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Sample records for biguanides

  1. Serine deprivation enhances antineoplastic activity of biguanides.

    Science.gov (United States)

    Gravel, Simon-Pierre; Hulea, Laura; Toban, Nader; Birman, Elena; Blouin, Marie-José; Zakikhani, Mahvash; Zhao, Yunhua; Topisirovic, Ivan; St-Pierre, Julie; Pollak, Michael

    2014-12-15

    Metformin, a biguanide widely used in the treatment of type II diabetes, clearly exhibits antineoplastic activity in experimental models and has been reported to reduce cancer incidence in diabetics. There are ongoing clinical trials to evaluate its antitumor properties, which may relate to its fundamental activity as an inhibitor of oxidative phosphorylation. Here, we show that serine withdrawal increases the antineoplastic effects of phenformin (a potent biguanide structurally related to metformin). Serine synthesis was not inhibited by biguanides. Instead, metabolic studies indicated a requirement for serine to allow cells to compensate for biguanide-induced decrease in oxidative phosphorylation by upregulating glycolysis. Furthermore, serine deprivation modified the impact of metformin on the relative abundance of metabolites within the citric acid cycle. In mice, a serine-deficient diet reduced serine levels in tumors and significantly enhanced the tumor growth-inhibitory actions of biguanide treatment. Our results define a dietary manipulation that can enhance the efficacy of biguanides as antineoplastic agents that target cancer cell energy metabolism. PMID:25377470

  2. Physical and Chemical Characterization of Poly(hexamethylene biguanide Hydrochloride

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    Luiz Henrique C. Mattoso

    2011-06-01

    Full Text Available We present the characterization of commercially available Poly(hexamethylene biguanide hydrochloride (PHMB, a polymer with biocidal activity and several interesting properties that make this material suitable as a building block for supramolecular chemistry and “smart” materials. We studied polymer structure in water solution by dynamic light scattering, surface tension and capacitance spectroscopy. It shows typical surfactant behavior due to amphiphilic structure and low molecular weight. Spectroscopic (UV/Vis, FT-NIR and thermal characterization (differential scanning calorimetry, DSC, and thermogravimetric analysis, TGA were performed to give additional insight into the material structure in solution and solid state. These results can be the foundation for more detailed investigations on usefulness of PHMB in new complex materials and devices.

  3. Regulation of the Proliferation of Colon Cancer Cells by Compounds that Affect Glycolysis, Including 3-Bromopyruvate, 2-Deoxyglucose and Biguanides

    OpenAIRE

    Lea, Michael A.; Qureshi, Mehreen S.; Buxhoeveden, Michael; Gengel, Nicolette; Kleinschmit, Jessica; desBordes, Charles

    2013-01-01

    In previous studies we observed that 2-deoxyglucose blocked the acidification of the medium used for culture of colon cancer cells caused by incubation with biguanides and had an additive inhibitory effect on growth. In the present work, we found that 3-bromopyruvate can also prevent the lowering of pH caused by biguanide treatment. 3-Bromopyruvate inhibited colonic cancer cell proliferation but the effect was not always additive to that of biguanides and an additive effect was more notable i...

  4. Energy metabolism determines the sensitivity of human hepatocellular carcinoma cells to mitochondrial inhibitors and biguanide drugs.

    Science.gov (United States)

    Hsu, Chia-Chi; Wu, Ling-Chia; Hsia, Cheng-Yuan; Yin, Pen-Hui; Chi, Chin-Wen; Yeh, Tien-Shun; Lee, Hsin-Chen

    2015-09-01

    Human hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide particularly in Asia. Deregulation of cellular energetics was recently included as one of the cancer hallmarks. Compounds that target the mitochondria in cancer cells were proposed to have therapeutic potential. Biguanide drugs which inhibit mitochondrial complex I and repress mTOR signaling are clinically used to treat type 2 diabetes mellitus patients (T2DM) and were recently found to reduce the risk of HCC in T2DM patients. However, whether alteration of energy metabolism is involved in regulating the sensitivity of HCC to biguanide drugs is still unclear. In the present study, we treated four HCC cell lines with mitochondrial inhibitors (rotenone and oligomycin) and biguanide drugs (metformin and phenformin), and found that the HCC cells which had a higher mitochondrial respiration rate were more sensitive to these treatments; whereas the HCC cells which exhibited higher glycolysis were more resistant. When glucose was replaced by galactose in the medium, the altered energy metabolism from glycolysis to mitochondrial respiration in the HCC cells enhanced the cellular sensitivity to mitochondrial inhibitors and biguanides. The energy metabolism change enhanced AMP-activated protein kinase (AMPK) activation, mTOR repression and downregulation of cyclin D1 and Mcl-1 in response to the mitochondrial inhibitors and biguanides. In conclusion, our results suggest that increased mitochondrial oxidative metabolism upregulates the sensitivity of HCC to biguanide drugs. Enhancing the mitochondrial oxidative metabolism in combination with biguanide drugs may be a therapeutic strategy for HCC.

  5. Relevance of the OCT1 transporter to the antineoplastic effect of biguanides

    Energy Technology Data Exchange (ETDEWEB)

    Segal, Eric D.; Yasmeen, Amber; Beauchamp, Marie-Claude; Rosenblatt, Joshua [Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, Quebec (Canada); Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, Quebec (Canada); Pollak, Michael [Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, Quebec (Canada); Department of Oncology, McGill University, Montreal, Quebec (Canada); Gotlieb, Walter H., E-mail: walter.gotlieb@mcgill.ca [Division of Gynecologic Oncology, Jewish General Hospital, McGill University, Montreal, Quebec (Canada); Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, Montreal, Quebec (Canada); Department of Oncology, McGill University, Montreal, Quebec (Canada)

    2011-11-04

    Highlights: Black-Right-Pointing-Pointer siRNA knockdown of OCT1 reduced sensitivity of EOC cells to metformin, but not to another biguanide, phenformin. Black-Right-Pointing-Pointer Suppression of OCT1 also affects the activation of AMP kinase in response to metformin, but not to phenformin. Black-Right-Pointing-Pointer Direct actions of metformin may be limited by low OCT1 expression in EOC tumors. Black-Right-Pointing-Pointer Phenformin could be used as an alternative biguanide. -- Abstract: Epidemiologic and laboratory data suggesting that metformin has antineoplastic activity have led to ongoing clinical trials. However, pharmacokinetic issues that may influence metformin activity have not been studied in detail. The organic cation transporter 1 (OCT1) is known to play an important role in cellular uptake of metformin in the liver. We show that siRNA knockdown of OCT1 reduced sensitivity of epithelial ovarian cancer cells to metformin, but interestingly not to another biguanide, phenformin, with respect to both activation of AMP kinase and inhibition of proliferation. We observed that there is heterogeneity between primary human tumors with respect to OCT1 expression. These results suggest that there may be settings where drug uptake limits direct action of metformin on neoplastic cells, raising the possibility that metformin may not be the optimal biguanide for clinical investigation.

  6. Regulation of the proliferation of colon cancer cells by compounds that affect glycolysis, including 3-bromopyruvate, 2-deoxyglucose and biguanides.

    Science.gov (United States)

    Lea, Michael A; Qureshi, Mehreen S; Buxhoeveden, Michael; Gengel, Nicolette; Kleinschmit, Jessica; Desbordes, Charles

    2013-02-01

    In previous studies performed by our group, we observed that 2-deoxyglucose blocked the acidification of the medium used for culture of colon cancer cells caused by incubation with biguanides and it had an additive inhibitory effect on growth. In the present work, we found that 3-bromopyruvate can also prevent the lowering of pH caused by biguanide treatment. 3-Bromopyruvate inhibited colonic cancer cell proliferation, but the effect was not always additive to that of biguanides and an additive effect was more notable in combined treatment with 3-bromopyruvate and 2-deoxyglucose. The induction of alkaline phosphatase activity by butyrate was not consistently affected by combination with other agents that modified glucose metabolism. The drug combinations that were examined inhibited proliferation of wild-type and p53-null cells and affected colonic cancer lines with different growth rates. PMID:23393330

  7. Biguanide-functionalized mesoporous SBA-15 silica as an efficient solid catalyst for interesterification of vegetable oils.

    Science.gov (United States)

    Xie, Wenlei; Hu, Libing

    2016-04-15

    The biguanide-functionalized SBA-15 materials were fabricated by grafting of organic biguanide onto the SBA-15 silica through covalent attachments, and then this organic-inorganic hybrid material was employed as solid catalysts for the interesterification of triacylglycerols for the modification of vegetable oils. The prepared catalyst was characterized by FTIR, XRD, SEM, TEM, nitrogen adsorption-desorption and elemental analysis. The biguanide base was successfully tethered onto the SBA-15 silica with no damage to the ordered mesoporous structure of the silica after the organo-functionalization. The solid catalyst had stronger base strength and could catalyze the interesterification of triacylglycerols. The fatty acid compositions and triacylglycerol profiles of the interesterified products were noticeably varied following the interesterification. The reaction parameters, namely substrate ratio, reaction temperature, catalyst loading and reaction time, were investigated for the interesterification of soybean oil with methyl decanoate. The catalyst could be reused for at least four cycles without significant loss of activity.

  8. 99mTc-labelled biguanide derivatives: chemical speciation modelling thereof and evaluation in vervets

    International Nuclear Information System (INIS)

    99mTc-DMSA (dimercaptosuccinic acid) is known to be a safe and effective agent for static renal imaging. However, it has a long uptake time which is a limiting factor in diagnostic procedures and also leads to a relatively high radiation dose being administered to patients. There is a constant search for possible new renal imaging agents with a good resolution, kidney/liver contrast and low radiation dose to all organs. A series of biguanide derivatives (potential as non-insulin-dependent diabetes mellitus agents) labelled with 99mTc were investigated as potential alternative kidney-imaging agents on theoretical grounds (in silico) and their biodistribution (in vivo) verified in a limited number of animal experiments. Such a dual approach has the benefit that it reduces the number of animal experiments needed to evaluate a potential radiopharmaceutical. The blood plasma model shows little or no complexation of the biguanide type ligands by the metal ions in blood plasma. It was therefore expected that these ligands will clear rapidly through the kidneys and liver (increased lipophilicity). These predictions were verified by studies on single vervets comparing them with 99mTc-DMSA as gold standard. All the biguanide derivatives labelled with 99mTc show liver, kidney and gallbladder uptake in vervets. It was shown that the agent 99mTc-CBIG (carboxylbiguanide) has a very fast kidney clearance, which will reduce the dose to organs (as experienced for 99mTc-DMSA), although it's potential as a kidney agent is limited by its gallbladder uptake. (author)

  9. Mixed-ligand complex formation equilibria of CuII with biguanide in presence of glycine as the auxiliary ligand

    Indian Academy of Sciences (India)

    Tannistha Roy Barman; G N Mukherjee

    2006-09-01

    Equilibrium study on the mixed ligand complex formation of CuII with biguanide(Bg) and glycine (HG), indicated the formation of the complexes: Cu(Bg)2+, Cu(Bg)$_{2}^{2+}$, Cu(Bg-H)(Bg)+, Cu(Bg-H)2, Cu(Bg)(OH)+, Cu(Bg-H)(OH); Cu(G)+, Cu(G)(OH), Cu(G)2; Cu(G)(Bg)+, Cu(G)(Bg-H); (G)Cu(Bg)Cu(G)2+, (G)Cu(Bg-H)Cu(G)+, and (G)Cu(Bg-2H)Cu(G). From the deprotonation constants of coordinated biguanide (Bg) in the complexes Cu(Bg)(OH)+, Cu(Bg-H)(Bg)+ and Cu(G)(Bg)+, the Lewis basicities of the coordinated ligand species (Bg-H)-, OH- and glycinate (G-) were found to be of the order: (Bg-H)- >> OH- > G-. Bridging (N1-N4, N2-N5) tetradentate mode of coordination by biguanide species Bg, (Bg-H)- and (Bg-2H)2- was indicated from the occurrence of biguanide-bridged dinuclear mixed ligand complexes (G)Cu(Bg)Cu(G)2+, (G)Cu(Bg-H)Cu(G)+, (G)Cu(Bg-2H)Cu(G) in the complexation equilibria.

  10. Maximum inhibitory dilution of mouthwashes containing chlorhexidine and polyhexamethylene biguanide against salivary staphylococcus aureus

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    Andresa Piacezzi Nascimento

    2008-10-01

    Full Text Available OBJECTIVE: The aim of the present study was to determine the in vitro maximum inhibitory dilution (MID of two chlorhexidinebased oral mouthwashes (CHX: Noplak®, Periogard®, and one polyhexamethylene biguanide-based mouthwash (PHMB: Sanifill Premium® against 28 field Staphylococcus aureus strains using the agar dilution method. MATERIALS AND METHODS: For each product, decimal dilutions ranging from 1/10 to 1/655,360 were prepared in distilled water and added to Mueller Hinton Agar culture medium. After homogenization, the culture medium was poured onto Petri dishes. Strains were inoculated using a Steers multipoint inoculator and dishes were incubated at 37ºC for 24hours. For reading, MID was considered as the maximum dilution of the mouthwash still capable of inhibiting microbial growth. RESULTS: Sanifill Premium® inhibited the growth of all strains at 1/40 dilution and of 1 strain at 1/80 dilution. Noplak® inhibited the growth of 23 strains at 1/640 dilution and of all 28 strains at 1/320 dilution. Periogard® showed inhibited growth of 7 strains at 1/640 dilution and of all 28 strains at 1/320 dilution. Data were submitted to Kruskal-Wallis statistical test, showing significant differences between the mouthwashes evaluated (p0.05. Sanifill Premium® was the least effective (p<0.05. CONCLUSION: It was concluded that CHX-based mouthwashes present better antimicrobial activity against S. Aureus than the PHMB-based mouthwash.

  11. Organic salts of biguanide - An attempt to crystal engineering of novel materials for second harmonic generation

    Science.gov (United States)

    Matulková, Irena; Němec, Ivan; Císařová, Ivana; Němec, Petr; Vaněk, Přemysl

    2010-03-01

    Three organic salts of biguanide with oxalic, succinic and L-tartaric acids have been prepared and X-ray structural analysis has been performed. Biguanidium(1+) oxalate hemihydrate ( a = 6.8330(2) Å, b = 10.0430(2) Å, c = 14.6230(4) Å, α = 90.236(1) , β = 90.333(1) , γ = 105.605(2) , V = 966.46(4) Å 3, Z = 1, R = 0.0393 for 3704 observed reflections) and biguanidium(1+) hydrogen succinate ( a = 6.4600(1) Å, b = 6.7670(2) Å, c = 11.4150(3) Å, α = 91.822(1) , β = 105.312(1) , γ = 90.922(1) , V = 480.89(2) Å 3, Z = 2, R = 0.0357 for 1880 observed reflections) belong to the triclinic space group P 1¯. Their crystal structures are based on biguanidium(1+) pairs connected by intermolecular N-H⋯N hydrogen bonds. The remaining ions (eventually water molecules) form a 3D structural network with these pairs. Furthermore, the formation of the cationic and anionic layers interconnected by intermolecular N-H⋯O hydrogen bonds was observed in the crystal structure of biguanidium(1+) hydrogen succinate. Biguanidium(2+) L-tartrate crystallizes in the orthorhombic space group P 2 12 12 1 ( a = 6.7170(2) Å, b = 9.2740(2) Å, c = 16.1500(4) Å, V = 1006.04(4) Å 3, Z = 4, R = 0.0432 for 2193 observed reflections). The crystal structure is based on L-tartrate chains, which are interconnected by isolated biguanidium(2+) cations via several types of N-H⋯O hydrogen bonds. The formation of L-tartrate chains is mediated by two types of intermolecular O-H⋯O hydrogen bonds connecting the hydroxyl and carboxylate groups. The FTIR and FT Raman spectra of all the compounds were recorded and discussed. The theoretical values of the first hyperpolarizability components were calculated for biguanidium(1+) and biguanidium(2+) cations at the B3LYP level with the 6-311G(d,p) basis set. Quantitative measurements of the second harmonic generation of powdered biguanidium(2+) L-tartrate at 800 nm were performed and a relative efficiency of 2% (compared to KDP) was

  12. Cu(II AND Zn(II COMPLEX COMPOUNDS WITH BIGUANIDES AROMATIC DERIVATIVES. SYNTHESIS, CHARACTERIZATION, BIOLOGICAL ACTIVITY

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    Ticuţa Negreanu-Pîrjol

    2011-05-01

    Full Text Available In this paper we report the synthesis, physical-chemical characterization and antimicrobial activity of some new complex compounds of hetero-aromatic biguanides ligands, chlorhexidine base (CHX and chlorhexidine diacetate (CHXac2 with metallic ions Cu(II and Zn(II, in different molar ratio. The synthesized complexes were characterized by elemental chemical analysis and differential thermal analysis. The stereochemistry of the metallic ions was determined by infrared spectra, UV-Vis, EPR spectroscopy and magnetic susceptibility in the aim to establish the complexes structures. The biological activity of the new complex compounds was identified in solid technique by measuring minimum inhibition diameter of bacterial and fungal culture, against three standard pathogen strains, Escherichia coli ATCC 25922, Staphilococcus aureus ATCC 25923 and Candida albicans ATCC 10231. The results show an increased specific antimicrobial activity for the complexes chlorhexidine:Cu(II 1:1 and 1:2 compared with the one of the Zn(II complexes.

  13. A new non-invasive approach based on polyhexamethylene biguanide increases the regression rate of HPV infection

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    Gentile Antonio

    2012-09-01

    Full Text Available Abstract Background HPV infection is a worldwide problem strictly linked to the development of cervical cancer. Persistence of the infection is one of the main factors responsible for the invasive progression and women diagnosed with intraepithelial squamous lesions are referred for further assessment and surgical treatments which are prone to complications. Despite this, there are several reports on the spontaneous regression of the infection. This study was carried out to evaluate the effectiveness of a long term polyhexamethylene biguanide (PHMB-based local treatment in improving the viral clearance, reducing the time exposure to the infection and avoiding the complications associated with the invasive treatments currently available. Method 100 women diagnosed with HPV infection were randomly assigned to receive six months of treatment with a PHMB-based gynecological solution (Monogin®, Lo.Li. Pharma, Rome - Italy or to remain untreated for the same period of time. Results A greater number of patients, who received the treatment were cleared of the infection at the two time points of the study (three and six months compared to that of the control group. A significant difference in the regression rate (90% Monogin group vs 70% control group was observed at the end of the study highlighting the time-dependent ability of PHMB to interact with the infection progression. Conclusions The topic treatment with PHMB is a preliminary safe and promising approach for patients with detected HPV infection increasing the chance of clearance and avoiding the use of invasive treatments when not strictly necessary. Trial registration ClinicalTrials.gov Identifier NCT01571141

  14. Adding liraglutide to the backbone therapy of biguanide in patients with coronary artery disease and newly diagnosed type-2 diabetes (the AddHope2 study)

    DEFF Research Database (Denmark)

    Anholm, Christian; Kumarathurai, Preman; Klit, Malene S;

    2014-01-01

    with a 2-week washout period. The primary cardiovascular end point is changes in left ventricular ejection fraction during stress echocardiography. The primary endocrine end point is β-cell function evaluated during a frequently sampled intravenous glucose tolerance test. Secondary end points include heart......INTRODUCTION: Newly diagnosed type 2 diabetes mellitus (T2DM) in patients with coronary artery disease (CAD) more than doubles the risk of death compared with otherwise matched glucose tolerant patients. The biguanide metformin is the drug of choice in treatment of T2DM and has shown to ameliorate...... cardiovascular morbidity in patients with T2DM and myocardial infarction (MI). The incretin hormone, glucagon-like peptide-1 (GLP-1) improves β-cell function, insulin sensitivity and causes weight loss and has been suggested to have beneficial effects on cardiac function. The GLP-1 receptor agonist (GLP-1RA...

  15. Rapid, simple and stability-indicating determination of polyhexamethylene biguanide in liquid and gel-like dosage forms by liquid chromatography with diode-array detection

    Institute of Scientific and Technical Information of China (English)

    Markus Küsters; Sören Beyer; Stephan Kutscher; Harald Schlesinger; Michael Gerhartz

    2013-01-01

    A rapid and simple method for the determination of polyhexamethylene biguanide (polyhexanide, PHMB) in liquid and gel-like pharmaceutical formulations by means of high performance liquid chromatography coupled to diode-array detection (HPLC-DAD) was developed. Best separation was achieved using a cyanopropyl bonded phase (Agilent Zorbax Eclipse XDB-CN column 4.6 mm75 mm with particle size of 3.5 mm) as well as gradient elution consisting of acetonitrile/deionized water at a flow rate of 1.0 mL/min. The optimized and applied chromatographic conditions permitted separation of polyhexanide from interacting matrix with subsequent detection at a wavelength of 235 nm with good sensitivity. The method validation was carried out with regard to the guidelines for analytical procedures demanded by the International Conference on Harmonisation (ICH). Mean recoveries of 102% and 101% for gel-like as well as liquid preparations were obtained. Suitable repeatability as well as intermediate precision could be achieved with limits of detection r0.004 mg/mL for both formulations, equivalent to r0.004% PHMB concerning sample preparation. Determination of PHMB was accomplished without tedious sample preparation. Interacting matrix could be eliminated by the chromatographic procedure with excellent performance of system suitability. All analytical requirements were fulfilled permitting a reliable and precise determination of PHMB in pharmaceuticals. Furthermore, the developed method was applied to stability testing of pharmaceutical preparations containing PHMB.

  16. The safety and efficacy of bacterial nanocellulose wound dressing incorporating sericin and polyhexamethylene biguanide: in vitro, in vivo and clinical studies.

    Science.gov (United States)

    Napavichayanun, Supamas; Yamdech, Rungnapha; Aramwit, Pornanong

    2016-03-01

    In our previous work, we have attempted to develop a novel bacterial nanocellulose wound dressing which composed of both polyhexamethylene biguanide (PHMB) as an antimicrobial agent and sericin as an accelerative wound healing component. The loading sequence and concentration of PHMB and sericin were optimized to provide the wound dressing with the most effective antimicrobial activity and enhanced collagen production. In this study, further in vitro, in vivo, and clinical studies of this novel wound dressing were performed to evaluate its safety, efficacy, and applicability. For the in vitro cytotoxic test with L929 mouse fibroblast cells, our novel dressing was not toxic to the cells and also promoted cell migration as good as the commercially available dressing, possibly due to the component of sericin released. When implanted subcutaneously in rats, the lower inflammation response was observed for the novel dressing implanted, comparing to the commercially available dressing. This might be that the antimicrobial PHMB component of the novel dressing played a role to reduce infection and inflammation reaction. The clinical trial patch test was performed on the normal skin of healthy volunteers to evaluate the irritation effect of the dressing. Our novel dressing did not irritate the skin of any volunteers, as characterized by the normal levels of erythema and melanin and the absence of edema, papule, vesicle, and bullae. Then, the novel dressing was applied for the treatment of full-thickness wounds in rats. The wounds treated with our novel dressing showed significantly lower percentage of wound size and higher extent of collagen formation mainly due to the activity of sericin. We concluded that our novel bacterial nanocellulose incorporating PHMB and sericin was a safe and efficient wound dressing material for further investigation in the wound healing efficacy in clinic. PMID:26796543

  17. The resistance of the yeast Saccharomyces cerevisiae to the biocide polyhexamethylene biguanide: involvement of cell wall integrity pathway and emerging role for YAP1

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    de Morais Marcos A

    2011-08-01

    Full Text Available Abstract Background Polyhexamethylene biguanide (PHMB is an antiseptic polymer that is mainly used for cleaning hospitals and pools and combating Acantamoeba infection. Its fungicide activity was recently shown by its lethal effect on yeasts that contaminate the industrial ethanol process, and on the PE-2 strain of Saccharomyces cerevisiae, one of the main fermenting yeasts in Brazil. This pointed to the need to know the molecular mechanism that lay behind the cell resistance to this compound. In this study, we examined the factors involved in PHMB-cell interaction and the mechanisms that respond to the damage caused by this interaction. To achieve this, two research strategies were employed: the expression of some genes by RT-qPCR and the analysis of mutant strains. Results Cell Wall integrity (CWI genes were induced in the PHMB-resistant Saccharomyces cerevisiae strain JP-1, although they are poorly expressed in the PHMB-sensitive Saccharomyces cerevisiae PE2 strain. This suggested that PHMB damages the glucan structure on the yeast cell wall. It was also confirmed by the observed sensitivity of the yeast deletion strains, Δslg1, Δrom2, Δmkk2, Δslt2, Δknr4, Δswi4 and Δswi4, which showed that the protein kinase C (PKC regulatory mechanism is involved in the response and resistance to PHMB. The sensitivity of the Δhog1 mutant was also observed. Furthermore, the cytotoxicity assay and gene expression analysis showed that the part played by YAP1 and CTT1 genes in cell resistance to PHMB is unrelated to oxidative stress response. Thus, we suggested that Yap1p can play a role in cell wall maintenance by controlling the expression of the CWI genes. Conclusion The PHMB treatment of the yeast cells activates the PKC1/Slt2 (CWI pathway. In addition, it is suggested that HOG1 and YAP1 can play a role in the regulation of CWI genes.

  18. NCW2, a Gene Involved in the Tolerance to Polyhexamethylene Biguanide (PHMB), May Help in the Organisation of β-1,3-Glucan Structure of Saccharomyces cerevisiae Cell Wall.

    Science.gov (United States)

    Elsztein, Carolina; de Lima, Rita de Cássia Pereira; de Barros Pita, Will; de Morais, Marcos Antonio

    2016-09-01

    In the present work, we provide biological evidences supporting the participation of NCW2 gene in the mechanism responsible for cell tolerance to polyhexamethylene biguanide (PHMB), an antifungal agent. The growth rate of yeast cells exposed to this agent was significantly reduced in ∆ncw2 strain and the mRNA levels of NCW2 gene in the presence of PHMB showed a 7-fold up-regulation. Moreover, lack of NCW2 gene turns yeast cell more resistant to zymolyase treatment, indicating that alterations in the β-glucan network do occur when Ncw2p is absent. Computational analysis of the translated protein indicated neither catalytic nor transmembrane sites and reinforced the hypothesis of secretion and anchoring to cell surface. Altogether, these results indicated that NCW2 gene codes for a protein which participates in the cell wall biogenesis in yeasts and that Ncw2p might play a role in the organisation of the β-glucan assembly.

  19. STUDY ON DISINFECTION RELATED PROPERTIES OF A COMPOUND POLY HEXAMETHYLENE BIGUANIDE HYDROCHLORIDE DISINFECTANT%一种复方聚六亚甲基盐酸双胍消毒液消毒相关性能研究

    Institute of Scientific and Technical Information of China (English)

    刘仲霞; 陆武韬; 苏伟东

    2011-01-01

    Objective To study the disinfection related properties of a poly hexamethylene biguanide hydrochloride disinfectant. Methods Suspensionr quantitative germicidal test and animal toxic experiment were used to observe the germicidal efficacy and the toxicity of the compound disinfectant in laboratory. Results The killing logarithm values of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa by the disinfectant solution containing poly hexamethylene biguanide hydrochloride 146 mg/L with 7.5 min contact time were all above 5.00. The killing logarithm value of Candida albicans and by the disinfectant solution containing poly hexamethylene biguanide hydrochloride 146 mg/L with 22.5 min contact time was 2.07. The LD50 of mice acute oral toxicity was > 5 000 mg/kg · bw. The disinfectant has slightly - irritating to rabbit eye and mucosa and has medium irritating to rabbit skin. The result of mouse bone marrow polychromatic erythrocyte micronucleus test was negative. Conclusions The compound poly hexamethylene biguanide hydrochloride disinfectant had good germicidal efficacy to vegetative forms of bacteria. It was low toxicity and has slightly - irritating to rabbit eye and skin.%目的 研究一种复方聚六亚甲基胍盐酸盐消毒液消毒相关性能.方法 采用悬液定量杀菌试验和动物毒性试验的方法,对该复方消毒液杀菌效果及其毒性进行了实验室观察.结果 用含聚六亚甲基盐酸双胍146 mg/L的该消毒液分别对悬液中的大肠杆菌、金黄色葡萄球菌、白色葡萄球菌及铜绿假单胞菌作用7.5 min,杀灭对数值均>5.00.用聚六亚甲基盐酸双胍146 mg/L的该复方消毒液对悬液内白色念珠菌作用22.5 min,杀灭对数值为2.07.该复方聚六亚甲基盐酸双胍消毒液对小鼠急性经口LD50值>5 000 mg/kg(体重);该消毒液原液对家兔眼睛黏膜和完整皮肤有轻刺激性和中等刺激性;该消毒液对小鼠骨髓嗜多染红细

  20. NCW2, a Gene Involved in the Tolerance to Polyhexamethylene Biguanide (PHMB), May Help in the Organisation of β-1,3-Glucan Structure of Saccharomyces cerevisiae Cell Wall.

    Science.gov (United States)

    Elsztein, Carolina; de Lima, Rita de Cássia Pereira; de Barros Pita, Will; de Morais, Marcos Antonio

    2016-09-01

    In the present work, we provide biological evidences supporting the participation of NCW2 gene in the mechanism responsible for cell tolerance to polyhexamethylene biguanide (PHMB), an antifungal agent. The growth rate of yeast cells exposed to this agent was significantly reduced in ∆ncw2 strain and the mRNA levels of NCW2 gene in the presence of PHMB showed a 7-fold up-regulation. Moreover, lack of NCW2 gene turns yeast cell more resistant to zymolyase treatment, indicating that alterations in the β-glucan network do occur when Ncw2p is absent. Computational analysis of the translated protein indicated neither catalytic nor transmembrane sites and reinforced the hypothesis of secretion and anchoring to cell surface. Altogether, these results indicated that NCW2 gene codes for a protein which participates in the cell wall biogenesis in yeasts and that Ncw2p might play a role in the organisation of the β-glucan assembly. PMID:27246500

  1. EFFECT OF TREATMENT OF DRINKING WATER WITH POLYMERIC BIGUANIDE (VANTOCIL IB UPON THE REDEMPTION AND SANITY OF BROILERS EFEITO DO TRATAMENTO DA ÁGUA DE BEBIDA COM BIGUANIDA POLIMÉRICA (VANTOCIL IB SOBRE O DESEMPENHO E SANIDADE DE FRANGOS DE CORTE

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    Marcos Barcellos Café

    2007-09-01

    Full Text Available

    The present work aimed to evaluate the effect of the water treated with polymeric biguanide (Vantocil IB in different dilutions upon the sanitary conditions of broilers. Five treatments and four repetitions were carried out with 200 broilers. Group 1: not treated water - negative witness; Group 2: sodium hypoclorite treated water (0.4-0.6 ppm - positive witness; Group 3: polymeric biguanide treated water (Vantocil IB - 1:2000; Group 4: polymeric biguanide treated water (Vantocil IB - 1:4000; Group 5: polymeric biguanide treated water (Vantocil IB - 1:6000. The experimental unit was represented by ten broilers, and the experiment was conducted from July to August, 1995, during 42 days. The results pointed out that there was no influence in ration consumption, weight gain and medium weight. Groups 5 and 4 presented the best performance while Group 3 presented the worst results. Polymeric biguanide as well as sodium hypoclorite proved to be efficient in the tested dilutions.

    KEY-WORDS: Water; polymeric biguanide; broilers.

    O presente trabalho tem por finalidade avaliar o efeito da qualidade da água tratada com biguanida polimérica (Vantocil IB em diferentes diluições, sobre o desempenho de frangos de corte, assim como verificar o estado sanitário destes frangos. Foram ensaiados cinco tratamentos e quatro repetições, com um total de 200 aves. Grupo 1: água não tratada - testemunha negativa; Grupo 2: água tratada com hipoclorito de sódio (0,4 - 0.6 ppm - testemunha positiva; Grupo 3: água tratada com biguanida polimérica (Vantocil IB - 1:2000; Grupo 4: água tratada com biguanida polimérica (Vantocil IB - 1:4000; Grupo 5 água tratada com biguanida polim

  2. ANTIBACTERIAL ACTIVITY AND QUANTIFICATION OF POLYHEXAMETHTYLENE BIGUANIDE HYDROCHLORIDE IN MUSCULAR TISSUES AND VISCERA OF BROILERS ATIVIDADE ANTIBACTERIANA E QUANTIFICAÇÃO DE CLORIDRATO DE POLIHEXAMETILENO BIGUANIDA (P.H.M.B. EM TECIDOS MUSCULARES E VÍCERAS DE FRANGOS

    Directory of Open Access Journals (Sweden)

    Albenones José de Mesquita

    2007-09-01

    Full Text Available

    Trials were carried out in order to check the viability of polyhexamethylene biguanide hydrochloride in the control of pathogenic and degenerating bacteria in carcass of chicken, as well as a spectrophotometric monitoring of the residual content of this polymer in the carcasses and viscera of chicken quenched with biguanide. The sanitizing power of this substance was high, although the previous analysis point out to the inefficacy of the residual monitoring method, due to the action of interferings.

    KEY-WORDS: Polyhexamethylene biguanide hydrochloride; carcass of chicken; sanitizer.

    Nos últimos anos, na procura de princípios sanitizantes ativos, certos polímeros sintéticos ou naturais modificados mereceram atenção especial por possuir uma ação antimicrobiana mais elevada, definida e por apresentar toxicidade reduzida, o que os tornam potencialmente úteis como sanitizantes nas indústrias alimentícias, onde se exigem condições higiênico-sanitárias satisfatórias. Nesta comunicação, foram ensaiados métodos para a viabilização do cloridrato de polihexametileno biguanida no controle de bactérias patogênicas ou deteriorantes em carcaças de frango, bem como um monitoramento espectrofotométrico do teor residual deste polímero nessas carcaças e vísceras de frangos dessedentados com biguanida. O poder sanitizante dessa substância foi elevado, no entanto as análises preliminares sugerem a ineficácia do método de monitoramento residual, devido à atuação de interferentes.

    PALAVRAS-CHAVE: Cloridrato de polihexametileno biguanida; carcaça de frango; sanitizante.

  3. Synthesis and purification of carbon-14 labelled 1, 1-hexamethylene-bis [5-(4-chlorophenyl)biguanide] (chlorhexidine, 'Hibitane')

    International Nuclear Information System (INIS)

    Two syntheses of [14C] chlorhexidine ('Hibitane') with the label specifically incorporated in two separate molecular positions are described. Ring labelled chlorhexidine prepared from p-chloro[U-14C]aniline was obtained with a molar specific activity of 27.9 mCi/mmol. Chain labelled material, where the 14C label was incorporated in the 1 and 6 positions of the hexamethylene bridge, was prepared from [1, 6 14C]-adiponitrile, with a molar specific activity of 11.5 mCi/mmol. Several methods of purification are described. (author)

  4. Poly (hexamethylene biguanide) adsorption on hydrogen peroxide treated Ti-Al-V alloys and effects on wettability, antimicrobial efficacy, and cytotoxicity.

    Science.gov (United States)

    Müller, Gerald; Benkhai, Hicham; Matthes, Rutger; Finke, Birgit; Friedrichs, Wenke; Geist, Norman; Langel, Walter; Kramer, Axel

    2014-07-01

    An effective amount of the antiseptic agent PHMB cannot simply be placed on the surface of titanium alloys where hydrocarbons were removed by different purification procedures. Pre-treatment of Ti6Al4V specimen with 5% H2O2 in 24 h results in extra introduced -OH and -COOH groups as well as an adsorbed water film on the surface, which provide the base for the subsequent formation of a relatively stable and multi-layered PHMB film. The superficially adhering PHMB film produces no adverse effects on MG63 cells within a 48 h-cell culture, but promotes the initial attachment and spreading of the osteoblasts on the modified Ti6Al4V surface within 15 min. After direct bacterial inoculation of the active sample, the PHMB film reacts antimicrobially against Gram-positive (Staphylococcus aureus, Staphylococcus epidermidis) and Gram-negative strains (Pseudomonas aeruginosa, Escherichia coli) after surface contact. The bactericidal efficacy is only slightly reduced after using of the same specimen for re-testing the antibacterial activity. MG63 cells adhere and proliferate within 48 h on a PHMB film-containing Ti6Al4V surface, which has been pre-contaminated with S. aureus. Bacterial biofilms were only revealed in controls without PHMB.

  5. Synthesis and purification of carbon-14 labelled 1, 1-hexamethylene-bis (5-(4-chlorophenyl)biguanide) (chlorhexidine, 'Hibitane')

    Energy Technology Data Exchange (ETDEWEB)

    Burns, J. (Imperial Chemical Industries Ltd., Macclesfield (UK). Pharmaceuticals Div.)

    1982-10-01

    Two syntheses of (/sup 14/C) chlorhexidine ('Hibitane') with the label specifically incorporated in two separate molecular positions are described. Ring labelled chlorhexidine prepared from p-chloro(U-/sup 14/C)aniline was obtained with a molar specific activity of 27.9 mCi/mmol. Chain labelled material, where the /sup 14/C label was incorporated in the 1 and 6 positions of the hexamethylene bridge, was prepared from (1, 6 /sup 14/C)-adiponitrile, with a molar specific activity of 11.5 mCi/mmol. Several methods of purification are described.

  6. Inhibition of glycolysis and growth of colon cancer cells by 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3PO in combination with butyrate, 2-deoxy glucose, 3-bromopyruvate or biguanides

    Directory of Open Access Journals (Sweden)

    Lea MA

    2015-09-01

    Full Text Available Introduction: Glycolysis shows a positive correlation with growth of human colon cancer cells. PFKFB3 is an important enzyme regulating glycolysis in many tumor cells and presents a target for cancer chemotherapy. We studied the action of an inhibitor of PFKFB3, 3-(3-pyridinyl-1-(4-pyridinyl-2-propen-1-one (3PO, as a single agent and in combination with other molecules that affect glycolysis. Materials and methods: Effects on growth were studied in four human colon cancer cell lines. Glucose metabolism was monitored by uptake from the incubation medium and lactic acid production was judged by acidification of the medium. Induction of alkaline phosphatase served as a marker of differentiation. Results: Growth of colon cancer cells was inhibited by 3PO and butyrate but only butyrate induced activation of alkaline phosphatase. Although metformin and phenformin can increase glucose metabolism, they inhibit colon cancer cell growth and can exert additive inhibitory effects in combination with 3PO. Additive growth inhibitory effects with 3PO were also observed with two compounds that inhibit glycolysis: 2-deoxyglucose and 3-bromopyruvate. Conclusion: 3PO was an inhibitor of growth of colon cancer cells and may be a useful agent in combination with other drugs that inhibit colon cancer cell proliferation.

  7. Inhibition of glycolysis and growth of colon cancer cells by 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) in combination with butyrate, 2-deoxy glucose, 3-bromopyruvate or biguanides

    OpenAIRE

    Lea MA; Geherty R; desBordes C

    2015-01-01

    Introduction: Glycolysis shows a positive correlation with growth of human colon cancer cells. PFKFB3 is an important enzyme regulating glycolysis in many tumor cells and presents a target for cancer chemotherapy. We studied the action of an inhibitor of PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), as a single agent and in combination with other molecules that affect glycolysis. Materials and methods: Effects on growth were studied in four human colon cancer cell lines. Gluco...

  8. Drug: D02206 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available pocytokine signaling pathway map07051 Antidiabetics Therapeutic category of drugs in Japan [BR:br08301] 3 Ag...ents affecting metabolism 39 Other agents affecting metabolism 396 Antidiabetic agents 3962 Biguanides D0220...D02206 Drug Buformin hydrochloride (JP16); Dibetos-B (TN) C6H15N5. HCl 193.1094 193.6777 D02206.gif Antidiab...etic [DS:H00409] Therapeutic category: 3962 ATC code: A10BA03 biguanides AMPK activ

  9. Metformin for cancer and aging prevention: is it a time to make the long story short?

    Science.gov (United States)

    Anisimov, Vladimir N.

    2015-01-01

    During the last decade, the burst of interest is observed to antidiabetic biguanide metformin as candidate drug for cancer chemoprevention. The analysis of the available data have shown that the efficacy of cancer preventive effect of metformin (MF) and another biguanides, buformin (BF) and phenformin (PF), has been studied in relation to total tumor incidence and to 17 target organs, in 21 various strains of mice, 4 strains of rats and 1 strain of hamsters (inbred, outbred, transgenic, mutant), spontaneous (non- exposed to any carcinogenic agent) or induced by 16 chemical carcinogens of different classes (polycycIic aromatic hydrocarbons, nitroso compounds, estrogen, etc.), direct or indirect (need metabolic transformation into proximal carcinogen), by total body X-rays and γ- irradiation, viruses, genetic modifications or special high fat diet, using one stage and two-stage protocols of carcinogenesis, 5 routes of the administration of antidiabetic biguanides (oral gavage, intraperitoneal or subcutaneous injections, with drinking water or with diet) in a wide ranks of doses and treatment regimens. In the majority of cases (86%) the treatment with biguanides leads to inhibition of carcinogenesis. In 14% of the cases inhibitory effect of the drugs was not observed. Very important that there was no any case of stimulation of carcinogenesis by antidiabetic biguanides. It was conclude that there is sufficient experimental evidence of anti-carcinogenic effect of antidiabetic biguanides. PMID:26583576

  10. Oncobiguanides: Paracelsus' law and nonconventional routes for administering diabetobiguanides for cancer treatment

    Science.gov (United States)

    Menendez, Javier A.; Quirantes-Piné, Rosa; Rodríguez-Gallego, Esther; Cufí, Sílvia; Corominas-Faja, Bruna; Cuyàs, Elisabet; Bosch-Barrera, Joaquim; Martin-Castillo, Begoña; Segura-Carretero, Antonio; Joven, Jorge

    2014-01-01

    “The dose makes the poison”, the common motto of toxicology first expressed by Paracelsus more than 400 years ago, may effectively serve to guide potential applications for metformin and related biguanides in oncology. While Paracelsus' law for the dose-response effect has been commonly exploited for the use of some anti-cancer drugs at lower doses in non-neoplastic diseases (e.g., methotrexate), the opposite scenario also holds true; in other words, higher doses of non-oncology drugs, such as anti-diabetic biguanides, might exert direct anti-neoplastic effects. Here, we propose that, as for any drug, there is a dose range for biguanides that is without any effect, one corresponding to “diabetobiguanides” with a pharmacological effect (e.g., insulin sensitization in type 2 diabetes, prevention of insulin-dependent carcinogenesis, indirect inhibition of insulin and growth factor-dependent cancer growth) but with minimal toxicity and another corresponding to “oncobiguanides” with pharmacological (i.e., direct and strong anticancer activity against cancer cells) as well as toxic effects. Considering that biguanides demonstrate a better safety profile than most oncology drugs in current use, we should contemplate the possibility of administering biguanides through non-conventional routes (e.g., inhaled for carcinomas of the lung, topical for skin cancers, intravenous as an adjunctive therapy, rectal suppositories for rectal cancer) to unambiguously investigate the therapeutic value of high-dose transient biguanide exposure in cancer. Perhaps then, the oncobiguanides, as we call them here, could be viewed as a mechanistically different type of anti-cancer drugs employed at doses notably higher than those used chronically when functioning as diabetobiguanides. PMID:24909934

  11. Metformin induced acute pancreatitis

    OpenAIRE

    Alsubaie, Sadeem; Almalki, Mussa H.

    2013-01-01

    Acute pancreatitis frequently presents with abdomen pain but may presents with various skin manifestations as rash and rarely, pancreatic panniculitis. Metformin, one of the most effective and valuable oral hypoglycemic agents in the biguanide class was linked to acute pancreatitis in few cases. Here, we report a case of metformin induce acute pancreatitis in young healthy man with normal renal function.

  12. Drug: D08351 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available [HSA:1565] Anatomical Therapeutic Chemical (ATC) classification [BR:br08303] A ALIMENTARY TRACT AND METABOLISM A10 DRUGS USED IN DIAB...ETES A10B BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS A10BA Biguanides A10BA01 Phe

  13. Drug: D00595 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available diabetics Anatomical Therapeutic Chemical (ATC) classification [BR:br08303] A ALIMENTARY TRACT AND METABOLISM A10 DRUGS USED IN DIABE...TES A10B BLOOD GLUCOSE LOWERING DRUGS, EXCL. INSULINS A10BA Biguanides A10BA03 Bufo

  14. Understanding the benefit of metformin use in cancer treatment

    Directory of Open Access Journals (Sweden)

    Goodwin Pamela J

    2011-04-01

    Full Text Available Abstract Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed.

  15. Activity of disinfectants against foodborne pathogens in suspension and adhered to stainless steel surfaces

    Directory of Open Access Journals (Sweden)

    Tatiane Karen Cabeça

    2012-09-01

    Full Text Available The purpose of this study was to investigate and compare the efficacy of various disinfectants on planktonic cells and biofilm cells of Listeria monocytogenes, Staphylococcus aureus and Escherichia coli. Numbers of viable biofilm cells decreased after treatment with all tested disinfectants (iodine, biguanide, quaternary ammonium compounds, peracetic acid and sodium hypochlorite. Sodium hypochlorite was the most effective disinfectant against biofilm cells, while biguanide was the least effective. Scanning electron microscopy observations revealed that cells adhered on stainless steel surface after treatment with the disinfectants. No viable planktonic cells were observed after treatment with the same disinfectants. Based on our findings, we concluded that biofilm cells might be more resistant to disinfectants than plancktonic cells.

  16. Decontamination of laryngoscope blades: Is our practice adequate?

    Directory of Open Access Journals (Sweden)

    Telang R

    2010-01-01

    Full Text Available Background : The laryngoscope has been identified as a potential source of cross-infection, because of blood and bacterial contamination. In India, there are no guidelines for cleaning and disinfection of anesthesia-related equipment. Practices for decontamination of laryngoscopes vary widely and in most healthcare institutes, laryngoscope blades are re-used after cleaning with tap-water. Materials and Methods: We prospectively compared two techniques for decontamination of laryngoscope blades - a washing with tap-water and b washing with tap-water followed by disinfection by immersing in 5% v/v (volume/volume, 1:20 dilution aldehyde-free biguanide agent for 10 min. We calculated the cost-effectiveness of using 5% v/v aldehyde-free biguanide agent for disinfection of laryngoscopes. We also conducted a survey to assess the decontamination practices in other Indian hospitals. Results : Overall bacterial growth was 58% (29 out of 50 blades after tap-water cleaning (of which 60% were pathogenic organisms versus 3.4% (one out of 29 blades after tap-water cleaning followed by immersion in disinfectant (all of which were commensals. The cost of disinfection with biguanide was Indian Rupees 1.13 (20 US cents per laryngoscope. Most hospitals in India do not have guidelines regarding laryngoscope decontamination between uses, and cleaning with tap water is a commonly used method. Conclusion : Cleaning of laryngoscope blades with tap-water is a commonly used but inadequate method for decontamination. Washing with tap-water followed by disinfection with 5% v/v aldehyde-free biguanide for at least 10 min is an effective and inexpensive alternative. National guidelines for the decontamination of anesthesia equipment are necessary.

  17. The efficiency of contact lens care regimens on protein removal from hydrogel and silicone hydrogel lenses

    OpenAIRE

    Luensmann, Doerte; Heynen, Miriam; Liu, Lina; Sheardown, Heather; Jones, Lyndon

    2010-01-01

    Purpose To investigate the efficiency of lysozyme and albumin removal from silicone hydrogel and conventional contact lenses, using a polyhexamethylene biguanide multipurpose solution (MPS) in a soaking or rubbing/soaking application and a hydrogen peroxide system (H2O2). Methods Etafilcon A, lotrafilcon B and balafilcon A materials were incubated in protein solutions for up to 14 days. Lenses were either placed in radiolabeled protein to quantify the amount deposited or in fluorescent-conjug...

  18. Meta-analysis of the ocular biocompatibility of a new multipurpose lens care system

    OpenAIRE

    Reindel W; Merchea MM; Rah MJ; Zhang L.

    2013-01-01

    William Reindel, Mohinder M Merchea, Marjorie J Rah, Lening Zhang Bausch & Lomb Incorporated, Rochester, NY, USA Background: The purpose of this paper is to evaluate the biocompatibility of a novel multipurpose solution (MPS) with a dual disinfectant system containing polyaminopropyl biguanide and polyquaternium-1 (Biotrue®) by analysis of biomicroscopy signs and adverse events in six large clinical trials. Methods: Data from six consecutive, prospective clinical trials conducted from...

  19. Meta-analysis of the ocular biocompatibility of a new multipurpose lens care system

    OpenAIRE

    Rah, Marjorie

    2013-01-01

    William Reindel, Mohinder M Merchea, Marjorie J Rah, Lening Zhang Bausch & Lomb Incorporated, Rochester, NY, USA Background: The purpose of this paper is to evaluate the biocompatibility of a novel multipurpose solution (MPS) with a dual disinfectant system containing polyaminopropyl biguanide and polyquaternium-1 (Biotrue®) by analysis of biomicroscopy signs and adverse events in six large clinical trials. Methods: Data from six consecutive, prospective clinical trials condu...

  20. Patenting Carboxyformin in the United States: How Does It Work and What Does It Mean?

    OpenAIRE

    Sheehan, Meghan E.; Wagner, Louis F.

    2013-01-01

    Carboxyformin, a new biguanide, shows promise as a treatment for type 2 diabetes mellitus (attributes assumed for the purpose of this article). But is a carboxyformin-based therapeutic formulation patentable? And if the formulation is patentable, what protection is afforded by the patent? This article examines the patent prosecution process, beginning with the initial discovery and continuing through the issuance of the patent. The article also briefly discusses issues of patent infringement ...

  1. Comparative analysis of Salmonella susceptibility and tolerance to the biocide chlorhexidine identifies a complex cellular defence network

    OpenAIRE

    SeamusFanning; OrlaCondell; KristianHandler; AineSheridan; KjellSergeant; JUANWANG; JarlathNally

    2014-01-01

    Chlorhexidine is one of the most widely used biocides in health and agricultural settings as well as in the modern food industry. It is a cationic biocide of the biguanide class. Details of its mechanism of action are largely unknown. The frequent use of chlorhexidine has been questioned recently, amidst concerns that an overuse of this compound may select for bacteria displaying an altered susceptibility to antimicrobials, including clinically important anti-bacterial agents. We generat...

  2. Effects of Metformin Treatment on Homocysteine Levels and Metabolic Parameters of Women With Polycystic Ovary Syndrome

    OpenAIRE

    Riahinejad, Soheila; Mirdamadi, Ahmad; Alizadeh, Elham

    2015-01-01

    Objective: Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. Metformin is a biguanide commonly used to improve PCOS symptoms. Effect of metformin on the levels of serum homocysteine (Hcy) in PCOS women is unclear. The aim of this study is evaluating the effect of metformin administration on serum Hcy levels and metabolic parameters of PCOS patients. Materials and methods: Thirty three patients with PCOS were enrolled in this study who were selected rando...

  3. Metformin in women with type 2 diabetes in pregnancy (MiTy): a multi-center randomized controlled trial

    OpenAIRE

    Feig, Denice S.; Murphy, Kellie; Asztalos, Elizabeth; Tomlinson, George; Sanchez, Johanna; Zinman, Bernard; Ohlsson, Arne; Edmond A Ryan; Fantus, I. George; Armson, Anthony B.; Lipscombe, Lorraine L.; Barrett, Jon F R; ,; Carson, George; Williams, Suzanne

    2016-01-01

    Background The incidence of type 2 diabetes in pregnancy is rising and rates of serious adverse maternal and fetal outcomes remain high. Metformin is a biguanide that is used as first-line treatment for non-pregnant patients with type 2 diabetes. We hypothesize that metformin use in pregnancy, as an adjunct to insulin, will decrease adverse outcomes by reducing maternal hyperglycemia, maternal insulin doses, maternal weight gain and gestational hypertension/pre-eclampsia. In addition, since m...

  4. REDUCTION OF CARDIOVASCULAR COMPLICATIONS OF MODERN HYPOGLYCEMIC THERAPY OF DIABETES MELLITUS TYPE 2: "FLORENTINE HERESY"

    OpenAIRE

    Aleksandrov, A. A.

    2016-01-01

    The classic hypoglycemic agents include biguanides, sulfonylurea drugs, meglitinides, glitazones and alpha-glucosidase inhibitors. Modern algorithm of hypoglycemic therapy in the first step considers lifestyle modification and metformin monotherapy, the second step — the combined therapy. However, the effect of combined hypoglycemic therapy on long-term cardiovascular prognosis in patients with type 2 diabetes mellitus is studied insufficiently. Combined therapy with glibenclamide and metform...

  5. A novel cationic lipid with intrinsic antitumor activity to facilitate gene therapy of TRAIL DNA.

    Science.gov (United States)

    Luo, Cong; Miao, Lei; Zhao, Yi; Musetti, Sara; Wang, Yuhua; Shi, Kai; Huang, Leaf

    2016-09-01

    Metformin (dimethylbiguanide) has been found to be effective for the treatment of a wide range of cancer. Herein, a novel lipid (1,2-di-(9Z-octadecenoyl)-3-biguanide-propane (DOBP)) was elaborately designed by utilizing biguanide as the cationic head group. This novel cationic lipid was intended to act as a gene carrier with intrinsic antitumor activity. When compared with 1,2-di-(9Z-octadecenoyl)-3-trimethylammonium-propane (DOTAP), a commercially available cationic lipid with a similar structure, the blank liposomes consisting of DOBP showed much more potent antitumor effects than DOTAP in human lung tumor xenografts, following an antitumor mechanism similar to metformin. Given its cationic head group, biguanide, DOBP could encapsulate TNF-related apoptosis-inducing ligand (TRAIL) plasmids into Lipid-Protamine-DNA (LPD) nanoparticles (NPs) for systemic gene delivery. DOBP-LPD-TRAIL NPs demonstrated distinct superiority in delaying tumor progression over DOTAP-LPD-TRAIL NPs, due to the intrinsic antitumor activity combined with TRAIL-induced apoptosis in the tumor. These results indicate that DOBP could be used as a versatile and promising cationic lipid for improving the therapeutic index of gene therapy in cancer treatment. PMID:27344367

  6. Interactions and adverse reactions of metformin and other drugs%二甲双胍与其他药物的相互作用及不良反应的研究进展

    Institute of Scientific and Technical Information of China (English)

    孙建然; 夏同佳; 许敏; 邓大同

    2016-01-01

    Biguanides are known to inhibit glycogen output,increase the use of glucose,and enhance insulin sensitivity.In practice,the biguanides also work along with insulin and other oral medications.However,when it combined with other drugs,the enzymology phar-macokinetics actions may occur.Biguanides can cause lactic acidosis,hepatotoxicity,and hypomagnesemia.This paper will give an over-view of the interactions and adverse reactions of metformin with other drugs.%双胍类药物抑制肝糖输出,增加葡萄糖的利用和胰岛素敏感性,可与其他口服降糖药及胰岛素联合降糖。但与其他药物联用时,可能发生与酶药动学相关的反应,双胍类药物可致乳酸性酸中毒、肝毒性、低镁血症。该文就二甲双胍与其他药物的相互作用及不良反应作一概述。

  7. Metformin inhibits cell growth by upregulating microRNA-26a in renal cancer cells

    OpenAIRE

    Yang, Feng-Qiang; Wang, Ji-Jiao; Yan, Jia-Sheng; Huang, Jian-Hua; Li, Wei; Che, Jian-Ping; Wang, Guang-Chun; Liu, Min; Zheng, Jun-Hua

    2014-01-01

    Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties and may reduce cancer risk and improve prognosis. However, the mechanism by which metformin affects various cancers, including renal cancer still unknown. MiR-26a induces cell growth, cell cycle and cell apoptosis progression via direct targeting of Bcl-2, clyclin D1 and PTEN in cancer cells. In the present study, we used 786-O human renal cancer cell lines to study the ef...

  8. Influence of Buformin retard on vitamin B12 absorption

    International Nuclear Information System (INIS)

    In 18 test persons with a healthy metabolism a significant reduction of the vitamin B12 absorption rate was observed when Buformin retard was administered 90 minutes before starting the Schilling test. This biguanide-induced reduction of vitamin B12 absorption was not detectable in preliminary examinations in which the interval between the last Buformin administration and the administering of 58Co-vitamin B12 was 14 hours. Thus could be shown that the reduction was due to the method used. There is no increased danger of an anemia provided that the therapeutic rules are obeyed i.e. Buformin should be taken after breakfast and supper, respectively

  9. Drug: D00944 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 81 165.6246 D00944.gif Antidiabetic [DS:H00409] Therapeutic category: 3962 ATC code: A10BA02 biguanides AMPK... SCL47A2 [HSA:146802] map07051 Antidiabetics map04150 mTOR signaling pathway Therapeutic category of drugs i...n Japan [BR:br08301] 3 Agents affecting metabolism 39 Other agents affecting metabolism 396 Antidiabetic...min D00944 Metformin hydrochloride (JP16/USP) USP drug classification [BR:br08302] Blood Glucose Regulators Antidiabetic

  10. Metformin Exhibits Radiation Countermeasures Efficacy When Used Alone or in Combination with Sulfhydryl Containing Drugs

    OpenAIRE

    Miller, Richard C.; Murley, Jeffrey S.; David J Grdina

    2014-01-01

    Metformin, a biguanide drug used in the treatment of type II diabetes, was evaluated alone and in combination with amifostine, captopril, MESNA or N-acetyl-cysteine (NAC) for its ability to protect when administered 24 h after irradiation. Mouse embryo fibroblasts (MEF), human microvascular endothelial cells (HMEC) and SA-NH mouse sarcoma cells were exposed to 4 Gy in vitro. C3H mice were exposed to 7 Gy and evaluated utilizing an endogenous spleen colony assay system. Amifostine and WR1065, ...

  11. Small molecule interactions with lipid bilayers: a molecular dynamics study of chlorhexidine

    Science.gov (United States)

    van Oosten, Brad; Marquardt, Drew; Sternin, Edward; Harroun, Thad

    2013-03-01

    Chlorhexidine presents an interesting modelling challenge with a hydrophobic hexane connecting two biguanides (arginine analogues) and two aromatic rings. We conducted molecular dynamic simulations using the GROMACS simulation software to reproduce the experimental environment of chlorhexidine in a 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) bilayer to produce atomic-level information. We constructed an all-atom force field of chlorhexidine from the CHARMM36 force field using well established parameters of certain amino acids. Partial charges were treated differently, which were calculated using GAUSSIAN software. We will compare and contrast the results of our model to that of our neutron scattering experiments previously done in our lab.

  12. [Selection of contrast media for hemodynamic studies and limitation of the associated risk].

    Science.gov (United States)

    Baralis, Giorgio; Steffenino, Giuseppe; Dellavalle, Antonio; La Scala, Eugenio; Uslenghi, Eugenio

    2004-02-01

    Both the choice of contrast media for use in the cardiac catheterization laboratory, and the practice for limiting patient damage, are relevant to the quality of health care. As part of our quality assurance program, and as a preliminary step to a critical reappraisal of our current protocols, an updated review has been made of existing evidence about contrast media for this use, and about measures to prevent adverse events. Consideration was also given to evidence-based measures or drug treatment in patients at risk for anaphylactoid reactions or with renal failure, as well as to the recommended course of action in diabetic patients receiving oral biguanide agents. PMID:15080534

  13. REDUCTION OF CARDIOVASCULAR COMPLICATIONS OF MODERN HYPOGLYCEMIC THERAPY OF DIABETES MELLITUS TYPE 2: "FLORENTINE HERESY"

    Directory of Open Access Journals (Sweden)

    A. A. Aleksandrov

    2010-01-01

    Full Text Available The classic hypoglycemic agents include biguanides, sulfonylurea drugs, meglitinides, glitazones and alpha-glucosidase inhibitors. Modern algorithm of hypoglycemic therapy in the first step considers lifestyle modification and metformin monotherapy, the second step — the combined therapy. However, the effect of combined hypoglycemic therapy on long-term cardiovascular prognosis in patients with type 2 diabetes mellitus is studied insufficiently. Combined therapy with glibenclamide and metformin can result in adverse cardiovascular effects, so that long term therapy should be avoided in patients with coronary heart disease. Adequate pharmacological approaches to hyperglycemia correction should be elaborated.

  14. A novel in vitro wound biofilm model used to evaluate low-frequency ultrasonic-assisted wound debridement

    DEFF Research Database (Denmark)

    Crone, S.; Garde, Christian; Bjarnsholt, T.;

    2015-01-01

    device (UA W) in the presence of saline irrigation and treatment with a polyhexamethylene biguanide (PHMB)-containing antiseptic. Confocal microscopy was used to evaluate the effect of treatments on biofilm disruption and cell viability counting measured the antibacterial effects. Results: Confocal...... microscopy showed that application of 10 seconds of moderate-intensity UA W could effectively disrupt semi-solid biofilms grown on both media settings. This treatment only had a small effect on the cell viability. A 24-hour treatment with PHMB was able to reduce the number of bacteria but not eradicate...

  15. ASSESSMENT OF ACTION OF DISINFECTANTS AGAINST LISTERIA MONOCYTOGENES BIOFILMS

    Directory of Open Access Journals (Sweden)

    T. K. CABEÇA

    2008-12-01

    Full Text Available

    The purpose of this study was to assess the action of various disinfectants used in food industry against biofilm cells of Listeria monocytogenes formed on stainless steel surfaces during 24, 72 and 120 hours. Numbers of viable biofilm cells decreased after treatment with all the tested disinfectants (iodine, biguanide, quaternary ammonium compounds, peracetic acid and sodium hypochlorite. Sodium hypochlorite was the most effective disinfectant against the biofilm cells, while biguanide and iodine were the least. Scanning electron microscopy observations demonstrated attached cells on stainless steel surfaces after treatment with all the disinfectants. These observations showed that microorganisms were not completely removed from stainless steel surfaces after treatment with the disinfectants, however, the attachment did not means the viability of remaining cells. The biofilm age in hours (24, 72 and 120 had no apparent influence on resistance of microbiological cells to the disinfectants under study. In conclusion biofilm cells of L. monocytogenes can withstand disinfectants action.

  16. Metformin in the treatment of breast cancer among patients with metabolic syndrome

    Directory of Open Access Journals (Sweden)

    R. V. Lyubota

    2015-01-01

    Full Text Available Breast cancer (BC is one of the most common cancer among women worldwide. In 2005, the International Diabetes Federation (International Diabetes Federation declared metabolic syndrome is one of the main problems of modern medicine, as it increases the total mortality and the prevalence has reached pandemic levels. Several studies have shown that the metabolic disorders associated with metabolic syndrome, affect the carcinogenesis of BC. Improving the efficiency of chemotherapy in patients with type 2 diabetes taking biguanides compared with patients who used other hypoglycemic agents, it has become a premise for the study of the possible antitumor mechanism of action of metformin. Therefore, adequate correction of metabolic disturbances caused by metabolic syndrome may be an additional area of special treatment, as well as a measure of primary and secondary prevention of BC. Improving the efficiency of tumor therapy in patientswith type 2 diabetes taking biguanides compared with patients who used other hypoglycemic agents, it has become a prerequisite for the study of the possible antitumor mechanism of action of metformin. This paper presents the results of studying the effect of metformin on the effectiveness of neoadjuvant systemic therapy for BC patients with the metabolic syndrome.

  17. Metformin and cancer: Technical and clinical implications for FDG-PET imaging

    Institute of Scientific and Technical Information of China (English)

    Selene; Capitanio; Cecilia; Marini; Gianmario; Sambuceti; Silvia; Morbelli

    2015-01-01

    Metformin is the most widely used hypoglycemic agent. Besides its conventional indications, increasing evidence demonstrate a potential efficacy of this biguanide as an anticancer drug. Possible mechanisms of actions seem to be independent from its hypoglycemic effect and seemto involve the interference with key pathways in cellular proliferation and glycolysis. To date, many clinical trials implying the use of metformin in cancer treatment are on-going. The increasing use of 18F-2-fluoro-2-deoxyd-glucose positron emission tomography(FDG-PET) in cancer evaluation raises a number of questions about the possible interference of the biguanide on FDG distribution. In particular, the interferences exerted by metformin on AMP-activated protein kinase pathway(the cellular energy sensor), on insulin levels and on Hexokinase could potentially have repercussion on glucose handling and thus on FDG distribution. A better comprehension of the impact of metformin on FDG uptake is needed in order to optimize the use of PET in this setting. This evaluation would be useful to ameliorate scans interpretation in diabetic patients under chronic metformin treatment and to critically interpret images in the context of clinical trials. Furthermore, collecting prospective data in this setting would help to verify whether FDG-PET could be a valid tool to appreciate the anticancer effect of this new therapeutic approach.

  18. Addition of 2-deoxyglucose enhances growth inhibition but reverses acidification in colon cancer cells treated with phenformin.

    Science.gov (United States)

    Lea, Michael A; Chacko, Jerel; Bolikal, Sandhya; Hong, Ji Y; Chung, Ryan; Ortega, Andres; desbordes, Charles

    2011-02-01

    A report that effects of butyrate on some cells may be mediated by activation of AMP-activated protein kinase (AMPK) prompted this study which examines if other AMPK activators can induce differentiation and inhibit proliferation of colon cancer cells in a manner similar to butyrate. Using induction of alkaline phosphatase as a marker, it was observed that compound C, an AMPK inhibitor, is able to reduce the differentiating effect of butyrate on SW1116 and Caco-2 colon cancer cells. Metformin was observed to be less effective than butyrate in the induction of alkaline phosphatase but was more effective as a growth inhibitor. Phenformin was found to be a more potent growth inhibitor than metformin and both compounds cause acidification of the medium when incubated with colon cancer cells. Combined incubation of 2-deoxyglucose with either of the biguanides prevented the acidification of the medium but enhanced the growth inhibitory effects. PMID:21378320

  19. Newer Approaches In The Treatment of Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Kamlesh Patel

    2013-01-01

    Full Text Available Diabetes Mellitus is a public health problem worldwide. The most effective anti-diabetic drugs currently available include insulin and newer insulin preparations, sulphonylureas, biguanides, meglitinides, thiazolidinediones, alpha- glucosidase inhibitors, incretins, guargum and glucomannan. However, the future therapies will need to focus on those patents who do not respond well to these treatments and who account for 50% of the health care costs of diabetes mellitus. Drug development for diabetes mellitus has been directed at improving currently available drugs and findings new compounds. In this review article, we will review the role of future new chemical entities able to target the metabolic disorder. Some of these new anti-diabetic treatment strategies may in the future not only control symptoms and modify the natural course of diabetes, but also potentially prevent or cure the disease.

  20. Metformin inhibits lung cancer cells proliferation through repressing microRNA-222.

    Science.gov (United States)

    Wang, Yuqi; Dai, Weimin; Chu, Xiangyang; Yang, Bo; Zhao, Ming; Sun, Yu'e

    2013-12-01

    Metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis. However, the mechanism by which metformin affects various cancers, including lung cancer, remains unknown. MiR-222 induces cell growth and cell cycle progression via direct targeting of p27, p57 and PTEN in cancer cells. In the present study, we used A549 and NCI-H358 human lung cancer cell lines to study the effects and mechanisms of metformin. Metformin treatment reduced expression of miR-222 in these cells (p metformin. Therefore, these data provide novel evidence for a mechanism that may contribute to the anti-neoplastic effects of metformin suggested by recent population studies and justifying further work to explore potential roles for it in lung cancer treatment. PMID:23974492

  1. Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Hermansen, Kjeld; Mortensen, Lene S

    2007-01-01

    The majority of patients with type 2 diabetes mellitus are overweight or obese at the time of diagnosis, and obesity is a recognised risk factor for type 2 diabetes and coronary heart disease (CHD). Conversely, weight loss has been shown to improve glycaemic control in patients with type 2 diabetes......, as well as to lower the risk of CHD. The traditional pharmacotherapies for type 2 diabetes can further increase weight and this may undermine the benefits of improved glycaemic control. Furthermore, patients' desire to avoid weight gain may jeopardise compliance with treatment, thereby limiting treatment...... success and indirectly increasing the risk of long-term complications. This review evaluates the influences of established and emerging therapies on bodyweight in type 2 diabetes.Improvement in glycaemic control with insulin secretagogues has been associated with weight gain. On the other hand, biguanides...

  2. Curing Kinetics and Thermal Stability of Diglycidyl Ether of Bisphenol-A Using Mixtures of Heterocyclic Derivatives of Stannanes and 4,4'-Diaminodiphenylsulfone

    Institute of Scientific and Technical Information of China (English)

    SINGH Vikram; DEEP Gagan; NARULA Anudeep Kumar

    2008-01-01

    Curing kinetics of diglycidyl ether of bisphenol-A (DGEBA) in the presence of varying molar ratios of derivafives of stannanes to 4,4'-diaminodiphenylsulfone (DDS) was investigated by the dynamic differential scanning calorimetry. The derivatives were synthesized by reacting 1 mole of biguanide (B) with 1 mole of phenylethyltindihydride (PETH) or phenylmethyltindihydride (PMTH) or phenylbutyltindihydride (PBTH) and designated as BPETH or BPMTH or BPBTH respectively. These derivatives were characterized by elemental analysis and spectroscopic techniques such as IR, 1H NMR, 13C NMR and 119Sn NMR. The mixtures of these derivatives to DDS at of epoxy resins. The thermal stability of the isothermally cured resins was also evaluated using dynamic thermogravimetry in a nitrogen atmosphere.

  3. Antimocrobial Polymer

    Energy Technology Data Exchange (ETDEWEB)

    McDonald, William F. (Utica, OH); Huang, Zhi-Heng (Walnut Creek, CA); Wright, Stacy C. (Columbus, GA)

    2005-09-06

    A polymeric composition having antimicrobial properties and a process for rendering the surface of a substrate antimicrobial are disclosed. The composition comprises a crosslinked chemical combination of (i) a polymer having amino group-containing side chains along a backbone forming the polymer, (ii) an antimicrobial agent selected from quaternary ammonium compounds, gentian violet compounds, substituted or unsubstituted phenols, biguanide compounds, iodine compounds, and mixtures thereof, and (iii) a crosslinking agent containing functional groups capable of reacting with the amino groups. In one embodiment, the polymer is a polyamide formed from a maleic anhydride or maleic acid ester monomer and alkylamines thereby producing a polyamide having amino substituted alkyl chains on one side of the polyamide backbone; the crosslinking agent is a phosphine having the general formula (A)3P wherein A is hydroxyalkyl; and the antimicrobial agent is chlorhexidine, dimethylchlorophenol, cetyl pyridinium chloride, gentian violet, triclosan, thymol, iodine, and mixtures thereof.

  4. Metformin: A Hopeful Promise in Aging Research.

    Science.gov (United States)

    Novelle, Marta G; Ali, Ahmed; Diéguez, Carlos; Bernier, Michel; de Cabo, Rafael

    2016-03-01

    Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and age-related pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector. PMID:26931809

  5. Cobalamin Deficiency in Elderly Patients: A Personal View

    Directory of Open Access Journals (Sweden)

    Emmanuel Andrès

    2008-01-01

    Full Text Available Cobalamin (vitamin B12 deficiency is particularly common in the elderly (>65 years of age but is often unrecognized because its clinical manifestations are subtle; however, they are also potentially serious, particularly from a neuropsychiatric and hematological perspective. In the elderly, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. Food-cobalamin malabsorption syndrome is a disorder characterized by the inability to release cobalamin from food or its binding proteins. This syndrome is usually caused by atrophic gastritis, related or unrelated to Helicobacter pylori infection, and long-term ingestion of antacids and biguanides. Management of cobalamin deficiency with cobalamin injections is currently well documented but new routes of cobalamin administration (oral and nasal are being studied, especially oral cobalamin therapy for food-cobalamin malabsorption.

  6. SGLT 2 Inhibitors: A New Therapeutic Target And Its Role In Current Clinical Practice

    Directory of Open Access Journals (Sweden)

    PV Shiji

    2015-10-01

    Full Text Available Diabetes, one of the major life style diseases, is associated with high morbidity and mortality owing to its microvascular and macrovascular complications. The chance of development of various complications can be effectively prevented by tight glycemic control. We have various groups of drugs like Biguanides, Sulfonyl ureas, Glitazones, Alpha-glucosidase inhibitors, Incretin based therapy, Insulin and Insulin analogues in the armamentarium to treat diabetes. But still, the number of patients attaining glycemic targets are relatively low and various adverse effect limit the use of some of these drugs, especially in special groups. Hence there is ongoing research to develop newer and newer drugs which provide sustained blood glucose reduction with minimal adverse effects. SGLT-2 inhibitors are a new group of drugs recently approved by FDA to treat Diabetes. In this review we discuss about mechanism of action, various adverse effects and the clinical role of various SGLT-2 Inhibitors.

  7. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes

    DEFF Research Database (Denmark)

    Zander, M; Taskiran, M; Toft-Nielsen, M B;

    2001-01-01

    OBJECTIVE: The incretin hormone glucagon-like peptide-1 (GLP-1) reduces plasma glucose in type 2 diabetic patients by stimulating insulin secretion and inhibiting glucagon secretion. The biguanide metformin is believed to lower plasma glucose without affecting insulin secretion. We conducted...... this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally......) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol x kg(-1) x min(-1)) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite. RESULTS: Fasting plasma glucose (day 2...

  8. FORMULATION AND EVALUATION OF MOUTH DISSOLVING TABLETS OF METFORMIN HYDROCHLORIDE

    Directory of Open Access Journals (Sweden)

    Shaikh T.H.

    2012-06-01

    Full Text Available Metformin HCl is a biguanide antihyperglycemic agent used for treating non-insulin-dependent diabetes mellitus (NIDDM. It improves glycemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin-mediated glucose uptake. In the present study an attempt has been made to prepare fast dissolving tablets of Metformin HCl in the oral cavity with enhanced dissolution rate. The tablets were prepared with three superdisintegrants e.g:, Croscarmellose sodium, Sodium starch glycolate and Crospovidone. The blend was examined for angle of repose, bulk density, tapped density, compressibility index and hausners ratio. The tablets were evaluated for hardenss, friability, disintegration time, dissolution rate,drug content, and were found to be within 1 min. It was concluded that the mouth dissolving tablets with proper hardness, rapidly disintegrating with enhanced dissolution can be made using selected superdisintegrants.

  9. Metformin: A Novel but Controversial Drug in Cancer Prevention and Treatment.

    Science.gov (United States)

    Sui, Xinbing; Xu, Yinghua; Wang, Xian; Han, Weidong; Pan, Hongming; Xiao, Mang

    2015-11-01

    Metformin, a biguanide derivative that is widely used for treating type 2 diabetes mellitus, has recently been shown to exert potential anticancer effects. Many retrospective data and laboratory studies suggest the idea that metformin has antineoplastic activity, but some other studies reach conflicting conclusions. Although the precise molecular mechanisms by which metformin affects various cancers have not been fully elucidated, activation of AMPK-dependent and AMPK-independent pathways along with energy metabolism aberration, cell cycle arrest and apoptosis or autophagy induction have emerged as crucial regulators in this process. In this Review, we describe the role of metformin in the prevention and treatment of a variety of cancers and summarize the molecular mechanisms that are currently well documented in the ability of metformin as an anticancer agent. In addition, the scientific and clinical hurdles regarding the potential role of metformin in cancer will be discussed.

  10. LOW LEVELS OF SERUM CYANOCOBALAMIN IN A METFORMIN-TREATED PATIENT. CASE REPORT AND COMPARISON WITH LITERATURE DATA.

    Science.gov (United States)

    Strugaru, Anca-Monica; Botnariu, Gina; Tuchiluş, Cristina; Anisie, Ecaterina; Agoroaei, Luminiţa; Grigoriu, Ioana-Cezara; Butnaru, Elena

    2016-01-01

    Metformin is a widely used oral antidiabetic biguanide compound. According to the literature, metformin may lower the serum cyanocobalamin levels. We present the case of a 71-old-male treated with metformin for 15 years. When presenting to a periodic checkup, low serum cyanocobalamin levels where found. Laboratory tests showed levels below normal range for hemoglobin (12.7 g/dL) and hematocrit (37.8%). After patient reevaluation, a change in antidiabetic treatment will be considered if metformin will be found the cause of low serum cyanocobalamin levels. Other cases reported in the literature support this hypothesis, justifying the study of the influence of metformin therapy on serum vitamin B12 levels in patients diagnosed with diabetes. The influence of patient age, metformin dosage, duration of treatment and time since diabetes diagnosis on serum levels of vitamin B12 also need to be determined.

  11. 瑞格列奈二甲双胍片中乙醇残留量的测定%Determination of repaglinide metformin tablets ethanol residues

    Institute of Scientific and Technical Information of China (English)

    刘芳; 张丽娟; 王建平

    2014-01-01

    瑞格列奈是一种非磺酰脲类促胰岛素分泌剂,盐酸二甲双胍是一种双胍类的降血糖药,其组成的固定复方降血糖药,治疗单独应用瑞格列奈或盐酸二甲双胍不能有效控制血糖或者已经服用瑞格列奈和盐酸二甲双胍治疗的2型糖尿病患者。%repaglinide is a non-sulfonylurea insulin secretagogue, a biguanide is metformin hydrochloride hypoglycemic agents, consisting of a fixed combination of hypoglycemic agents, the treatment of repaglinide or metformin hydrochloride alone can not effectively control blood sugar or already taking repaglinide and metformin hydrochloride treatment of type 2 diabetes.

  12. Risk of cardiovascular disease

    DEFF Research Database (Denmark)

    Gejl, Michael; Starup-Linde, Jakob; Thomsen, Jan Lykke Scheel;

    2015-01-01

    AIMS: Type 2 diabetes (DM) increases the risk of cardiovascular disease. We investigated the effects of antidiabetic drugs on the composite endpoint (CE) of ischemic heart disease, heart failure or stroke in DM patients. METHODS: We conducted a nested case-control study. Cases were DM patients who......% CI: 16.88-24.12), neuropathy (OR=1.39, 95% CI: 1.05-1.85) and peripheral artery disease (OR=1.31, 95% CI: 1.02-1.69) increased the risk of CE. Biguanides (OR=0.62 95% CI; 0.54-0.71) and liraglutide (OR=0.48 95% CI; 0.38-0.62) significantly decreased the risk of CE as did statin treatment (OR=0.63, 95...

  13. ROLE FAILURE CORRECTION OF 25(OHD IN PATIENTS WITH POLYCYSTIC OVARY SYNDROME

    Directory of Open Access Journals (Sweden)

    M. V. Matveyeva

    2015-01-01

    Full Text Available Objective. To estimate the correction failure 25 (OH D in patients with polycystic ovary syndrome.Material and Methods. The study involved 44 patients with polycystic ovary syndrome, aged 31.32 ± 5.05, who were randomly assigned to 2 groups: 1st – obtained coca biguanides and Kolekaltsiferol, second – combined oral contraceptive (combined hormonal and biguanides. The comparison group consisted of 22 healthy women matched for age and sex. Polycystic Ovarian Syndrome (PCOS was verified on theОригинальные статьиБюллетень сибирской медицины, 2015, том 14, № 5, с. 47–53 53basis of diagnostic criteria ESHRE / ASRM (2012. 25 (OH vitamin D was determined by enzyme-linked immunosorbent assay (ELISA ng/ml. Examined glucose and fasting insulin, HOMA index of insulin re-sistance. Depression was assessed using the Beck test. Statistical analysis – R-system.Results. The patients with PCOS defined by the expression deficit of 25 (OH D, which is associated with hyperandrogenism, hyperglycemia, hyperinsulinemia, insulin resistance, as well as depression. Ad-mission kolekaltsiferola leads to improved glucose metabolism and manifestations of PCOS, and also significantly reduces the parameters of OT, OT / OB, depression.Conclusion. Failure correction of 25 (OH D contributes to the improvement of metabolic and psycho-logical parameters of fertility.

  14. Antitumor mechanisms of metformin: Signaling, metabolism, immunity and beyond

    Directory of Open Access Journals (Sweden)

    Ismael Samudio

    2010-08-01

    Full Text Available Metformin is a synthetic biguanide first described in the 1920´s as a side product of the synthesis of N,N-dimethylguanidine. Like otherrelated biguanides, metformin displays antihyperglycemic properties, and has become the most widely prescribed oral antidiabetic medicinearound the world. Intriguing recent evidence suggests that metformin has chemopreventive and direct antitumor properties, and severalongoing clinical studies around the world are using this agent alone or in combination with chemotherapeutic schemes to determineprospectively its safety and efficacy in the treatment of human cancer. Notably, immune activating effects of metformin have recently beendescribed, and may support a notion put forth in the 1950s that this agent possessed antiviral and antimalarial effects. However, how theseeffects may contribute to its observed antitumor effects in retrospective studies has not been discussed. Mechanistically, metformin has beenshown to activate liver kinase B1 (LKB1 and its downstream target AMP-activated kinase (AMPK. The activation of AMPK has beenproposed to mediate metformin´s glucose lowering effect, although recent evidence suggests that this agent can inhibit electron transport inhepatocyte mitochondria resulting in AMPK-independent inhibition of hepatic gluconeogenesis. Likewise, albeit activation of AMPK andthe resulting inhibition of the mammalian target of rapamycin (mTOR signaling have been suggested to mediate the antitumor effects ofmetformin, AMPK-independent growth inhibitory properties of this agent in tumor cells have also been described. Here we present a briefreview of the signaling, metabolic, and immune effects of metformin and discuss how their interplay may orchestrate the antitumor effectsof this agent. In addition, we provide the rationale for a compassionate use study of metformin in combination with metronomic chemotherapy.

  15. Acanthamoeba encystment: multifactorial effects of buffers, biocides, and demulcents present in contact lens care solutions

    Directory of Open Access Journals (Sweden)

    Kovacs CJ

    2015-10-01

    Full Text Available Christopher J Kovacs, Shawn C Lynch, Marjorie J Rah, Kimberly A Millard, Timothy W Morris Bausch & Lomb Incorporated, Rochester, NY, USA Purpose: To determine whether agents which are purportedly capable of inducing encystment of Acanthamoeba can recapitulate the signal when tested in differing formulations. Methods: In accordance with the International Standard ISO 19045, Acanthamoeba castellanii ATCC 50370 trophozoites were cultured in antibiotic-free axenic medium, treated with test solutions, and encystment rates plus viability were measured via bright field and fluorescent microscopy. Test solutions included phosphate-buffered saline (PBS, borate-buffered saline, biguanide- and hydrogen peroxide (H2O2-based biocides, propylene glycol (PG and povidone (POV ophthalmic demulcents, and one-step H2O2-based contact lens disinfection systems. Results: Only PBS solutions with 0.25 ppm polyaminopropyl biguanide (PAPB and increasing concentrations of PG and POV stimulated A. castellanii encystment in a dose-dependent manner, whereas PBS solutions containing 3% H2O2 and increasing concentrations of PG and POV did not stimulate encystment. Borate-buffered saline and PBS/citrate solutions containing PG also did not stimulate encystment. In addition, no encystment was observed after 24 hours, 7 days, or 14 days of exposures of trophozoites to one-step H2O2 contact lens disinfection products or related solutions. Conclusion: The lack of any encystment observed when trophozoites were treated with existing or new one-step H2O2 contact lens care products, as well as when trophozoites were exposed to various related test solutions, confirms that Acanthamoeba encystment is a complex process which depends upon simultaneous contributions of multiple factors including buffers, biocides, and demulcents. Keywords: propylene glycol, contact lens care system, hydrogen peroxide disinfecting solution

  16. Metformin-associated lactic acidosis: Current perspectives on causes and risk.

    Science.gov (United States)

    DeFronzo, Ralph; Fleming, G Alexander; Chen, Kim; Bicsak, Thomas A

    2016-02-01

    Although metformin has become a drug of choice for the treatment of type 2 diabetes mellitus, some patients may not receive it owing to the risk of lactic acidosis. Metformin, along with other drugs in the biguanide class, increases plasma lactate levels in a plasma concentration-dependent manner by inhibiting mitochondrial respiration predominantly in the liver. Elevated plasma metformin concentrations (as occur in individuals with renal impairment) and a secondary event or condition that further disrupts lactate production or clearance (e.g., cirrhosis, sepsis, or hypoperfusion), are typically necessary to cause metformin-associated lactic acidosis (MALA). As these secondary events may be unpredictable and the mortality rate for MALA approaches 50%, metformin has been contraindicated in moderate and severe renal impairment since its FDA approval in patients with normal renal function or mild renal insufficiency to minimize the potential for toxic metformin levels and MALA. However, the reported incidence of lactic acidosis in clinical practice has proved to be very low (metformin are too conservative, thus depriving a substantial number of type 2 diabetes patients from the potential benefit of metformin therapy. On the other hand, the success of metformin as the first-line diabetes therapy may be a direct consequence of conservative labeling, the absence of which could have led to excess patient risk and eventual withdrawal from the market, as happened with earlier biguanide therapies. An investigational delayed-release metformin currently under development could potentially provide a treatment option for patients with renal impairment pending the results of future studies. This literature-based review provides an update on the impact of renal function and other conditions on metformin plasma levels and the risk of MALA in patients with type 2 diabetes.

  17. 社区医院2008~2010年口服降糖药物应用分析%Analysis of oral hypoglycemic drug use in community hospitals: 2008 ~ 2010

    Institute of Scientific and Technical Information of China (English)

    赵大贵; 杜伟

    2011-01-01

    目的 分析社区医院口服降糖药的应用特点和发展趋势,为临床合理用药提供参考.方法对宜宾市南岸文化广场社区卫生服务中心2008~2010年口服降糖药应用品种、销售金额、用药频度(DDDs)和日均费用(DDC)进行回顾性分析.结果 3年口服降糖药销售金额占抗糖尿病药总金额80%以上;销售金额、DDDs排序前3位的依次是:双胍类、磺酰脲类、餐时血糖调节剂;3年中,二甲双胍缓释片、格列吡嗪缓释片、瑞格列奈位列单品种销售金额前3位;噻唑烷二酮类DDC最高,二甲双胍缓释片、格列吡嗪缓释片DDC较低,在使用上占主导地位.结论社区口服降糖药用药较合理,双胍类、磺酰脲类、餐时血糖调节剂的应用,与社区医院药物治疗糖尿病策略是相符的.%Objective To analyze retrospectively the status quo and tendency of oral hypoglycemic drug use in community hospitals,and provide basis for rational drug use. Methods The article analyzed statistically oral hypoglycemic drugs used during the period of 2008 ~ 2010 in respect of varieties, sales amount,drug daily dosages (DDDS) and defined daily consumption ( DDC). Results The sales amount of oral hypoglycemic drug accounted for more than 80% of the total sales amount of antidiabetic for three successive years. The top three oral hypoglycemic drugs according to sales amount and DDDS were Biguanide,sulfonylurea and prandial glucose regulator. The top three oral hypoglycemic drugs according to sale of single-species were Biguanide,Glipizide Sustained-Release Tablets and Repaglinide. The DDC of thiazolidinediones was the highest,and those of Glipizide Sustained-Release Tablets and Repaglinide were lower,which became the most frequently used drugs in clinic. Conclusion The study shows that the utilization of oral hypoglycemic a-gents in community hospitals is basically rational. Biguanide, sulfonylurea and prandial glucose regulator are used in the way

  18. Arterial stiffness, as monitored by cardio–ankle vascular index, is affected by obstructive sleep apnea, blood glucose control, and body weight – a case with 8 years follow up

    Directory of Open Access Journals (Sweden)

    Shimizu K

    2016-08-01

    Full Text Available Kazuhiro Shimizu,1 Tomoyuki Yamamoto,2,3 Kohji Shirai2,4 1Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan; 2Department of Vascular Function, Toho University Sakura Medical Center, Chiba, Japan; 3Biological Information Analysis Section, Fukuda Denshi Co., Ltd., Tokyo, Japan; 4Department of Internal Medicine, Mihama Hospital, Chiba, Japan Abstract: The cardio–ankle vascular index (CAVI is an indicator of arterial stiffness from the heart to the ankles. The CAVI increases as arteriosclerosis progresses, but it can be decreased by appropriate treatment. There are several risk factors for coronary artery disease, however, the degree of stress caused by each separate risk factor to arteries cannot be assessed. CAVI increases with age and according to the severity of atherosclerosis. We found that CAVI also changes in response to the control of risk factors, which may be associated with the functional stiffness of arteries. CAVI can be a useful indicator of risk control for coronary artery disease. We followed a patient aged 71 years who had diabetes mellitus and obstructive sleep apnea (OSA by measuring CAVI for 8 years from age 63. He underwent coronary artery bypass grafting due to angina pectoris when he was 63 years old. Before coronary artery bypass grafting, CAVI was 11.8 on the right and 11.5 on the left. Three years later he was found to have OSA and received treatment with continuous positive airway pressure. There was a marked improvement in CAVI after continuous positive airway pressure (age 68; right 10.4, left 10.2. However, following a gradual increase in body weight and worsening of diabetes mellitus, CAVI showed an increasing trend. CAVI decreased with biguanides treatment, but increased again with an increase in body weight. In conclusion, CAVI responded to the patient’s conditions including obesity, diabetes mellitus, and OSA. CAVI is not only a marker of arterial stiffness, but can also be a

  19. Evaluation, efficacy and tolerability of GlucoNovax tablet in type 2 diabetic patients.

    Science.gov (United States)

    Ali, Zubair; Daniyal, Muhammad; S I, Ismailov; Usmanghani, Khan; Naveed, Safila

    2016-07-01

    Type 2 diabetes mellitus (T2D) is a chronic metabolic disease regarded as insulin resistance and progressive failure of β cells. Beta cells secretagogues are useful to reach satisfactory glycemic control. Glimepiride is a second-generation sulfonylurea excites pancreatic beta cells to discharge insulin. Glimepiride may be safer to use in patients with cardiovascular disease due to lack of destructive effects on ischemic preconditioning. It is effective in dropping fasting plasma glucose (FPG), postprandial glucose and glycated hemoglobin levels and is a useful and cost-effective option treatment for the management of T2D. Total 40 patients were selected from OPD setting at RSNPMTS Endocrinology center Ministry of Health Republic of Uzbekistan, and corresponding to criteria for inclusion / exclusion. 10 patients with T2D switched from receiving other forms of Glimepiride (Amaryl) on an identical dose of GlucoNovax in combination with biguanides (Metformin) denoted as group 1. At the same time the dose of biguanides (Metformin) was not altered for the period of the study. 10 patients with T2D switched from receiving other forms of Glimepiride (Amaryl) on an identical dose of GlucoNovax denoted as group 2.10 patients with T2D switched to the drug GlucoNovax from the drug Glibenclamide denoted as group 3. The control group received monotherapy with Amaryl it consist of 10 patients with T2D denoted as group 4. The severity of diabetic complaints in patients receiving the combination drug GlucoNovax with metformin significantly decreased by the end of the observation period and had an inclination to reduction in the 2nd and 3rd groups, along with the control group. 30 patients, receiving the drug Gluco Novax, 7 achieved blood glucose level parameters that corresponding to the high effectiveness of the drug (4 of them from 1st group (GlucoNovax+ Metformin), 1 in the 2nd group, 2 in the 3rd group). 6 patients achieved blood glucose levels parameters, meeting the criteria

  20. Oncometabolic mutation IDH1 R132H confers a metformin-hypersensitive phenotype

    Science.gov (United States)

    Cuyàs, Elisabet; Fernández-Arroyo, Salvador; Corominas-Faja, Bruna; Rodríguez-Gallego, Esther; Bosch-Barrera, Joaquim; Martin-Castillo, Begoña; De Llorens, Rafael; Joven, Jorge; Menendez, Javier A.

    2015-01-01

    Metabolic flexibility might be particularly constrained in tumors bearing mutations in isocitrate dehydrogenase 1 (IDH1) leading to the production of the oncometabolite 2-hydroxygluratate (2HG). To test the hypothesis that IDH1 mutations could generate metabolic vulnerabilities for therapeutic intervention, we utilized an MCF10A cell line engineered with an arginine-to-histidine conversion at position 132 (R132H) in the catalytic site of IDH1, which equips the enzyme with a neomorphic α-ketoglutarate to 2HG reducing activity in an otherwise isogenic background. IDH1 R132H/+ and isogenic IDH1 +/+ parental cells were screened for their ability to generate energy-rich NADH when cultured in a standardized high-throughput Phenotype MicroArrayplatform comprising >300 nutrients. A radical remodeling of the metabotype occurred in cells carrying the R132H mutation since they presented a markedly altered ability to utilize numerous carbon catabolic fuels. A mitochondria toxicity-screening modality confirmed a severe inability of IDH1-mutated cells to use various carbon substrates that are fed into the electron transport chain at different points. The mitochondrial biguanide poisons, metformin and phenformin, further impaired the intrinsic weakness of IDH1-mutant cells to use certain carbon-energy sources. Additionally, metabolic reprogramming of IDH1-mutant cells increased their sensitivity to metformin in assays of cell proliferation, clonogenic potential, and mammosphere formation. Targeted metabolomics studies revealed that the ability of metformin to interfere with the anaplerotic entry of glutamine into the tricarboxylic acid cycle could explain the hypersensitivity of IDH1-mutant cells to biguanides. Moreover, synergistic interactions occurred when metformin treatment was combined with the selective R132H-IDH1 inhibitor AGI-5198. Together, these results suggest that therapy involving the simultaneous targeting of metabolic vulnerabilities with metformin, and 2HG

  1. Spectroscopic and molecular modelling studies of binding mechanism of metformin with bovine serum albumin

    Science.gov (United States)

    Sharma, Deepti; Ojha, Himanshu; Pathak, Mallika; Singh, Bhawna; Sharma, Navneet; Singh, Anju; Kakkar, Rita; Sharma, Rakesh K.

    2016-08-01

    Metformin is a biguanide class of drug used for the treatment of diabetes mellitus. It is well known that serum protein-ligand binding interaction significantly influence the biodistribution of a drug. Current study was performed to characterize the binding mechanism of metformin with serum albumin. The binding interaction of the metformin with bovine serum albumin (BSA) was examined using UV-Vis absorption spectroscopy, fluorescence, circular dichroism, density functional theory and molecular docking studies. Absorption spectra and fluorescence emission spectra pointed out the weak binding of metformin with BSA as was apparent from the slight change in absorbance and fluorescence intensity of BSA in presence of metformin. Circular dichroism study implied the significant change in the conformation of BSA upon binding with metformin. Density functional theory calculations showed that metformin has non-planar geometry and has two energy states. The docking studies evidently signified that metformin could bind significantly to the three binding sites in BSA via hydrophobic, hydrogen bonding and electrostatic interactions. The data suggested the existence of non-covalent specific binding interaction in the complexation of metformin with BSA. The present study will certainly contribute to the development of metformin as a therapeutic molecule.

  2. Inhibition of the anti-staphylococcal activity of the antiseptic polihexanide by mucin.

    Science.gov (United States)

    Ansorg, Rainer; Rath, Peter-Michael; Fabry, Werner

    2003-01-01

    The antiseptic Lavasept (LS), containing the polymeric biguanide polihexanide (CAS 28757-48-4), possesses microbicidal activity against a broad spectrum of bacteria including Staphylococcus aureus. It is used for antiseptic wound care in concentrations corresponding to 0.2-0.4 mg polihexanide per ml. To obtain basic data on its ability to eradicate S. aureus colonizing the nasal mucosa, the influence of mucin on the anti-staphylococcal activity was investigated. A disk agar-diffusion method was applied. Two reference strains of S. aureus (methicillin-sensitive S. aureus ATCC 29213 and methicillin-resistant S. aureus ATCC 33591) and 20 fresh clinical isolates were used. In the absence of mucin, the growth of all strains was inhibited by polihexanide concentrations of 0.1 mg/ml. In the presence of 0.25% mucin in the test medium, a concentration of 0.4 mg/ml was necessary to inhibit all strains. Mucin concentrations of 0.5% and 1%, that are even lower than the mucin concentrations in healthy nasal secretions, abolished the activity of the therapeutic concentrations of polihexanide. It is concluded that the inactivation of LS by mucin obstructs a reliable clearance of nasal S. aureus carriage.

  3. Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB.

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    Rebuma Firdessa

    Full Text Available Cutaneous leishmaniasis (CL is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed.Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide, a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN. PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB.Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators.

  4. Noninsulin pharmacological management of type 1 diabetes mellitus

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    Vishvas Garg

    2011-01-01

    Full Text Available The injectable nature and other shortcomings of insulin have stimulated interest in studying the noninsulin pharmacological therapies to manage type 1 diabetes mellitus (T1DM. The purpose of this study is to conduct a systematic literature review of noninsulin pharmacological therapies for the management of T1DM. For this, the following PubMed search was conducted: Diabetes Mellitus, Type 1/therapy"[Mesh] Limits: Review Sort by: Publication Date. After applying various inclusion and exclusion criteria, a total of 63 studies were reviewed. Based on this review, noninsulin pharmacological therapies can be divided into following classes: (1 Insulin-sensitizing agents (biguanides and thiazolidinediones, (2 gastrointestinal nutrient absorption modulators (α-Glucosidase inhibitors and amylin, (3 immunotherapeutic agents, (4 incretin-based therapies, (5 recombinant human insulin-like growth factors, and (6 other promising therapeutics. Some of these are already used either as monotherapy or adjuvant to insulin, whereas, to manage T1DM, the benefits and risks of the others are still under evaluation. Nonetheless, insulin still remains the cornerstone to manage the T1DM.

  5. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk.

    Science.gov (United States)

    Lien, Fleur; Berthier, Alexandre; Bouchaert, Emmanuel; Gheeraert, Céline; Alexandre, Jeremy; Porez, Geoffrey; Prawitt, Janne; Dehondt, Hélène; Ploton, Maheul; Colin, Sophie; Lucas, Anthony; Patrice, Alexandre; Pattou, François; Diemer, Hélène; Van Dorsselaer, Alain; Rachez, Christophe; Kamilic, Jelena; Groen, Albert K; Staels, Bart; Lefebvre, Philippe

    2014-03-01

    The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis. PMID:24531544

  6. Component Analysis of Multipurpose Contact Lens Solutions To Enhance Activity against Pseudomonas aeruginosa and Staphylococcus aureus.

    Science.gov (United States)

    Lin, Leo; Kim, Janie; Chen, Hope; Kowalski, Regis; Nizet, Victor

    2016-07-01

    More than 125 million people wear contact lenses worldwide, and contact lens use is the single greatest risk factor for developing microbial keratitis. We tested the antibacterial activity of multipurpose contact lens solutions and their individual component preservatives against the two most common pathogens causing bacterial keratitis, Pseudomonas aeruginosa and Staphylococcus aureus The in vitro antibacterial activity of five multipurpose contact lens solutions (Opti-Free GP, Boston Simplus, Boston Advance, Menicare GP, and Lobob) was assayed by the standard broth dilution method. Synergy between the preservative components found in the top performing solutions was assayed using checkerboard and time-kill assays. The ISO 14729 criteria and the standard broth dilution method were used to define an optimized contact lens solution formulation against a clinical panel of drug-susceptible and drug-resistant P. aeruginosa and S. aureus strains. Preservatives with the biguanide function group, chlorhexidine and polyaminopropylbiguanide (PAPB), had the best antistaphylococcal activity, while EDTA was the best antipseudomonal preservative. The combination of chlorhexidine and EDTA had excellent synergy against P. aeruginosa A solution formulation containing chlorhexidine (30 ppm), PAPB (5 ppm), and EDTA (5,000 ppm) had three to seven times more antipseudomonal activity than anything available to consumers today. A multipurpose contact lens solution containing a combination of chlorhexidine, PAPB, and EDTA could help to reduce the incidence of microbial keratitis for contact lens users worldwide. PMID:27139484

  7. Cost analysis study of oral antidiabetic drugs available in Indian market

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    Nisharani B Jadhav, Manisha S Bhosale, Charles V Adhav

    2013-01-01

    Full Text Available There exists a wide range of variation in the prices of drugs marketed in India and other countries of the world. Very few studies have been conducted to reveal such price variations in the open market. Aim & Objectives: To evaluate the cost of oral anti-diabetics of different generic classes and different brand names of one compound, To evaluate the difference in cost of different brands for the same active drug by calculating percentage variation of cost. Methods: Cost of a particular drug being manufactured by different companies, in the same strength, number and dosage form was compared. The difference in the maximum and minimum price of the same drug manufactured by different pharmaceutical companies and the percentage variation in price was calculated. Results: In Single drug therapy, among sulfonylurea group of drugs, Glimepiride (1 mg shows maximum price variation of 655.38%, while Glipizide (10mg shows variation of 38.88%. In Biguanides & Thizolidinediones groups of drugs, Metformin (500 mg & Pioglitazone (15 mg show maximum price variation of 308.33% & 542% respectively. In α-glucosidases inhibitor group of drugs, Miglitol shows maximum price variation of 135.50 %. In combination therapies, Glipizide & Metformin combination shows the maximum variation up to 399.04 %. Conclusion: The average percentage price variation of different brands of the same drug manufactured in India is very wide and the appraisal and management of marketing drugs should be directed toward maximizing the benefits of therapy and minimizing negative personal and economic consequences

  8. Biofilms of Enterococcus faecalis and Enterococcus faecium isolated from the processing of ricotta and the control of these pathogens through cleaning and sanitization procedures.

    Science.gov (United States)

    da Silva Fernandes, Meg; Kabuki, Dirce Yorika; Kuaye, Arnaldo Yoshiteru

    2015-05-01

    The biofilm formation of Enterococcus faecalis and Enterococcus faecium isolated from the processing of ricotta on stainless steel coupons was evaluated, and the effect of cleaning and sanitization procedures in the control of these biofilms was determined. The formation of biofilms was observed while varying the incubation temperature (7, 25 and 39°C) and time (0, 1, 2, 4, 6 and 8 days). At 7°C, the counts of E. faecalis and E. faecium were below 2 log10 CFU/cm(2). For the temperatures of 25 and 39°C, after 1 day, the counts of E. faecalis and E. faecium were 5.75 and 6.07 log10 CFU/cm(2), respectively, which is characteristic of biofilm formation. The tested sanitation procedures a) acid-anionic tensioactive cleaning, b) anionic tensioactive cleaning+sanitizer and c) acid-anionic tensioactive cleaning+sanitizer were effective in removing the biofilms, reducing the counts to levels below 0.4 log10 CFU/cm(2). The sanitizer biguanide was the least effective, and peracetic acid was the most effective. These studies revealed the ability of enterococci to form biofilms and the importance of the cleaning step and the type of sanitizer used in sanitation processes for the effective removal of biofilms.

  9. Pharmacogenomics in type 2 diabetes: oral antidiabetic drugs.

    Science.gov (United States)

    Daniels, M A; Kan, C; Willmes, D M; Ismail, K; Pistrosch, F; Hopkins, D; Mingrone, G; Bornstein, S R; Birkenfeld, A L

    2016-10-01

    Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.

  10. Recent Trends in Therapeutic Approaches for Diabetes Management: A Comprehensive Update.

    Science.gov (United States)

    Tiwari, Pragya

    2015-01-01

    Diabetes highlights a growing epidemic imposing serious social economic crisis to the countries around the globe. Despite scientific breakthroughs, better healthcare facilities, and improved literacy rate, the disease continues to burden several sections, especially middle and low income countries. The present trends indicate the rise in premature death, posing a major threat to global development. Scientific and technological advances have witnessed the development of newer generation of drugs like sulphonylureas, biguanides, alpha glucosidase inhibitors, and thiazolidinediones with significant efficacy in reducing hyperglycemia. Recent approaches in drug discovery have contributed to the development of new class of therapeutics like Incretin mimetics, Amylin analogues, GIP analogs, Peroxisome proliferator activated receptors, and dipeptidyl peptidase-4 inhibitor as targets for potential drugs in diabetes treatment. Subsequently, the identification and clinical investigation of bioactive substances from plants have revolutionized the research on drug discovery and lead identification for diabetes management. With a focus on the emerging trends, the review article explores the current statistical prevalence of the disease, discussing the benefits and limitations of the commercially available drugs. Additionally, the critical areas in clinical diabetology are discussed, with respect to prospects of statins, nanotechnology, and stem cell technology as next generation therapeutics and why the herbal formulations are consistently popular choice for diabetes medication and management.

  11. The Prelude on Novel Receptor and Ligand Targets Involved in the Treatment of Diabetes Mellitus

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    Venu Gopal Jonnalagadda

    2014-05-01

    Full Text Available Metabolic disorders are a group of disorders, due to the disruption of the normal metabolic process at a cellular level. Diabetes Mellitus and Tyrosinaemia are the majorly reported metabolic disorders. Among them, Diabetes Mellitus is a one of the leading metabolic syndrome, affecting 5 to 7 % of the population worldwide and mainly characterised by elevated levels of glucose and is associated with two types of physiological event disturbances such as impaired insulin secretion and insulin resistance. Up to now, various treatment strategies are like insulin, alphaglucosidase inhibitors, biguanides, incretins were being followed. Concurrently, various novel therapeutic strategies are required to advance the therapy of Diabetes mellitus. For the last few decades, there has been an extensive research in understanding the metabolic pathways involved in Diabetes Mellitus at the cellular level and having the profound knowledge on cell-growth, cell-cycle, and apoptosis at a molecular level provides new targets for the treatment of Diabetes Mellitus. Receptor signalling has been involved in these mechanisms, to translate the information coming from outside. To understand the various receptors involved in these pathways, we must have a sound knowledge on receptors and ligands involved in it. This review mainly summarises the receptors and ligands which are involved the Diabetes Mellitus. Finally, researchers have to develop the alternative chemical moieties that retain their affinity to receptors and efficacy. Diabetes Mellitus being a metabolic disorder due to the glucose surfeit, demands the need for regular exercise along with dietary changes.

  12. Interaction and effectiveness of antimicrobials along with healing-promoting agents in a novel biocellulose wound dressing.

    Science.gov (United States)

    Napavichayanun, Supamas; Amornsudthiwat, Phakdee; Pienpinijtham, Prompong; Aramwit, Pornanong

    2015-10-01

    An ideal wound dressing should keep the wound moist, allow oxygen permeation, adsorb wound exudate, accelerate re-epithelialization for wound closure, reduce pain and healing time, and prevent infection. Our novel biocellulose-based wound dressing was composed of three components: 1) biocellulose (BC), intended to create a moist and oxygen-permeated environment with exudate adsorption; 2) silk sericin (SS) known for its enhancement of collagen type I production, which is critical for re-epithelialization; and 3) the antiseptic polyhexamethylene biguanide (PHMB). To deliver an effective BC wound dressing, the interactions between the components (PHMB vs. SS) needed to be thoroughly analyzed. In this study, we investigated important parameters such as the loading sequence, loading concentration, and loading amount of the active compounds to ensure that the BC wound dressing could provide both antimicrobial activity and promote collagen production during healing. The loading sequence of SS and PHMB into BC was critical to maintain PHMB antimicrobial activity; silk sericin needed to be loaded before PHMB to avoid any negative impacts. The minimum PHMB concentration was 0.3% w/v for effective elimination of all tested bacteria (Bacillus subtilis, Staphylococcus aureus, methicillin-resistant S. aureus, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa). The amounts of SS and PHMB in BC were optimized to ensure that the dressings released the optimal amounts of both SS to enhance fibroblast collagen production and PHMB for effective antimicrobial activity. PMID:26117743

  13. The effect of metformin on the myocardial tolerance to ischemia-reperfusion injury in the rat model of diabetes mellitus type II.

    Science.gov (United States)

    Kravchuk, Ekaterina; Grineva, Elena; Bairamov, Alekber; Galagudza, Michael; Vlasov, Timur

    2011-01-01

    In recent years, evidence has been accumulated that metformin, an antidiabetic drug in the biguanide class, in addition to its well-recognized glucose-lowering effect, can also reduce cardiovascular mortality in the patients with type 2 diabetes mellitus (T2DM). Besides, there are a few experimental studies on the possibility of the direct anti-ischemic effect of the drug in both type 1 diabetes mellitus and T2DM. In our study, myocardial tolerance to ischemia in rats with neonatal streptozotocin T2DM was investigated using the model of global ischemia-reperfusion of the isolated perfused heart. Metformin was administered i.p. at a dose of 200 mg/kg/day for 3 days prior to isolated heart perfusion. The results showed that both the infarct size and postischemic recovery of left ventricular function were not different between controls and metformin-treated animals. At the same time, the infarct size in the T2DM animals was significantly lower than that in the controls (24.4 ± 7.6% versus 45.0 ± 10.4%, resp., P < .01), indicative of the metabolic preconditioning in T2DM. It follows that the protocol of metformin administration used in this study had not elicited cardioprotective effect in animals with T2DM so that the different mechanism(s) may underlie the beneficial effect of metformin on cardiovascular complications in patients with T2DM which, however, would need further investigation.

  14. The Effect of Metformin on the Myocardial Tolerance to Ischemia-Reperfusion Injury in the Rat Model of Diabetes Mellitus Type II

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    Ekaterina Kravchuk

    2011-01-01

    Full Text Available In recent years, evidence has been accumulated that metformin, an antidiabetic drug in the biguanide class, in addition to its well-recognized glucose-lowering effect, can also reduce cardiovascular mortality in the patients with type 2 diabetes mellitus (T2DM. Besides, there are a few experimental studies on the possibility of the direct anti-ischemic effect of the drug in both type 1 diabetes mellitus and T2DM. In our study, myocardial tolerance to ischemia in rats with neonatal streptozotocin T2DM was investigated using the model of global ischemia-reperfusion of the isolated perfused heart. Metformin was administered i.p. at a dose of 200 mg/kg/day for 3 days prior to isolated heart perfusion. The results showed that both the infarct size and postischemic recovery of left ventricular function were not different between controls and metformin-treated animals. At the same time, the infarct size in the T2DM animals was significantly lower than that in the controls (24.4 ± 7.6% versus 45.0 ± 10.4%, resp., P<.01, indicative of the metabolic preconditioning in T2DM. It follows that the protocol of metformin administration used in this study had not elicited cardioprotective effect in animals with T2DM so that the different mechanism(s may underlie the beneficial effect of metformin on cardiovascular complications in patients with T2DM which, however, would need further investigation.

  15. Use of metformin alone is not associated with survival outcomes of colorectal cancer cell but AMPK activator AICAR sensitizes anticancer effect of 5-fluorouracil through AMPK activation.

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    Xinbing Sui

    Full Text Available Colorectal cancer (CRC is still the third most common cancer and the second most common causes of cancer-related death around the world. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been shown to have a suppressive effect on CRC risk and mortality, but not all laboratory studies suggest that metformin has antineoplastic activity. Here, we investigated the effect of metformin and AMPK activator AICAR on CRC cells proliferation. As a result, metformin did not inhibit cell proliferation or induce apoptosis for CRC cell lines in vitro and in vivo. Different from metformin, AICAR emerged antitumor activity and sensitized anticancer effect of 5-FU on CRC cells in vitro and in vivo. In further analysis, we show that AMPK activation may be a key molecular mechanism for the additive effect of AICAR. Taken together, our results suggest that metformin has not antineoplastic activity for CRC cells as a single agent but AMPK activator AICAR can induce apoptosis and enhance the cytotoxic effect of 5-FU through AMPK activation.

  16. New poly(ester urea) derived from L-leucine: electrospun scaffolds loaded with antibacterial drugs and enzymes.

    Science.gov (United States)

    Díaz, Angélica; del Valle, Luis J; Tugushi, David; Katsarava, Ramaz; Puiggalí, Jordi

    2015-01-01

    Electrospun scaffolds from an amino acid containing poly(ester urea) (PEU) were developed as promising materials in the biomedical field and specifically in tissue engineering applications. The selected poly(ester urea) was obtained with a high yield and molecular weight by reaction of phosgene with a bis(α-aminoacyl)-α,ω-diol-diester monomer. The polymer having L-leucine, 1,6-hexanediol and carbonic acid units had a semicrystalline character and relatively high glass transition and melting temperatures. Furthermore it was highly soluble in most organic solvents, an interesting feature that facilitated the electrospinning process and the effective incorporation of drugs with bactericidal activity (e.g. biguanide derivatives such as clorhexidine and polyhexamethylenebiguanide) and enzymes (e.g. α-chymotrypsin) that accelerated the degradation process. Continuous micro/nanofibers were obtained under a wide range of processing conditions, being diameters of electrospun fibers dependent on the drug and solvent used. Poly(ester urea) samples were degradable in media containing lipases and proteinases but the degradation rate was highly dependent on the surface area, being specifically greater for scaffolds with respect to films. The high hydrophobicity of new scaffolds had repercussions on enzymatic degradability since different weight loss rates were found depending on how samples were exposed to the medium (e.g. forced or non-forced immersion). New scaffolds were biocompatible, as demonstrated by adhesion and proliferation assays performed with fibroblast and epithelial cells.

  17. Effect of oral hypoglycaemic agents on bone metabolism in patients with type 2 diabetes mellitus

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    B. Siddhartha Kumar

    2012-04-01

    Full Text Available Diabetes mellitus (DM and osteoporosis are the two important public health problems in India. The burden of both these conditions is expected to increase in the near future in view of changing lifestyle habits and ageing population. Indians are at risk of osteoporosis due to their low body mass index (BMI, genetic predisposition and nutritional factors. The diseases type 1 DM and type 2 DM (T2DM are associated with increased fracture risk in the disease population, in spite of difference in the bone mineral density (BMD. An increase in fracture risk is also reported among older patients with T2DM despite frequently reported normal or increased BMD. Administration of insulin stimulates osteoblast activity and bone mineral apposition rates. The impact of endogenous insulin production, insulin sensitivity, and exogenous insulin administration as an anabolic agent for bone in T2DM has not been clarified. Biguanides and sulphonylureas do not appear to have adverse effects on BMD. Preclinical evidence suggests that incretin-based drugs may be beneficial for bone, but clinical evidence to support this hypothesis is not yet available. Thiazolidinedione (TZD group of agents have been implicated in causing osteoporosis in various animal studies and some human studies available till date. The debate regarding this is issue is still ongoing. Randomized controlled studies with larger sample size preferably involving multiple centres, multiple ethnicities are required to answer these queries.

  18. Metformin inhibits cell growth by upregulating microRNA-26a in renal cancer cells.

    Science.gov (United States)

    Yang, Feng-Qiang; Wang, Ji-Jiao; Yan, Jia-Sheng; Huang, Jian-Hua; Li, Wei; Che, Jian-Ping; Wang, Guang-Chun; Liu, Min; Zheng, Jun-Hua

    2014-01-01

    Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties and may reduce cancer risk and improve prognosis. However, the mechanism by which metformin affects various cancers, including renal cancer still unknown. MiR-26a induces cell growth, cell cycle and cell apoptosis progression via direct targeting of Bcl-2, clyclin D1 and PTEN in cancer cells. In the present study, we used 786-O human renal cancer cell lines to study the effects and mechanisms of metformin. Metformin treatment inhibited RCC cells proliferation by increasing expression of miR-26a in 786-O cells (P metformin. Also over-expression of miR-26a can inhibited cell proliferation by down-regulating Bcl-2, cyclin D1 and up-regulating PTEN expression. Therefore, these data for the first time provide novel evidence for a mechanism that the anticancer activities of metformin are due to upregulation of miR-26a and affect its downstream target gene. PMID:25419360

  19. Versatile synthesis of PHMB-stabilized silver nanoparticles and their significant stimulating effect on fodder beet (Beta vulgaris L.).

    Science.gov (United States)

    Gusev, Alexander А; Kudrinsky, Alexey A; Zakharova, Olga V; Klimov, Alexey I; Zherebin, Pavel M; Lisichkin, George V; Vasyukova, Inna A; Denisov, Albert N; Krutyakov, Yurii A

    2016-05-01

    Silver nanoparticles (AgNPs) are well-known bactericidal agents. However, information about the influence of AgNPs on the morphometric parameters and biochemical status of most important agricultural crops is limited. The present study reports the influence of AgNPs stabilized with cationic polymer polyhexamethylene biguanide hydrochloride (PHMB) on growth, development, and biochemical status of fodder beet Beta vulgaris L. under laboratory and greenhouse conditions. PHMB-stabilized AgNPs were obtained via sodium borohydride reduction of silver nitrate in an aqueous solution. The average diameter of thus prepared AgNPs was 10 nm. It appears that the results of experiments with laboratory-grown beets in the nanosilver-containing medium, where germination of seeds and growth of roots were suppressed, do not correlate with the results of greenhouse experiments. The observed growth-stimulating action of PHMB-stabilized AgNPs can be explained by the change of activity of oxidases and, consequently, by the change of auxins amount in plant tissues. In beets grown in the presence of PHMB-stabilized AgNPs no negative deviations of biological parameters from normal values were registered. Furthermore, the SEM/EDS examination revealed no presence of silver in the tissues of the studied plants. PMID:26952409

  20. Alterations in cellular energy metabolism associated with the antiproliferative effects of the ATM inhibitor KU-55933 and with metformin.

    Science.gov (United States)

    Zakikhani, Mahvash; Bazile, Miguel; Hashemi, Sina; Javeshghani, Shiva; Avizonis, Daina; St Pierre, Julie; Pollak, Michael N

    2012-01-01

    KU-55933 is a specific inhibitor of the kinase activity of the protein encoded by Ataxia telangiectasia mutated (ATM), an important tumor suppressor gene with key roles in DNA repair. Unexpectedly for an inhibitor of a tumor suppressor gene, KU-55933 reduces proliferation. In view of prior preliminary evidence suggesting defective mitochondrial function in cells of patients with Ataxia Telangiectasia (AT), we examined energy metabolism of cells treated with KU-55933. The compound increased AMPK activation, glucose uptake and lactate production while reducing mitochondrial membrane potential and coupled respiration. The stimulation of glycolysis by KU-55933 did not fully compensate for the reduction in mitochondrial functions, leading to decreased cellular ATP levels and energy stress. These actions are similar to those previously described for the biguanide metformin, a partial inhibitor of respiratory complex I. Both compounds decreased mitochondrial coupled respiration and reduced cellular concentrations of fumarate, malate, citrate, and alpha-ketogluterate. Succinate levels were increased by KU-55933 levels and decreased by metformin, indicating that the effects of ATM inhibition and metformin are not identical. These observations suggest a role for ATM in mitochondrial function and show that both KU-55933 and metformin perturb the TCA cycle as well as oxidative phosphorylation. PMID:23185347

  1. Carbon source and myc expression influence the antiproliferative actions of metformin.

    Science.gov (United States)

    Javeshghani, Shiva; Zakikhani, Mahvash; Austin, Shane; Bazile, Miguel; Blouin, Marie-José; Topisirovic, Ivan; St-Pierre, Julie; Pollak, Michael N

    2012-12-01

    Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in "glutamine addiction". Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound. PMID:23041548

  2. Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    John M Stafford

    2007-09-01

    Full Text Available John M Stafford1, Tom Elasy21Division of Diabetes Endocrinology and Metabolism, Vanderbilt University; 2Vanderbilt Eskind Diabetes Clinic, Vanderbilt University Medical CenterAbstract: Type 2 diabetes mellitus (DM2 is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.Keywords: thiazolidinediones; metformin; Type 2 diabetes

  3. Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    John M Stafford

    2007-10-01

    Full Text Available John M Stafford1, Tom Elasy21Division of Diabetes Endocrinology and Metabolism, Vanderbilt University; 2Vanderbilt Eskind Diabetes Clinic, Vanderbilt University Medical CenterAbstract: Type 2 diabetes mellitus (DM2 is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.Keywords: thiazolidinediones; metformin; Type 2 diabetes

  4. Metformin and prostate cancer stem cells: a novel therapeutic target.

    Science.gov (United States)

    Mayer, M J; Klotz, L H; Venkateswaran, V

    2015-12-01

    Prostate cancer is the second most frequently diagnosed cancer in the world. Localized disease can be effectively treated with radiation therapy or radical prostatectomy. However, advanced prostate cancer is more difficult to treat and if metastatic, is incurable. There is a need for more effective therapy for advanced prostate cancer. One potential target is the cancer stem cell (CSC). CSCs have been described in several solid tumors, including prostate cancer, and contribute to therapeutic resistance and tumor recurrence. Metformin, a common oral biguanide used to treat type 2 diabetes, has been demonstrated to have anti-neoplastic effects. Specifically, metformin targets CSCs in breast cancer, pancreatic cancer, glioblastoma and colon cancer. Metformin acts directly on the mitochondria to inhibit oxidative phosphorylation and reduce mitochondrial ATP production. This forces tumor cells to compensate by increasing the rate of glycolysis. CSCs rely heavily on mitochondrial oxidative phosphorylation for energy production. The glycolytic switch results in an energy crisis in these cells. Metformin could be used to exploit this metabolic weakness in CSCs. This would increase CSC sensitivity to conventional cancer therapies, circumventing treatment resistance and enhancing treatment efficacy. This review will explore the characteristics of prostate CSCs, their role in tumor propagation and therapeutic resistance and the role of metformin as a potential prostate CSC sensitizer to current anticancer therapies. PMID:26215782

  5. Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells.

    Science.gov (United States)

    Liu, Zhao; Ren, Lidong; Liu, Chenghao; Xia, Tiansong; Zha, Xiaoming; Wang, Shui

    2015-01-01

    Breast cancer remains a world-wide challenge, and additional anti-cancer therapies are still urgently needed. Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin. However, little attention has been given to the role of phenformin in breast cancer. In this study, we reveal the role of phenformin in cell death of the MCF7, ZR-75-1, MDA-MB-231 and SUM1315 breast cancer cell lines. The respective IC50 values of phenformin in MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were 1.184±0.045 mM, 0.665±0.007 mM, 2.347±0.010 mM and 1.885±0.015 mM (mean± standard error). Phenformin induced cell cycle change and apoptosis in breast cancer cells via the AMPK/mTOR/p70s6k and MAPK/ERK pathways. Interestingly, phenformin induced MET (mesenchymal-epithelial transition) and decreased the migration rate in breast cancer cell lines. Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice. Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer. PMID:26114294

  6. Phenformin Induces Cell Cycle Change, Apoptosis, and Mesenchymal-Epithelial Transition and Regulates the AMPK/mTOR/p70s6k and MAPK/ERK Pathways in Breast Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Zhao Liu

    Full Text Available Breast cancer remains a world-wide challenge, and additional anti-cancer therapies are still urgently needed. Emerging evidence has demonstrated the potent anti-tumor effect of biguanides, among which phenformin was reported to potentially be a more active anti-cancer agent than metformin. However, little attention has been given to the role of phenformin in breast cancer. In this study, we reveal the role of phenformin in cell death of the MCF7, ZR-75-1, MDA-MB-231 and SUM1315 breast cancer cell lines. The respective IC50 values of phenformin in MCF7, ZR-75-1, MDA-MB-231 and SUM1315 cells were 1.184±0.045 mM, 0.665±0.007 mM, 2.347±0.010 mM and 1.885±0.015 mM (mean± standard error. Phenformin induced cell cycle change and apoptosis in breast cancer cells via the AMPK/mTOR/p70s6k and MAPK/ERK pathways. Interestingly, phenformin induced MET (mesenchymal-epithelial transition and decreased the migration rate in breast cancer cell lines. Furthermore, our results suggest that phenformin inhibits breast cancer cell metastasis after intracardiac injection into nude mice. Taken together, our study further confirms the potential benefit of phenformin in breast cancer treatment and provides novel mechanistic insight into its anti-cancer activity in breast cancer.

  7. Anticancer effect of metformin on estrogen receptor-positive and tamoxifen-resistant breast cancer cell lines.

    Science.gov (United States)

    Kim, Jinkyoung; Lee, Jiyun; Jang, Soon Young; Kim, Chungyeul; Choi, Yoojin; Kim, Aeree

    2016-05-01

    Acquisition of tamoxifen resistance (TR) during anti-estrogenic therapy using tamoxifen is a major obstacle in the treatment of estrogen receptor (ER)-positive breast cancer. As a biguanide derivative, metformin is commonly used to treat type II diabetes. It has recently emerged as a potential anticancer agent. The objective of the present study was to investigate the anticancer activity of metformin in relation to ERα expression and its signaling pathway in ERα-positive MCF-7 and MDA-MB-361 breast cancer cells as well as TR MCF-7 breast cancer cells. Metformin inhibited both protein and mRNA levels of ERα in the presence or absence of estrogen (E2) in the MCF-7, TR MCF-7 and MDA-MB-361 cells. Metformin repressed E2-inducible estrogen response element (ERE) luciferase activity, protein levels and mRNA levels of E2/ERα-regulated genes [including c-Myc, cyclin D1, progesterone receptor (PR) and pS2] to a greater degree than tamoxifen, resulting in inhibition of cell proliferation of MCF-7, TR MCF-7 and MDA-MB-361 cells. Collectively, our results suggest that one of the anticancer mechanisms of metformin could be attributable to the repression of expression and transcriptional activity of ERα. Metformin may be a good therapeutic agent for treating ERα-positive breast cancer by inhibiting the expression and function of ERα. In addition, metformin may be useful to treat tamoxifen-resistant breast cancer. PMID:26986571

  8. Recent Trends in Therapeutic Approaches for Diabetes Management: A Comprehensive Update

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    Pragya Tiwari

    2015-01-01

    Full Text Available Diabetes highlights a growing epidemic imposing serious social economic crisis to the countries around the globe. Despite scientific breakthroughs, better healthcare facilities, and improved literacy rate, the disease continues to burden several sections, especially middle and low income countries. The present trends indicate the rise in premature death, posing a major threat to global development. Scientific and technological advances have witnessed the development of newer generation of drugs like sulphonylureas, biguanides, alpha glucosidase inhibitors, and thiazolidinediones with significant efficacy in reducing hyperglycemia. Recent approaches in drug discovery have contributed to the development of new class of therapeutics like Incretin mimetics, Amylin analogues, GIP analogs, Peroxisome proliferator activated receptors, and dipeptidyl peptidase-4 inhibitor as targets for potential drugs in diabetes treatment. Subsequently, the identification and clinical investigation of bioactive substances from plants have revolutionized the research on drug discovery and lead identification for diabetes management. With a focus on the emerging trends, the review article explores the current statistical prevalence of the disease, discussing the benefits and limitations of the commercially available drugs. Additionally, the critical areas in clinical diabetology are discussed, with respect to prospects of statins, nanotechnology, and stem cell technology as next generation therapeutics and why the herbal formulations are consistently popular choice for diabetes medication and management.

  9. Importance of Porins for Biocide Efficacy against Mycobacterium smegmatis▿

    Science.gov (United States)

    Frenzel, Elrike; Schmidt, Stefan; Niederweis, Michael; Steinhauer, Katrin

    2011-01-01

    Mycobacteria are among the microorganisms least susceptible to biocides but cause devastating diseases, such as tuberculosis, and increasingly opportunistic infections. The exceptional resistance of mycobacteria to toxic solutes is due to an unusual outer membrane, which acts as an efficient permeability barrier, in synergy with other resistance mechanisms. Porins are channel-forming proteins in the outer membrane of mycobacteria. In this study we used the alamarBlue assay to show that the deletion of Msp porins in isogenic mutants increased the resistance of Mycobacterium smegmatis to isothiazolinones (methylchloroisothiazolinone [MCI]/methylisothiazolinone [MI] and octylisothiazolinone [2-n-octyl-4-isothiazolin-3-one; OIT]), formaldehyde-releasing biocides {hexahydrotriazine [1,3,5-tris (2-hydroxyethyl)-hexahydrotriazine; HHT] and methylenbisoxazolidine [N,N′-methylene-bis-5-(methyloxazolidine); MBO]}, and the lipophilic biocides polyhexamethylene biguanide and octenidine dihydrochloride 2- to 16-fold. Furthermore, the susceptibility of the porin triple mutant against a complex disinfectant was decreased 8-fold compared to wild-type (wt) M. smegmatis. Efficacy testing in the quantitative suspension test EN 14348 revealed 100-fold improved survival of the porin mutant in the presence of this biocide. These findings underline the importance of porins for the susceptibility of M. smegmatis to biocides. PMID:21398489

  10. Importance of porins for biocide efficacy against Mycobacterium smegmatis.

    Science.gov (United States)

    Frenzel, Elrike; Schmidt, Stefan; Niederweis, Michael; Steinhauer, Katrin

    2011-05-01

    Mycobacteria are among the microorganisms least susceptible to biocides but cause devastating diseases, such as tuberculosis, and increasingly opportunistic infections. The exceptional resistance of mycobacteria to toxic solutes is due to an unusual outer membrane, which acts as an efficient permeability barrier, in synergy with other resistance mechanisms. Porins are channel-forming proteins in the outer membrane of mycobacteria. In this study we used the alamarBlue assay to show that the deletion of Msp porins in isogenic mutants increased the resistance of Mycobacterium smegmatis to isothiazolinones (methylchloroisothiazolinone [MCI]/methylisothiazolinone [MI] and octylisothiazolinone [2-n-octyl-4-isothiazolin-3-one; OIT]), formaldehyde-releasing biocides {hexahydrotriazine [1,3,5-tris (2-hydroxyethyl)-hexahydrotriazine; HHT] and methylenbisoxazolidine [N,N'-methylene-bis-5-(methyloxazolidine); MBO]}, and the lipophilic biocides polyhexamethylene biguanide and octenidine dihydrochloride 2- to 16-fold. Furthermore, the susceptibility of the porin triple mutant against a complex disinfectant was decreased 8-fold compared to wild-type (wt) M. smegmatis. Efficacy testing in the quantitative suspension test EN 14348 revealed 100-fold improved survival of the porin mutant in the presence of this biocide. These findings underline the importance of porins for the susceptibility of M. smegmatis to biocides. PMID:21398489

  11. Acidosis láctica grave asociada a intoxicación por metformina Severe lactic acidosis associated to metformin intoxication

    Directory of Open Access Journals (Sweden)

    M. S. Holanda Peña

    2007-02-01

    Full Text Available La metformina es una biguanida ampliamente utilizada en el tratamiento de la diabetes mellitus tipo II. Entre los efectos secundarios derivados de su empleo destaca por su baja frecuencia de presentación pero potencial gravedad la acidosis láctica. El diagnóstico de la misma se basa generalmente en la coexistencia de la acidosis láctica en un paciente en tratamiento con metformina con uno o mas factores de riesgo para la presentación de la misma. El desarrollo de acidosis láctica en relación con el tratamiento con metformina conlleva una mortalidad que oscila entre 50-80%.Metformin is a biguanide extensively used in the treatment of type II diabetes mellitus. Between the nocive effects of the metformin emphasizes tha lactic acidosis because of its low frecuency but potential severity. The diagnosis of the poisoning due to metformin is based on the coexistence of lactic acidosis and one or more of the risk factors. The development of lactic acidosis in metformin poisoning is associated to a range of 50-80% of mortality.

  12. Antimicrobial mouthrinse use as an adjunct method in peri-implant biofilm control

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    Vinicius PEDRAZZI

    2014-01-01

    Full Text Available Great possibilities for oral rehabilitation emerged as a result of scientific consolidation, as well as a large number of dental implant applications. Along with implants appeared diseases such as mucositis and peri-implantitis, requiring management through several strategies applied at different stages. Biofilm accumulation is associated with clinical signs manifest by both tooth and implant inflammation. With this in mind, regular and complete biofilm elimination becomes essential for disease prevention and host protection. Chemical control of biofilms, as an adjuvant to mechanical oral hygiene, is fully justified by its simplicity and efficacy proven by studies based on clinical evidence. The purpose of this review was to present a consensus regarding the importance of antimicrobial mouthrinse use as an auxiliary method in chemical peri-implant biofilm control. The active ingredients of the several available mouthrinses include bis-biguanide, essential oils, phenols, quaternary ammonium compounds, oxygenating compounds, chlorine derivatives, plant extracts, fluorides, antibiotics and antimicrobial agent combinations. It was concluded that there is strong clinical evidence that at least two mouthrinses have scientifically proven efficacy against different oral biofilms, i.e., chlorhexidine digluconate and essential oils; however, 0.12% chlorhexidine digluconate presents a number of unwanted side effects and should be prescribed with caution. Chemical agents seem beneficial in controlling peri-implant inflammation, although they require further investigation. We recommend a scientifically proven antiseptic, with significant short and long term efficacy and with no unwanted side effects, for the prevention and/or treatment of peri-implant disease.

  13. 1,1-Dimethylbiguanidium(2+ dinitrate

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    Michaela Fridrichová

    2012-01-01

    Full Text Available In the crystal structure of the title compound, C4H13N52+·2NO3−, the main intermolecular interactions are the N—H...O hydrogen bonds between the cationic amino groups and the O atoms of the nitrate ions. All amino H atoms and nitrate O atoms are involved in the three-dimensional hydrogen-bond network. There are two graph-set motifs R22(8, which include the amino groups connected to the N atoms in the biguanide 3-, 4- and 5-positions, and the O atoms of a nitrate ion. They are extended along the a axis. An O atom of the second nitrate ion is involved in a graph-set motif C(4 that is a part of a helix-like N—H...O...H—N—H...O... chain oriented along the b axis. There are also two weak C—H...O interactions in the crystal structure.

  14. Insulin resistance and response to antiviral therapy in chronic hepatitis C: mechanisms and management.

    Science.gov (United States)

    del Campo, José A; López, Reyes Aparcero; Romero-Gómez, Manuel

    2010-01-01

    Insulin resistance has been found to be an independent factor predicting sustained response to peginterferon plus ribavirin in patients with chronic hepatitis C. Insulin resistance seems to be involved in decreased sensitivity to interferon and could block interferon intracellular signaling. Insulin resistance promotes steatosis and fibrosis progression, induces pro-inflammatory cytokine secretion and increases adipose tissue, decreasing interferon availability. Moreover, suppressor of cytokines 3 and protein tyrosine-phosphatase seems to be able to block interferon and insulin signaling, building a feed-forward loop. Insulin resistance can be treated with exercise, diet or through the use of drugs that improve insulin sensitivity, like biguanides or glitazones. A recent controlled, randomized, double-blind clinical trial (TRIC-1) examined the effect of adding metformin to standard therapy in the treatment of hepatitis C. This study demonstrated that women infected with hepatitis C virus genotype 1 and HOMA >2 treated with metformin showed a greater drop in viral load during the first 12 weeks and a doubled sustained viral response in comparison with females receiving placebo. Pioglitazone has been used in previous nonresponders and naïve patients with disappointing results in two pilot trials. The mechanisms by which the virus promotes insulin resistance seems to be genotype-dependent and could explain, at least in part, the discrepancies between insulin sensitizers. Insulin resistance is a new target in the challenging management of chronic hepatitis C. PMID:20460925

  15. Pharmacogenetic studies update in type 2 diabetes mellitus.

    Science.gov (United States)

    Singh, Shalini; Usman, Kauser; Banerjee, Monisha

    2016-08-10

    Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment. PMID:27555891

  16. Alterations in cellular energy metabolism associated with the antiproliferative effects of the ATM inhibitor KU-55933 and with metformin.

    Directory of Open Access Journals (Sweden)

    Mahvash Zakikhani

    Full Text Available KU-55933 is a specific inhibitor of the kinase activity of the protein encoded by Ataxia telangiectasia mutated (ATM, an important tumor suppressor gene with key roles in DNA repair. Unexpectedly for an inhibitor of a tumor suppressor gene, KU-55933 reduces proliferation. In view of prior preliminary evidence suggesting defective mitochondrial function in cells of patients with Ataxia Telangiectasia (AT, we examined energy metabolism of cells treated with KU-55933. The compound increased AMPK activation, glucose uptake and lactate production while reducing mitochondrial membrane potential and coupled respiration. The stimulation of glycolysis by KU-55933 did not fully compensate for the reduction in mitochondrial functions, leading to decreased cellular ATP levels and energy stress. These actions are similar to those previously described for the biguanide metformin, a partial inhibitor of respiratory complex I. Both compounds decreased mitochondrial coupled respiration and reduced cellular concentrations of fumarate, malate, citrate, and alpha-ketogluterate. Succinate levels were increased by KU-55933 levels and decreased by metformin, indicating that the effects of ATM inhibition and metformin are not identical. These observations suggest a role for ATM in mitochondrial function and show that both KU-55933 and metformin perturb the TCA cycle as well as oxidative phosphorylation.

  17. Pharmacogenetic studies update in type 2 diabetes mellitus

    Science.gov (United States)

    Singh, Shalini; Usman, Kauser; Banerjee, Monisha

    2016-01-01

    Type 2 diabetes mellitus (T2DM) is a silent progressive polygenic metabolic disorder resulting from ineffective insulin cascading in the body. World-wide, about 415 million people are suffering from T2DM with a projected rise to 642 million in 2040. T2DM is treated with several classes of oral antidiabetic drugs (OADs) viz. biguanides, sulfonylureas, thiazolidinediones, meglitinides, etc. Treatment strategies for T2DM are to minimize long-term micro and macro vascular complications by achieving an optimized glycemic control. Genetic variations in the human genome not only disclose the risk of T2DM development but also predict the personalized response to drug therapy. Inter-individual variability in response to OADs is due to polymorphisms in genes encoding drug receptors, transporters, and metabolizing enzymes for example, genetic variants in solute carrier transporters (SLC22A1, SLC22A2, SLC22A3, SLC47A1 and SLC47A2) are actively involved in glycemic/HbA1c management of metformin. In addition, CYP gene encoding Cytochrome P450 enzymes also play a crucial role with respect to metabolism of drugs. Pharmacogenetic studies provide insights on the relationship between individual genetic variants and variable therapeutic outcomes of various OADs. Clinical utility of pharmacogenetic study is to predict the therapeutic dose of various OADs on individual basis. Pharmacogenetics therefore, is a step towards personalized medicine which will greatly improve the efficacy of diabetes treatment.

  18. Introduction of biocides into clinical practice and the impact on antibiotic-resistant bacteria.

    Science.gov (United States)

    Russell, A D

    2002-01-01

    Biocides and other antimicrobial agents have been employed for centuries. Much later, iodine found use as a wound disinfectant, chlorine water in obstetrics, alcohol as a hand disinfectant and phenol as a wound dressing and in antiseptic surgery. In the early part of the twentieth century, other chlorine-releasing agents (CRAs), and acridine and other dyes were introduced, as were some quaternary ammonium compounds (QACs, although these were only used as biocides from the 1930s). Later still, various phenolics and alcohols, formaldehyde and hydrogen peroxide were introduced and subsequently (although some had actually been produced at an earlier date) biguanides, iodophors, bisphenols, aldehydes, diamidines, isocyanurates, isothiazolones and peracetic acid. Antibiotics were introduced clinically in the 1940s, although sulphonamides had been synthesized and used previously. After penicillin came streptomycin and other aminoglycosides-aminocyclitols, tetracyclines, chloramphenicol, macrolides, semi-synthetic beta-lactams, glycopeptides, lincosamides, 4-quinolones and diaminopyrimidines. Bacterial resistance to antibiotics is causing great concern. Mechanisms of such resistance include cell impermeability, target site mutation, drug inactivation and drug efflux. Bacterial resistance to biocides was described in the 1950s and 1960s and is also apparently increasing. Of the biocides listed above, cationic agents (QACs, chlorhexidine, diamidines, acridines) and triclosan have been implicated as possible causes for the selection and persistence of bacterial strains with low-level antibiotic resistance. It has been claimed that the chronological emergence of qacA and qacB determinants in clinical isolates of Staphylococcus aureus mirrors the introduction and usage of cationic biocides.

  19. Autophagy inhibitors as a potential antiamoebic treatment for Acanthamoeba keratitis.

    Science.gov (United States)

    Moon, Eun-Kyung; Kim, So-Hee; Hong, Yeonchul; Chung, Dong-Il; Goo, Youn-Kyoung; Kong, Hyun-Hee

    2015-07-01

    Acanthamoeba cysts are resistant to extreme physical and chemical conditions. Autophagy is an essential pathway for encystation of Acanthamoeba cells. To evaluate the possibility of an autophagic Acanthamoeba encystation mechanism, we evaluated autophagy inhibitors, such as 3-methyladenine (3MA), LY294002, wortmannin, bafilomycin A, and chloroquine. Among these autophagy inhibitors, the use of 3MA and chloroquine showed a significant reduction in the encystation ratio in Acanthamoeba cells. Wortmannin also inhibited the formation of mature cysts, while LY294002 and bafilomycin A did not affect the encystation of Acanthamoeba cells. Transmission electron microscopy revealed that 3MA and wortmannin inhibited autophagy formation and that chloroquine interfered with the formation of autolysosomes. Inhibition of autophagy or autolysosome formation resulted in a significant block in the encystation in Acanthamoeba cells. Clinical treatment with 0.02% polyhexamethylene biguanide (PHMB) showed high cytopathic effects on Acanthamoeba trophozoites and cysts; however, it also revealed high cytopathic effects on human corneal epithelial cells. In this study, we investigated effects of the combination of a low (0.00125%) concentration of PHMB with each of the autophagy inhibitors 3MA, wortmannin, and chloroquine on Acanthamoeba and human corneal epithelial cells. These new combination treatments showed low cytopathic effects on human corneal cells and high cytopathic effects on Acanthamoeba cells. Taken together, these results provide fundamental information for optimizing the treatment of Acanthamoeba keratitis.

  20. Presumed late recurrence of Acanthamoeba keratitis exacerbated by exposure to topical corticosteroids

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    Dipika V Patel

    2013-01-01

    Full Text Available A 28-year-old female with a history of contact lens wear presented with a 1 week history of pain and photophobia in her left eye. In vivo confocal microscopy (IVCM and corneal scrape confirmed the diagnosis of Acanthamoeba keratitis (AK which was treated with intensive topical propamidine isethionate (0.1% and chlorhexidine (0.02% with tapering dosage over 11 months. Five years after complete resolution of AK and cessation of all contact lens wear, the subject presented to her optometrist with a history of ocular discomfort and mild photophobia. Without further investigation she was prescribed topical corticosteroids. Three weeks later she presented with pain and reduced vision in the left eye. Slit-lamp examination revealed focal, inferior corneal stromal edema. IVCM confirmed widespread Acanthamoeba cysts. Treatment with topical polyhexamethylene biguanide (PHMB 0.02% and propamidine isethionate 0.1% resulted in resolution of the AK. Despite an initially mild AK, this subject presumably retained viable Acanthamoeba cysts in her cornea 5 years after the initial episode. This report highlights the importance of caution when using corticosteroids in patients with a previous history of AK, even in the relatively distant past. Patients with AK should be warned regarding the risks of recurrence following presumed resolution.

  1. Relationship between Legionella pneumophila and Acanthamoeba polyphaga: Physiological status and susceptibility to chemical inactivation

    Energy Technology Data Exchange (ETDEWEB)

    Barker, J.; Farrell, I. (Aston Univ., Aston Triangle, Birmingham (United Kingdom)); Brown, M.R.W.; Collier, P.J.; Gilbert, P. (Univ. of Manchester (United Kingdom))

    1992-08-01

    Survival studies were conducted on Legionella pneumophila cells that had been grown intracellulary in Acanthamoeba polyphaga and then exposed to polyhexamethylene biguanide (PHMB), benzisothiazolone (BIT), and 5-chloro-N-methylisothiazolone (CMIT). Susceptibilities were also determined for L. pneumophila grown under iron-sufficient and iron-depleted conditions. BIT was relatively ineffective against cells to PHMB and CMIT. The activities of all three biocides were greatly reduced against L. pneumophila grown in amoebae. PHMB (1 [times] MIC) gave 99.99% reductions in viability for cultures grown in broth within 6 h and no detectable survivors at 24 h but only 90 and 99.9% killing at 6 h and 24 h, respectively, for cells grown in amoebae. The antimicrobial properties of the three biocides against A. polyphaga were also determined. The majority of amoebae recovered from BIT treatment, but few, if any, survived CMIT treatment or exposure of PHMB. This study not only shows the profound effect that intra-amoebal growth has on the physiological status and antimicrobial susceptibility of L. pneumophila but also reveals PHMB to be a potential biocide for effective water treatment. In this respect, PHMB has significant activity, below its recommended use concentrations, against both the host amoeba and L. pneumophila.

  2. Use of multiple immunosuppressive agents in recalcitrant ACANTHAMOEBA scleritis.

    Science.gov (United States)

    Igras, Estera; Murphy, Conor

    2015-01-01

    A 48-year-old woman who is a contact lens wearer presented with unilateral ACANTHAMOEBA keratitis, confirmed by PCR, which responded initially to topical polyhexamethylene biguanide (PHMB) and brolene. Three months later, despite continued treatment, she developed diffuse anterior scleritis with severe pain and marked scleral injection but without evidence of recurrence keratitis. Oral non-steroidal anti-inflammatories and oral high-dose corticosteroids were added without success. Subsequent treatment with intravenous methylprednisolone and high-dose cyclosporine led to a temporary improvement. Re-presenting with signs of recurrent scleritis and severe pain, the antitumor necrosis factor monoclonal antibody adalimumab, and later oral cyclophosphamide, were added. This led to complete quiescence of the scleritis. Unfortunately, frequent recurrences of ACANTHAMOEBA keratitis and anterior uveitis occurred on immunosuppression requiring continued treatment with PHMB, brolene and topical corticosteroids. This is the first case of severe refractory ACANTHAMOEBA scleritis requiring the concomitant use of four immunosuppressive agents to achieve continued disease control. The challenges in managing this case are discussed.

  3. Secular Trends in the Clinical Characteristics of Type 2 Diabetic Patients With Severe Hypoglycemia Between 2008 and 2013

    Science.gov (United States)

    Ito, Hiroyuki; Tsugami, Emiko; Ando, Shigenori; Imai, Ayano; Matsumoto, Suzuko; Omoto, Takashi; Shinozaki, Masahiro; Nishio, Shinya; Abe, Mariko; Antoku, Shinichi; Mifune, Mizuo; Togane, Michiko

    2016-01-01

    Background We investigated the trends in the clinical characteristics and prescriptions of type 2 diabetic patients with severe hypoglycemia because the prescription rate of antidiabetic agents has significantly changed recently. Methods A total of 193 patients with type 2 diabetes with severe hypoglycemia induced by antidiabetic agents between 2008 and 2013 were divided into three groups based on the period of visit: 2008 - 2009, 2010 - 2011 and 2012 - 2013. Results While the proportion of patients with severe hypoglycemia using insulin (from 55% to 74%), biguanides (from 6% to 20%), glinides, and dipeptidyl peptidase-4 inhibitors significantly increased, those using sulfonylureas (from 45% to 20%) significantly decreased. Errors of drug use significantly increased as a trigger of hypoglycemia in recent years. The number of antidiabetic agents (from 1.9 ± 0.6 to 2.3 ± 0.7), non-diabetic agents (from 2.3 ± 2.4 to 4.3 ± 3.3), and total drugs prescribed were significantly higher in recent years among patients receiving insulin therapy. Conclusions Polypharmacy especially in patients receiving insulin therapy and errors of drug use have increased in type 2 diabetic patients with severe hypoglycemia in recent years. Intensive education in the usage rule of drugs is considered to be important in order to prevent severe hypoglycemia.

  4. Synthesis and in vitro anticancer evaluation of some 4,6-diamino-1,3,5-triazine-2-carbohydrazides as Rad6 ubiquitin conjugating enzyme inhibitors.

    Science.gov (United States)

    Kothayer, Hend; Spencer, Sebastian M; Tripathi, Kaushlendra; Westwell, Andrew D; Palle, Komaraiah

    2016-04-15

    Series of 4-amino-6-(arylamino)-1,3,5-triazine-2-carbohydrazides (3a-e) and N'-phenyl-4,6-bis(arylamino)-1,3,5-triazine-2-carbohydrazides (6a-e), for ease of readership, we will abbreviate our compound names as 'new triazines', have been synthesized, based on the previously reported Rad6B-inhibitory diamino-triazinylmethyl benzoate anticancer agents TZ9 and 4-amino-N'-phenyl-6-(arylamino)-1,3,5-triazine-2-carbohydrazides. Synthesis of the target compounds was readily accomplished in two steps from either bis-aryl/aryl biguanides via reaction of phenylhydrazine or hydrazinehydrate with key 4-amino-6-bis(arylamino)/(arylamino)-1,3,5-triazine-2-carboxylate intermediates. These new triazine derivatives were evaluated for their abilities to inhibit Rad6B ubiquitin conjugation and in vitro anticancer activity against several human cancer cell lines: ovarian (OV90 and A2780), lung (H1299 and A549), breast (MCF-7 and MDA-MB231) and colon (HT29) cancer cells by MTS assays. All the 10 new triazines exhibited superior Rad6B inhibitory activities in comparison to selective Rad6 inhibitor TZ9 that was reported previously. Similarly, new triazines also showed better IC50 values in survival assays of various tumor cell lines. Particularly, new triazines 6a-c, exhibited lower IC50 (3.3-22μM) values compared to TZ9. PMID:26965855

  5. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice

    Science.gov (United States)

    Anisimov, Vladimir N.; Berstein, Lev M.; Popovich, Irina G.; Zabezhinski, Mark A.; Egormin, Peter A.; Piskunova, Tatiana S.; Semenchenko, Anna V.; Tyndyk, Margarita L.; Yurova, Maria N.; Kovalenko, Irina G.; Poroshina, Tatiana E.

    2011-01-01

    Hyperglycemia and hyperinsulinemia accelerate both aging and cancer. Antidiabetic biguanides such as metformin decrease glucose, insulin and IGF-1 level. Metformin increases lifespan and prevents cancer in mice, although its effects vary, depending on mice strain and gender. Here we showed that chronic treatment of female outbred SHR mice with metformin started at the age of 3, 9 or 15 months decreased body temperature and postponed age-related switch-off of estrous function. Surprisingly, metformin did not affect levels of serum cholesterol, triglycerides, glucose and insulin. Treatment with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. The treatment started at the age of 9 months insignificantly increased mean life span by only 6%, whereas the treatment started at the age of 15 months failed to increase life span. The mean life span of tumor-free mice was increased by 21% in ‘the youngest group’, by 7% in ‘middle-aged group’ and in contrast was reduced by 13% in ‘the oldest group’. When started at the age of 3 and 9 months, metformin delayed the first tumor detection by 22% and 25%, correspondingly. Thus, in female SHR mice, metformin increased life span and postponed tumors when started at the young and middle but not at the old age. In contrast, metformin improves reproductive function when started at any age. PMID:21386129

  6. Gender differences in metformin effect on aging, life span and spontaneous tumorigenesis in 129/Sv mice

    Science.gov (United States)

    Anisimov, Vladimir N.; Piskunova, Tatiana S.; Popovich, Irina G.; Zabezhinski, Mark A.; Tyndyk, Margarita L.; Egormin, Peter A.; Yurova, Maria N.; Rosenfeld, Svetlana V.; Semenchenko, Anna V.; Kovalenko, Irina G.; Poroshina, Tatiana E.; Berstein, Lev M.

    2010-01-01

    Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which mimetic effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. Antidiabetic biguanides are most promising among them. The chronic treatment of inbred 129/Sv mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but failed to influence the dynamics of body weight, decreased by 13.4% the mean life span of male mice and slightly increased the mean life span of female mice (by 4.4%). The treatment with metformin failed influence spontaneous tumor incidence in male 129/Sv mice, decreased by 3.5 times the incidence of malignant neoplasms in female mice while somewhat stimulated formation of benign vascular tumors in the latter. PMID:21164223

  7. Energy disruptors: rising stars in anticancer therapy?

    Science.gov (United States)

    Bost, F; Decoux-Poullot, A-G; Tanti, J F; Clavel, S

    2016-01-01

    The metabolic features of tumor cells diverge from those of normal cells. Otto Warburg was the first to observe that cancer cells dramatically increase their glucose consumption to generate ATP. He also claimed that cancer cells do not have functional mitochondria or oxidative phosphorylation (OXPHOS) but simply rely on glycolysis to provide ATP to the cell, even in the presence of oxygen (aerobic glycolysis). Several studies have revisited this observation and demonstrated that most cancer cells contain metabolically efficient mitochondria. Indeed, to sustain high proliferation rates, cancer cells require functional mitochondria to provide ATP and intermediate metabolites, such as citrate and cofactors, for anabolic reactions. This difference in metabolism between normal and tumors cells causes the latter to be more sensitive to agents that can disrupt energy homeostasis. In this review, we focus on energy disruptors, such as biguanides, 2-deoxyglucose and 5-aminoimidazole-4-carboxamide ribonucleotide, that interfere with the main metabolic pathways of the cells, OXPHOS, glycolysis and glutamine metabolism. We discuss the preclinical data and the mechanisms of action of these disruptors at the cellular and molecular levels. Finally, we consider whether these drugs can reasonably contribute to the antitumoral therapeutic arsenal in the future. PMID:26779810

  8. Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus.

    Science.gov (United States)

    Tahrani, Abd A; Barnett, Anthony H; Bailey, Clifford J

    2016-10-01

    Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

  9. Prescribing pattern of antidiabetic drugs in Indore city hospital

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    Vengurlekar Sudha

    2008-01-01

    Full Text Available Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, glycosuria, and sometimes ketonemia. The present study was carried out to assess prescribing practice and general trend of diabetes among patients at the Bombay Hospital, Indore. Prescriptions and complete records of diabetic patients were monitored and data was filed as per WHO prescription proforma. The study revealed that prescription of metformin (27% and glimepiride (22.60% were found to be maximum among various available antidiabetic drugs. Category wise the maximum prescribed drugs are glimepride (22.60%, sulfonylurea category, metformin (27%, biguanide category and pioglitazones (13.90%, glitazone category. Insulin prescription was found to be very less (4.5%. Combination of metformin and glimepiride (20.86% was prescribed most commonly. Most common disease associated with diabetes mellitus was found to be hypertension (35%. Highest prevalence of disease was found to be in the age group of 51 to 60 followed by age group of 41 to 50. Men patients (66.36% were found to be predominated over women patients (33.64%.

  10. COMPARATIVE IN VITRO DRUG RELEASE STUDIES OF GLIMEPIRIDE SOLID DISPERSIONS & METFORMIN MICROCAPSULES

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    B.V. Ramana*, D.S. Spandana Anand P, C. Triveni, V. Pavan Kumar, P. Venkateshwar Reddy and U. Chandra Sekhar

    2013-11-01

    Full Text Available The study was undertaken to compare the efficacy and safety of Glimepiride and Metformin in the management of patients with type 2 DM. The present invention is directed to a pharmaceutical composition in the form of a capsule with increased bioavailability as well as the process for obtaining said composition. The tablet of the present invention comprises two active ingredients comprising two oral hypoglycemic agents: one phase with a sulphonylurea, such as immediate release Glimepiride and second phase with a biguanide, such as extended release Metformin hydrochloride (Metformin HCL. This composition of capsule, which can include over 500mg of Metformin HCL (i.e. up to daily requirements of each patient, is to be orally administered once or twice a day. The combination of these hypoglycemic agents has a synergic effect. Finally we can explain that the availability of Metformin-Glimepiride combination can minimize the effects of diabetic conditions. From the complete work we assume that these hypoglycemic agents have a synergistic effect and therefore a greater effectiveness in controlling the blood glucose level in patients with type II diabetes mellitus.

  11. Metformin Is a Substrate and Inhibitor of the Human Thiamine Transporter, THTR-2 (SLC19A3).

    Science.gov (United States)

    Liang, Xiaomin; Chien, Huan-Chieh; Yee, Sook Wah; Giacomini, Marilyn M; Chen, Eugene C; Piao, Meiling; Hao, Jia; Twelves, Jolyn; Lepist, Eve-Irene; Ray, Adrian S; Giacomini, Kathleen M

    2015-12-01

    The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, metformin is transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic cation transporter 1, OCT1, the major hepatic uptake transporter for metformin, was also the primary hepatic uptake transporter for thiamine, vitamin B1. In this study, we tested the reverse, i.e., that metformin is a substrate of thiamine transporters (THTR-1, SLC19A2, and THTR-2, SLC19A3). Our study demonstrated that human THTR-2 (hTHTR-2), SLC19A3, which is highly expressed in the small intestine, but not hTHTR-1, transports metformin (Km = 1.15 ± 0.2 mM) and other cationic compounds (MPP(+) and famotidine). The uptake mechanism for hTHTR-2 was pH and electrochemical gradient sensitive. Furthermore, metformin as well as other drugs including phenformin, chloroquine, verapamil, famotidine, and amprolium inhibited hTHTR-2 mediated uptake of both thiamine and metformin. Species differences in the substrate specificity of THTR-2 between human and mouse orthologues were observed. Taken together, our data suggest that hTHTR-2 may play a role in the intestinal absorption and tissue distribution of metformin and other organic cations and that the transporter may be a target for drug-drug and drug-nutrient interactions.

  12. Metformin displays in vitro and in vivo antitumor effect against osteosarcoma

    Science.gov (United States)

    Ko, Yunmi; Choi, Aery; Lee, Minyoung

    2016-01-01

    Purpose Patients with unresectable, relapsed, or refractory osteosarcoma need a novel therapeutic agent. Metformin is a biguanide derivative used in the treatment of type II diabetes, and is recently gaining attention in cancer research. Methods We evaluated the effect of metformin against human osteosarcoma. Four osteosarcoma cell lines (KHOS/NP, HOS, MG-63, U-2 OS) were treated with metformin and cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were evaluated using flow cytometric analysis, and migration and wound healing assay were performed. Fourteen female Balb/c-nude mice received KHOS/NP cell grafts in their thigh, and were allowed access to metformin containing water (2 mg/mL) ad libitum. Tumor volume was measured every 3–4 days for a period of 4 weeks. Results Metformin had a significant antiproliferative effect on human osteosarcoma cells. In particular, metformin inhibited the proliferation and migration of KHOS/NP cells by activation of AMP-activated protein kinase and consequent inhibition of the mammalian target of rapamycin pathway. It also inhibited the proliferation of cisplatin-resistant KHOS/NP clone cells. Analysis of KHOS/NP xenograft Balb/c-nude models indicated that metformin displayed potent in vivo antitumor effects. Conclusion Further studies are necessary to explore metformin's therapeutic potential and the possibilities for its use as an adjuvant agent for osteosarcoma.

  13. Autophagy and protein kinase RNA-like endoplasmic reticulum kinase (PERK)/eukaryotic initiation factor 2 alpha kinase (eIF2α) pathway protect ovarian cancer cells from metformin-induced apoptosis.

    Science.gov (United States)

    Moon, Hee-Sun; Kim, Boyun; Gwak, HyeRan; Suh, Dong Hoon; Song, Yong Sang

    2016-04-01

    Metformin, an oral biguanide for the treatment of type II diabetes, has been shown to have anticancer effects in ovarian cancer. Energy starvation induced by metformin causes endoplasmic reticulum stress-mediated unfolded protein response (UPR) and autophagy. UPR and autophagy act as a survival or death mechanism in cells. In this study, we observed that metformin-induced apoptosis was relieved by autophagy and the PERK/eIF2α pathway in ovarian cancer cells, but not in peripheral blood mononuclear cells (PBMC) or 'normal' ovarian surface epithelial cells (OSE). Increased PARP cleavage and increased LC3B-II with ATG5-ATG12 complex suggested the induction of apoptosis and autophagy, respectively, in metformin-treated ovarian cancer cells. Accumulation of acidic vacuoles in the cytoplasm and downregulation of p62 further supported late-stage autophagy. Interestingly, metformin induced interdependent activation between autophagy and the UPR, especially the PERK/eIF2α pathway. Inhibition of autophagy-induced PERK inhibition, and vice versa, were demonstrated using small molecular inhibitors (PERK inhibitor I, GSK2606414; autophagy inhibitor, 3-MA, and BafA1). Moreover, autophagy and PERK activation protected ovarian cancer cells against metformin-induced apoptosis. Metformin treatment in the presence of inhibitors of PERK and autophagy, however, had no cytotoxic effects on OSE or PBMC. In conclusion, these results suggest that inhibition of autophagy and PERK can enhance the selective anticancer effects of metformin on ovarian cancer cells. © 2015 Wiley Periodicals, Inc.

  14. 二甲双胍的心血管保护作用%Cardiovascular protective effects of metformin

    Institute of Scientific and Technical Information of China (English)

    方丽娟; 刘乃丰

    2011-01-01

    二甲双胍(Metformin)属双胍类药物,作为口服降糖药应用于2型糖尿病(T2DM)已有50年的历程,其降糖作用已得到公认.近年越来越多的研究发现,二甲双胍具有降糖以外的心血管保护作用,能抑制动脉粥样硬化(Atherosclerosis,AS)、心衰、心肌梗死等心血管病的发生和发展.但二甲双胍确切的心血管保护机制仍不明确,本文综述了二甲双胍对心血管疾病的作用,并探讨其可能的作用机制.%Metformin belongs to biguanide drugs, used as oral hypoglycemic agents in type 2 diabetes (T2DM) for 50 years, and its anti-hyperglycemic effect has been recognized.Furthermore, in recent years more and more studies found that metformin has additional cardiovascular protective effects, including the inhibition of atherosclerosis (AS), heart failure and myocardial infarction.However, the specific effect of metformin on cardiovascular protection is still unclear.This article reviews the effect of metformin in cardiovascular disease and discusses its possible mechanisms.

  15. Metformin and insulin receptors

    Energy Technology Data Exchange (ETDEWEB)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific /sup 125/I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific /sup 125/I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded.

  16. Synergistic interaction between metformin and sulfonylureas on diclofenac-induced antinociception measured using the formalin test in rats

    Science.gov (United States)

    Ortiz, Mario I

    2013-01-01

    BACKGROUND There is evidence that biguanides and sulfonylureas block diclofenac-induced antinociception (DIA) in rat models. However, little is known about the interaction between these hypoglycemics with respect to DIA. OBJECTIVE: To determine whether metformin-sulfonylurea combinations affect DIA during the formalin test. METHODS: Rats received the appropriate vehicle or diclofenac before 1% formaldehyde was injected into the paw. Rats were also pretreated with vehicle, glibenclamide, glipizide, metformin or glibenclamide/metformin and glipizide/metformin combinations before the diclofenac and formaldehyde injections, and the effect on antinociception was assessed. Isobolograms of the combinations were constructed to test for a synergistic interaction. RESULTS: Systemic injection of diclofenac resulted in antinociception during the second phase of the test. Systemic pretreatment with the combinations of glibenclamide (0.56 mg/kg to 10 mg/kg)/metformin (10 mg/kg to 180 mg/kg) and glipizide (0.56 mg/kg to10 mg/kg)/metformin (10 mg/kg to 180 mg/kg) blocked DIA. The derived theoretical effective doses for 50% of subjects (ED50) for the glibenclamide/metformin and glipizide/metformin combinations were 32.52 mg/kg and 32.42 mg/kg, respectively, and were significantly higher than the actual observed experimental ED50 values (7.57 mg/kg and 8.43 mg/kg, respectively). CONCLUSION: Pretreatment with glibenclamide, glipizide or metformin blocked DIA in a dose-dependent manner, and combining either sulfonylurea with metformin produced even greater effects. The observed ED50s for the combinations were approximately fourfold lower than the calculated additive effects. These data indicate that sulfonylureas interact to produce antagonism of DIA. Combination therapy is a common second-line treatment for patients with diabetes and metabolic syndrome, a group that experiences pain from multiple sources. The results suggest that at least some anti-inflammatory agents may not be

  17. Comparative analysis of Salmonella susceptibility and tolerance to the biocide chlorhexidine identifies a complex cellular defence network

    Directory of Open Access Journals (Sweden)

    Orla eCondell

    2014-08-01

    Full Text Available Chlorhexidine is one of the most widely used biocides in health and agricultural settings as well as in the modern food industry. It is a cationic biocide of the biguanide class. Details of its mechanism of action are largely unknown. The frequent use of chlorhexidine has been questioned recently, amidst concerns that an overuse of this compound may select for bacteria displaying an altered susceptibility to antimicrobials, including clinically important anti-bacterial agents.We generated a Salmonella enterica serovar Typhimurium isolate (ST24CHX that exhibited a high-level tolerant phenotype to chlorhexidine, following several rounds of in vitro selection, using sub-lethal concentrations of the biocide. This mutant showed altered suceptibility to a panel of clinically important antimicrobial compounds. Here we describe a genomic, transcriptomic, proteomic, and phenotypic analysis of the chlorhexidine tolerant S. Typhimurium compared with its isogenic sensitive progenitor. Results from this study describe a chlorhexidine defence network that functions in both the reference chlorhexidine sensitive isolate and the tolerant mutant. The defence network involved multiple cell targets including those associated with the synthesis and modification of the cell wall, the SOS response, virulence, and a shift in cellular metabolism towards anoxic pathways, some of which were regulated by CreB and Fur. In addition, results indicated that chlorhexidine tolerance was associated with more extensive modifications of the same cellular processes involved in this proposed network, as well as a divergent defence response involving the up-regulation of additional targets such as the flagellar apparatus and an altered cellular phosphate metabolism.These data show that sub-lethal concentrations of chlorhexidine induce distinct changes in exposed Salmonella, and our findings provide insights into the mechanisms of action and tolerance to this biocidal agent.

  18. OUTPATIENT UTILIZATION OF ANTI-DIABETIC DRUGS IN THE SOUTH EASTERN NIGERIA

    Directory of Open Access Journals (Sweden)

    ADIBE M.O. (M.PHARM, PROF. AGUWA C.N. (PHARM D, UKWE C.V. (PH.D, OKONTA J.M. (PH.D, PHARM. UDEOGARANYA P.O (M.PHARM

    2009-12-01

    Full Text Available Background Recent study in the tertiary hospitals in Nigeria showed that prevalence of diabetes mellitus (DM is on theincrease. With this increase, the prescription volume of anti diabetic drugs, morbidity and ultimately mortality rates areexpected to assume an upward trend especially in regions of the world like Nigeria where healthcare services are suboptimalfor the rapidly expanding populations.Aim To determine the outpatient utilization of anti diabetic drugs in south-eastern Nigeria.Methods This prospective cross-sectional study was undertaken for 20 weeks between July 2008 and November, 2008 in thethree tertiary hospitals which were randomly selected. All prescriptions issued to patients attending endocrinology clinicduring this period following each day’s consultation were copied out from the case files and recorded in case record forms.Cost of the prescribed drugs was obtained from drug price list of the hospital pharmacies.Results Oral hypoglycaemic agents (OHAs ((15.21 DDDs/1000 diabetic patients /day were 4.5 times more utilized thaninsulin (3.4 DDDs/1000 diabetic patients /day. Among OHAs, Biguanide (Metformin was the most utilized (11.3DDDs/1000 diabetic patients /day, it was likely to be prescribed to diabetic patient daily compared to Sulphonylureas(Glibenclamide, Chlorpropamide and Thiazolidinediones (Rosiglitazone with 3.8 DDDs/1000 diabetic patients /day and0.09 DDDs/1000 diabetic patients /day respectively.Conclusion Metformin was the most utilized anti-diabetic drugs and the costs of anti-diabetic drugs were high in the southeasternNigeria. Government should come up with appropriate policies such as free health care for diabetic patients,subsidies for anti-diabetic drugs and finally low import tariff for anti-diabetic drugs. All these measures will reduce theprovocative high cost of anti-diabetic drugs in the zone.

  19. Bactericidal Effects and Mechanism of Action of Olanexidine Gluconate, a New Antiseptic.

    Science.gov (United States)

    Hagi, Akifumi; Iwata, Koushi; Nii, Takuya; Nakata, Hikaru; Tsubotani, Yoshie; Inoue, Yasuhide

    2015-08-01

    Olanexidine gluconate [1-(3,4-dichlorobenzyl)-5-octylbiguanide gluconate] (development code OPB-2045G) is a new monobiguanide compound with bactericidal activity. In this study, we assessed its spectrum of bactericidal activity and mechanism of action. The minimal bactericidal concentrations of the compound for 30-, 60-, and 180-s exposures were determined with the microdilution method using a neutralizer against 320 bacterial strains from culture collections and clinical isolates. Based on the results, the estimated bactericidal olanexidine concentrations with 180-s exposures were 869 μg/ml for Gram-positive cocci (155 strains), 109 μg/ml for Gram-positive bacilli (29 strains), and 434 μg/ml for Gram-negative bacteria (136 strains). Olanexidine was active against a wide range of bacteria, especially Gram-positive cocci, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and had a spectrum of bactericidal activity comparable to that of commercial antiseptics, such as chlorhexidine and povidone-iodine. In vitro experiments exploring its mechanism of action indicated that olanexidine (i) interacts with the bacterial surface molecules, such as lipopolysaccharide and lipoteichoic acid, (ii) disrupts the cell membranes of liposomes, which are artificial bacterial membrane models, (iii) enhances the membrane permeability of Escherichia coli, (iv) disrupts the membrane integrity of S. aureus, and (v) denatures proteins at relatively high concentrations (≥160 μg/ml). These results indicate that olanexidine probably binds to the cell membrane, disrupts membrane integrity, and its bacteriostatic and bactericidal effects are caused by irreversible leakage of intracellular components. At relatively high concentrations, olanexidine aggregates cells by denaturing proteins. This mechanism differs slightly from that of a similar biguanide compound, chlorhexidine.

  20. Intracerebroventricular Injection of Metformin Induces Anorexia in Rats

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    Chang Koo Lee

    2012-08-01

    Full Text Available BackgroundMetformin, an oral biguanide insulin-sensitizing agent, is well known to decrease appetite. Although there is evidence that metformin could affect the brain directly, the exact mechanism is not yet known.MethodsTo evaluate whether metformin induces anorexia via the hypothalamus, various concentrations of metformin were injected into the lateral ventricle of rats through a chronically implanted catheter and food intake was measured for 24 hours. The hypothalamic neuropeptides associated with regulation of food intake were also analyzed following 1 hour of intracerebroventricular (ICV injections of metformin.ResultsAn ICV injection of metformin decreased food intake in a dose-dependent manner in unrestrained conscious rats. Hypothalamic phosphorylated AMP-activated protein kinase (pAMPK increased by 3 µg with metformin treatment, but there was no further increase in pAMPK with increases in metformin dosage. The hypothalamic phosphorylated signal transducer and activator of transcription 3 (pSTAT3 increased by 3 µg with metformin treatment, but, there was no further increase in pSTAT3 level following increases of metformin dosage. Hypothalamic proopiomelanocortin was elevated with metformin treatment, while neuropeptide Y was not significantly changed.ConclusionOur results suggest that metformin induces anorexia via direct action in the hypothalamus and the increase in pSTAT3, at least in part, is involved in the process. However, hypothalamic pAMPK appears not to contribute to metformin-induced appetite reduction in normal rats. Further studies exploring new pathways connecting metformin and feeding regulation are needed.

  1. Addition of sitagliptin or metformin to insulin monotherapy improves blood glucose control via different effects on insulin and glucagon secretion in hyperglycemic Japanese patients with type 2 diabetes.

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    Otsuka, Yuichiro; Yamaguchi, Suguru; Furukawa, Asami; Kosuda, Minami; Nakazaki, Mitsuhiro; Ishihara, Hisamitsu

    2015-01-01

    This study aimed to explore the effects of the dipeptidyl peptidase-4 inhibitor sitagliptin and the biguanide metformin on the secretion of insulin and glucagon, as well as incretin levels, in Japanese subjects with type 2 diabetes mellitus poorly controlled with insulin monotherapy. This was a single-center, randomized, open-label, parallel group study, enrolling 25 subjects. Eleven patients (hemoglobin A1c [HbA1c] 8.40 ± 0.96%) and 10 patients (8.10 ± 0.54%) on insulin monotherapy completed 12-week treatment with sitagliptin (50 mg) and metformin (750 mg), respectively. Before and after treatment, each subject underwent a meal tolerance test. The plasma glucose, glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), C-peptide, and glucagon responses to a meal challenge were measured. HbA1c reductions were similar in patients treated with sitagliptin (0.76 ± 0.18%) and metformin (0.77 ± 0.17%). In the sitagliptin group, glucose excursion during a meal tolerance test was reduced and accompanied by elevations in active GLP-1 and active GIP concentrations. C-peptide levels were unaltered despite reduced glucose responses, while glucagon responses were significantly suppressed (-7.93 ± 1.95% of baseline). In the metformin group, glucose excursion and incretin responses were unaltered. C-peptide levels were slightly increased but glucagon responses were unchanged. Our data indicate that sitagliptin and metformin exert different effects on islet hormone secretion in Japanese type 2 diabetic patients on insulin monotherapy. A glucagon suppressing effect of sitagliptin could be one of the factors improving blood glucose control in patients inadequately controlled with insulin therapy. PMID:25328079

  2. Amputación corporal por accidente de trabajo en auxiliar de enfermería

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    Alexander Finol Muñoz

    2014-12-01

    Full Text Available Los auxiliares de enfermería son un rango profesional expuesto a múltiples riesgos por las actividades inherentes a su trabajo, expuestos constantemente a sustancias desinfectantes que sin el uso apropiado de equipos de protección individual, puede provocar efectos adversos y lesiones en el trabajador. Caso Clínico: Mujer de 51 años de edad, auxiliar de enfermería, con antecedentes de Diabetes Mellitus tipo I y Síndrome de Túnel Carpiano. Presenta derrame accidental de líquido mientras llenaba envase de Biguanid®, cayéndole en todo el cuerpo, por lo que decide cambiarse el uniforme entero, conservando calcetines y zapatos por el resto del turno. Posteriormente presenta lesiones en región dorsal de 4tº dedo de pie izquierdo, las cuales reciben tratamiento médico y seguimiento, con evolución tórpida, se evidencia edema y osteomielitis de la falange por lo que se decide amputar el dedo afectado. Una vez recuperada, fue estudiada con pruebas de provocación, evidenciando la susceptibilidad de la trabajadora a dicho desinfectante. Se propone al Instituto Nacional de Seguridad Social (INSS como accidente de trabajo y una indemnización por lesión permanente no invalidante, ambas peticiones con respuesta favorable para la trabajadora. Actualmente sigue desempeñando sus funciones como auxiliar en el hospital. El cumplimiento y vigilancia de las normas de prevención, basados en los riesgos laborales permitirá evitar este tipo de incidentes en la población laboral, evitando a largo plazo lesiones corporales, discapacidades y bajas laborales que alteran la calidad de vida del trabajador y de su entorno profesional.

  3. Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

    Science.gov (United States)

    Thomas, Simmy; Sharma, Natasha; Gonzalez, Reyna; Pao, Peng-Wen; Hofman, Florence M; Chen, Thomas C; Louie, Stan G; Pirrung, Michael C; Schönthal, Axel H

    2013-01-01

    Verrucosidin (VCD) belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78) expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose), but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin). However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin) might act in a similar GRP78-independent fashion will be discussed. PMID:23755268

  4. Pioglitazone improves the cardio-ankle vascular index in patients with type 2 diabetes mellitus treated with metformin

    Directory of Open Access Journals (Sweden)

    Ohira M

    2014-07-01

    , in patients with type 2 diabetes mellitus treated with metformin. Keywords: biguanide, thiazolidinediones, sulfonylurea, blood pressure, cardiovascular disease, arterial stiffness

  5. Type 2 Diabetes Mellitus: A Review of Current Trends

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    Abdulfatai B. Olokoba

    2012-07-01

    Full Text Available Type 2 diabetes mellitus (DM is a chronic metabolic disorder in which prevalence has been increasing steadily all over the world. As a result of this trend, it is fast becoming an epidemic in some countries of the world with the number of people affected expected to double in the next decade due to increase in ageing population, thereby adding to the already existing burden for healthcare providers, especially in poorly developed countries. This review is based on a search of Medline, the Cochrane Database of Systemic Reviews, and citation lists of relevant publications. Subject heading and key words used include type 2 diabetes mellitus, prevalence, current diagnosis, and current treatment. Only articles in English were included. Screening and diagnosis is still based on World Health Organization (WHO and American Diabetes Association (ADA criteria which include both clinical and laboratory parameters. No cure has yet been found for the disease; however, treatment modalities include lifestyle modifications, treatment of obesity, oral hypoglycemic agents, and insulin sensitizers like metformin, a biguanide that reduces insulin resistance, is still the recommended first line medication especially for obese patients. Other effective medications include non-sulfonylurea secretagogues, thiazolidinediones, alpha glucosidase inhibitors, and insulin. Recent research into the pathophysiology of type 2 DM has led to the introduction of new medications like glucagon-like peptide 1 analogoues: dipeptidyl peptidase-IV inhibitors, inhibitors of the sodium-glucose cotransporter 2 and 11ß-hydroxysteroid dehydrogenase 1, insulin-releasing glucokinase activators and pancreatic-G-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, metabolic inhibitors of hepatic glucose output and quick-release bromocriptine. Inhaled insulin was licensed for use in 2006 but has been withdrawn from the market because of low patronage.

  6. Meta-analysis of the ocular biocompatibility of a new multipurpose lens care system

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    Reindel W

    2013-10-01

    Full Text Available William Reindel, Mohinder M Merchea, Marjorie J Rah, Lening Zhang Bausch & Lomb Incorporated, Rochester, NY, USA Background: The purpose of this paper is to evaluate the biocompatibility of a novel multipurpose solution (MPS with a dual disinfectant system containing polyaminopropyl biguanide and polyquaternium-1 (Biotrue® by analysis of biomicroscopy signs and adverse events in six large clinical trials. Methods: Data from six consecutive, prospective clinical trials conducted from February 2008 to March 2010 were combined for meta-analysis. Subjects used the new MPS daily for periods of 2 weeks to 6 months. Slit-lamp signs were graded at each follow-up visit using an ordinal scale (0, one; 1, trace; 2, mild; 3, moderate; 4, severe. Analysis for biocompatibility included tracking of greater than grade 2 slit-lamp findings and number of adverse events. Results: A total of 1,567 subjects (3,134 eyes and 81 clinical investigators participated in the six studies, with 1,499 subjects completing the studies. Based on subject days in the studies, there were 72,904 exposures to the MPS and 7,212 biomicroscopy examinations. The completion rate for the studies was 96.3%. Per observation incidence of any finding greater than grade 2 at the follow-up visits were: corneal staining 0.08%, limbal injection 0.04%, bulbar injection 0.04%, tarsal conjunctiva abnormality 0.09%, and neovascularization 0.01%. There were no other slit-lamp signs greater than grade 2 and no statistically significant difference between hydrogels and silicone hydrogels for any finding. There were no reports of adverse events during the trials. Conclusion: Analysis of over 72,000 daily exposures and 7,212 eye examinations showed that the novel MPS exhibited excellent biocompatibility in subjects using daily wear hydrogel or silicone hydrogel lenses. Keywords: contact lens, solutions, disinfection, meta-analysis, silicone, hydrogel

  7. Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo.

    Science.gov (United States)

    Miyoshi, Hisaaki; Kato, Kiyohito; Iwama, Hisakazu; Maeda, Emiko; Sakamoto, Teppei; Fujita, Koji; Toyota, Yuka; Tani, Joji; Nomura, Takako; Mimura, Shima; Kobayashi, Mitsuyoshi; Morishita, Asahiro; Kobara, Hideki; Mori, Hirohito; Yoneyama, Hirohito; Deguchi, Akihiro; Himoto, Takashi; Kurokohchi, Kazutaka; Okano, Keiichi; Suzuki, Yasuyuki; Murao, Koji; Masaki, Tsutomu

    2013-12-30

    Metformin is a commonly used oral anti-hyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle‑related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs. PMID:24378856

  8. Antitumor effect of metformin in esophageal cancer: in vitro study.

    Science.gov (United States)

    Kobayashi, Mitsuyoshi; Kato, Kiyohito; Iwama, Hisakazu; Fujihara, Shintaro; Nishiyama, Noriko; Mimura, Shima; Toyota, Yuka; Nomura, Takako; Nomura, Kei; Tani, Joji; Miyoshi, Hisaaki; Kobara, Hideki; Mori, Hirohito; Murao, Koji; Masaki, Tsutomu

    2013-02-01

    Recent studies suggest that metformin, which is a member of the biguanide family and commonly used as an oral anti-hyperglycemic agent, may reduce cancer risk and improve prognosis of numerous types of cancer. However, the mechanisms underlying the antitumor effect of metformin on esophageal cancer remain unknown. The goal of the present study was to evaluate the effects of metformin on the proliferation of human ESCC in vitro, and to study changes in the expression profile of microRNAs (miRNAs), since miRNAs have previously been associated with the antitumor effects of metformin in other human cancers. The human ESCC cell lines T.T, KYSE30 and KYSE70 were used to study the effects of metformin on human ESCC in vitro. In addition, we used miRNA array tips to explore the differences between miRNAs in KYSE30 cells with and without metformin treatment. Metformin inhibited the proliferation of T.T, KYSE30 and KYSE70 cells in vitro. Metformin blocked the cell cycle in G0/G1 in vitro. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, as well as decreases in cyclin-dependent kinase (Cdk)4, Cdk6 and phosphorylated retinoblastoma protein (Rb). In addition, the expression of miRNAs was markedly altered with the treatment of metformin in vitro. Metformin inhibited the growth of three ESCC cell lines, and this inhibition may have involved reductions in cyclin D1, Cdk4 and Cdk6. PMID:23229592

  9. Metformin: multi-faceted protection against cancer.

    Science.gov (United States)

    Del Barco, Sonia; Vazquez-Martin, Alejandro; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Bosch-Barrera, Joaquim; Joven, Jorge; Martin-Castillo, Begoña; Menendez, Javier A

    2011-12-01

    The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics. PMID:22203527

  10. The anti-diabetic drug metformin inhibits pancreatic cancer cell proliferation in vitro and in vivo: Study of the microRNAs associated with the antitumor effect of metformin.

    Science.gov (United States)

    Kato, Kiyohito; Iwama, Hisakazu; Yamashita, Takuma; Kobayashi, Kiyoyuki; Fujihara, Shintaro; Fujimori, Takayuki; Kamada, Hideki; Kobara, Hideki; Masaki, Tsutomu

    2016-03-01

    Recent studies suggest that metformin, which is a commonly used oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, yet the detailed mechanisms by which metformin affects various types of cancers, including pancreatic cancer, remain unknown. The aim of the present study was to evaluate the effects of metformin on human pancreatic cancer cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin. We used the human pancreatic cancer cell lines Panc1, PK1 and PK9 to study the effects of metformin on human pancreatic cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 5 weeks, and the expression of cell cycle-related proteins was determined. In addition, we used miRNA microarray tips to explore the differences in the levels of miRNAs in Panc1 cells and xenograft tumors treated with metformin or without. Metformin inhibited the proliferation of Panc1, PK1 and PK9 cells in vitro. This inhibition was accompanied by a strong decrease in G1 cyclins (particularly in cyclin D1) and retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor (EGFR), particularly the phosphorylation of EGFR at Tyr845, and insulin-like growth factor 1 receptor (IGF-1R) in vitro and in vivo. miRNA expression was markedly altered by the treatment with metformin in vitro and in vivo. Our results revealed that metformin inhibits human pancreatic cancer cell proliferation and tumor growth, possibly by suppressing the cell cycle-related molecules via alteration of miRNAs. PMID:26708419

  11. The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo.

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    Kato, Kiyohito; Gong, Jian; Iwama, Hisakazu; Kitanaka, Akira; Tani, Joji; Miyoshi, Hisaaki; Nomura, Kei; Mimura, Shima; Kobayashi, Mitsuyoshi; Aritomo, Yuuichi; Kobara, Hideyuki; Mori, Hirohito; Himoto, Takashi; Okano, Keiichi; Suzuki, Yasuyuki; Murao, Koji; Masaki, Tsutomu

    2012-03-01

    Recent studies suggest that metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, but the mechanisms by which metformin affects various cancers, including gastric cancer, remains unknown. The goal of the present study was to evaluate the effects of metformin on human gastric cancer cell proliferation in vitro and in vivo and to study microRNAs (miRNA) associated with antitumor effect of metformin. We used MKN1, MKN45, and MKN74 human gastric cancer cell lines to study the effects of metformin on human gastric cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 4 weeks, and the expression of cell-cycle-related proteins was determined. In addition, we used miRNA array tips to explore the differences among miRNAs in MKN74 cells bearing xenograft tumors treated with or without metformin in vitro and in vivo. Metformin inhibited the proliferation of MKN1, MKN45, and MKN74 in vitro. Metformin blocked the cell cycle in G(0)-G(1)in vitro and in vivo. This blockade was accompanied by a strong decrease of G(1) cyclins, especially in cyclin D1, cyclin-dependent kinase (Cdk) 4, Cdk6 and by a decrease in retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor-1 receptor in vitro and in vivo. The miRNA expression was markedly altered with the treatment of metformin in vitro and in vivo. Various miRNAs altered by metformin also may contribute to tumor growth in vitro and in vivo. PMID:22222629

  12. Effect of the anti-diabetic drug metformin in hepatocellular carcinoma in vitro and in vivo.

    Science.gov (United States)

    Miyoshi, Hisaaki; Kato, Kiyohito; Iwama, Hisakazu; Maeda, Emiko; Sakamoto, Teppei; Fujita, Koji; Toyota, Yuka; Tani, Joji; Nomura, Takako; Mimura, Shima; Kobayashi, Mitsuyoshi; Morishita, Asahiro; Kobara, Hideki; Mori, Hirohito; Yoneyama, Hirohito; Deguchi, Akihiro; Himoto, Takashi; Kurokohchi, Kazutaka; Okano, Keiichi; Suzuki, Yasuyuki; Murao, Koji; Masaki, Tsutomu

    2014-07-01

    Metformin is a commonly used oral anti-hyperglycemic agent of the biguanide family. Recent studies suggest that metformin may reduce cancer risk and improve prognosis. However, the antitumor mechanism of metformin in several types of cancers, including hepatocellular carcinoma (HCC), has not been elucidated. The goal of the present study was to evaluate the effects of metformin on HCC cell proliferation in vitro and in vivo, and to study microRNAs (miRNAs) associated with the antitumor effect of metformin in vitro. We used the cell lines Alex, HLE and Huh7, and normal hepatocytes to study the effects of metformin on human HCC cells. In an in vivo study, athymic nude mice bearing xenograft tumors were treated with metformin or left untreated. Tumor growth was recorded after 4 weeks, and the expression of cell cycle-related proteins was determined. Metformin inhibited the proliferation of Alex, HLE and Huh7 cells in vitro and in vivo. Metformin blocked the cell cycle in G0/G1 in vitro and in vivo. This blockade was accompanied by a strong decrease of G1 cyclins, especially cyclin D1, cyclin E and cyclin-dependent kinase 4 (Cdk4). In addition, microRNA (miRNA) expression was markedly altered by the treatment with metformin in vitro and in vivo. In addition, various miRNAs induced by metformin also may contribute to the suppression of tumor growth. Our results demonstrate that metformin inhibits the growth of HCC, possibly by inducing G1 cell cycle arrest through the alteration of microRNAs. PMID:24806290

  13. 二甲双胍治疗青春期多囊卵巢综合征的疗效分析及安全性评价%The Clinical Effect and Safety of Metformin to Treat Polycystic Ovarian Syndrome

    Institute of Scientific and Technical Information of China (English)

    董业芳

    2015-01-01

    目的:评价二甲双胍治疗青春期多囊卵巢综合征的疗效和安全性。方法78例患者,分成两组,对照组患者进行优思明治疗,实验组患者进行优思明+二甲双胍治疗。结果实验组患者的多毛、痤疮等临床症状较对照组显著改善,T、LH、FSH、FINS、FPG、BMI指标较对照组显著下降(P<0.05)。结论在优思明治疗的基础上,应用二甲双胍治疗青春期多囊卵巢综合征效果显著,可以改善胰岛素抵抗,减少不良反应。%Objective To evaluate the efficacy and safety of metformin in the treatment of adolescent polycystic ovary syndrome. Methods 78 cases, 39 cases in each. control group were treated with Yasmin treatment, experimental group were Yasmin+dimethyl biguanide treatment. Results The clinical symptoms of patients in the experimental group of hirsutism, acne and other than in the control group improved signiifcantly, t, LH, FSH, fins, FPG, BMI group decreased significantly compared with the control group (P0.05. Conclusion Based Yasmin treatment , application of metformin in the treatment of adolescent polycystic ovary syndrome has better effects can improve insulin resistance and reduce the adverse reactions.

  14. Buformin exhibits anti-proliferative and anti-invasive effects in endometrial cancer cells

    Science.gov (United States)

    Kilgore, Joshua; Jackson, Amanda L; Clark, Leslie H; Guo, Hui; Zhang, Lu; Jones, Hannah M; Gilliam, Timothy P; Gehrig, Paola A; Zhou, Chunxiao; Bae-Jump, Victoria L

    2016-01-01

    Objective: Biguanides are anti-diabetic drugs that are thought to have anti-tumorigenic effects. Most pre-clinical studies have focused on metformin for cancer treatment and prevention; however, buformin may be potentially more potent than metformin. Given this, our goal was to evaluate the effects of buformin on cell growth, adhesion and invasion in endometrial cancer cell lines. Methods: The ECC-1 and Ishikawa endometrial cancer cell lines were used. Cell proliferation was assessed by MTT assay. Apoptosis and cell cycle analysis was performed by FITC Annexin V assay and propidium iodide staining, respectively. Adhesion was analyzed using the laminin adhesion assay. Invasion was assessed using the transwell invasion assay. The effects of buformin on the AMPK/mTOR pathway were determined by Western immunoblotting. Results: Buformin and metformin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines. IC50s were 1.4-1.6 mM for metformin and 8-150 μM for buformin. Buformin induced cell cycle G1 phase arrest in the ECC-1 cells and G2 phase arrest in the Ishikawa cells. For both ECC-1 and Ishikawa cells, treatment with buformin resulted in induction of apoptosis, reduction in adhesion and invasion, activation of AMPK and inhibition of phosphorylated-S6. Buformin potentiated the anti-proliferative effects of paclitaxel in both cell lines. Conclusion: Buformin has significant anti-proliferative and anti-metastatic effects in endometrial cancer cells through modulation of the AMPK/mTOR pathway. IC50 values were lower for buformin than metformin, suggesting that buformin may be more potent for endometrial cancer treatment and worthy of further investigation. PMID:27398153

  15. Empagliflozin and metformin combination therapy in Type 2 diabetes mellitus

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    R. Jeyalalitha

    2015-12-01

    Full Text Available Diabetes mellitus (DM is a spectrum of metabolic disorder characterized by chronic hyperglycemia either due to an absolute or a relative insulin deficiency. The prevalence of diabetes varies between various countries and ethnic groups and of late, it has reached epidemic proportions in both the developed as well as in the developing countries. There is an intense need for new and effective therapies for Type 2 DM (T2DM with improved safety and tolerability profiles to reduce the outcome of the acute and chronic complications of this condition. Empagliflozin is a new class of selective sodium glucose cotransporter-2 inhibitor approved for the treatment of T2DM in 2014. It has a novel and a unique mechanism of action in that it inhibits the reabsorption of glucose in the kidneys, promotes excessive glucose excretion through a non-insulin dependent mechanism and induces glycosuria. Metformin is the only biguanide which is currently the widely accepted first-line drug for T2DM. It is effective as monotherapy and as combination therapy and has proven beneficial effects on microvascular and macrovascular complications of DM. Recently, the US Food and Drug Administration has approved the fixed dose combination of empagliflozin with metformin hydrochloride during August 2015. The combination of empagliflozin/metformin hydrochloride can be used as an adjunctive therapy to diet and exercise in patients those who are not adequately controlled with monotherapy of either empagliflozin or metformin. This drug update focuses on the insulin-independent unique mechanism of action of empagliflozin and its beneficial effects alone and in combination with metformin in patients with T2DM. [Int J Basic Clin Pharmacol 2015; 4(6.000: 1323-1327

  16. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

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    Kato, Haruo, E-mail: hal.kato@gunma-u.ac.jp; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-05-22

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling.

  17. Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Antonella Napolitano

    Full Text Available Metformin, a biguanide derivate, has pleiotropic effects beyond glucose reduction, including improvement of lipid profiles and lowering microvascular and macrovascular complications associated with type 2 diabetes mellitus (T2DM. These effects have been ascribed to adenosine monophosphate-activated protein kinase (AMPK activation in the liver and skeletal muscle. However, metformin effects are not attenuated when AMPK is knocked out and intravenous metformin is less effective than oral medication, raising the possibility of important gut pharmacology. We hypothesized that the pharmacology of metformin includes alteration of bile acid recirculation and gut microbiota resulting in enhanced enteroendocrine hormone secretion. In this study we evaluated T2DM subjects on and off metformin monotherapy to characterize the gut-based mechanisms of metformin. Subjects were studied at 4 time points: (i at baseline on metformin, (ii 7 days after stopping metformin, (iii when fasting blood glucose (FBG had risen by 25% after stopping metformin, and (iv when FBG returned to baseline levels after restarting the metformin. At these timepoints we profiled glucose, insulin, gut hormones (glucagon-like peptide-1 (GLP-1, peptide tyrosine-tyrosine (PYY and glucose-dependent insulinotropic peptide (GIP and bile acids in blood, as well as duodenal and faecal bile acids and gut microbiota. We found that metformin withdrawal was associated with a reduction of active and total GLP-1 and elevation of serum bile acids, especially cholic acid and its conjugates. These effects reversed when metformin was restarted. Effects on circulating PYY were more modest, while GIP changes were negligible. Microbiota abundance of the phylum Firmicutes was positively correlated with changes in cholic acid and conjugates, while Bacteroidetes abundance was negatively correlated. Firmicutes and Bacteroidetes representation were also correlated with levels of serum PYY. Our study suggests that

  18. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    International Nuclear Information System (INIS)

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling

  19. Coordination equilibria in the complex formation of guanylurea with CuII: Formation and stability of binary CuII-guanylurea and ternary CuII-guanylurea-glycinate complexes

    Indian Academy of Sciences (India)

    Tannistha Roy Barman; G N Mukherjee

    2008-07-01

    Combined pH-metric and spectrophotometric investigations on the complex formation equilibria of CuII with guanylurea (H$_{2}^{1}$NC(=O) 2NH.C(=3NH) 4NH2), hereafter, GuH, in the absence and in the presence of glycine (GlyH), in aqueous solution indicates variety of binary and mixed-ligand complexes: Cu(Gu)+, Cu(Gu)(OH); Cu(Gu)2, Cu(Gu-H)(Gu)-, Cu(Gu-H)$_{2}^{2-}$, Cu(Gu-H)(Gu-2H)3-; Cu(Gly)+, Cu(Gly) (OH); Cu(Gly)(Gu); Cu(Gly)(Gu-H)-, Cu(Gly)(Gu-2H)2-; (Gly)Cu(Gu)Cu(Gly)+, (Gly)Cu(Gu-H)Cu(Gly) and (Gly)Cu(Gu-2H)Cu(Gly)-. At pH < 6, guanylurea anion (Gu-) acts as a [(C=O), 3N-] or [=1NH, 3N-] bidentate ligand and above pH 7 it is transformed through a coordination equilibrium into a (=1N-, =3N-) bidentate ligand, similar to biguanide dianion. Occurrence of dinuclear complex species, (Gly) Cu(Gu)Cu(Gly)+, in the complexation equilibria, indicates bridging double bidentate [(1NH2, 3N-), (C=O, 4NH2)] and/or [(1NH2, 4NH2), (C=O, 3N-)] chelation by Gu- ion in an isomeric equilibrium. Above pH 6.5, the dinuclear complex decomposes mostly to the mononuclear species, Cu(Gly)(OH) and Cu(Gu)(OH) and only partly deprotonates to (Gly)Cu(Gu-H)Cu(Gly) and (Gly)Cu(Gu-2H)Cu(Gly)-. Electronic spectral shifts, with change of pH have been correlated with the possible modes of coordination of guanylurea species.

  20. New poly(ester urea) derived from L-leucine: Electrospun scaffolds loaded with antibacterial drugs and enzymes

    Energy Technology Data Exchange (ETDEWEB)

    Díaz, Angélica; Valle, Luis J. del [Departament d' Enginyeria Química, Universitat Politècnica de Catalunya, Av. Diagonal 647, Barcelona E-08028 (Spain); Tugushi, David; Katsarava, Ramaz [Institute of Chemistry and Molecular Engineering, Agricultural University of Georgia, 13 km. David Aghmashenebeli Alley, Tblisi 0131, Georgia (United States); Puiggalí, Jordi, E-mail: Jordi.Puiggali@upc.edu [Departament d' Enginyeria Química, Universitat Politècnica de Catalunya, Av. Diagonal 647, Barcelona E-08028 (Spain)

    2015-01-01

    Electrospun scaffolds from an amino acid containing poly(ester urea) (PEU) were developed as promising materials in the biomedical field and specifically in tissue engineering applications. The selected poly(ester urea) was obtained with a high yield and molecular weight by reaction of phosgene with a bis(α-aminoacyl)-α,ω-diol-diester monomer. The polymer having L-leucine, 1,6-hexanediol and carbonic acid units had a semicrystalline character and relatively high glass transition and melting temperatures. Furthermore it was highly soluble in most organic solvents, an interesting feature that facilitated the electrospinning process and the effective incorporation of drugs with bactericidal activity (e.g. biguanide derivatives such as clorhexidine and polyhexamethylenebiguanide) and enzymes (e.g. α-chymotrypsin) that accelerated the degradation process. Continuous micro/nanofibers were obtained under a wide range of processing conditions, being diameters of electrospun fibers dependent on the drug and solvent used. Poly(ester urea) samples were degradable in media containing lipases and proteinases but the degradation rate was highly dependent on the surface area, being specifically greater for scaffolds with respect to films. The high hydrophobicity of new scaffolds had repercussions on enzymatic degradability since different weight loss rates were found depending on how samples were exposed to the medium (e.g. forced or non-forced immersion). New scaffolds were biocompatible, as demonstrated by adhesion and proliferation assays performed with fibroblast and epithelial cells. - Highlights: • Electrospun scaffolds from a biodegradable poly(ester urea) have been prepared. • Scaffolds were effectively loaded with bactericide agents. • Enzymatic degradability of the L-leucine derived poly(ester urea) was demonstrated. • Enzymes that accelerate degradation were incorporated in the electrospun fibers. • Cell adhesion/proliferation assays demonstrated

  1. Biofilm-forming activity of bacteria isolated from toilet bowl biofilms and the bactericidal activity of disinfectants against the isolates.

    Science.gov (United States)

    Mori, Miho; Gomi, Mitsuhiro; Matsumune, Norihiko; Niizeki, Kazuma; Sakagami, Yoshikazu

    2013-01-01

    To evaluate the sanitary conditions of toilets, the bacterial counts of the toilet bowl biofilms in 5 Kansai area and 11 Kansai and Kanto area homes in Japan were measured in winter and summer seasons, respectively. Isolates (128 strains) were identified by analyzing 16S ribosomal RNA sequences. The number of colonies and bacterial species from biofilms sampled in winter tended to be higher and lower, respectively, than those in summer. Moreover, the composition of bacterial communities in summer and winter samples differed considerably. In summer samples, biofilms in Kansai and Kanto areas were dominated by Blastomonas sp. and Mycobacterium sp., respectively. Methylobacterium sp. was detected in all toilet bowl biofilms except for one sample. Methylobacterium sp. constituted the major presence in biofilms along with Brevundimonas sp., Sphingomonas sp., and/or Pseudomonas sp. The composition ratio of the sum of their genera was 88.0 from 42.9% of the total bacterial flora. The biofilm formation abilities of 128 isolates were investigated, and results suggested that Methylobacterium sp. and Sphingomonas sp. were involved in biofilm formation in toilet bowls. The biofilm formation of a mixed bacteria system that included bacteria with the highest biofilm-forming ability in a winter sample was greater than mixture without such bacteria. This result suggests that isolates possessing a high biofilm-forming activity are involved in the biofilm formation in the actual toilet bowl. A bactericidal test against 25 strains indicated that the bactericidal activities of didecyldimethylammonium chloride (DDAC) tended to be higher than those of polyhexamethylene biguanide (PHMB) and N-benzyl-N,N-dimethyldodecylammonium chloride (ADBAC). In particular, DDAC showed high bactericidal activity against approximately 90% of tested strains under the 5 h treatment.

  2. Does high-dose metformin cause lactic acidosis in type 2 diabetic patients after CABG surgery? A double blind randomized clinical trial

    Directory of Open Access Journals (Sweden)

    Rahman Ghafari

    2011-06-01

    Full Text Available Metformin is a dimethyl biguanide oral anti-hyperglycemic agent. Lactic acidosis due to metformin is a fatal metabolic condition that limits its use in patients in poor clinical condition, consequently reducing the number of patients who benefit from this medication. In a double blind randomized clinical trial, we investigated 200 type 2 diabetic patients after coronary artery bypass surgery in the open heart ICU of the Mazandaran Heart Center, and randomly assigned them to equal intervention and control groups. The intervention group received regular insulin infusion along with 2 metformin 500 mg tablets every twelve hours, while the control group received only intravenous insulin with 2 placebo tablets every twelve hours. Lactate level, pH, base excess, blood glucose and serum creatinine were measured over five 12 h periods, with data averaged for each period. The primary outcome in this study was high lactate levels. Comparison between the 2 groups was made by independent Student’s t-test. To compare changes in multiple measures in each group and analysis of group interaction, a repeated measurement ANOVA test was used. There was no significant difference between the 2 groups regarding pH, base excess, or bicarbonate intake (P>0.05. No patient showed lactic acidosis in either group. Lactate levels were 23.0 vs 23.4 in the insulin-metformin and insulin only groups when the study was started, respectively. At the end of the study, those levels were 18.7 vs 18.9, respectively. In addition, the ANOVA repeated measurement test did not show a significant difference in terms of changes in the amount of lactate level between the 2 groups during the five measurement tests of the study period (P>0.05. High-dose metformin (1,000 mg twice daily with insulin does not cause lactic acidosis in type 2 diabetic patients after coronary artery

  3. Diabetes mellitus in dogs and cats: diagnosis and therapy

    Directory of Open Access Journals (Sweden)

    Mot, T.,

    2008-12-01

    Full Text Available Diabetes mellitus (DM is a disease of humans and animals, which causes increased levels of blood sugar (glucose. Normally,glucose is brought into the cells by a hormone - insulin.The cells then metabolize glucose to make energy used for all functions of the body. Animals suffering from DM either lack insulin, or the cells cannotuse the insulin that is there. As a result, blood glucose levels increase, and the cells have to use other substances for energy. When blood glucose levels become too high, glucose is found in the urine, causing increased frequency of urination and increased drinking. When blood glucose remains elevated over a period of time, other metabolic changes can occur, such as weight loss, acidosis, seizures, coma, blindness, cataracts, and nerve damage. Animals that are eating normally and not showing signs of illness may only require a blood or urine test to diagnose DM. Concurrent diseases (such as infection, Cushing’s disease, hyperthyroidism, pancreatitis, gastroenteritis, inflammatory bowel disease, hepatic lipidosis, or kidney disease make diabetes more difficult to diagnose and manage. A complete blood screen and other specific tests may be recommended to obtain the diagnosis and baseline values for treatment and future monitoring. The treatment for diabetes in dogs is similar to the treatment for diabetes in humans, through diet and insulin therapy. Dogs and cats with DM are usually treated with insulin. Insulin is a protein and, as such, not suitable for oral administration. Thus, it is administered once or several times daily by the subcutaneous route. Adjustment of the blood glucose concentration demands long hospital care, and subsequently the owner constantly has to keep a strict schedule at home. In veterinary practice the main groups of oral antidiabetic (used in human medicine either are: carbohydrate absorption inhibitors (e.g. acarbose; insulin sensitisers (biguanides such as metformin, thiazolidinedions

  4. PHARMACOTHERAPY BASED PROBLEMS WITH THE RECENT ADVANCES IN THE MANAGEMENT OF DIABETIS MELLITUS

    Directory of Open Access Journals (Sweden)

    LAKHAVAT SUDHAKAR

    2013-01-01

    Full Text Available Objectives : To review the drug treatments and some of the popular , non traditional remedies now available for type-2 diabetis mellitus, as well as selected investigational agents , to describe each medications place in the overal approach to treatment.Material and Methods : Data source from english language journals, pharmacolgy text books, abstracts, review articles and news paper accounts.Results :Older drugs like Sulfonyl ureas and Meglinitide analogues stimulate production and release of insulin.These drugs must be used in patients with intact pancreas and are associated with risk of hypoglycaemic .Biguanides (metformin reduces hepatic glucose production and increases peripheral glucose utilization, but its use is hampered by a high percentage of adverse reaction like metallic taste and diarrhoea.Thiazolidinediones induce PPARץ which express relevant genes increase glucose transport and utilization.but the disadvantage is increased risk of cardiovascular problems.£ -glucosidase inhibitors inhibit enzymes £ -glucosidases present in the intestinal brush borders and there by prevent the absorption and delay the digestion of carbohydrates .Abdominal distension and diarrhea had restricted their use.Conclusion :. Hence there is continuous ongoing work in development of newer drugs ,which are safe ,efficacious and potent as well as free of undesirable effects such as sustained hypoglycemia. Fortunately there are newer drug , few of them approved while other still knocking the door from the classes of drug such as GLP1 Mimetic ,DPP-4 Inhibitors, SGLT-2 Inhibitors , insulin new class of drugs. Here we have tried to cover adverse effects and pharmacotherapy based problems in brief.

  5. Systematic review: Preventive and therapeutic applicationsof metformin in liver disease

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Metformin, a biguanide derivative, is the most commonlyprescribed medication in the treatment of type 2 diabetesmellitus. More recently, the use of metformin has shownpotential as a preventive and therapeutic agent for abroad spectrum of conditions, including liver diseaseand hepatic malignancies. In this systematic review,we critically analyze the literature behind the potentialuse of metformin across the spectrum of liver diseaseand malignancies. The PubMed and Ovid MEDLINEdatabases were searched from 2000 to March 2015,using a combination of relevant text words and MeSHterms: metformin and mammalian target of rapamycin,hepatitis B virus (HBV), hepatitis B virus (HCV), nonalcoholicfatty liver disease (NAFLD), hepatocellularcarcinoma (HCC) or cholangiocarcinoma. The searchresults were evaluated for pertinence to the issue ofmetformin in liver disease as well as for quality of studydesign. Metformin has a number of biochemical effectsthat would suggest a benefit in treating chronic liverdiseases, particularly in the context of insulin resistanceand inflammation. However, the literature thus far doesnot support any independent therapeutic role in NAFLDor HCV. Nonetheless, there is Level Ⅲ evidence fora chemopreventive role in patients with diabetes andchronic liver disease, with decreased incidence of HCCand cholangiocarcinoma. The use of metformin seemsto be safe in patients with cirrhosis, and provides asurvival benefit. Once hepatic malignancies are alreadyestablished, metformin does not offer any therapeuticpotential. In conclusion, there is insufficient evidence torecommend use of metformin in the adjunctive treatmentof chronic liver diseases, including NAFLD and HCV.However, there is good evidence for a chemopreventiverole against HCC among patients with diabetes andchronic liver disease, and metformin should be continuedin patients even with cirrhosis to provide this benefit.

  6. Antiseptics and disinfectants for the treatment of bacterial vaginosis: A systematic review

    Directory of Open Access Journals (Sweden)

    Verstraelen Hans

    2012-06-01

    Full Text Available Abstract Background The study objective was to assess the available data on efficacy and tolerability of antiseptics and disinfectants in treating bacterial vaginosis (BV. Methods A systematic search was conducted by consulting PubMed (1966-2010, CINAHL (1982-2010, IPA (1970-2010, and the Cochrane CENTRAL databases. Clinical trials were searched for by the generic names of all antiseptics and disinfectants listed in the Anatomical Therapeutic Chemical (ATC Classification System under the code D08A. Clinical trials were considered eligible if the efficacy of antiseptics and disinfectants in the treatment of BV was assessed in comparison to placebo or standard antibiotic treatment with metronidazole or clindamycin and if diagnosis of BV relied on standard criteria such as Amsel’s and Nugent’s criteria. Results A total of 262 articles were found, of which 15 reports on clinical trials were assessed. Of these, four randomised controlled trials (RCTs were withheld from analysis. Reasons for exclusion were primarily the lack of standard criteria to diagnose BV or to assess cure, and control treatment not involving placebo or standard antibiotic treatment. Risk of bias for the included studies was assessed with the Cochrane Collaboration’s tool for assessing risk of bias. Three studies showed non-inferiority of chlorhexidine and polyhexamethylene biguanide compared to metronidazole or clindamycin. One RCT found that a single vaginal douche with hydrogen peroxide was slightly, though significantly less effective than a single oral dose of metronidazole. Conclusion The use of antiseptics and disinfectants for the treatment of BV has been poorly studied and most studies are somehow methodologically flawed. There is insufficient evidence at present to advocate the use of these agents, although some studies suggest that some antiseptics may have equal efficacy compared to clindamycin or metronidazole. Further study is warranted with special regard to

  7. Uso del agente antimicrobiano PHMB para prevenir la infección de heridas The use of the antimicrobial agent PHMB to prevent wounds infection

    Directory of Open Access Journals (Sweden)

    Keith Moore

    2008-09-01

    Full Text Available La infección de heridas postoperatorias puede provocar una cicatrización tardía, una estancia prolongada en el hospital y mayores costes. El aumento de bacterias resistentes a los antibióticos es un factor en contra del uso profiláctico de los antibióticos. Una alternativa eficaz es el uso de antisépticos, que presentan menos probabilidades de generar resistencia. Los apósitos AMD TM usan polihexametileno biguanida (PHMB, que tiene una baja toxicidad para las células de las heridas y es eficaz para acabar con las bacterias resistentes a los antibióticos. En este artículo, se revisan las pruebas de la eficacia y rentabilidad de los apósitos AMD en la prevención de las infecciones en la herida quirúrgica si se usan de forma rutinaria en los protocolos estándar para el cuidado de heridas.Post-operative wound infections may result in delayed healing, extended hospital stay and increased costs. The increase in antibiotic-resistant bacteria mitigates against the prophylactic use of antibiotics. An effective alternative is the use of antiseptics that are less likely to generate resistance. AMD TM wound dressings use polyhexamethylene biguanide (PHMB which has a low toxicity for wound cells and is effective in killing antibiotic-resistant bacteria. This paper reviews the evidence for the efficacy and cost-effectiveness of AMD dressings in the prevention of surgical site infections when routinely used in standard wound care protocols.

  8. Clinical profile of newly presenting diabetic patients at the University of Uyo Teaching Hospital, Nigeria

    International Nuclear Information System (INIS)

    Diabetes Mellitus is emerging as a major health challenge with the incidence and prevalence of the disease on the increase. It also contributes to overall morbidity and mortality with complications like cardiovascular disease, neuropathy, nephropathy, retinopathy and lower extremity amputation. There are few local studies on the clinical characteristics of the disease in our wet up and this study therefore set out to characterize the clinical profile of newly presenting diabetic patients in a health facility in Nigeria. It is a cross sectional, descriptive study carried out at the diabetes clinic of the University of Uyo Teaching Hospital between January 2007 and September 2008. Data obtained included age, sex, anthropometric indices, symptomatology, co-morbidities, complications and treatment of diabetes. Data was analyzed using SPSS version 10. A total of two hundred and seventy patients were studied (120 males, 150 females). About 89.2% were Type 2 DM patients and majority of the study subjects were overweight. Diabetic neuropathy was the commonest complication present in 38.8% of the subjects. Polyuria was the commonest symptom and hypertension the commonest comorbidity. Majority of the subjects were on oral hypolgycaemic agents for the management of their disease with the sulphonyureas and biguanides being the most common medication that was taken by them. A few of the patients were also taking herbal medication for treatment of their disease. Majority of the patients presenting in our facility have Type 2 diabetes, were hypertensive and overweight. Hypertension was the commonest co-morbidity and diabetic neuropathy the commonest complication. Adequate health education, subsidies on medications and proper funding of the health sector is necessary to stem the tide of the burden attributable to the disease. (author)

  9. Metabolic and molecular action of Trigonella foenum-graecum (fenugreek) and trace metals in experimental diabetic tissues

    Indian Academy of Sciences (India)

    Najma Zaheer Baquer; Pardeep Kumar; Asia Taha; R K Kale; S M Cowsik; P McLean

    2011-06-01

    Diabetes mellitus is a heterogeneous metabolic disorder characterized by hyperglycaemia resulting in defective insulin secretion, resistance to insulin action or both. The use of biguanides, sulphonylurea and other drugs are valuable in the treatment of diabetes mellitus; their use, however, is restricted by their limited action, pharmaco-kinetic properties, secondary failure rates and side effects. Trigonella foenum-graecum, commonly known as fenugreek, is a plant that has been extensively used as a source of antidiabetic compounds from its seeds and leaf extracts. Preliminary human trials and animal experiments suggest possible hypoglycaemic and anti-hyperlipedemic properties of fenugreek seed powder taken orally. Our results show that the action of fenugreek in lowering blood glucose levels is almost comparable to the effect of insulin. Combination with trace metal showed that vanadium had additive effects and manganese had additive effects with insulin on in vitro system in control and diabetic animals of young and old ages using adipose tissue. The Trigonella and vanadium effects were studied in a number of tissues including liver, kidney, brain peripheral nerve, heart, red blood cells and skeletal muscle. Addition of Trigonella to vanadium significantly removed the toxicity of vanadium when used to reduce blood glucose levels. Administration of the various combinations of the antidiabetic compounds to diabetic animals was found to reverse most of the diabetic effects studied at physiological, biochemical, histochemical and molecular levels. Results of the key enzymes of metabolic pathways have been summarized together with glucose transporter, Glut-4 and insulin levels. Our findings illustrate and elucidate the antidiabetic/insulin mimetic effects of Trigonella, manganese and vanadium.

  10. Repositioning of Verrucosidin, a purported inhibitor of chaperone protein GRP78, as an inhibitor of mitochondrial electron transport chain complex I.

    Directory of Open Access Journals (Sweden)

    Simmy Thomas

    Full Text Available Verrucosidin (VCD belongs to a group of fungal metabolites that were identified in screening programs to detect molecules that preferentially kill cancer cells under glucose-deprived conditions. Its mode of action was proposed to involve inhibition of increased GRP78 (glucose regulated protein 78 expression during hypoglycemia. Because GRP78 plays an important role in tumorigenesis, inhibitors such as VCD might harbor cancer therapeutic potential. We therefore sought to characterize VCD's anticancer activity in vitro. Triple-negative breast cancer cell lines MDA-MB-231 and MDA-MB-468 were treated with VCD under different conditions known to trigger increased expression of GRP78, and a variety of cellular processes were analyzed. We show that VCD was highly cytotoxic only under hypoglycemic conditions, but not in the presence of normal glucose levels, and VCD blocked GRP78 expression only when glycolysis was impaired (due to hypoglycemia or the presence of the glycolysis inhibitor 2-deoxyglucose, but not when GRP78 was induced by other means (hypoxia, thapsigargin, tunicamycin. However, VCD's strictly hypoglycemia-specific toxicity was not due to the inhibition of GRP78. Rather, VCD blocked mitochondrial energy production via inhibition of complex I of the electron transport chain. As a result, cellular ATP levels were quickly depleted under hypoglycemic conditions, and common cellular functions, including general protein synthesis, deteriorated and resulted in cell death. Altogether, our study identifies mitochondria as the primary target of VCD. The possibility that other purported GRP78 inhibitors (arctigenin, biguanides, deoxyverrucosidin, efrapeptin, JBIR, piericidin, prunustatin, pyrvinium, rottlerin, valinomycin, versipelostatin might act in a similar GRP78-independent fashion will be discussed.

  11. Effect of Sitagliptin and Metformin on Prediabetes Progression to Type 2 Diabetes - A Randomized, Double-Blind, Double-Arm, Multicenter Clinical Trial: Protocol for the Sitagliptin and Metformin in PreDiabetes (SiMePreD) Study

    Science.gov (United States)

    2016-01-01

    Background The high prevalence and incidence of type 2 diabetes mellitus (DM), and its associated morbidity and mortality, has prompted growing international interest and effort in the primary prevention of this disease. Primary prevention is possible since type 2 DM is preceded by prediabetes, offering a window opportunity to treat patients, and prevent the emergence of advanced disease. Sitagliptin is an oral dipeptidyl peptidase-IV inhibitor that preserves existing beta cell function and increases beta cell mass. These two effects have been demonstrated both in vitro and in animal studies, and current clinical data show that sitagliptin is safe. Metformin, a biguanide, reduces insulin resistance and inhibits hepatic gluconeogenesis, and has an excellent safety profile. The combination of metformin and sitagliptin, targeting both characteristics of prediabetes (insulin resistance and progressive beta cell degeneration), may potentially slow or halt the progression from prediabetes to type 2 DM. This paper describes the rationale and design of the Sitagliptin and Metformin in PreDiabetes (SiMePreD) study. Objective The aim of this study is to determine the effect of sitagliptin and metformin on progression from prediabetes to type 2 DM. The objectives of the study are to determine the effects of metformin and placebo on glycemic endpoints, the effects of sitagliptin and metformin on glycemic endpoints, the effects of metformin and placebo on incidence of cardiovascular disease and death, and the effects of sitagliptin and metformin on incidence of cardiovascular disease and death. Methods This is a randomized, double-blind, multicenter clinical study that will determine if the combination of metformin and sitagliptin is effective in preventing the progression from prediabetes to type 2 DM. The study will contain two arms (metformin/sitagliptin and metformin/placebo). Primary endpoints include the number of subjects progressing from prediabetes to type 2 DM, the

  12. Enzyme-responsive nanocomposites for wound infection prophylaxis in burn management: in vitro evaluation of their compatibility with healing processes

    Directory of Open Access Journals (Sweden)

    Grützner V

    2015-06-01

    Full Text Available Verena Grützner,1 Ronald E Unger,1 Grit Baier,2 Lars Choritz,3 Christian Freese,1 Thomas Böse,1 Katharina Landfester,2 C James Kirkpatrick11REPAIR-Lab, Institute of Pathology, University Medical Center, Mainz, 2Max Planck Institute for Polymer Research, Mainz, Germany; 3Department of Ophthalmology, University Clinic, Magdeburg, GermanyAbstract: Responsive, theranostic nanosystems, capable of both signaling and treating wound infections, is a sophisticated approach to reduce the most common and potentially traumatizing side effects of burn wound treatment: slowed wound healing due to prophylactic anti-infective drug exposure as well as frequent painful dressing changes. Antimicrobials as well as dye molecules have been incorporated into biodegradable nanosystems that release their content only in the presence of pathogens. Following nanocarrier degradation by bacterial enzymes, any infection will thus emit a visible signal and be effectively treated at its source. In this study, we investigated the effect of fluorescent-labeled hyaluronan nanocapsules containing polyhexanide biguanide and poly-L-lactic acid nanoparticles loaded with octenidine on primary human dermal microvascular endothelial cells, which play a major role in cutaneous wound healing. Microscopic and flow cytometric analysis indicated a time-dependent uptake of both the nanocapsules and the nanoparticles. However, enzyme immunoassays showed no significant influence on the expression of pro-inflammatory cell adhesion molecules and cytokines by the endothelial cells. Under angiogenic-stimulating conditions, the potential to form capillary-like structures in co-culture with dermal fibroblasts was not inhibited. Furthermore, cytotoxicity studies (the MTS and crystal violet assay after short- and long-term exposure to the materials demonstrated that both systems exhibited less toxicity than solutions of the antiseptic agents alone in comparable concentrations. The results indicate

  13. Serotonin in the solitary tract nucleus shortens the laryngeal chemoreflex in anaesthetized neonatal rats.

    Science.gov (United States)

    Donnelly, William T; Bartlett, Donald; Leiter, J C

    2016-07-01

    What is the central question of this study? Failure to terminate apnoea and arouse is likely to contribute to sudden infant death syndrome (SIDS). Serotonin is deficient in the brainstems of babies who died of SIDS. Therefore, we tested the hypothesis that serotonin in the nucleus of the solitary tract (NTS) would shorten reflex apnoea. What is the main finding and its importance? Serotonin microinjected into the NTS shortened the apnoea and respiratory inhibition associated with the laryngeal chemoreflex. Moreover, this effect was achieved through a 5-HT3 receptor. This is a new insight that is likely to be relevant to the pathogenesis of SIDS. The laryngeal chemoreflex (LCR), an airway-protective reflex that causes apnoea and bradycardia, has long been suspected as an initiating event in the sudden infant death syndrome. Serotonin (5-HT) and 5-HT receptors may be deficient in the brainstems of babies who die of sudden infant death syndrome, and 5-HT seems to be important in terminating apnoeas directly or in causing arousals or as part of the process of autoresuscitation. We hypothesized that 5-HT in the brainstem would limit the duration of the LCR. We studied anaesthetized rat pups between 7 and 21 days of age and made microinjections into the cisterna magna or into the nucleus of the solitary tract (NTS). Focal, bilateral microinjections of 5-HT into the caudal NTS significantly shortened the LCR. The 5-HT1a receptor antagonist, WAY 100635, did not affect the LCR consistently, nor did a 5-HT2 receptor antagonist, ketanserin, alter the duration of the LCR. The 5-HT3 specific agonist, 1-(3-chlorophenyl)-biguanide, microinjected bilaterally into the caudal NTS significantly shortened the LCR. Thus, endogenous 5-HT released within the NTS may curtail the respiratory depression that is part of the LCR, and serotonergic shortening of the LCR may be attributed to activation of 5-HT3 receptors within the NTS. 5-HT3 receptors are expressed presynaptically on C

  14. Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4 inhibitors and human glucagon-like peptide-1 (GLP-1 analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review.

    Directory of Open Access Journals (Sweden)

    Martin C S Wong

    Full Text Available The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4 inhibitors and the human glucagon-like peptide-1 (GLP-1 analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59-0.90% and 0.77-1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major

  15. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Higurashi Takuma

    2012-03-01

    Full Text Available Abstract Background Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF. ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients. Methods/Design This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation. Discussion This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with

  16. Antimicrobial efficacy assessment of multi-use solution to disinfect hydrophilic contact lens, in vitro Avaliação da ação antimicrobiana de soluções multiuso para desinfecção de lentes de contato hidrofílicas, in vitro

    Directory of Open Access Journals (Sweden)

    Aline Cristina Fioravanti Lui

    2009-10-01

    Full Text Available PURPOSE: To evaluate the efficacy of disinfecting solutions in hydrophilic contact lenses (CL. METHODS: Two multi-use solutions denominated solution A (0.001% polyquaternium-1 and 0.0005% myristamidopropyl dimethylamine and solution B (0.0001% polyaminopropyl biguanide were used. The solutions were tested in hydrophilic contact lenses infected with Pseudomonas aeruginosa (ATCC27583, Staphylococcus epidermidis (ATCC1226, Klebsiella pneumoniae (ATCC13883, Staphylococcus aureus (ATCC25923 and Candida albicans (ATCC 10231 and the decrease in microorganisms growth after the hydrophilic contact lenses were cleaned with the respective solutions was verified. The manufacture's instructions were followed. RESULTS: A decrease of 90% of Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus aureus, Candida albicans and a decrease 100% of Klebsiella pneumoniae was observed. CONCLUSION: The solutions decreased the amount of microorganisms tested.OBJETIVO: Avaliar a influência da ação antimicrobiana das soluções multiuso para desinfecção de lentes de contato hidrofílicas. MÉTODOS: Duas soluções multiuso denominadas solução A (poliquaternário-1 a 0,001% e miristamidopropil dimetilamina a 0,0005% e solução B (poliaminopropil biguanida a 0,0001% foram testadas em lentes de contato hidrofílicas contaminadas com Pseudomonas aeruginosa (ATCC27583, Staphylococcus epidermidis (ATCC1226, Klebsiella pneumoniae (ATCC13883, Staphylococcus aureus (ATCC25923 e Candida albicans (ATCC 10231 para verificar a quantidade de redução do crescimento dos microrganismos após o enxágue com as soluções. Foram seguidas as instruções preconizadas pelos fabricantes. RESULTADOS: Houve redução de 90% do crescimento de Pseudomonas aeruginosa, Staphylococcus epidermidis, Staphylococcus aureus e Candida albicans. Não houve crescimento de Klebsiella pneumoniae. CONCLUSÃO: As soluções testadas neste trabalho mostraram redução do número de

  17. Dendritic immune cell densities in the central cornea associated with soft contact lens types and lens care solution types: a pilot study

    Directory of Open Access Journals (Sweden)

    Sindt CW

    2012-03-01

    Full Text Available Christine W Sindt1, Trudy K Grout1, D Brice Critser1, Jami R Kern2, David L Meadows21University of Iowa Hospitals and Clinics, Iowa City, IA; 2Alcon Research Ltd, Fort Worth, TX, USABackground: The purpose of this study was to assess whether differences in central corneal dendritic immune cell densities associated with combinations of soft contact lenses and lens care solutions could be detected by in vivo confocal microscopy.Methods: Participants were adults naïve to contact lens wear (n = 10 or who wore soft contact lenses habitually on a daily-wear schedule (n = 38 or on a study-assigned schedule for 30 days with daily disposable silicone hydrogel lenses (n = 15. Central corneas were scanned using an in vivo confocal microscope. Cell densities were compared among groups by demographic parameters, lens materials, and lens care solutions (polyhexamethylene biguanide [PHMB], polyquaternium-1 and myristamidopropyl dimethylamine [PQ/MAPD], peroxide, or blister pack solution [for daily disposable lenses].Results: Among lens wearers, no associations were observed between immune cell densities and age, gender, or years of lens-wearing experience. Mean cell density was significantly lower (P < 0.01 in nonwearers (29 ± 23 cells/mm2, n = 10 than in lens wearers (64 ± 71 cells/mm2, n = 53. Mean cell density was lower (P = 0.21 with traditional polymer lenses (47 ± 44 cells/mm2, n = 12 than with silicone hydrogel lenses (69 ± 77 cells/mm2, n = 41. Lowest to highest mean density of immune cells among lens wearers was as follows: PQ/MAPD solution (49 ± 28 cells/mm2, blister pack solution (63 ± 81 cells/mm2, PHMB solution (66 ± 44 cells/mm2, and peroxide solution (85 ± 112 cells/mm2.Conclusion: In this pilot study, in vivo confocal microscopy was useful for detecting an elevated immune response associated with soft contact lenses, and for identifying lens-related and solution-related immune responses that merit further research.Keywords: Clear Care

  18. Current management of diabetes mellitus and future directions in care.

    Science.gov (United States)

    Chatterjee, Sudesna; Davies, Melanie J

    2015-11-01

    The last 90 years have seen considerable advances in the management of type 1 and type 2 diabetes. Prof MacLean of Guy's Hospital wrote in the Postgraduate Medical Journal in 1926 about the numerous challenges that faced patients and their healthcare professionals in delivering safe and effective diabetes care at that time. The discovery of insulin in 1922 heralded a new age in enabling long-term glycaemic control, which reduced morbidity and mortality. Thirty years later, the first oral agents for diabetes, the biguanides and sulfonylureas, appeared and freed type 2 patients from having to inject insulin following diagnosis. Improvements in insulin formulations over the decades, including rapid-acting and long-acting insulin analogues that more closely mimic physiological insulin secretion, have increased the flexibility and efficacy of type 1 diabetes management. The last two decades have seen major advances in technology, which has manifested in more accurate glucose monitoring systems and insulin delivery devices ('insulin pump'). Increased understanding of the pathophysiological deficits underlying type 2 diabetes has led to the development of targeted therapeutic approaches such as on the small intestine (glucagon-like peptide-1 receptor analogues and dipeptidyl-peptidase IV inhibitors) and kidneys (sodium-glucose cotransporter-2 inhibitors). A patient-centred approach delivered by a multidisciplinary team is now advocated. Glycaemic targets are set according to individual circumstances, taking into account factors such as weight, hypoglycaemia risk and patient preference. Stepwise treatment guidelines devised by international diabetes organisations standardise and rationalise management. Structured education programmes and psychological support are now well-established as essential for improving patient motivation and self-empowerment. Large multicentre randomised trials have confirmed the effectiveness of intensive glycaemic control on microvascular

  19. Behavior of Listeria monocytogenes in a multi-species biofilm with Enterococcus faecalis and Enterococcus faecium and control through sanitation procedures.

    Science.gov (United States)

    da Silva Fernandes, Meg; Kabuki, Dirce Yorika; Kuaye, Arnaldo Yoshiteru

    2015-05-01

    The formation of mono-species biofilm (Listeria monocytogenes) and multi-species biofilms (Enterococcus faecium, Enterococcus faecalis, and L. monocytogenes) was evaluated. In addition, the effectiveness of sanitation procedures for the control of the multi-species biofilm also was evaluated. The biofilms were grown on stainless steel coupons at various incubation temperatures (7, 25 and 39°C) and contact times (0, 1, 2, 4, 6 and 8 days). In all tests, at 7°C, the microbial counts were below 0.4 log CFU/cm(2) and not characteristic of biofilms. In mono-species biofilm, the counts of L. monocytogenes after 8 days of contact were 4.1 and 2.8 log CFU/cm(2) at 25 and 39°C, respectively. In the multi-species biofilms, Enterococcus spp. were present at counts of 8 log CFU/cm(2) at 25 and 39°C after 8 days of contact. However, the L. monocytogenes in multi-species biofilms was significantly affected by the presence of Enterococcus spp. and by temperature. At 25°C, the growth of L. monocytogenes biofilms was favored in multi-species cultures, with counts above 6 log CFU/cm(2) after 8 days of contact. In contrast, at 39°C, a negative effect was observed for L. monocytogenes biofilm growth in mixed cultures, with a significant reduction in counts over time and values below 0.4 log CFU/cm(2) starting at day 4. Anionic tensioactive cleaning complemented with another procedure (acid cleaning, disinfection or acid cleaning+disinfection) eliminated the multi-species biofilms under all conditions tested (counts of all micro-organisms<0.4 log CFU/cm(2)). Peracetic acid was the most effective disinfectant, eliminating the multi-species biofilms under all tested conditions (counts of the all microorganisms <0.4 log CFU/cm(2)). In contrast, biguanide was the least effective disinfectant, failing to eliminate biofilms under all the test conditions.

  20. Energy metabolism and metabolic sensors in stem cells: the metabostem crossroads of aging and cancer.

    Science.gov (United States)

    Menendez, Javier A; Joven, Jorge

    2014-01-01

    We are as old as our adult stem cells are; therefore, stem cell exhaustion is considered a hallmark of aging. Our tumors are as aggressive as the number of cancer stem cells (CSCs) they bear because CSCs can survive treatments with hormones, radiation, chemotherapy, and molecularly targeted drugs, thus increasing the difficulty of curing cancer. Not surprisingly, interest in stem cell research has never been greater among members of the public, politicians, and scientists. But how can we slow the rate at which our adult stem cells decline over our lifetime, reducing the regenerative potential of tissues, while efficiently eliminating the aberrant, life-threatening activity of "selfish", immortal, and migrating CSCs? Frustrated by the gene-centric limitations of conventional approaches to aging diseases, our group and other groups have begun to appreciate that bioenergetic metabolism, i.e., the production of fuel & building blocks for growth and division, and autophagy/mitophagy, i.e., the quality-control, self-cannibalistic system responsible for "cleaning house" and "recycling the trash", can govern the genetic and epigenetic networks that facilitate stem cell behaviors. Indeed, it is reasonable to suggest the existence of a "metabostem" infrastructure that operates as a shared hallmark of aging and cancer, thus making it physiologically plausible to maintain or even increase the functionality of adult stem cells while reducing the incidence of cancer and extending the lifespan. This "metabostemness" property could lead to the discovery of new drugs that reprogram cell metabotypes to increase the structural and functional integrity of adult stem cells and positively influence their lineage determination, while preventing the development and aberrant function of stem cells in cancer tissues. While it is obvious that the antifungal antibiotic rapamycin, the polyphenol resveratrol, and the biguanide metformin already belong to this new family of metabostemness

  1. In Vitro Anti-Echinococcal and Metabolic Effects of Metformin Involve Activation of AMP-Activated Protein Kinase in Larval Stages of Echinococcus granulosus.

    Science.gov (United States)

    Loos, Julia A; Cumino, Andrea C

    2015-01-01

    Metformin (Met) is a biguanide anti-hyperglycemic agent, which also exerts antiproliferative effects on cancer cells. This drug inhibits the complex I of the mitochondrial electron transport chain inducing a fall in the cell energy charge and leading 5'-AMP-activated protein kinase (AMPK) activation. AMPK is a highly conserved heterotrimeric complex that coordinates metabolic and growth pathways in order to maintain energy homeostasis and cell survival, mainly under nutritional stress conditions, in a Liver Kinase B1 (LKB1)-dependent manner. This work describes for the first time, the in vitro anti-echinococcal effect of Met on Echinococcus granulosus larval stages, as well as the molecular characterization of AMPK (Eg-AMPK) in this parasite of clinical importance. The drug exerted a dose-dependent effect on the viability of both larval stages. Based on this, we proceeded with the identification of the genes encoding for the different subunits of Eg-AMPK. We cloned one gene coding for the catalytic subunit (Eg-ampkɑ) and two genes coding for the regulatory subunits (Eg-ampkβ and Eg-ampkγ), all of them constitutively transcribed in E. granulosus protoscoleces and metacestodes. Their deduced amino acid sequences show all the conserved functional domains, including key amino acids involved in catalytic activity and protein-protein interactions. In protoscoleces, the drug induced the activation of AMPK (Eg-AMPKɑ-P176), possibly as a consequence of cellular energy charge depletion evidenced by assays with the fluorescent indicator JC-1. Met also led to carbohydrate starvation, it increased glucogenolysis and homolactic fermentation, and decreased transcription of intermediary metabolism genes. By in toto immunolocalization assays, we detected Eg-AMPKɑ-P176 expression, both in the nucleus and the cytoplasm of cells as in the larval tegument, the posterior bladder and the calcareous corpuscles of control and Met-treated protoscoleces. Interestingly, expression of Eg

  2. Lactic acidosis induced by metformin: incidence, management and prevention.

    Science.gov (United States)

    Lalau, Jean-Daniel

    2010-09-01

    Lactic acidosis associated with metformin treatment is a rare but important adverse event, and unravelling the problem is critical. First, this potential event still influences treatment strategies in type 2 diabetes mellitus, particularly in the many patients at risk of kidney failure, in those presenting contraindications to metformin and in the elderly. Second, the relationship between metformin and lactic acidosis is complex, since use of the drug may be causal, co-responsible or coincidental. The present review is divided into three parts, dealing with the incidence, management and prevention of lactic acidosis occurring during metformin treatment. In terms of incidence, the objective of this article is to counter the conventional view of the link between metformin and lactic acidosis, according to which metformin-associated lactic acidosis is rare but is still associated with a high rate of mortality. In fact, the direct metformin-related mortality is close to zero and metformin may even be protective in cases of very severe lactic acidosis unrelated to the drug. Metformin has also inherited a negative class effect, since the early biguanide, phenformin, was associated with more frequent and sometimes fatal lactic acidosis. In the second part of this review, the objective is to identify the most efficient patient management methods based on our knowledge of how metformin acts on glucose/lactate metabolism and how lactic acidosis may occur (at the organ and cellular levels) during metformin treatment. The liver appears to be a key organ for both the antidiabetic effect of metformin and the development of lactic acidosis; the latter is attributed to mitochondrial impairment and subsequent adenosine triphosphate depletion, acceleration of the glycolytic flux, increased glucose uptake and the generation of lactate, which effluxes into the circulation rather than being oxidized further. Haemodialysis should systematically be performed in severe forms of lactic

  3. Predictors of mortality subsequent to a fracture in diabetes mellitus patients

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    Jakob eStarup-Linde

    2015-04-01

    Full Text Available Background: Type-1 and type-2 Diabetes Mellitus (DM is associated with an increased fracture risk and possibly an increased risk of death following a fracture.Aim: To investigate the association between diabetes related drugs and mortality following a fracture. Methods: A nested case-control study was conducted. Cases were patients with DM who died following a fracture; controls were DM patients not dying after a fracture. We identified DM patients using the Danish National Hospital Discharge Register (1977-2011 and included information on date of DM diagnosis, date of fracture and comorbidities. From the Danish Cause of Death Register the date of death was collected (2008-2011. From the Central Region of Jutland, Denmark, medication use was collected (2008-2011. Analysis was performed by unconditional logistic regression.Results: 2,621 diabetes patients with a fracture following the diabetes diagnosis and with information on medication use were included. Of these 229 died. In a multivariate analysis, statin use (n= 1,106 (42% statin users, odds ratio (OR = 0.60, 95 % confidence interval, p=0.012 decreased the risk of dying subsequent to a fracture. Male gender (OR=1.57, p=0.005, increasing age (OR=1.08, p<0.001, a diagnosis of retinopathy (OR=2.12, p=0.008, heart failure (OR= 1.68, p=0.004 and use of glucocorticoids (OR=2.22, p=0.001 were associated with an increased risk of death. None of the antidiabetics; biguanides, glucagon-like receptor agonists, β-cell stimulants, glitazones, and insulin were associated with mortality.Conclusion: Co-morbidity reflected by late onset complications, heart failure and glucocorticoid use was associated with an increased risk of mortality subsequent to a fracture. Statin use may reduce mortality subsequent to a fracture in diabetes patients. Clinical trials are needed to determine whether diabetes patients with a fracture should initiate statin treatment.

  4. Extending the TIME concept: what have we learned in the past 10 years?(*).

    Science.gov (United States)

    Leaper, David J; Schultz, Gregory; Carville, Keryln; Fletcher, Jacqueline; Swanson, Theresa; Drake, Rebecca

    2012-12-01

    The TIME acronym (tissue, infection/inflammation, moisture balance and edge of wound) was first developed more than 10 years ago, by an international group of wound healing experts, to provide a framework for a structured approach to wound bed preparation; a basis for optimising the management of open chronic wounds healing by secondary intention. However, it should be recognised that the TIME principles are only a part of the systematic and holistic evaluation of each patient at every wound assessment. This review, prepared by the International Wound Infection Institute, examines how new data and evidence generated in the intervening decade affects the original concepts of TIME, and how it is translated into current best practice. Four developments stand out: recognition of the importance of biofilms (and the need for a simple diagnostic), use of negative pressure wound therapy (NPWT), evolution of topical antiseptic therapy as dressings and for wound lavage (notably, silver and polyhexamethylene biguanide) and expanded insight of the role of molecular biological processes in chronic wounds (with emerging diagnostics and theranostics). Tissue: a major advance has been the recognition of the value of repetitive and maintenance debridement and wound cleansing, both in time-honoured and novel methods (notably using NPWT and hydrosurgery). Infection/inflammation: clinical recognition of infection (and non infective causes of persisting inflammation) is critical. The concept of a bacterial continuum through contamination, colonisation and infection is now widely accepted, together with the understanding of biofilm presence. There has been a return to topical antiseptics to control bioburden in wounds, emphasised by the awareness of increasing antibiotic resistance. Moisture: the relevance of excessive or insufficient wound exudate and its molecular components has led to the development and use of a wide range of dressings to regulate moisture balance, and to protect

  5. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

    International Nuclear Information System (INIS)

    Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients. This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation. This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been

  6. Metformin lowers the threshold for stress-induced senescence: a role for the microRNA-200 family and miR-205.

    Science.gov (United States)

    Cufí, Sílvia; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Quirantes, Rosa; Segura-Carretero, Antonio; Micol, Vicente; Joven, Jorge; Bosch-Barrera, Joaquim; Del Barco, Sonia; Martin-Castillo, Begoña; Vellon, Luciano; Menendez, Javier A

    2012-03-15

    We have tested the hypothesis that the antidiabetic biguanide metformin can be used to manipulate the threshold for stress-induced senescence (SIS), thus accelerating the onset of cancer-protective cellular senescence in response to oncogenic stimuli. Using senescence-prone murine embryonic fibroblasts (MEFs), we assessed whether metformin treatment modified the senescence phenotype that is activated in response to DNA damaging inducers. Metformin significantly enhanced the number of MEFs entering a senescent stage in response to doxorubicin, an anthracycline that induces cell senescence by activating DNA damage signaling pathways (e.g., ATM/ATR) in a reactive oxygen species (ROS)-dependent manner. Using WI-38 and BJ-1 human diploid fibroblasts (HDFs), we explored whether metformin supplementation throughout their entire replicative lifespan may promote the early appearance of the biomarkers of replicative senescence. Chronic metformin significantly reduced HDFs' lifespan by accelerating both the loss of replicative potential and the acquisition of replicative senescence-related biomarkers (e.g., enlarged and flattened cell shapes, loss of arrayed arrangement, accumulation of intracellular and extracellular debris and SA-β-gal-positive staining). Metformin functioned as a bona fide stressful agent, inducing monotonic, dose-dependent, SIS-like responses in BJ-1 HDFs, which are highly resistant to ROS-induced premature senescence. Metformin-induced SIS in BJ-1 fibroblasts was accompanied by the striking activation of several microRNAs belonging to the miR-200s family (miR-200a, miR-141 and miR429) and miR-205, thus mimicking a recently described ability of ROS to chemosensitize cancer cells by specifically upregulating anti-EMT (epithelial-to-mesenchymal transition) miR-200s. Because the unlimited proliferative potential of stem cells results from their metabolic refractoriness to SIS, we finally tested if metformin treatment could circumvent the stress (e.g., ROS

  7. The phenomenon of acquired resistance to metformin in breast cancer cells: The interaction of growth pathways and estrogen receptor signaling.

    Science.gov (United States)

    Scherbakov, Alexander M; Sorokin, Danila V; Tatarskiy, Victor V; Prokhorov, Nikolay S; Semina, Svetlana E; Berstein, Lev M; Krasil'nikov, Mikhail A

    2016-04-01

    Metformin, a biguanide antidiabetic drug, is used to decrease hyperglycemia in patients with type 2 diabetes. Recently, the epidemiological studies revealed the potential of metformin as an anti-tumor drug for several types of cancer, including breast cancer. Anti-tumor metformin action was found to be mediated, at least in part, via activation of adenosine monophosphate-activated protein kinase (AMPK)-intracellular energy sensor, which inhibits the mammalian target of rapamycin (mTOR) and some other signaling pathways. Nevertheless, some patients can be non-sensitive or resistant to metformin action. Here we analyzed the mechanism of the formation of metformin-resistant phenotype in breast cancer cells and its role in estrogen receptor (ER) regulation. The experiments were performed on the ER-positive MCF-7 breast cancer cells and metformin-resistant MCF-7 subline (MCF-7/M) developed due to long-term metformin treatment. The transcriptional activity of NF-κB and ER was measured by the luciferase reporter gene analysis. The protein expression was determined by immunoblotting (Snail1, (phospho)AMPK, (phospho)IκBα, (phospho)mTOR, cyclin D1, (phospho)Akt and ERα) and immunohistochemical analysis (E-cadherin). We have found that: 1) metformin treatment of MCF-7 cells is accompanied with the stimulation of AMPK and inhibition of growth-related proteins including IκBα, NF-κB, cyclin D1 and ERα; 2) long-term metformin treatment lead to the appearance and progression of cross-resistance to metformin and tamoxifen; the resistant cells are characterized with the unaffected AMPK activity, but the irreversible ER suppression and constitutive activation of Akt/Snail1 signaling; 3) Akt/Snail1 signaling is involved into progression of metformin resistance. The results presented may be considered as the first evidence of the progression of cross-resistance to metformin and tamoxifen in breast cancer cells. Importantly, the acquired resistance to both drugs is based on the

  8. In Vitro Anti-Echinococcal and Metabolic Effects of Metformin Involve Activation of AMP-Activated Protein Kinase in Larval Stages of Echinococcus granulosus.

    Science.gov (United States)

    Loos, Julia A; Cumino, Andrea C

    2015-01-01

    Metformin (Met) is a biguanide anti-hyperglycemic agent, which also exerts antiproliferative effects on cancer cells. This drug inhibits the complex I of the mitochondrial electron transport chain inducing a fall in the cell energy charge and leading 5'-AMP-activated protein kinase (AMPK) activation. AMPK is a highly conserved heterotrimeric complex that coordinates metabolic and growth pathways in order to maintain energy homeostasis and cell survival, mainly under nutritional stress conditions, in a Liver Kinase B1 (LKB1)-dependent manner. This work describes for the first time, the in vitro anti-echinococcal effect of Met on Echinococcus granulosus larval stages, as well as the molecular characterization of AMPK (Eg-AMPK) in this parasite of clinical importance. The drug exerted a dose-dependent effect on the viability of both larval stages. Based on this, we proceeded with the identification of the genes encoding for the different subunits of Eg-AMPK. We cloned one gene coding for the catalytic subunit (Eg-ampkɑ) and two genes coding for the regulatory subunits (Eg-ampkβ and Eg-ampkγ), all of them constitutively transcribed in E. granulosus protoscoleces and metacestodes. Their deduced amino acid sequences show all the conserved functional domains, including key amino acids involved in catalytic activity and protein-protein interactions. In protoscoleces, the drug induced the activation of AMPK (Eg-AMPKɑ-P176), possibly as a consequence of cellular energy charge depletion evidenced by assays with the fluorescent indicator JC-1. Met also led to carbohydrate starvation, it increased glucogenolysis and homolactic fermentation, and decreased transcription of intermediary metabolism genes. By in toto immunolocalization assays, we detected Eg-AMPKɑ-P176 expression, both in the nucleus and the cytoplasm of cells as in the larval tegument, the posterior bladder and the calcareous corpuscles of control and Met-treated protoscoleces. Interestingly, expression of Eg

  9. In Vitro Anti-Echinococcal and Metabolic Effects of Metformin Involve Activation of AMP-Activated Protein Kinase in Larval Stages of Echinococcus granulosus.

    Directory of Open Access Journals (Sweden)

    Julia A Loos

    Full Text Available Metformin (Met is a biguanide anti-hyperglycemic agent, which also exerts antiproliferative effects on cancer cells. This drug inhibits the complex I of the mitochondrial electron transport chain inducing a fall in the cell energy charge and leading 5'-AMP-activated protein kinase (AMPK activation. AMPK is a highly conserved heterotrimeric complex that coordinates metabolic and growth pathways in order to maintain energy homeostasis and cell survival, mainly under nutritional stress conditions, in a Liver Kinase B1 (LKB1-dependent manner. This work describes for the first time, the in vitro anti-echinococcal effect of Met on Echinococcus granulosus larval stages, as well as the molecular characterization of AMPK (Eg-AMPK in this parasite of clinical importance. The drug exerted a dose-dependent effect on the viability of both larval stages. Based on this, we proceeded with the identification of the genes encoding for the different subunits of Eg-AMPK. We cloned one gene coding for the catalytic subunit (Eg-ampkɑ and two genes coding for the regulatory subunits (Eg-ampkβ and Eg-ampkγ, all of them constitutively transcribed in E. granulosus protoscoleces and metacestodes. Their deduced amino acid sequences show all the conserved functional domains, including key amino acids involved in catalytic activity and protein-protein interactions. In protoscoleces, the drug induced the activation of AMPK (Eg-AMPKɑ-P176, possibly as a consequence of cellular energy charge depletion evidenced by assays with the fluorescent indicator JC-1. Met also led to carbohydrate starvation, it increased glucogenolysis and homolactic fermentation, and decreased transcription of intermediary metabolism genes. By in toto immunolocalization assays, we detected Eg-AMPKɑ-P176 expression, both in the nucleus and the cytoplasm of cells as in the larval tegument, the posterior bladder and the calcareous corpuscles of control and Met-treated protoscoleces. Interestingly

  10. II型糖尿病及口服降糖药物综述%Type 2 Diabetes and Oral Antihyperglycemic Drugs

    Institute of Scientific and Technical Information of China (English)

    孙广田; 李娟娟

    2015-01-01

    Ⅱ型糖尿病主要是由于环境或者遗传引起的内源性疾病,因其高昂的治疗费用及难于根治而成为摆在全世界卫生组织和各政府面前的一道难题。Ⅱ型糖尿病的治疗已经乏力几十年了,至今还没有一个安全的单独治疗药物的出现。现有的口服降血糖药物大致可以分为磺酰脲类药物、双胍类药物、葡萄糖苷酶、氯茴苯酸类药物,DPP-4抑制剂和噻唑烷二酮类药物,但这些药物的安全性和疗效值得关注。在这篇文章里,我们分析了这六种药物的优缺点,讨论几种治疗Ⅱ型糖尿病新型药物的趋势。%Type II diabetes is a heterogeneous disease where environment and genetics are important factors for the expression of the disease.The high cost for treating complications of diabetes is a burden for public health systems and governments worldwide. Type II diabeteshas been causing debilitation worldwide for many decades, and a single drug that safely treats the disease has yet to be discovered.Sulfonylureas, biguanides, α-glucosidase, meglitinides, DPP-4 inhibitors and thiazolidinediones are among the classes of oral hypoglycemicdrugs available to treat Type II diabetes, but concerns exist regarding safety and efficacy of these drugs. In this article we presentthe pros and cons of the six classes and discuss some of the latest advances towards the development of new drugs for the treatment ofType II diabetes.

  11. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes.

    Science.gov (United States)

    Fisman, Enrique Z; Tenenbaum, Alexander

    2015-01-01

    The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50% of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25%. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins-also called dipeptidyl peptidase 4 (DPP4) inhibitors--are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials--notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years--did not show an increased risk for ischemic

  12. Analysis on Use of Hypoglycemic Drugs in Our Hospital during 2008-2010%2008-2010年我院降血糖药物用药分析

    Institute of Scientific and Technical Information of China (English)

    林国强; 沈斌

    2012-01-01

    Objective To investigate the current situation and the development trend of the hypoglycemic drugs used in our hospital to provide reference for the clinical application of antidiabetic drugs and its management. Methods The data of hypoglycemic drugs in the medical supply store were collected based on the used amount, defined daily dosages (DDDs) and the sums of money for statistical analysis during 2008 - 2010. Results The average annual increasing rate of the consumption amount of antidiabetic drugs was 40% during these three years. Acarbose occupied the first place in the list of the sum of consumption money and DDDs. Sulfonylureas and biguanides were most commonly used hypoglycemic drugs in clinic during successive 3 years, accounting for 32% of the total value of DDDs in whole antidiabetic drugs. The first line of antidiabetic drugs included metformin, gliclazide, acarbose, glipizide and insulin. Conclusion The used amounts of hypoglycemic drugs are gradually increased with the increase of diabetic patients year by year. Therefore, more attention should be paid to the curative effects and safety in medication.%目的 为降血糖药物的临床应用和管理提供参考.方法 对2008年至2010年医院药库出库的降血糖药物使用金额、用药频度(DDDs)、用药金额、各年度DDDs前10位药物等进行统计分析.结果 3年间降血糖药物销售金额年平均增长率为40%.销售金额及DDDs居首位的是阿卡渡糖,磺酰脲类和双胍类连续3年为临床主要使用的降血糖药物,占所有降血糖药物DDDs总值的32%;二甲双胍、格列齐特、阿卡波糖、格列美脲、胰岛素等为临床一线用药.结论 降血糖药物的用量随着糖尿病患者的增加逐年增长,因此临床用药应注意药物疗效及安全性.

  13. The DiabCare Asia 2008 study – Outcomes on control and complications of type 2 diabetic patients in Indonesia

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    Pradana Soewondo

    2010-11-01

    Full Text Available Aim: To collect information on diabetes management, diabetes complications, and awareness of self-control in diabetic population of the country. This study also evaluated the physician perspectives, psychological aspects, and quality of life of diabetic patients.Methods: This was a non-interventional, cross-sectional study, which recruited 1832 patients from secondary and tertiary medical centers across Indonesia. Data on demography, medical history, risk factors and clinical examination reports including laboratory assessments were collected from medical records of patients. Blood samples of all patients were collected for centralized HbA1c measurements.Results: Among 1832 patients, 1785 individuals were eligible for analysis. The mean age of the patients was 58.9+9.6 years. The mean duration of diabetes was 8.5+7.0 years. Majority (97.5% of the patients had type 2 diabetes. 67.9% had poor control of diabetes (A1c:8.1 ± 2.0%. 47.2% had FPG>130 mg/dL (161.6±14.6 mg/dL. Dyslipidemia was reported in 60%  (834/1390 and 74% (617/834 of those received lipid lowering treatment. Neuropathy was most common  complication (63.5%; other complications were: Diabetic retinopathy 42%, nephropathy 7.3%, severe late complications 16.9%, macrovascular complications 16%, microvascular complications 27.6%. About 81.3% of patients were on OADs (± insulin, 37.7% were on insulin (±OADs. Majority used biguanides followed by sulfonylureas. Human insulin was used by 73.2%, premix regimen 58.5%, analogues usage was 24.9%. Majority of the WHO-5 well being index responses fell in positive territoryConclusion: Poor glycaemic control in majority of patients is a concern. There is a need for a large proportion of patients to be adjusted to more intensive pharmacotherapy and a multi-disciplinary approach for management should be adopted. The study fi ndings should be communicated to policymakers and physicians to help them provide proper healthcare and its facilities in

  14. Immunomodulatory effects of oral antidiabetic drugs in lymphocyte cultures from patients with type 2 diabetes Efeito imunomodulador de hipoglicemiantes orais em cultura de linfócitos de pacientes com diabetes tipo 2

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    Karina Faccio Mello

    2011-02-01

    Full Text Available INTRODUCTION AND OBJECTIVE: It has been suggested that type 2 diabetes is an inflammatory response manifestation. The main drugs used to treat type 2 diabetes are sulphonylureas and biguanides. The aim of this study was to demonstrate the modulatory effects of oral hypoglycemic drugs (chlorpropamide and metformin on lymphocyte proliferation in vitro and ex vivo. METHODS: Peripheral blood mononuclear cells were isolated from human blood by gradient centrifugation. T-lymphocytes were stimulated by phytohemagglutinin (PHA and oral hypoglycemic drugs. RESULTS: In both in vitro and ex vivo experiments, there was a reduction in cell proliferation after treatment with oral hypoglycemic drugs. When both drugs were used in combination, a high level of cytotoxicity was observed, which made analysis of immunomodulatory effects unfeasible. DISCUSSION AND CONCLUSION: We demonstrated that diabetes itself may reduce cell proliferation significantly when stimulated by PHA, which may indicate that diabetic patients have difficulties in promoting an efficient inflammatory response. Moreover, the use of oral hypoglycemic drugs may aggravate this situation.INTRODUÇÃO E OBJETIVOS: Tem sido sugerido que o diabetes mellitus tipo 2 (DM2 é uma manifestação da resposta inflamatória. As principais drogas utilizadas no tratamento do DM2 são as sulfonilureias e as biguanidas. O objetivo deste trabalho é demonstrar os efeitos moduladores na proliferação de linfócitos causada pelos hipoglicemiantes orais (clorpropamida e metformina, in vitro e ex vivo. MÉTODOS: Células mononucleares de sangue periférico foram isoladas de seres humanos por gradiente de centrifugação. Os linfócitos T foram estimulados com fito-hemaglutinina (PHA e hipoglicemiantes. RESULTADOS: Nos experimentos in vitro e ex vivo, mostramos a redução da proliferação celular quando do tratamento com drogas hipoglicemiantes orais. Quando as drogas foram utilizadas em combinação, foi

  15. Acidosis láctica por metformina desencadenada por una insuficiencia renal aguda Metformin-induced lactic acidosis due to acute renal failure

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    M.D. Macías-Robles

    2011-04-01

    Full Text Available La acidosis láctica es una complicación grave pero infrecuente asociada al empleo de metformina. Se discuten los mecanismos fisiopatológicos implicados en la acidosis láctica, con especial atención al papel potencial del fármaco. Presentamos un caso severo de este efecto secundario de la metformina en una paciente con diabetes tipo 2 que ingresó en el Servicio de Urgencias Hospitalario por un cuadro de insuficiencia renal aguda. El diagnóstico quedó apoyado por unos niveles séricos elevados de la biguanida, procedimiento escasamente utilizado en la práctica clínica. El tratamiento consiste en suspender la administración del fármaco e iniciar de forma inmediata la hemodiálisis con bicarbonato, lo cual proporciona un tratamiento sintomático y etiológico al eliminar del suero tanto el lactato como el antidiabético oral. Los síntomas de la acidosis láctica por metformina son inespecíficos y el comienzo es sutil, lo que hace necesario un alto nivel de sospecha para establecer un diagnostico precoz.Lactic acidosis is a serious but uncommon side effect of metformin use. We discuss the pathophysiological mechanisms of lactic acidosis with particular regard to the role played by the drug as a potential cause of the entity. We report on a severe case of this kind of drug toxicity in a patient with type 2 diabetes mellitus, admitted to the emergency department with acute renal failure symptoms. The diagnosis was supported by elevated serum levels of the biguanide, a procedure scarcely used in clinical practice. The management of this complication consists in drug discontinuation and hemodialysis with bicarbonate that provides symptomatic and ethiological treatment by removing both the lactate and the hypoglycemic agent from the serum. Since the symptoms of metformin-associated lactic acidosis are unspecific and its onset is subtle, a high level of suspicion is needed to establish an early diagnosis.

  16. Comparative Clinical Study of Bactigras and Telfa AMD for Skin Graft Donor-Site Dressing

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    Pornanong Aramwit

    2011-08-01

    Full Text Available The Bactigras® paraffin tulle coated with chlorhexidine is normally used for the treatment of donor-site wounds in burn patients who received split-thickness skin grafts in several centers. It has some disadvantages, such as adhesion to wound surfaces and pain from the irritation caused by this dressing. The Telfa AMD®, a non-adherent wound dressing which consists of absorbent cotton fibers impregnated with polyhexamethylene biguanide enclosed in a sleeve of thermoplastic polymers, is a new option for donor-site wound care which causes less adherence to the wound. The purpose of this study was to compare clinical efficacy of these two dressings for the management of donor-site wounds. Thirty-two patients who received split-thickness skin grafts by donor site harvesting from the thigh were enrolled in this study and randomized into two groups receiving either the Bactigras® or the Telfa AMD® wound treatment. Re-epithelialization, pain, infection and cost-effectiveness analyses were compared between both groups. The results showed that there was no significant difference in age, area of donor sites or length of hospital stays between the groups (p > 0.05. However, the day of re-epithelialization (≥90% was significantly shorter in patients treated with the Telfa AMD® compared to the Bactigras® group (14.00 ± 3.05 vs. 9.25 ± 1.88 days for Bactigras® and Telfa AMD® groups, respectively, p < 0.001. The average pain score was also significantly lower in the Telfa AMD® group (1.57 ± 0.55 vs. 4.70 ± 1.16, p < 0.001. There was no difference in the cost of treatment between the groups (4.64 ± 1.97 vs. 5.72 ± 2.54 USD, p = 0.19. This study indicated that the Telfa AMD® was an effective dressing for the treatment of donor-site wounds.

  17. Metformin therapy in a hyperandrogenic anovulatory mutant murine model with polycystic ovarian syndrome characteristics improves oocyte maturity during superovulation

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    Sabatini Mary E

    2011-05-01

    Full Text Available Abstract Background Metformin, an oral biguanide traditionally used for the treatment of type 2 diabetes, is widely used for the management of polycystic ovary syndrome (PCOS-related anovulation. Because of the significant prevalence of insulin resistance and glucose intolerance in PCOS patients, and their putative role in ovulatory dysfunction, the use of metformin was touted as a means to improve ovulatory function and reproductive outcomes in PCOS patients. To date, there has been inconsistent evidence to demonstrate a favorable effect of metformin on oocyte quality and competence in women with PCOS. Given the heterogeneous nature of this disorder, we hypothesized that metformin may be beneficial in mice with aberrant metabolic characteristics similar to a significant number of PCOS patients. The aim of this study was to gain insight into the in vitro and in vivo effects of metformin on oocyte development and ovulatory function. Methods We utilized metformin treatment in the transgenic ob/ob and db/db mutant murine models which demonstrate metabolic and reproductive characteristics similar to women with PCOS. Results: Metformin did not improve in vitro oocyte maturation nor did it have an appreciable effect on in vitro granulosa cell luteinization (progesterone production in any genotype studied. Although both mutant strains have evidence of hyperandrogenemia, anovulation, and hyperinsulinemia, only db/db mice treated with metformin had a greater number of mature oocytes and total overall oocytes compared to control. There was no observed impact on body mass, or serum glucose and androgens in any genotype. Conclusions Our data provide evidence to suggest that metformin may optimize ovulatory performance in mice with a specific reproductive and metabolic phenotype shared by women with PCOS. The only obvious difference between the mutant murine models is that the db/db mice have elevated leptin levels raising the questions of whether their

  18. Serotonin in the solitary tract nucleus shortens the laryngeal chemoreflex in anaesthetized neonatal rats.

    Science.gov (United States)

    Donnelly, William T; Bartlett, Donald; Leiter, J C

    2016-07-01

    What is the central question of this study? Failure to terminate apnoea and arouse is likely to contribute to sudden infant death syndrome (SIDS). Serotonin is deficient in the brainstems of babies who died of SIDS. Therefore, we tested the hypothesis that serotonin in the nucleus of the solitary tract (NTS) would shorten reflex apnoea. What is the main finding and its importance? Serotonin microinjected into the NTS shortened the apnoea and respiratory inhibition associated with the laryngeal chemoreflex. Moreover, this effect was achieved through a 5-HT3 receptor. This is a new insight that is likely to be relevant to the pathogenesis of SIDS. The laryngeal chemoreflex (LCR), an airway-protective reflex that causes apnoea and bradycardia, has long been suspected as an initiating event in the sudden infant death syndrome. Serotonin (5-HT) and 5-HT receptors may be deficient in the brainstems of babies who die of sudden infant death syndrome, and 5-HT seems to be important in terminating apnoeas directly or in causing arousals or as part of the process of autoresuscitation. We hypothesized that 5-HT in the brainstem would limit the duration of the LCR. We studied anaesthetized rat pups between 7 and 21 days of age and made microinjections into the cisterna magna or into the nucleus of the solitary tract (NTS). Focal, bilateral microinjections of 5-HT into the caudal NTS significantly shortened the LCR. The 5-HT1a receptor antagonist, WAY 100635, did not affect the LCR consistently, nor did a 5-HT2 receptor antagonist, ketanserin, alter the duration of the LCR. The 5-HT3 specific agonist, 1-(3-chlorophenyl)-biguanide, microinjected bilaterally into the caudal NTS significantly shortened the LCR. Thus, endogenous 5-HT released within the NTS may curtail the respiratory depression that is part of the LCR, and serotonergic shortening of the LCR may be attributed to activation of 5-HT3 receptors within the NTS. 5-HT3 receptors are expressed presynaptically on C

  19. Glycemic control and antidiabetic drugs in type 2 diabetes mellitus patients with renal complications

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    Huri HZ

    2015-08-01

    Full Text Available Hasniza Zaman Huri,1,2 Lay Peng Lim,1 Soo Kun Lim3 1Department of Pharmacy, Faculty of Medicine, University of Malaya, 2Clinical Investigation Centre, University Malaya Medical Centre, 3Renal Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia Background: Good glycemic control can delay the progression of kidney diseases in type 2 diabetes mellitus (T2DM patients with renal complications. To date, the association between antidiabetic agents and glycemic control in this specific patient population is not well established.Purpose: This study aimed to identify antidiabetic regimens as well as other factors that associated with glycemic control in T2DM patients with different stages of chronic kidney disease (CKD.Patients and methods: This retrospective, cross-sectional study involved 242 T2DM inpatients and outpatients with renal complications from January 2009 to March 2014 and was conducted in a tertiary teaching hospital in Malaysia. Glycated hemoglobin (A1C was used as main parameter to assess patients’ glycemic status. Patients were classified to have good (A1C <7% or poor glycemic control (A1C ≥7% based on the recommendations of the American Diabetes Association.Results: Majority of the patients presented with CKD stage 4 (43.4%. Approximately 55.4% of patients were categorized to have poor glycemic control. Insulin (57.9% was the most commonly prescribed antidiabetic medication, followed by sulfonylureas (43%. Of all antidiabetic regimens, sulfonylureas monotherapy (P<0.001, insulin therapy (P=0.005, and combination of biguanides with insulin (P=0.038 were found to be significantly associated with glycemic control. Other factors including duration of T2DM (P=0.004, comorbidities such as anemia (P=0.024 and retinopathy (P=0.033, concurrent medications such as erythropoietin therapy (P=0.047, a-blockers (P=0.033, and antigouts (P=0.003 were also correlated with A1C.Conclusion: Identification of

  20. Metformin and cancer: doses, mechanisms and the dandelion and hormetic phenomena.

    Science.gov (United States)

    Martin-Castillo, Begoña; Vazquez-Martin, Alejandro; Oliveras-Ferraros, Cristina; Menendez, Javier A

    2010-03-15

    In the early 1970s, Professor Vladimir Dilman originally developed the idea that antidiabetic biguanides may be promising as geroprotectors and anticancer drugs ("metabolic rehabilitation").  In the early 2000s, Anisimov´s experiments revealed that chronic treatment of female transgenic HER2-/neu mice with metformin significantly reduced the incidence and size of mammary adenocarcinomas and increased the mean latency of the tumors.  Epidemiological studies have confirmed that metformin, but not other anti-diabetic drugs, significantly reduces cancer incidence and improves cancer patients' survival in type 2 diabetics.  At present, pioneer work by Dilman & Anisimov at the Petrov Institute of Oncology (St. Petersburg, Russia) is rapidly evolving due to ever-growing preclinical studies using human tumor-derived cultured cancer cells and animal models. We herein critically review how the antidiabetic drug metformin is getting reset to metabolically fight cancer. Our current perception is that metformin may constitute a novel "hybrid anti-cancer pill" physically combining both the long-lasting effects of antibodies -by persistently lowering levels of blood insulin and glucose- and the immediate potency of a cancer cell-targeting molecular agent -by suppressing the pivotal AMPK/mTOR/S6K1 axis and several protein kinases at once, including tyrosine kinase receptors such as HER1 and HER2-.  In this scenario, we discuss the relevance of metformin doses in pre-clinical models regarding metformin's mechanisms of action in clinical settings. We examine recent landmark studies demonstrating metformin's ability to specifically target the cancer-initiating stem cells from which tumor cells develop, thereby preventing cancer relapse when used in combination with cytotoxic chemotherapy (dandelion hypothesis).  We present the notion that, by acting as an efficient caloric restriction mimetic, metformin enhanced intrinsic capacity of mitotically competent cells to self

  1. Relationship of plasma creatinine and lactic acid in type 2 diabetic patients without renal dysfunction

    Institute of Scientific and Technical Information of China (English)

    LIU Fang; LU Jun-xi; TANG Jun-ling; LI Li; LU Hui-juan; HOU Xu-hong; JIA Wei-ping; XIANG Kun-san

    2009-01-01

    Background As one of most widely-used biguanides,metformin can induce the lactic acidosis in patients with renal failure though its incidence is very low.However,lactic acidemia induced by mefformin was reported in patients without renal dysfunction.It is unclear that whether lactatemia exists in diabetic patients with normal renal function in Chinese or not and its influencing factors.This study aimed to clarify the influencing factors of lactic acid,and identify a practiced clinical marker to predict the hyperlactacidemia in diabetics with normal renal function.Methods The clinical data and venous blood samples of 1024 type 2 diabetic patients treated with(n=426)or without metformin(n=599)were collected.The lactic acid was assayed by enzyme-electrode method.The biochemical indexes included creatinine(Cr)and hepatase were measured with enzymatic procedures.The lactic acid concentrations of different Cr subgroups were compared,and the correlation and receiver operating characteristic curve analysis were used.Results The mean lactic acid level and the proportion of hyperlactatemia of metformin group were significantly higher than that of non-metformin group(P<0.01),but no lactic acidosis was found in all patients.The correlation and multiple stepwise regression analysis indicated that the correlative factors of lactic acid in turn were Cr,metformin,alanine transferase(ALT),body mass index(BMI),Urine albumin(Ualb),and blood urea nitrogen(BUN)in total patients;and Cr,ALT,BMI and BUN in non-metformin treated patients;Cr and ALT in metformin-group.The lactate concentration increased with the increment of Cr levels,and reached its peak at Cr 111-130 μmol/L,and the optimal cutoff of Cr in predicting hyperlactacidemia was 96.5 μmol/L.Conclusions Metformin can increase the incidence of lactatemia in type 2 diabetic patients without renal dysfunction.Cr,ALT,and BMI are independent associated factors of blood lactic acid levels.There is low proportion of lactatemia in

  2. Effects of A Low-Carbohydrate Diet and A Low-Fat Diet on Weight and Glycemic Control in Type 2 Diabetics Mellitus%低碳水化合物饮食和低脂肪饮食对2型糖尿病患者体质量及血糖的影响

    Institute of Scientific and Technical Information of China (English)

    曹爱华; 孙丽珍; 崔静稳; 张宪静

    2011-01-01

    目的 比较低碳水化合物饮食和低脂肪饮食1年对2型糖尿病(T2DM)患者体质量及血糖的影响.方法 采用随机对照的方法,将90例超重T2DM患者随机分为低碳水化合物饮食+双胍类药物治疗组(A组)和低脂肪饮食+双胍类药物治疗组(B组),各45例.A组患者给予低碳水化合物饮食+双胍类药物治疗;B组患者给予低脂肪饮食+双胍类药物治疗.分别在治疗前及治疗3、6、12个月检测两组患者的体质量、糖化血红蛋白(HbA1c)、血压和血脂.结果 两组患者治疗前后体质量及高密度脂蛋白(HDL)水平变化比较,差异有统计学意义(P<0.01);而两组患者血压及血清总胆固醇(TC)、低密度脂蛋白(LDL)、三酰甘油(TG)、HbA1c水平变化比较,差异无统计学意义(P>0.05).两组患者体质量明显下降及HbA1c的减少主要发生在治疗的前3个月,A组、B组体质量平均下降1.8 kg/月和1.0 kg/月,HbA1c均下降0.6%;但在1年里两组患者体质量减轻均为3.4 kg.结论 对于超重的T2DM患者,1年的低碳水化合物饮食及低脂肪饮食对HbA1c的影响类似,血压未受影响;但低碳水化合物饮食者体质量下降较低脂肪饮食者快,且较后者能显著提高HDL水平.%Objective To compare the effects of a 1 - year intervention with a low - carbohydrate and a low - fat diet on weight and glycemic control in patients with type 2 diabetes mellitus. Methods The randomized controlled clinical trial was taken to assign 90 0verweight patients with type 2 diabetes mellitus to the low - carbohydrate diet ( A ) group and low - fat diet ( B ) group, with 45 patients in each. The patients in the group A were given a low - carbohydrate diet and biguanides; while those in the group B were given a low - fat diet and biguanides. The body weight, glycosylated hemoglobin ( HbA1c ), blood pressure and lipids were detected before treatment and 3 , 6. and 12 months after the treatment. Results Before and after the

  3. Avaliação de um novo produto na desinfecção do tonômetro de aplanação de Goldmann The evaluation of a new product in the desinfection of the applanation tonometer

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    Nelson Maimone

    2001-11-01

    Full Text Available Objetivo: Avaliar a eficácia de um produto usado habitualmente para limpeza de lentes de contato (CompleteÒ: poliexametileno de biguanida (TrisChemTM, tiloxapol, trometamina e EDTA em solução isotônica estéril na desinfecção do cone do tonômetro de aplanação. Métodos: O cone permaneceu imerso na solução no período médio de 28 minutos. Foi utilizado um recipiente para limpeza de lentes de contato e um suporte de isopor. Ao final de cada dia, durante 22 dias, foram realizadas culturas para fungos e bactérias, exames diretos para fungos e bacterioscopia por Gram. Foi testado "in vitro" o poder bactericida e fungicida do produto para S. aureus ATCC#25923, E. coli ATCC#25922, P. aeruginosa ATCC#27853, C. albicans ATCC# 76615, A. niger ATCC#16404. Resultados: Nas culturas, nos exames diretos para fungos e nas bacterioscopias por Gram não foram identificados microrganismos. No estudo "in vitro", foram necessárias 48 horas para eliminação completa de todas cepas estudadas. Conclusão: Não foram encontradas bactérias e fungos em todos exames realizados da solução e recipiente. No entanto, os testes "in vitro" demonstraram que o tempo de imersão do cone na solução (média de 28 minutos é insuficiente para eliminação completa dos microrganismos, o que inviabiliza o uso desse produto na desinfecção do cone plástico do tonômetro de aplanação.Purpose: To evaluate the efficacy of a product which is normally used for cleaning of contact lenses (CompleteÒ: polyhexamethylene biguanide (Tris ChemTM, Tyloxapol, USP, Tromethamine, USP, and Edetate disodium, USP, in sterile isotonic solution in the disinfection of the cone of the applanation tonometer. Methods: The cone remained immersed in the solution for an average period of 28 minutes. A container for cleaning the contact lenses and a polystyrene support were used. At the end of each day, for 22 days, cultures for fungi and bacteria were carried out as well as direct

  4. Analysis of Application of Oral Hypoglycemic Drugs in Outpatient Department of the Central Hospital of Nanchong during 2012-2014%2012—2014年南充市中心医院门诊口服降糖药应用分析

    Institute of Scientific and Technical Information of China (English)

    徐秀华; 冯婧; 王龙飞

    2015-01-01

    目的:分析南充市中心医院(以下简称"我院")2012—2014年门诊口服降糖药的应用情况和发展趋势,为糖尿病药物治疗提供参考.方法:回顾性统计分析我院2012—2014年门诊降糖药的销售数量、销售总金额、用药频度( defined daily dose system,DDDs)、限定日费用( daily drug cost,DDC),并根据各药的DDDs排序和销售金额排序,算出排序比.结果:我院门诊口服降糖药销售金额整体呈上升趋势,磺酰脲类、双胍类、α-葡萄糖苷酶抑制剂的销售金额增幅大;二甲双胍使用频率高,连续3年居第1位;二甲双胍日平均费用较低,排序比连续3年大于1.结论:我院2012—2014年门诊口服降糖药临床使用基本合理,二甲双胍使用频率高,符合安全、有效、经济的用药原则.%OBJECTIVE:To analyze the status quo and development tendency of oral hypoglycemic drugs for outpatients in the Central Hospital of Nanchong( hereinafter referred to as "our hospital") during 2012-2014,and to provide reference for the medication of diabetes.METHODS: Retrospective analysis was conducted in terms of the consumption amount,consumption sum,defined daily dose system ( DDDs ),and daily drug cost ( DDC ); and the ranking ratio was calculated based on the ranking of DDDs and medication cost of oral hypoglycemic drugs.RESULTS:The consumption sum of oral hypoglycemic drugs for outpatients in our hospital showed an increase tendency in general,especially for sulfonylurea,biguanides and alpha glucosidase inhibitors.The use frequency of metformin continuously dominated the first place during the three years,which had a low cost per day,and the ranking ratio was over 1 during the three years.CONCLUSIONS: The application of oral hypoglycemic drugs for inpatients in our hospital is basically rational during 2012-2014,and metformin has a high frequency of usage,which is conform to the principle of safe,effective and economic medication.

  5. A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease

    Directory of Open Access Journals (Sweden)

    Fisman Enrique Z

    2009-07-01

    Full Text Available Abstract Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1, the dipeptidyl peptidase 4 (DPP-4 inhibitors, dual peroxisome proliferator-activated receptors (PPAR agonists (glitazars and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD. Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM

  6. Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile.

    Science.gov (United States)

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cuyàs, Elisabet; Corominas-Faja, Bruna; Rodríguez-Gallego, Esther; Fernández-Arroyo, Salvador; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A

    2014-01-01

    Therapeutic interventions based on metabolic inhibitor-based therapies are expected to be less prone to acquired resistance. However, there has not been any study assessing the possibility that the targeting of the tumor cell metabolism may result in unforeseeable resistance. We recently established a pre-clinical model of estrogen-dependent MCF-7 breast cancer cells that were chronically adapted to grow (> 10 months) in the presence of graded, millimolar concentrations of the anti-diabetic biguanide metformin, an AMPK agonist/mTOR inhibitor that has been evaluated in multiple in vitro and in vivo cancer studies and is now being tested in clinical trials. To assess what impact the phenomenon of resistance might have on the metformin-like "dirty" drugs that are able to simultaneously hit several metabolic pathways, we employed the ingenuity pathway analysis (IPA) software to functionally interpret the data from Agilent whole-human genome arrays in the context of biological processes, networks, and pathways. Our findings establish, for the first time, that a "global" targeting of metabolic reprogramming using metformin certainly imposes a great selective pressure for the emergence of new breast cancer cellular states. Intriguingly, acquired resistance to metformin appears to trigger a transcriptome reprogramming toward a metastatic stem-like profile, as many genes encoding the components of the degradome (KLK11, CTSF, FREM1, BACE-2, CASP, TMPRSS4, MMP16, HTRA1), cancer cell migration and invasion factors (TP63, WISP2, GAS3, DKK1, BCAR3, PABPC1, MUC1, SPARCL1, SEMA3B, SEMA6A), stem cell markers (DCLK1, FAK), and key pro-metastatic lipases (MAGL and Cpla2) were included in the signature. Because this convergent activation of pathways underlying tumor microenvironment interactions occurred in low-proliferative cancer cells exhibiting a notable downregulation of the G 2/M DNA damage checkpoint regulators that maintain genome stability (CCNB1, CCNB2, CDC20, CDC25C, AURKA

  7. Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile

    Science.gov (United States)

    Oliveras-Ferraros, Cristina; Vazquez-Martin, Alejandro; Cuyàs, Elisabet; Corominas-Faja, Bruna; Rodríguez-Gallego, Esther; Fernández-Arroyo, Salvador; Martin-Castillo, Begoña; Joven, Jorge; Menendez, Javier A

    2014-01-01

    Therapeutic interventions based on metabolic inhibitor-based therapies are expected to be less prone to acquired resistance. However, there has not been any study assessing the possibility that the targeting of the tumor cell metabolism may result in unforeseeable resistance. We recently established a pre-clinical model of estrogen-dependent MCF-7 breast cancer cells that were chronically adapted to grow (> 10 months) in the presence of graded, millimolar concentrations of the anti-diabetic biguanide metformin, an AMPK agonist/mTOR inhibitor that has been evaluated in multiple in vitro and in vivo cancer studies and is now being tested in clinical trials. To assess what impact the phenomenon of resistance might have on the metformin-like “dirty” drugs that are able to simultaneously hit several metabolic pathways, we employed the ingenuity pathway analysis (IPA) software to functionally interpret the data from Agilent whole-human genome arrays in the context of biological processes, networks, and pathways. Our findings establish, for the first time, that a “global” targeting of metabolic reprogramming using metformin certainly imposes a great selective pressure for the emergence of new breast cancer cellular states. Intriguingly, acquired resistance to metformin appears to trigger a transcriptome reprogramming toward a metastatic stem-like profile, as many genes encoding the components of the degradome (KLK11, CTSF, FREM1, BACE-2, CASP, TMPRSS4, MMP16, HTRA1), cancer cell migration and invasion factors (TP63, WISP2, GAS3, DKK1, BCAR3, PABPC1, MUC1, SPARCL1, SEMA3B, SEMA6A), stem cell markers (DCLK1, FAK), and key pro-metastatic lipases (MAGL and Cpla2) were included in the signature. Because this convergent activation of pathways underlying tumor microenvironment interactions occurred in low-proliferative cancer cells exhibiting a notable downregulation of the G2/M DNA damage checkpoint regulators that maintain genome stability (CCNB1, CCNB2, CDC20, CDC25C

  8. A Research Report on the Prescription Rights of Chinese Nurses☆

    Institute of Scientific and Technical Information of China (English)

    Shi-Fan Han; Rui-Fang Zhu; Hui-Hui Han

    2015-01-01

    undergraduate added with nurse authority of prescription related courses. Results: The physician is not considered to be the best decision-making main body of clinical nursing work and graded nurs-ing, nurses can participate in the work of decision-making. The qualification of hierarchical decision-making nurse and nurse prescribing applicants have been determined. The hierarchical nursing decision-making nurses’ position description and training outline have been compiled. Experts suggest that clinical nurses with certain qualifications should be given the rights of some prescription form ( independent prescription, prescription, prescription protocol extension) to prescribe specific drugs in high fe-ver, hypoglycemia, hypertension, anaphylactic shock and other 11 specific circumstances. The nurses of the diabetes should be given the right of prescribing sulfonylureas, biguanides, glucosidase inhibitor, and protamine zinc insulin, and the right to write the prescription and consultation for part of medical equipment, health education, and four routine tests, which contains blood sugar monitoring, urine glucose monitoring, glycosylated hemoglobin assay, and oral glucose tolerance test. Tumor specialist nurses should be given the right to write the prescription of 7 specific circumstances including blood routine tests, electrocardio-gram, blood biochemistry and other 9 laboratory tests, constipation, phlebitis, and cancer pain, and the right of 5 tumor emer-gency prescription including chemotherapy drug allergy, hemorrhagic shock, acute upper gastrointestinal bleeding. Nurses in e-mergency department with certain qualification should be given the right to prescribe specific drugs in 15 circumstances which include cardiac arrest, ventricular fibrillation, and acute cardiogenic chest pain. Community nurses with certain qualification should be given the right to write the prescriptions on 14 contents including disinfection and cleaning, sterile infusion type, and wound care

  9. 铜绿假单胞菌的耐药性及耐药基因研究%The drug resistance and drug resistance genes of Pseudomonas aeruginosa

    Institute of Scientific and Technical Information of China (English)

    陈璐; 查筑红; 冷应蓉; 程永素; 黄冰; 王敏; 罗光英

    2014-01-01

    OBJECTIVE To detect the relationship between drug resistance genes and drug resistance of P .aerugi-nosa isolated from patients with analyzing the drug resistance and probing the drug resistance genes .METHODS Microscan WalkAway 40 system was used to detect the genes and carry on the drug sensitive test .The resistance genes TEM ,CARB ,OXA-10 ,VIM ,VEB ,IMP ,DHA ,aac(6′)-Ⅰb ,aac(6′)-Ⅱ ,ant(2′)-Ⅰ ,qacE△1-sul1 and oprD2 were determined by polymerase chain reaction(PCR) .RESULTS The drug resistance of 67 strains P . aeruginosa was serious ,which was 100 .0% resistance to piperacillin/tazobactam ,piperacillin ,ticarcillin/clavu-lanic acid .the positive rates of TEM ,CARB ,OXA-10 ,VIM ,VEB ,aac(6′)-Ⅰ b ,aac(6′)-Ⅱ ,ant(2′)-Ⅰ , qacE△1-sul1 ,and op rD2 were 98 .6% ,82 .1% ,88 .1% ,92 .6% ,92 .6% ,71 .7% and 83 .6% ,13 .4% ,and 1 .5% ,respectively .The gene of IMP and DHA were not detected .CONCLUSION The P .aeruginosa were not sensitive to β-lactams because of the combined effect of multi-mechanism .Relations between high detection rate of aminoglycosides modifying enzymes (AM Es ) genes and P .aeruginosa resistance to aminoglycoside antibiotics should have further investigation .Most of the P .aeruginosa separated from our hospital were highly resistant to quaternary amine and biguanides disinfectant .%目的:分析临床分离铜绿假单胞菌的耐药性,检测耐药基因,探讨耐药基因与耐药性的关系。方法采用美国德灵Microscan WalkAway 40系统对病原菌进行鉴定及药敏试验;采用PCR扩增技术对临床分离铜绿假单胞菌耐药性相关基因 TEM、CARB、OXA-10、VIM、VEB、IMP、DHA、aac(6′)-Ⅰ b、aac(6′)-Ⅱ、ant(2′)-Ⅰ、qacE△1-sul1、op rD2进行检测。结果67株铜绿假单胞菌耐药严重,对哌拉西林/他唑巴坦、哌拉西林、替卡西林/克拉维酸的耐药率达100.0%;检出 TEM、CARB、OXA-10、aac(6′)-Ⅰ b、aac(6

  10. This Issue at A Glance

    Directory of Open Access Journals (Sweden)

    Hormoz Chams

    2014-05-01

    Full Text Available In the retrospective investigation titled “Risk factors evaluation of threshold retinopathy of prematurity” at a tertiary ophthalmic center in Tehran, Iran, the authors have studied 859 premature neonates during one year (2008-2009. 791 eyes have had retinopathy of prematurity (ROP and 7.4% of them presented threshold retinopathy (TROP. The investigators aim has been to present and compare the risk factors of ROP and TROP and also to emphasize that the proposed criteria1 for investigation of ROP and TROP are not very precise and valuable for the developing countries. For example they remark that 33% of their TROP had birth weight of more than 1,500 grams. In this investigation the most important risk factors for TROP have been delay in initial examination, low weight, low gestation age, and duration of oxygen therapy. In another presentation, the authors have investigated “The prevalence of viral conjunctivitis in patients who referred to eye specialist hospitals in Tehran, Iran”. They received 150 swap samples and after DNA extraction, and multiplex real-time PCR they found 14.6% of samples were positive for adenovirus and 3.3% positive for herpes simplex 1 (HSV-1. The results for herpes simplex 2 (HSV-2 and varicella-Zoster (VZV were negative. In other investigations2,3 of viral conjunctivitis adenoviruses, HSV-1, HSV-2 and VZV have been reported to be the most important causes of viral conjunctivitis. The authors propose a more extensive investigation on number of patients and the emerging viruses particularly in this part of the world. Rahimi et al in their presentation “Clinical outcomes in acanthamoeba keratitis treated with polyhexamethylene biguanide as monotherapy” have studied 27 eyes of 25 patients presenting Acanthamoeba keratitis (AK. They emphasize the importance of confocal biomicroscopy to find the cysts or trophozoites of the amoeba, indicating 96.3% of positive results compared to 81.5% of positivity in the culture

  11. [A 50-year history of new drugs in Japan-the development and progress of anti-diabetic drugs and the epidemiological aspects of diabetes mellitus].

    Science.gov (United States)

    Ozawa, Hikaru; Murai, Yuriko; Ozawa, Terutaka

    2003-01-01

    recombinant products prevailed throughout the 1990s. Human insulin analogues (i.e., Insulin lispro and Insulin aspart) appeared in 2001. These are applied for after-meal glycosmia owing to their ultrarapid onset of activity. Self-injection by DM patients was legalized in 1981. To make the infection technique sure and easy, cartridge (pen-type) and disposable kit-type needles were devised in the 1990s. 2) Oral hypoglycemic drugs: Instead of the exclusive parenteral usage of insulins, there was also demand for oral dosage forms. The first of the sulfonyrlurea (SU) group, BZ-55, was used for DM clinically in 1955 in Germany. But it was soon withdrawn because of its antibacterial action. This led to the development of various SU groups. Tolbutamide (1956), chlorpropamide (1959), acetohexamide (1964) and tolazamide (1961) were introduced to Japan as first-generation SUs. Then glyclopyramide (Kyorin, 1965), glybenclamide (1971), gliclazide (1984) and glimepiride (1999) appeared as the second-generation SUs. These were used orally for Type 2 diabetes. Biguanide (BG) group, phenformin HC1 (1959), metformin HC1 (1961) and buformin HC1 (1961) had also been in use by oral treatment of Type 2 diabetes. SU appears to act by increasing the sensitivity of b-cells, which secrete insulin. BG probably exerts by increasing glucose transport across the membranes of target organs. 3) New types of antidiabetic drugs: a-Glucosidase inhibitors (i.e., acarbose: Bayer, 1993; and voglibose: Takeda, 1994) act on hyperglycemia after meals by decreasing glucose absorption. Thiazolidinedione compounds, such as troglitazone (Sankyo, 1995) and pioglitazone HC1 (Takeda, 1994) act by increasing the insulin sensitivity of the target tissues. These are useful for Type 2 DM patients when SUs are ineffective. Nevertheless, troglitazone was discontinued in 2000 due to severe liver damage. Nateglinide (Ajinomoto Co., 1999), which is a D-phenylalanine derivative acting similar to SUs, is useful orally for after

  12. Analysis on the adverse drug reaction signal and its impact factors induced by oral hypoglycemic agents%口服抗糖尿病药物不良反应信号及其相关因素分析

    Institute of Scientific and Technical Information of China (English)

    柯俊; 汤文璐; 薛浩; 庞露微

    2012-01-01

    ,but new ADR reports marked as moderate and severe which were not recorded in drug instructions and references increased significantly during the period of 2009 to 2010,and the most frequently involved agents were biguanides and sulfonylureas (SU).The logistic regression analysis of ADR and its influence factors showed female,the high frequency of taking drug and single medication were risk factors of gastrointestinal damage,weight was the risk factor of skin damage,and combined medication and patients' age were the risk factors of hypoglycemia caused by SU.The results of measures of disproportionality found some ADR signals induced by OHAs.CONCLUSION The ADR of oral hypoglycemic agents could involve multiple systems and organs.Risk factors such as gender,age,weight,frequency of taking drug and drug combination had effects on the occurrence of ADR in different degree,so in order to take OHAs safely and reasonably,we should strengthen the ADR monitoring and put emphasis on controlling the risk factors of ADR in clinical practice.

  13. Effects of low-fat diet on body mass, blood lipids and sugar control in obese patients with type 2 diabetes mellitus%低脂肪饮食对肥胖2型糖尿病患者体质量、血脂及血糖的影响

    Institute of Scientific and Technical Information of China (English)

    曹爱华; 尚艳菲; 辛波

    2012-01-01

    Objective To study the effects of low-fat diet on body mass,blood lipids and sugar in obese patients with type 2 diabetes mellitus(T2DM). Methods 120 obese patients with T2DM were randomized to the two groups, research groups60 obese patients with T2MD got routine treatment of low-fat associated with biguanides diet,control group:60 obese patients with T2MD were advised on the treatment of the routine diabetic diet. Outcome measures of body mass, HbA1 c, blood pressure and blood lipids were obtained before and after treatment. Results After one year of treatment,body mass and HbA, c in research group reduced by (6. 6± 1. 4) kg and (2.8±0. 3) % ,and those in control group reduced by (3. 4±1. 2) kg,(l. 0±0. 2)%( P <0. 05). Before treatment.TC and LDL-C in research group were (4.44±0. 82) mmol/L and (2. 56±0. 61) mmol/L,and those in control group were (4. 38±0. 84) mmoI/L and (2. 54± 0. 70) mmol/L. After treatment.TC and LDL-C in research group were (3.90±0. 73) mmol/L,(2. 04±0.62) mmol/L,and those in control group were (4. 26 ± 0. 72) mmol/L, (2. 48 ± 0. 65) mmol/L, and two groups showed statistical significance after treatment P <0. 05). Conclusion Low-fat diet can improve body mass, HbA,c,TC and LDL-C of T2DM patients and curative effect is better than the conventional control group, and it is an effective way in the treatment of obese patients with T2DM.%目的 观察低脂肪饮食对肥胖2型糖尿病患者体质量、血脂和血糖的影响.方法 120例肥胖2型糖尿病患者随机分配至低脂肪饮食+双胍类药物治疗组(实验组)和常规糖尿病饮食+双胍类药物治疗组(对照组),各60倒.在治疗前及治疗1年后检测两组患者的体质量(BM)、糖化血红蛋白(HbA1c)、血压和血脂.结果 治疗1年后,实验组与对照组BM分别下降(6.6±1.4)kg和(3.4±1.2)kg,HbA1c分别下降(2.8±0.3)%和(1.0±0.2)%(P<0.05);实验组治疗前总胆固醇(TC)为(4.44±0.82) mmol/L、低密度