotic therapy, resistant Escherichia coli, Haemophilus influenzae and Staphylococcus epidermidis can be detected in the normal flora of volunteers or patients. Horizontal spread of the resistance genes to other species, e.g. SALMONELLA: spp., Staphylococcus aureus and Streptococcus pneumoniae, occurs by conjugation or transformation. An ecologically sound antibiotic policy favours the use of antibiotics with little or no impact on the normal flora. Prodrug antibiotics which are not active against the bacteria in the mouth and the intestine (before absorption) and which are not excreted to a significant degree via the intestine, saliva or skin are therefore preferred. Prodrugs such as pivampicillin, bacampicillin, pivmecillinam and cefuroxime axetil are favourable from an ecological point of view. Experience from Scandinavia supports this, since resistance to mecillinam after 20 years of use is low (about 5%) and stable. PMID:10969054

  2. Ecological antibiotic policy.

    PubMed

    Høiby, N

    2000-09-01

    Development of resistance to antibiotics is a major problem worldwide. The normal oropharyngeal flora, the intestinal flora and the skin flora play important roles in this development. Within a few days after the onset of antibiotic therapy, resistant Escherichia coli, Haemophilus influenzae and Staphylococcus epidermidis can be detected in the normal flora of volunteers or patients. Horizontal spread of the resistance genes to other species, e.g. Salmonella spp., Staphylococcus aureus and Streptococcus pneumoniae, occurs by conjugation or transformation. An ecologically sound antibiotic policy favours the use of antibiotics with little or no impact on the normal flora. Prodrug antibiotics which are not active against the bacteria in the mouth and the intestine (before absorption) and which are not excreted to a significant degree via the intestine, saliva or skin are therefore preferred. Prodrugs such as pivampicillin, bacampicillin, pivmecillinam and cefuroxime axetil are favourable from an ecological point of view. Experience from Scandinavia supports this, since resistance to mecillinam after 20 years of use is low (about 5%) and stable. PMID:11051626

  3. Antibiotics in dental practice: how justified are we.

    PubMed

    Oberoi, Sukhvinder S; Dhingra, Chandan; Sharma, Gaurav; Sardana, Divesh

    2015-02-01

    Antibiotics are prescribed by dentists in dental practice, during dental treatment as well as for prevention of infection. Indications for the use of systemic antibiotics in dentistry are limited because most dental and periodontal diseases are best managed by operative intervention and oral hygiene measures. The use of antibiotics in dental practice is characterised by empirical prescription based on clinical and bacteriological epidemiological factors, resulting in the use of a very narrow range of broad-spectrum antibiotics for short periods of time. This has led to the development of antimicrobial resistance (AMR) in a wide range of microbes and to the consequent inefficacy of commonly used antibiotics. Dentists can make a difference by the judicious use of antimicrobials--prescribing the correct drug, at the standard dosage and appropriate regimen--only when systemic spread of infection is evident. The increasing resistance problems of recent years are probably related to the over- or misuse of broad-spectrum agents. There is a clear need for the development of prescribing guidelines and educational initiatives to encourage the rational and appropriate use of drugs in dentistry. This paper highlights the need for dentists to improve antibiotic prescribing practices in an attempt to curb the increasing incidence of antibiotic resistance and other side effects of antibiotic abuse. The literature provides evidence of inadequate prescribing practices by dentists for a number of factors, ranging from inadequate knowledge to social factors. PMID:25510967

  4. Glyphosate Resistance as a Novel Select-Agent-Compliant, Non-Antibiotic-Selectable Marker in Chromosomal Mutagenesis of the Essential Genes asd and dapB of Burkholderia pseudomallei▿

    PubMed Central

    Norris, Michael H.; Kang, Yun; Lu, Diana; Wilcox, Bruce A.; Hoang, Tung T.

    2009-01-01

    Genetic manipulation of the category B select agents Burkholderia pseudomallei and Burkholderia mallei has been stifled due to the lack of compliant selectable markers. Hence, there is a need for additional select-agent-compliant selectable markers. We engineered a selectable marker based on the gat gene (encoding glyphosate acetyltransferase), which confers resistance to the common herbicide glyphosate (GS). To show the ability of GS to inhibit bacterial growth, we determined the effective concentrations of GS against Escherichia coli and several Burkholderia species. Plasmids based on gat, flanked by unique flip recombination target (FRT) sequences, were constructed for allelic-replacement. Both allelic-replacement approaches, one using the counterselectable marker pheS and the gat-FRT cassette and one using the DNA incubation method with the gat-FRT cassette, were successfully utilized to create deletions in the asd and dapB genes of wild-type B. pseudomallei strains. The asd and dapB genes encode an aspartate-semialdehyde dehydrogenase (BPSS1704, chromosome 2) and dihydrodipicolinate reductase (BPSL2941, chromosome 1), respectively. Mutants unable to grow on media without diaminopimelate (DAP) and other amino acids of this pathway were PCR verified. These mutants displayed cellular morphologies consistent with the inability to cross-link peptidoglycan in the absence of DAP. The B. pseudomallei 1026b Δasd::gat-FRT mutant was complemented with the B. pseudomallei asd gene on a site-specific transposon, mini-Tn7-bar, by selecting for the bar gene (encoding bialaphos/PPT resistance) with PPT. We conclude that the gat gene is one of very few appropriate, effective, and beneficial compliant markers available for Burkholderia select-agent species. Together with the bar gene, the gat cassette will facilitate various genetic manipulations of Burkholderia select-agent species. PMID:19648360

  5. Antibiotic activity in space.

    PubMed

    Lapchine, L; Moatti, N; Gasset, G; Richoilley, G; Templier, J; Tixador, R

    1986-01-01

    Environmental factors in space exert an influence on the behaviour of bacteria, particularly on their sensitivity to antibiotics. Thus, G. Taylor and S. Zaloguev observed that bacterial samples collected on the crew during flight in the Apollo-Soyouz Test Project Mission presented higher antibiotic resistance than controls. This paper presents the results of two experiments performed in 1982 and 1985 (Cytos 2 during the French-Soviet Mission and "Antibio" in the Biorack programme of the European Space Agency). The results show an increase of antibiotic resistance in bacteria growth in flight and a modification in the structure of the cell wall. All these modifications are transitory. Two hypotheses are put forward to explain the phenomenon. PMID:3569006

  6. N-O Chemistry for Antibiotics: Discovery of N-Alkyl-N-(pyridin-2-yl)hydroxylamine Scaffolds as Selective Antibacterial Agents Using Nitroso Diels-Alder and Ene Chemistry

    PubMed Central

    Wencewicz, Timothy A.; Yang, Baiyuan; Rudloff, James R.; Oliver, Allen G.; Miller, Marvin J.

    2011-01-01

    The discovery, syntheses, and structure-activity relationships (SAR) of a new family of heterocyclic antibacterial compounds based on N-alkyl-N-(pyridin-2-yl)hydroxylamine scaffolds are described. A structurally diverse library of ~100 heterocyclic molecules generated from Lewis acid-mediated nucleophilic ring opening reactions with nitroso Diels-Alder cycloadducts and nitroso ene reactions with substituted alkenes was evaluated in whole cell antibacterial assays. Compounds containing the N-alkyl-N-(pyridin-2-yl)hydroxylamine structure demonstrated selective and potent antibacterial activity against the Gram-positive bacterium Micrococcus luteus ATCC 10240 (MIC90 = 2.0 μM or 0.41 μg/mL) and moderate activity against other Gram-positive strains including antibiotic resistant strains of Staphylococcus aureus (MRSA) and Enterococcus faecalis (VRE). A new synthetic route to the active core was developed using palladium-catalyzed Buchwald-Hartwig amination reactions of N-alkyl-O-(4-methoxybenzyl)hydroxylamines with 2-halo-pyridines that facilitated SAR studies and revealed the simplest active structural fragment. This work shows the value of using a combination of diversity-oriented synthesis (DOS) and parallel synthesis for identifying new antibacterial scaffolds. PMID:21859126

  7. The structure-dependent toxicity, pharmacokinetics and anti-tumour activity of HPMA copolymer conjugates in the treatment of solid tumours and leukaemia.

    PubMed

    Tomalova, Barbora; Sirova, Milada; Rossmann, Pavel; Pola, Robert; Strohalm, Jiri; Chytil, Petr; Cerny, Viktor; Tomala, Jakub; Kabesova, Martina; Rihova, Blanka; Ulbrich, Karel; Etrych, Tomas; Kovar, Marek

    2016-02-10

    Polymer drug carriers that are based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been widely used in the development and synthesis of high-molecular-weight (HMW) drug delivery systems for cancer therapy. In this study, we compared linear (Mw ~27kDa, Rh ~4nm) and non-degradable star (Mw ~250kDa, Rh ~13nm) HPMA copolymer conjugates bearing anthracycline antibiotic doxorubicin (DOX) bound via pH-sensitive hydrazone bond. We determined the in vitro and in vivo toxicity of both conjugates and their maximum tolerated dose (MTD). We also compared their anti-tumour activity in mouse B-cell leukaemia (BCL1) and a mouse T-cell lymphoma (EL4) model. We found that MTD was higher for the linear conjugate (85mgDOX/kg) and lower for the star conjugate (22.5mgDOX/kg). An evaluation of the intestinal barrier integrity using FITC-dextran as a gut permeability tracer proved that no pathology was caused by the MTD of either conjugate. However, free DOX showed some damage to the gut barrier. The therapy of BCL1 leukaemia by both of the polymeric conjugates using the MTD or its fraction (i.e., equitoxic dosage) showed better results in the case of the star conjugate. On the other hand, treatment of EL4 lymphoma seemed to be more efficient when the linear conjugate was used. We suppose that the anti-cancer treatment of solid tumours and leukaemias requires different types of drug conjugates. We hypothesise that the most suitable HPMA copolymer-DOX conjugate for the treatment of solid tumours should have an HMW structure with increased Rh that would be stable for three to four days after the conjugate administration and then rapidly disintegrate in the short polymer chains, which are excretable from the body by glomerular filtration. On the other hand, the treatment of leukaemia requires a drug conjugate with a long circulation half-life. This would provide an active drug, whilst slowly degrading to excretable fragments. PMID:26708020

  8. [Appropriate use of antibiotics--practices we should employ now: appropriate use of antibiotics for pharmacists in general hospitals].

    PubMed

    Yamada, Kazunori

    2010-07-01

    An authorization system regarding infection has been devised for various occupations in the field of infection control. An infection control team (ICT) consists of authorized, specialized staff, and plays an important role in clinical practice, considering the appropriate use of antibiotics. Board-certified infection control pharmacy specialists also belong to this team. The appropriate use of antibiotics, which I emphasize, indicates the absence of the inappropriate selection of broad-spectrum agents and chronic administration, considering the following 3 points: the selection of antibiotics whose spectra involve causative bacteria (drug sensitivity), prescription of antibiotics using an appropriate administration method/dose based on their transfer to the infected site (pharmacokinetics), and relief of symptoms of infectious diseases (therapeutic effects). In this study, we introduce cases of pharmacists' intervention in Nakamura Memorial South Hospital with respect to the appropriate use of antibiotics by general hospital pharmacists. The contents of pharmacists' intervention included accompanying physicians on their rounds/support regarding prescription, therapeutic drug monitoring, the preparation of guidelines for the hospital use of antibiotics, culture data collection/preparation of antibiograms, ICT/Infection Control Committee (ICC) activities, hospital rounds, preparation of antibiotic injections, and gram staining of sputum. In the future, health care professionals should always consider the appropriate use of antibiotics, contributing to a medical environment in which current options can be maintained for future infectious disease treatment. PMID:20715514

  9. Antibiotic prophylaxis in otolaryngologic surgery

    PubMed Central

    Ottoline, Ana Carolina Xavier; Tomita, Shiro; Marques, Marise da Penha Costa; Felix, Felippe; Ferraiolo, Priscila Novaes; Laurindo, Roberta Silveira Santos

    2013-01-01

    Summary Aim: Antibiotic prophylaxis aims to prevent infection of surgical sites before contamination or infection occurs. Prolonged antibiotic prophylaxis does not enhance the prevention of surgical infection and is associated with higher rates of antibiotic-resistant microorganisms. This review of the literature concerning antibiotic prophylaxis, with an emphasis on otolaryngologic surgery, aims to develop a guide for the use of antibiotic prophylaxis in otolaryngologic surgery in order to reduce the numbers of complications stemming from the indiscriminate use of antibiotics. PMID:25991999

  10. Antibiotics in Animal Products

    NASA Astrophysics Data System (ADS)

    Falcão, Amílcar C.

    The administration of antibiotics to animals to prevent or treat diseases led us to be concerned about the impact of these antibiotics on human health. In fact, animal products could be a potential vehicle to transfer drugs to humans. Using appropri ated mathematical and statistical models, one can predict the kinetic profile of drugs and their metabolites and, consequently, develop preventive procedures regarding drug transmission (i.e., determination of appropriate withdrawal periods). Nevertheless, in the present chapter the mathematical and statistical concepts for data interpretation are strictly given to allow understanding of some basic pharma-cokinetic principles and to illustrate the determination of withdrawal periods

  11. Tackling antibiotic resistance

    PubMed Central

    Bush, Karen; Courvalin, Patrice; Dantas, Gautam; Davies, Julian; Eisenstein, Barry; Huovinen, Pentti; Jacoby, George A.; Kishony, Roy; Kreiswirth, Barry N.; Kutter, Elizabeth; Lerner, Stephen A.; Levy, Stuart; Lewis, Kim; Lomovskaya, Olga; Miller, Jeffrey H.; Mobashery, Shahriar; Piddock, Laura J. V.; Projan, Steven; Thomas, Christopher M.; Tomasz, Alexander; Tulkens, Paul M.; Walsh, Timothy R.; Watson, James D.; Witkowski, Jan; Witte, Wolfgang; Wright, Gerry; Yeh, Pamela; Zgurskaya, Helen I.

    2014-01-01

    The development and spread of antibiotic resistance in bacteria is a universal threat to both humans and animals that is generally not preventable, but can nevertheless be controlled and must be tackled in the most effective ways possible. To explore how the problem of antibiotic resistance might best be addressed, a group of thirty scientists from academia and industry gathered at the Banbury Conference Centre in Cold Spring Harbor, New York, May 16-18, 2011. From these discussions emerged a priority list of steps that need to be taken to resolve this global crisis. PMID:22048738

  12. Methodology in improving antibiotic implementation policies.

    PubMed

    Özgenç, Onur

    2016-06-26

    The basic requirements of antibiotic prescribing are components of methodology; knowledge, logical reasoning, and analysis. Antimicrobial drugs are valuable but limited resources, different from other drugs and they are among the most commonly prescribed drugs all over the world. They are the only drugs which do not intentionally affect the patient. They affect the pathogens which invade the host. The emergence and spread of antibiotic-resistant pathogens are accelerated by heavy antibiotic usage. The effective antimicrobial stewardship and infection control program have been shown to limit the emergence of antimicrobial-resistant bacteria. In this respect, education for antibiotic prescribing could be designed by going through the steps of scientific methodology. A defined leadership and a coordinated multidisciplinary approach are necessary for optimizing the indication, selection, dosing, route of administration, and duration of antimicrobial therapy. In scenarios, knowledge is also as important as experience for critical decision making as is designated. In this setting, the prevalence and resistance mechanisms of antimicrobials, and their interactions with other drugs need to be observed. In this respect, infectious disease service should play an important role in improving antimicrobial use by giving advice on the appropriate use of antimicrobial agents, and implementing evidence-based guidelines. PMID:27376019

  13. Methodology in improving antibiotic implementation policies

    PubMed Central

    Özgenç, Onur

    2016-01-01

    The basic requirements of antibiotic prescribing are components of methodology; knowledge, logical reasoning, and analysis. Antimicrobial drugs are valuable but limited resources, different from other drugs and they are among the most commonly prescribed drugs all over the world. They are the only drugs which do not intentionally affect the patient. They affect the pathogens which invade the host. The emergence and spread of antibiotic-resistant pathogens are accelerated by heavy antibiotic usage. The effective antimicrobial stewardship and infection control program have been shown to limit the emergence of antimicrobial-resistant bacteria. In this respect, education for antibiotic prescribing could be designed by going through the steps of scientific methodology. A defined leadership and a coordinated multidisciplinary approach are necessary for optimizing the indication, selection, dosing, route of administration, and duration of antimicrobial therapy. In scenarios, knowledge is also as important as experience for critical decision making as is designated. In this setting, the prevalence and resistance mechanisms of antimicrobials, and their interactions with other drugs need to be observed. In this respect, infectious disease service should play an important role in improving antimicrobial use by giving advice on the appropriate use of antimicrobial agents, and implementing evidence-based guidelines. PMID:27376019

  14. Polyene antibiotic that inhibits membrane transport proteins

    PubMed Central

    te Welscher, Yvonne Maria; van Leeuwen, Martin Richard; de Kruijff, Ben; Dijksterhuis, Jan; Breukink, Eefjan

    2012-01-01

    The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains. PMID:22733749

  15. Polyene antibiotic that inhibits membrane transport proteins.

    PubMed

    te Welscher, Yvonne Maria; van Leeuwen, Martin Richard; de Kruijff, Ben; Dijksterhuis, Jan; Breukink, Eefjan

    2012-07-10

    The limited therapeutic arsenal and the increase in reports of fungal resistance to multiple antifungal agents have made fungal infections a major therapeutic challenge. The polyene antibiotics are the only group of antifungal antibiotics that directly target the plasma membrane via a specific interaction with the main fungal sterol, ergosterol, often resulting in membrane permeabilization. In contrast to other polyene antibiotics that form pores in the membrane, the mode of action of natamycin has remained obscure but is not related to membrane permeabilization. Here, we demonstrate that natamycin inhibits growth of yeasts and fungi via the immediate inhibition of amino acid and glucose transport across the plasma membrane. This is attributable to ergosterol-specific and reversible inhibition of membrane transport proteins. It is proposed that ergosterol-dependent inhibition of membrane proteins is a general mode of action of all the polyene antibiotics, of which some have been shown additionally to permeabilize the plasma membrane. Our results imply that sterol-protein interactions are fundamentally important for protein function even for those proteins that are not known to reside in sterol-rich domains. PMID:22733749

  16. Antibiotics and antibiotic resistance in agroecosystems: State of the science

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This review article proposes a simple causal model depicting relationships involved in dissemination of antibiotics and antibiotic resistance in agroecosystems and potential effects on human health, functioning of natural ecosystems, and agricultural productivity. Available evidence for each causal ...

  17. Status Report from the Scientific Panel on Antibiotic Use in Dermatology of the American Acne and Rosacea Society

    PubMed Central

    Gallo, Richard L.; Thiboutot, Diane; Webster, Guy F.; Rosen, Ted; Leyden, James J.; Walker, Clay; Zhanel, George; Eichenfield, Lawrence

    2016-01-01

    In this second part of a three-part series addressing several issues related to antibiotic use in dermatology, potential effects of antibiotic use on the human microbiota and microbiome are reviewed. Data from available literature on the microbiologic effects of specific therapeutic agents commonly used in dermatology, including oral isotretinoin, tetracycline agents, and sub-antimicrobial (sub-antibiotic) dose doxycycline, are also discussed.

  18. Antibiotics, probiotics and prebiotics in IBD.

    PubMed

    Bernstein, Charles N

    2014-01-01

    The dysbiosis theory of inflammatory bowel disease (IBD) posits that there is an alteration in the gut microbiome as an important underpinning of disease etiology. It stands to reason then, that administering agents that could impact on the balance of microbes on the gut could be impactful on the course of IBD. Herein is a review of the controlled trials undertaken to assess the use of antibiotics that would kill or suppress potentially injurious microbes, probiotics that would overpopulate the gut with potentially beneficial microbes or prebiotics that provide a metabolic substrate that enhances the growth of potentially beneficial microbes. With regard to antibiotics, the best data are for the use of nitroimadoles postoperatively in Crohn's disease (CD) to prevent disease recurrence. Otherwise, the data are limited with the regard to any lasting benefit of antibiotics sustaining remission in either CD or ulcerative colitis (UC). A recent meta-analysis concluded that antibiotics are superior to placebo at inducing remission in CD or UC, although the meta-analysis grouped a variety of antibiotics with different spectra of activity. Despite the absence of robust clinical trial data, antibiotics are widely used to treat perineal fistulizing CD and acute and chronic pouchitis. Probiotics have not been shown to have a beneficial role in CD. However, Escherichia coli Nissle 1917 has comparable effects to low doses of mesalamine in maintaining remission in UC. VSL#3, a combination of 8 microbes, has been shown to have an effect in inducing remission in UC and preventing pouchitis. Prebiotics have yet to be shown to have an effect in any form of IBD, but to date controlled trials have been small. The use of antibiotics should be balanced against the risks they pose. Even probiotics may pose some risk and should not be assumed to be innocuous especially when ingested by persons with a compromised epithelial barrier. Prebiotics may not be harmful but may cause

  19. [Antibiotical prophylaxy in gynecology].

    PubMed

    Záhumenský, J; Menzlová, E; Zmrhal, J; Kučera, E

    2013-08-01

    Gynecological surgery is considered to be clear with possible contamination by gram-positive cocci from the skin, gram-negatives from the perineum or groins or polymicrobial biocenosis from vagina, depending on the surgical approach. Antibiotical prophylaxy enforces the natural mechanisms of immunity and helps to exclude present infection. There were presented many studies comparing useful effect of prophylaxis in gynecological surgery. The benefits of antibiotical prophylaxy before IUD insertion, before the cervical surgery and before hysteroscopies were not verified. On the other hand the prophylaxy of vaginal surgery including vaginal hysterectomy decreases the number of postoperative febrile complications. The positive influence of prophylaxis before the simple laparoscopy and laparoscopy without bowel injury or the opening of the vagina was not evidently verified. In abdominal hysterectomy the antibiotical prophylaxy decreases the incidence of postoperative complications significantly. The administration of 2 g of cefazolin can be recommended. In procedures taking more than 3 hours the repeated administration of cefazolin is suitable. New urogynecological procedures, using mesh implants, were not sufficiently evaluated as for postoperative infections and the posible antibiotical effect. The presence of implant in possibly non sterile area should be considered as high risc of postoperative complications. PMID:24040985

  20. Mechanisms of Antibiotic Resistance.

    PubMed

    Munita, Jose M; Arias, Cesar A

    2016-04-01

    Emergence of resistance among the most important bacterial pathogens is recognized as a major public health threat affecting humans worldwide. Multidrug-resistant organisms have not only emerged in the hospital environment but are now often identified in community settings, suggesting that reservoirs of antibiotic-resistant bacteria are present outside the hospital. The bacterial response to the antibiotic "attack" is the prime example of bacterial adaptation and the pinnacle of evolution. "Survival of the fittest" is a consequence of an immense genetic plasticity of bacterial pathogens that trigger specific responses that result in mutational adaptations, acquisition of genetic material, or alteration of gene expression producing resistance to virtually all antibiotics currently available in clinical practice. Therefore, understanding the biochemical and genetic basis of resistance is of paramount importance to design strategies to curtail the emergence and spread of resistance and to devise innovative therapeutic approaches against multidrug-resistant organisms. In this chapter, we will describe in detail the major mechanisms of antibiotic resistance encountered in clinical practice, providing specific examples in relevant bacterial pathogens. PMID:27227291

  1. Antibiotics before surgery.

    PubMed

    Kaatz, B

    1996-01-01

    The antimicrobial era (along with greater surgical skill and precision) has brought us relative safety for procedures that previously were fraught with danger. Civil War amputation surgeries, for example, had an extraordinarily high incidence of infections and mortality. Staying aware of and avoiding the small, but real, risks associated with surgical antibiotic prophylaxis will help sustain the advances we enjoy today. PMID:8650524

  2. Antibiotic therapy of cholera*

    PubMed Central

    Lindenbaum, John; Greenough, William B.; Islam, M. R.

    1967-01-01

    Recent clinical trials having established the value of tetracycline as an adjunct to fluid and electrolyte replacement in cholera treatment, a controlled trial of antibiotic therapy was conducted in Dacca on 318 adults hospitalized for cholera. The effects of 4 antibiotics orally administered in varying dosage schedules were studied. Cholera therapy with tetracycline or chloramphenicol caused a highly significant reduction in the duration of diarrhoea and of positive culture, in stool volume, and in intravenous fluid requirement as compared with the results in controls who received intravenous fluid therapy only. Streptomycin was also effective, but to a lesser degree; paromomycin was of little value. The severity of dehydration on admission was significantly related to subsequent duration of diarrhoea regardless of whether antibiotics were given. Increasing age was associated with more prolonged purging in patients receiving antibiotics. Increasing the dose of tetracycline to 2 to 3 times that usually administered, or prolonging treatment from 2 to 4 days, did not enhance the therapeutic results. The effect of tetracycline was apparent within a few hours of administration. Bacteriological relapses were seen after discontinuation of therapy in all treatment groups, but were not due to the development of resistant bacteria. PMID:4865453

  3. Resistance-Resistant Antibiotics

    PubMed Central

    Oldfield, Eric; Feng, Xinxin

    2014-01-01

    New antibiotics are needed because as drug resistance is increasing, the introduction of new antibiotics is decreasing. Here, we discuss six possible approaches to develop ‘resistance-resistant’ antibiotics. First, multi-target inhibitors in which a single compound inhibits more than one target may be easier to develop than conventional combination therapies with two new drugs. Second, inhibiting multiple targets in the same metabolic pathway is expected to be an effective strategy due to synergy. Third, discovering multiple-target inhibitors should be possible by using sequential virtual screening. Fourth, re-purposing existing drugs can lead to combinations of multi-target therapeutics. Fifth, targets need not be proteins. Sixth, inhibiting virulence factor formation and boosting innate immunity may also lead to decreased susceptibility to resistance. Although it is not possible to eliminate resistance, the approaches reviewed here offer several possibilities for reducing the effects of mutations and in some cases suggest that sensitivity to existing antibiotics may be restored, in otherwise drug resistant organisms. PMID:25458541

  4. Anti-tumour immune effect of oral administration of Lactobacillus plantarum to CT26 tumour-bearing mice.

    PubMed

    Hu, Jingtao; Wang, Chunfeng; Ye, Liping; Yang, Wentao; Huang, Haibin; Meng, Fei; Shi, Shaohua; Ding, Zhuang

    2015-06-01

    Colorectal cancer (CRC) is one of the most prevalent forms of cancer that shows a high mortality and increasing incidence. There are numerous successful treatment options for CRC, including surgery, chemotherapy, radiotherapy and immunotherapy; however, their side effects and limitations are considerable. Probiotics may be an effective strategy for preventing and inhibiting tumour growth through stimulation of host innate and adaptive immunity. We investigated and compared potential anti-tumour immune responses induced by two isolated Lactobacillus strains, Lactobacillus plantarum A and Lactobacillus rhamnosus b, by pre-inoculating mice with lactobacilli for 14 days. Subsequently, subcutaneous and orthotopic intestinal tumours were generated in the pre-inoculated mice using CT26 murine adenocarcinoma cells and were assessed for response against the tumour. Our results indicated that oral administration with L. plantarum inhibited CT26 cell growth in BALB/c mice and prolonged the survival time of tumour-bearing mice compared with mice administered L. rhamnosus. L. plantarum produced protective immunity against the challenge with CT26 cells by increasing the effector functions of CD8+ and natural killer (NK) cell infiltration into tumour tissue, up-regulation of IFN-gamma (but not IL-4 or IL-17) production, and promotion of Th1-type CD4+ T differentiation. Consequently, our results suggest that L. plantarum can enhance the anti-tumour immune response and delay tumour formation. PMID:25963256

  5. Chemical composition of the essential oils of Annona pickelii and Annona salzmannii (Annonaceae), and their antitumour and trypanocidal activities.

    PubMed

    Costa, Emmanoel Vilaça; Dutra, Lívia Macedo; Salvador, Marcos José; Ribeiro, Luis Henrique Gonzaga; Gadelha, Fernanda Ramos; de Carvalho, João Ernesto

    2013-01-01

    The essential oils from the leaves of Annona pickelii and Annona salzmannii (Annonaceae) were obtained by hydrodistillation using a Clevenger apparatus, and analysed by GC-MS and GC-FID. A total of 21 compounds were identified in the essential oil of A. pickelii and 23 in that of A. salzmannii; sesquiterpenes predominated in both essential oils. Bicyclogermacrene (38.0%), (E)-caryophyllene (27.8%), α-copaene (6.9%) and α-humulene (4.0%) were the main components of A. pickelii, while δ-cadinene (22.6%), (E)-caryophyllene (21.4%), α-copaene (13.3%), bicyclogermacrene (11.3%) and germacrene D (6.9%) were the main components of A. salzmannii. The biological activities of the essential oils against Trypanosoma cruzi epimastigote forms and cytotoxicity against tumour cell lines (antitumour) were investigated. The essential oils showed potent trypanocidal and antitumour activities with values of IC50 lower than 100 µg mL(-1). PMID:22583044

  6. Anti-tumour promoting activity and antioxidant properties of girinimbine isolated from the stem bark of Murraya koenigii S.

    PubMed

    Kok, Yih Yih; Mooi, Lim Yang; Ahmad, Kartini; Sukari, Mohd Aspollah; Mat, Nashriyah; Rahmani, Mawardi; Ali, Abdul Manaf

    2012-01-01

    Girinimbine, a carbazole alkaloid isolated from the stem bark of Murraya koenigii was tested for the in vitro anti-tumour promoting and antioxidant activities. Anti-tumour promoting activity was determined by assaying the capability of this compound to inhibit the expression of early antigen of Epstein-Barr virus (EA-EBV) in Raji cells that was induced by the tumour promoter, phorbol 12-myristate 13-acetate. The concentration of this compound that gave an inhibition rate at fifty percent was 6.0 µg/mL and was not cytotoxic to the cells. Immunoblotting analysis of the expression of EA-EBV showed that girinimbine was able to suppress restricted early antigen (EA-R). However, diffused early antigen (EA-D) was partially suppressed when used at 32.0 µg/mL. Girinimbine exhibited a very strong antioxidant activity as compared to a-tocopherol and was able to inhibit superoxide generation in the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced differentiated premyelocytic HL-60 cells more than 95%, when treated with the compound at 5.3 and 26.3 µg/mL, respectively. However girinimbine failed to scavenge the stable diphenyl picryl hydrazyl (DPPH)-free radical. PMID:22522395

  7. Matrix metalloproteinases inhibition promotes the polyfunctionality of human natural killer cells in therapeutic antibody-based anti-tumour immunotherapy.

    PubMed

    Zhou, Q; Gil-Krzewska, A; Peruzzi, G; Borrego, F

    2013-07-01

    Activation of human natural killer (NK) cells is associated with the cleavage of CD16 from the cell surface, a process mediated by matrix metalloproteinases (MMPs). In this report, we examined whether inhibition of MMPs would lead to improved NK cell antibody-dependent cell-mediated cytotoxicity (ADCC) function. Using an in-vitro ADCC assay, we tested the anti-tumour function of NK cells with three different therapeutic monoclonal antibodies (mAbs) in the presence of MMPs inhibitor GM6001 or its control. Loss of CD16 was observed when NK cells were co-cultured with tumour targets in the presence of specific anti-tumour antibodies, and was found particularly on the majority of degranulating NK responding cells. Treatment with MMPs inhibitors not only prevented CD16 down-regulation, but improved the quality of the responding cells significantly, as shown by an increase in the percentage of polyfunctional NK cells that are capable of both producing cytokines and degranulation. Furthermore, MMPs inhibition resulted in augmented and sustained CD16-mediated signalling, as shown by increased tyrosine phosphorylation of CD3ζ and other downstream signalling intermediates, which may account for the improved NK cell function. Collectively, our results provide a foundation for combining MMPs inhibitors and therapeutic mAbs in new clinical trials for cancer treatment. PMID:23607800

  8. Design, characterization and anti-tumour cytotoxicity of a panel of recombinant, mammalian ribonuclease-based immunotoxins.

    PubMed Central

    Deonarain, M. P.; Epenetos, A. A.

    1998-01-01

    Bovine seminal ribonuclease (BSRNase) is an unusual member of the ribonuclease superfamily, because of its remarkable anti-tumour and immunosuppressive properties. We describe here the construction, expression, purification and characterization of a panel of six immunotoxins based upon this enzyme and show that we can increase its anti-tumour activity by over 2 x 10(4)-fold. This is achieved by improving tumour cell targeting using a single-chain Fv (scFv) directed against the oncofetal antigen placental alkaline phosphatase. As well as the simple scFv-BSRNase fusion protein, we have constructed five other derivatives with additional peptides designed to improve folding and intracellular trafficking and delivery. We find that the molecule most cytotoxic to antigen (PLAP)-positive cells in vitro is one that contains a C-terminal 'KDEL' endoplasmic reticulum retention signal and a peptide sequence derived from diphtheria toxin. All these molecules are produced in Escherichia coli (E. coli) as insoluble inclusion bodies and require extensive in vitro processing to recover antigen binding and ribonuclease activity. Despite incomplete ribonuclease activity and quaternary assembly, these molecules are promising reagents for specific chemotherapy of cancer and are potentially less harmful and immunogenic than current immunotoxins. Images Figure 2 PMID:9484808

  9. Bacterial cheating limits antibiotic resistance

    NASA Astrophysics Data System (ADS)

    Xiao Chao, Hui; Yurtsev, Eugene; Datta, Manoshi; Artemova, Tanya; Gore, Jeff

    2012-02-01

    The widespread use of antibiotics has led to the evolution of resistance in bacteria. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removing the antibiotic. The cooperative nature of this growth suggests that a cheater strain---which does not contribute to breaking down the antibiotic---may be able to take advantage of cells cooperatively inactivating the antibiotic. Here we find experimentally that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We observe stable coexistence between the two strains and find that a simple model successfully explains the behavior as a function of antibiotic concentration and cell density. We anticipate that our results will provide insight into the evolutionary origin of phenotypic diversity and cooperative behaviors.

  10. Lyme Disease 'Biofilm' Eludes Antibiotics

    MedlinePlus

    ... news/fullstory_157467.html Lyme Disease 'Biofilm' Eludes Antibiotics: Report Germ forms slimy layer that makes it ... bacteria that causes Lyme disease protects itself from antibiotics by forming a slime-like layer called a ...