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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. Polyhexamethylene biguanide functionalized cationic silver nanoparticles for enhanced antimicrobial activity

    Science.gov (United States)

    Ashraf, Sumaira; Akhtar, Nasrin; Ghauri, Muhammad Afzal; Rajoka, Muhammad Ibrahim; Khalid, Zafar M.; Hussain, Irshad

    2012-05-01

    Polyhexamethylene biguanide (PHMB), a broad spectrum disinfectant against many pathogens, was used as a stabilizing ligand for the synthesis of fairly uniform silver nanoparticles. The particles formed were characterized using UV-visible spectroscopy, FTIR, dynamic light scattering, electrophoretic mobility, and TEM to measure their morphology and surface chemistry. PHMB-functionalized silver nanoparticles were then evaluated for their antimicrobial activity against a gram-negative bacterial strain, Escherichia coli. These silver nanoparticles were found to have about 100 times higher bacteriostatic and bactericidal activities, compared to the previous reports, due to the combined antibacterial effect of silver nanoparticles and PHMB. In addition to other applications, PHMB-functionalized silver nanoparticles would be extremely useful in textile industry due to the strong interaction of PHMB with cellulose fabrics.

  3. 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.

  4. 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...

  5. Metformin (dimethyl-biguanide induced DNA damage in mammalian cells

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    Rubem R. Amador

    2012-01-01

    Full Text Available Metformin (dimethyl-biguanide is an insulin-sensitizing agent that lowers fasting plasma-insulin concentration, wherefore it's wide use for patients with a variety of insulin-resistant and prediabetic states, including impaired glucose tolerance. During pregnancy it is a further resource for reducing first-trimester pregnancy loss in women with the polycystic ovary syndrome. We tested metformin genotoxicity in cells of Chinese hamster ovary, CHO-K1 (chromosome aberrations; comet assays and in mice (micronucleus assays. Concentrations of 114.4 µg/mL and 572 µg/mL were used in in vitro tests, and 95.4 mg/kg, 190.8 mg/kg and 333.9 mg/kg in assaying. Although the in vitro tests revealed no chromosome aberrations in metaphase cells, DNA damage was detected by comet assaying after 24 h of incubation at both concentrations. The frequency of DNA damage was higher at concentrations of 114.4 µg/mL. Furthermore, although mortality was not observed in in vitro tests, the highest dose of metformin suppressed bone marrow cells. However, no statistically significant differences were noted in micronuclei frequencies between treatments. In vitro results indicate that chronic metformin exposure may be potentially genotoxic. Thus, pregnant woman undergoing treatment with metformin should be properly evaluated beforehand, as regards vulnerability to DNA damage.

  6. Toxicological assessment of polyhexamethylene biguanide for water treatment

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    Asiedu-Gyekye Isaac J.

    2015-12-01

    Full Text Available Polyhexamethylene biguanide (PHMB is an antiseptic with antiviral and antibacterial properties used in a variety of products including wound care dressings, contact lens cleaning solutions, perioperative cleansing products, and swimming pool cleaners. There are regulatory concerns with regard to its safety in humans for water treatment. We decided to assess the safety of this chemical in Sprague-Dawley rats. PHMB was administered in a single dose by gavage via a stomach tube as per the manufacturer’s instruction within a dose range of 2 mg/kg to 40 mg/kg. Subchronic toxicity studies were also conducted at doses of 2 mg/kg, 8 mg/kg and 32 mg/kg body weight and hematological, biochemical and histopathological findings of the major organs were assessed. Administration of a dose of 25.6 mg/kg, i.e. 1.6 mL of 0.4% PHMB solution (equivalent to 6.4×103 mg/L of 0.1% solution resulted in 50% mortality. Histopathological analysis in the acute toxicity studies showed that no histopathological lesions were observed in the heart and kidney samples but 30% of the animals had mild hydropic changes in zone 1 of their liver samples, while at a dosage of 32 mg/kg in the subchronic toxicity studies, 50% of the animals showed either mild hepatocyte cytolysis with or without lymphocyte infiltration and feathery degeneration. Lymphocyte infiltration was, for the first time, observed in one heart sample, whereas one kidney sample showed mild tubular damage. The acute studies showed that the median lethal dose (LD50 is 25.6 mg/kg (LC50 of 1.6 mL of 0.4% PHMB. Subchronic toxicological studies also revealed few deleterious effects on the internal organs examined, as seen from the results of the biochemical parameters evaluated. These results have implications for the use of PHMB to make water potable.

  7. 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.

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

    International Nuclear Information System (INIS)

    Highlights: ► siRNA knockdown of OCT1 reduced sensitivity of EOC cells to metformin, but not to another biguanide, phenformin. ► Suppression of OCT1 also affects the activation of AMP kinase in response to metformin, but not to phenformin. ► Direct actions of metformin may be limited by low OCT1 expression in EOC tumors. ► 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.

  9. Copper-catalyzed arylation of biguanide derivatives via C-N cross-coupling reactions.

    Science.gov (United States)

    Zhang, Chen; Huang, Bo; Bao, Ai-Qing; Li, Xiao; Guo, Shunna; Zhang, Jin-Quan; Xu, Jun-Zhi; Zhang, Rihao; Cui, Dong-Mei

    2015-12-21

    An efficient copper-catalyzed cross-coupling reaction of biguanide hydrochloride derivatives with both aryl iodides and bromides under mild conditions has been developed. The reaction occurred in good yields and tolerated aryl halides containing functionalities such as nitriles, sulfonamides, ethers, and halogens. Alkyl and cyclic substituted biguanidines were also well tolerated. PMID:26444146

  10. 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)

  11. 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

  12. 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.

  13. Mucoadhesive system formed by liquid crystals for buccal administration of poly(hexamethylene biguanide) hydrochloride.

    Science.gov (United States)

    Souza, Carla; Watanabe, Evandro; Borgheti-Cardoso, Livia Neves; De Abreu Fantini, Márcia Carvalho; Lara, Marilisa Guimarães

    2014-12-01

    Antimicrobial approaches are valuable in controlling the development of buccal diseases, but some antibacterial agents have a short duration of activity. Therefore, the development of prolonged delivery systems would be advantageous. Liquid crystalline systems comprising monoolein (GMO)/water have been considered to be a potential vehicle to deliver drugs to the buccal mucosa because of the phase properties that allow for controlled drug release as well as its mucoadhesive properties. Therefore, the aim of this study was to develop a GMO/water system for the slow release of poly(hexamethylene biguanide) hydrochloride (PHMB) on the buccal mucosa and test the properties of this system with regard to swelling, release profile, antimicrobial activity, and strength of mucoadhesion, with the overall goal of treating buccal infections. The tested systems were capable of modulating drug release, which is controlled by diffusion of the drug throughout the system. Furthermore, PHMB appeared to improve the mucoadhesive properties of the system and may synergistically act with the drug to promote antimicrobial activity against S. mutas and C. albicans, indicating that liquid crystals may be suitable for the administration of PHMB on the buccal mucosa. Therefore, this system could be proposed as a novel system for mucoadhesive drug delivery. PMID:25336429

  14. 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.

  15. 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.

  16. Antifungal Effect of Non-Woven Textiles Containing Polyhexamethylene Biguanide with Sophorolipid: A Potential Method for Tinea Pedis Prevention

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    Hiromi Sanada

    2014-04-01

    Full Text Available Tinea pedis is a preventable skin disease common in elderly or diabetic patients. Daily foot washing is effective for prevention, but can be difficult for many patients. Additionally, conventional methods cannot eliminate fungi within the stratum corneum, a common site for fungal invasion. This study investigates the antifungal effects, cytotoxicity, permeability, and efficacy of non-woven textiles containing polyhexamethylene biguanide (PHMB mixed with sophorolipid. Permeability of PHMB with varying concentrations of sophorolipid was assessed via a cultured skin model. Stratum corneum PHMB concentration was quantified by polyvinylsulphuric acid potassium salt titration and cytotoxicity was assayed via 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide. Antifungal effects were evaluated via a new cultured skin/Trichophyton mentagrophytes model, with varying PHMB exposure duration. Clinically-isolated Trichophyton were applied to the feet of four healthy volunteers and then immediately treated with the following methods: washing with soap, a non-woven textile with PHMB, the textile without PHMB, or without washing. Fungal colony forming units (CFUs were evaluated after one of these treatments were performed. Sophorolipid with various concentrations significantly facilitated PHMB permeation into the stratum corneum, which was not in a dose-dependent manner. Significant PHMB antifungal effects were achieved at 30 min, with low cytotoxicity. Textiles containing PHMB significantly reduced CFU of fungi in healthy volunteers to levels comparable to soap washing. Our results indicate the utility of this product for tinea pedis prevention in clinical settings.

  17. 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

  18. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro

    International Nuclear Information System (INIS)

    As a class, the biguanides induce lactic acidosis, a hallmark of mitochondrial impairment. To assess potential mitochondrial impairment, we evaluated the effects of metformin, buformin and phenformin on: 1) viability of HepG2 cells grown in galactose, 2) respiration by isolated mitochondria, 3) metabolic poise of HepG2 and primary human hepatocytes, 4) activities of immunocaptured respiratory complexes, and 5) mitochondrial membrane potential and redox status in primary human hepatocytes. Phenformin was the most cytotoxic of the three with buformin showing moderate toxicity, and metformin toxicity only at mM concentrations. Importantly, HepG2 cells grown in galactose are markedly more susceptible to biguanide toxicity compared to cells grown in glucose, indicating mitochondrial toxicity as a primary mode of action. The same rank order of potency was observed for isolated mitochondrial respiration where preincubation (40 min) exacerbated respiratory impairment, and was required to reveal inhibition by metformin, suggesting intramitochondrial bio-accumulation. Metabolic profiling of intact cells corroborated respiratory inhibition, but also revealed compensatory increases in lactate production from accelerated glycolysis. High (mM) concentrations of the drugs were needed to inhibit immunocaptured respiratory complexes, supporting the contention that bioaccumulation is involved. The same rank order was found when monitoring mitochondrial membrane potential, ROS production, and glutathione levels in primary human hepatocytes. In toto, these data indicate that biguanide-induced lactic acidosis can be attributed to acceleration of glycolysis in response to mitochondrial impairment. Indeed, the desired clinical outcome, viz., decreased blood glucose, could be due to increased glucose uptake and glycolytic flux in response to drug-induced mitochondrial dysfunction

  19. 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

  20. 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.

  1. 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

  2. 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

  3. Metformin and Other Biguanides in Oncology: Advancing the Research Agenda

    OpenAIRE

    Pollak, Michael

    2010-01-01

    Retrospective studies suggest that diabetics treated with metformin have a substantially reduced cancer burden compared with other diabetics, studies that may be impractical to confirm prospectively. It is unclear if this reflects a chemopreventive effect, an effect on transformed cells, or both. It also remains to be established if these data have relevance to people without diabetes. Laboratory models, however, provide independent impressive evidence for activity of metformin and other bigu...

  4. Biguanides Inhibit Complex I, II and IV of Rat Liver Mitochondria and Modify Their Functional Properties

    Czech Academy of Sciences Publication Activity Database

    Drahota, Zdeněk; Páleníčková, E.; Endlicher, R.; Milerová, Marie; Brejchová, Jana; Vošahlíková, Miroslava; Svoboda, Petr; Kazdová, L.; Kalous, M.; Červinková, Z.; Cahová, M.

    2014-01-01

    Roč. 63, č. 1 (2014), s. 1-11. ISSN 0862-8408 R&D Projects: GA MŠk(CZ) LL1204; GA ČR(CZ) GAP207/12/0919 Grant ostatní: Univerzita Karlova(CZ) PRVOUK P37/02 Institutional support: RVO:67985823 Keywords : metformin * phenformin * mitochondrial enzymes * mitochondrial permeability transition pore * membrane fluidity Subject RIV: ED - Physiology Impact factor: 1.293, year: 2014

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

    Czech Academy of Sciences Publication Activity Database

    Matulková, Irena; Němec, I.; Císařová, I.; Němec, P.; Vaněk, Přemysl

    2010-01-01

    Roč. 966, 1-3 (2010), s. 23-32. ISSN 0022-2860 R&D Projects: GA ČR GA203/09/0878 Institutional research plan: CEZ:AV0Z40400503; CEZ:AV0Z10100520 Keywords : biguanidium(1+) oxalate hemihydrate * biguanidium(1+) hydrogen succinate * biguanidium(2+) tartrate Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 1.599, year: 2010

  6. Inorganic salts of biguanide - Searching for new materials for second harmonic generation

    Czech Academy of Sciences Publication Activity Database

    Matulková, Irena; Němec, I.; Císařová, I.; Němec, P.; Mička, Z.

    2008-01-01

    Roč. 886, 1-3 (2008), s. 103-120. ISSN 0022-2860 Institutional research plan: CEZ:AV0Z40400503 Keywords : biguanidium(2+) nitrate * biguanidium(2+) carbonate monohydrate * biguanidium(1+) phosphite trihydrate Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 1.594, year: 2008

  7. Kinetics of the methylglyoxal scavenging by antidiabetic biguanide drugs investigated using ion transfer voltammetry and capillary electrophoresis

    Czech Academy of Sciences Publication Activity Database

    Langmaier, Jan; Samec, Zdeněk; Tůma, P.; Samcová, E.

    2015-01-01

    Roč. 61, č. 3 (2015), s. 215-215. ISSN 0034-6691. [Annual Meeting of the Polarographic Society of Japan /61./. 24.11.2015-25.11.2015, Himeji] R&D Projects: GA ČR(CZ) GA15-03139S Institutional support: RVO:61388955 Keywords : electrochemistry * methylglyoxal * electrophoresis Subject RIV: CG - Electrochemistry

  8. 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)

  9. 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

    function during dobutamine stress. METHODS AND ANALYSES: 40 patients with CAD and newly diagnosed T2DM will receive the intervention liraglutide+metformin and placebo+metformin in this investigator-initiated, double blind, randomised, placebo-controlled, cross-over 12 plus 12 weeks intervention study with...... heart rate variability, diurnal blood pressure, glucagon suppression and inflammatory response (urine, blood and adipose tissue). ETHICS AND DISSEMINATION: This study is approved by the Danish Medicines Agency, the Danish Dataprotection Agency and the Regional Committee on Biomedical Research Ethics of...

  10. 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.

  11. 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.

  12. 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...

  13. 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

  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...

  15. 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.

  16. 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

  17. 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

  18. Bis(2-phenylbiguanidium) adipate tetrahydrate

    Czech Academy of Sciences Publication Activity Database

    Matulková, Irena; Císařová, I.; Němec, A.

    2011-01-01

    Roč. 67, JAN 2011 (2011), O118-U2378. ISSN 1600-5368 Institutional research plan: CEZ:AV0Z40400503 Keywords : biguanide derivatives * hypoglycemic agents * complexes Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 0.347, year: 2011

  19. 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.

  20. Lack of Effect of Metformin on Mammary Carcinogenesis in Non-Diabetic Rat and Mouse Models

    OpenAIRE

    Thompson, Matthew D.; Clinton J. Grubbs; Bode, Ann M.; Reid, Joel M.; McGovern, Renee; Bernard, Phillip S.; Stijleman, Inge J.; Green, Jeffery E.; Bennett, Christina; Juliana, M. Margaret; Moeinpour, Fariba; Steele, Vernon E.; Lubet, Ronald A.

    2015-01-01

    Epidemiologic studies have shown that diabetics receiving the biguanide metformin, as compared to sulfonylureas or insulin, have a lower incidence of breast cancer. Metformin increases levels of activated AMPK and decreases circulating IGF-1; encouraging its potential use in both cancer prevention and therapeutic settings. In anticipation of clinical trials in non-diabetic women, the efficacy of metformin in non-diabetic rat and mouse mammary cancer models was evaluated.

  1. Effect of Metformin or Gliclazide on Lipid Peroxidation and Antioxidant Levels in Patients with Diabetes Mellitus

    OpenAIRE

    MEMİŞOĞULLARI, Ramazan; TÜRKELİ, Mehmet; BAKAN, Ebubekir; AKÇAY, Fatih

    2008-01-01

    Aim: The association between oxidative stress and diabetic complications is well known. The main goal of antidiabetic therapy is to prevent the complications of diabetes. Gliclazide (sulfonylurea) and metformin (biguanide) are two oral antidiabetic drugs that have been proven to prevent diabetic complications. In this study, we aimed to investigate the antioxidant effects of gliclazide or metformin. Materials and Methods: In this study, we evaluated 46 patients with type 2 diabetes mellitus...

  2. 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.

  3. Convergence of IPMK and LKB1-AMPK Signaling Pathways on Metformin Action

    OpenAIRE

    Bang, Sookhee; Chen, Yong; Ahima, Rexford S.; Kim, Sangwon F.

    2014-01-01

    Metformin is a biguanide drug that is widely prescribed for type 2 diabetes. Metformin suppresses hepatic gluconeogenesis and increases fatty acid oxidation. Although studies have suggested that metformin acts, at least in part, via activation of the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) pathway, the specific molecular mechanisms underlying metformin's regulation of glucose and lipid metabolism have not been well delineated. Recently, we have shown that inositol polyphosp...

  4. 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...

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

    OpenAIRE

    A. A. Aleksandrov

    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...

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

    OpenAIRE

    Mario I. Ortiz

    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, glipiz...

  7. Exocrine pancreatic function in diabetes mellitus.

    OpenAIRE

    Dandona, P; Freedman, D B; Foo, Y.; Perkins, J.; Katrak, A; Mikhailidis, D P; Rosalki, S B; Beckett, A. G.

    1984-01-01

    An investigation of serum immunoreactive trypsin concentration and pancreatic isoamylase activity in patients with diabetes mellitus has shown that exocrine pancreatic deficit is maximal in insulin dependent diabetics, intermediate in those controlled with sulphonylureas, and absent in patients controlled with biguanides or diet or both. A significant correlation between the serum concentrations of both these pancreatic enzymes and C peptide was found. Serum pancreatic enzyme concentrations w...

  8. Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade

    OpenAIRE

    Shang, Fenqing; Zhang, Jiao; Li, Zhao; Zhang, Jin; Yin, Yanjun; Wang, Yaqiong; Marin, Traci L.; Gongol, Brendan; Xiao, Han; Zhang, You-Yi; Chen, Zhen; Shyy, John Y-J; Lei, Ting

    2016-01-01

    Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated pro...

  9. 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...

  10. 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...

  11. 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...

  12. 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...

  13. 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 ...

  14. [Evaluation of the association between the use of oral anti-hyperglycemic agents and hypoglycemia in Japan by data mining of the Japanese Adverse Drug Event Report (JADER) database].

    Science.gov (United States)

    Umetsu, Ryogo; Nishibata, Yuri; Abe, Junko; Suzuki, Yukiya; Hara, Hideaki; Nagasawa, Hideko; Kinosada, Yasutomi; Nakamura, Mitsuhiro

    2014-01-01

    Hypoglycemia due to treatment with oral anti-hyperglycemic agents (OHAs) is a major clinical problem in patients with type 2 diabetes mellitus. The aim of the present study was to evaluate the risk of hypoglycemia due to OHA use by using the Japanese Adverse Drug Event Report (JADER) database. To this end, reports of hypoglycemia events included in the JADER database between 2004 and 2012 were analyzed by calculating the reporting odds ratio (OR). The Medical Dictionary for Regulatory Activities Preferred Terms was used to identify hypoglycemia; 254392 reports were found in the JADER database, of which 13269 were excluded because the age and sex of the patient were not reported. Finally, 241123 reports were analyzed. Among OHAs, sulfonylureas showed the highest adjusted OR (adjusted OR, 10.13; 95% confidence interval, 9.08-11.26). The adjusted ORs for meglitinides, biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were significantly lower than that of sulfonylureas. The adjusted OR of meglitinides (3.17; 95% confidence interval, 2.23-4.36) was significantly higher than that of alpha-glucosidase inhibitors or thiazolidinedione. We observed no difference between the adjusted ORs for biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors. Data mining of the JADER database was useful for analyzing OHA-associated hypoglycemia events. The results of our study suggested a low risk of hypoglycemia associated with biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors in clinical practice. PMID:24492232

  15. 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

  16. 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。

  17. 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...

  18. 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

  19. 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, ...

  20. [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

  1. 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

  2. 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.

  3. Renoprotective Effects of Metformin

    Directory of Open Access Journals (Sweden)

    Running Hamid Nasri

    2013-05-01

    Full Text Available Metformin as a biguanid drug entered to the market 50 years ago and now is generally recommended as the first-line treatment in type 2 diabetes, especially in overweight patients, however in recent years new indications for its use have emerged . It improves peripheral and liver sensitivity to insulin, reduces basal hepatic glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases hunger and causes weight reduction.Recently, much attention has been made toward the possible kidney protective efficacy of metformin. Recent studies have proven that metformin, possesses antioxidant properties, too.

  4. 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.

  5. 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.

  6. 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.

  7. Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade.

    Science.gov (United States)

    Shang, Fenqing; Zhang, Jiao; Li, Zhao; Zhang, Jin; Yin, Yanjun; Wang, Yaqiong; Marin, Traci L; Gongol, Brendan; Xiao, Han; Zhang, You-Yi; Chen, Zhen; Shyy, John Y-J; Lei, Ting

    2016-01-01

    Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose) polymerase 1 (PARP1). Biguanides and angiotensin II receptor blockers (ARBs) such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs), diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK) phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosyl)ation (PARylation), but increased endothelial nitric oxide synthase (eNOS) activity and silent mating type information regulation 2 homolog 1 (SIRT1) expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction. PMID:26986624

  8. Cardiovascular Protective Effect of Metformin and Telmisartan: Reduction of PARP1 Activity via the AMPK-PARP1 Cascade.

    Directory of Open Access Journals (Sweden)

    Fenqing Shang

    Full Text Available Hyperglycemia and hypertension impair endothelial function in part through oxidative stress-activated poly (ADP-ribose polymerase 1 (PARP1. Biguanides and angiotensin II receptor blockers (ARBs such as metformin and telmisartan have a vascular protective effect. We used cultured vascular endothelial cells (ECs, diabetic and hypertensive rodent models, and AMPKα2-knockout mice to investigate whether metformin and telmisartan have a beneficial effect on the endothelium via AMP-activated protein kinase (AMPK phosphorylation of PARP1 and thus inhibition of PARP1 activity. The results showed that metformin and telmisartan, but not glipizide and metoprolol, activated AMPK, which phosphorylated PARP1 Ser-177 in cultured ECs and the vascular wall of rodent models. Experiments using phosphorylated/de-phosphorylated PARP1 mutants show that AMPK phosphorylation of PARP1 leads to decreased PARP1 activity and attenuated protein poly(ADP-ribosylation (PARylation, but increased endothelial nitric oxide synthase (eNOS activity and silent mating type information regulation 2 homolog 1 (SIRT1 expression. Taken together, the data presented here suggest biguanides and ARBs have a beneficial effect on the vasculature by the cascade of AMPK phosphorylation of PARP1 to inhibit PARP1 activity and protein PARylation in ECs, thereby mitigating endothelial dysfunction.

  9. Anti-proliferative activity of oral anti-hyperglycemic agents on human vascular smooth muscle cells: thiazolidinediones (glitazones have enhanced activity under high glucose conditions

    Directory of Open Access Journals (Sweden)

    de Dios Stephanie T

    2007-10-01

    Full Text Available Abstract Background Inhibition of vascular smooth muscle cell (vSMC proliferation by oral anti-hyperglycemic agents may have a role to play in the amelioration of vascular disease in diabetes. Thiazolidinediones (TZDs inhibit vSMC proliferation but it has been reported that they anomalously stimulate [3H]-thymidine incorporation. We investigated three TZDs, two biguanides and two sulfonylureas for their ability of inhibit vSMC proliferation. People with diabetes obviously have fluctuating blood glucose levels thus we determined the effect of media glucose concentration on the inhibitory activity of TZDs in a vSMC preparation that grew considerably more rapidly under high glucose conditions. We further explored the mechanisms by which TZDs increase [3H]-thymidine incorporation. Methods VSMC proliferation was investigated by [3H]-thymidine incorporation into DNA and cell counting. Activation and inhibition of thymidine kinase utilized short term [3H]-thymidine uptake. Cell cycle events were analyzed by FACS. Results VSMC cells grown for 3 days in DMEM with 5% fetal calf serum under low (5 mM glucose and high (25 mM glucose increased in number by 2.5 and 4.7 fold, respectively. Rosiglitazone and pioglitazone showed modest but statistically significantly greater inhibitory activity under high versus low glucose conditions (P 3H]-thymidine into DNA but did not increase cell numbers. Troglitazone inhibited serum mediated thymidine kinase induction in a concentration dependent manner. FACS analysis showed that troglitazone and rosiglitazone but not pioglitazone placed a slightly higher percentage of cells in the S phase of a growing culture. Of the biguanides, metformin had no effect on proliferation assessed as [3H]-thymidine incorporation or cell numbers whereas phenformin was inhibitory in both assays albeit at high concentrations. The sulfonylureas chlorpropamide and gliclazide had no inhibitory effect on vSMC proliferation assessed by either [3H

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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...

  15. 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

  16. Computational chemistry and metal-based radiopharmaceuticals

    International Nuclear Information System (INIS)

    Computer-assisted techniques have found extensive use in the design of organic pharmaceuticals but have not been widely applied on metal complexes, particularly on radiopharmaceuticals. Some examples of computer generated structures of complexes of In, Ga and Tc with N, S, O and P donor ligands are referred. Besides parameters directly related with molecular geometries, molecular properties of the predicted structures, as ionic charges or dipole moments, are considered to be related with biodistribution studies. The structure of a series of oxo neutral Tc-biguanide complexes are predicted by molecular mechanics calculations, and their interactions with water molecules or peptide chains correlated with experimental data of partition coefficients and percentage of human protein binding. The results stress the interest of using molecular modelling to predict molecular properties of metal-based radiopharmaceuticals, which can be successfully correlated with results of in vitro studies. (author)

  17. 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.

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

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    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.

  19. 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.

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

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    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.

  1. 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.

  2. 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

  3. 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.

  4. Pattern of antidiabetic drugs use in type-2 diabetic patients in a medicine outpatient clinic of a tertiary care teaching hospital

    Directory of Open Access Journals (Sweden)

    Bela Patel

    2013-08-01

    Full Text Available Background: Diabetes mellitus (DM is an important public health problem in developing countries. Drug utilisation study of antidiabetic agents is of paramount importance to promote rational drug use in diabetics and make available valuable information for the healthcare team. The aim of study was to investigate the drug utilization pattern in type-2 diabetic patients. Methods: A prospective, cross-sectional study was carried out in medicine outpatient clinic of tertiary care hospital, Ahmedabad for eight weeks. Patients with type-2 diabetes and on drug therapy for at least one month were included. Patients’ socio-demographic and clinical data were noted in a pre-designed proforma. Data was analysed by using SPSS version 20 and Excel 2007. Results: Total 114 patients were enrolled with mean (± standard deviation age and duration of diabetes of 56.8 ± 10.5 and 8.3 ± 9.4 years respectively. Male: Female ratio was 0.72:1. Mean fasting and postprandial blood glucose levels were 147.5 ± 73.1 and 215.6 ± 97.3 mg/dl respectively. Most common symptom was weakness/fatigue (77.2%. Hypertension (70.2% was most common co-morbid illness. Mean number of drugs prescribed were 7.8 ± 2.5. Total numbers of patients receiving more than five drugs were 89.5%. Most commonly used drug group was biguanides (87.7% followed by sulphonylureas (68.4%. Conclusion: Metformin (biguanide was the most utilized (87.7% antidiabetic drug for type-2 diabetes. This study revealed that the pattern of antidiabetic prescription was rational and largely compliant with NICE (National Institute for Health and Clinical Excellence guidelines. [Int J Basic Clin Pharmacol 2013; 2(4.000: 485-491

  5. 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

  6. Metformin and insulin receptors

    International Nuclear Information System (INIS)

    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 125I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125I-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

  7. 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

  8. 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

  9. 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

  10. Simultaneous irrigation and negative pressure wound therapy enhances wound healing and reduces wound bioburden in a porcine model.

    Science.gov (United States)

    Davis, Kathryn; Bills, Jessica; Barker, Jenny; Kim, Paul; Lavery, Lawrence

    2013-01-01

    Infected foot wounds are one of the most common reasons for hospitalization and amputation among persons with diabetes. The objective of the study was to investigate a new wound therapy system that employs negative pressure wound therapy (NPWT) with simultaneous irrigation therapy. For this study, we used a porcine model with full-thickness excisional wounds, inoculated with Pseudomonas aeruginosa. Wounds were treated for 21 days of therapy with either NPWT, NPWT with simultaneous irrigation therapy using normal saline or polyhexanide biguanide (PHMB) at low or high flow rates, or control. Data show that NPWT with either irrigation condition improved wound healing rates over control-treated wounds, yet did not differ from NPWT alone. NPWT improved bioburden over control-treated wounds. NPWT with simultaneous irrigation further reduced bioburden over control and NPWT-treated wounds; however, flow rate did not affect these outcomes. Together, these data show that NPWT with simultaneous irrigation therapy with either normal saline or PHMB has a positive effect on bioburden in a porcine model, which may translate clinically to improved wound healing outcomes. PMID:24134060

  11. Disinfection protocols for necropsy equipment in rabies laboratories: Safety of personnel and diagnostic outcome.

    Science.gov (United States)

    Aiello, Roberta; Zecchin, Barbara; Tiozzo Caenazzo, Silvia; Cattoli, Giovanni; De Benedictis, Paola

    2016-08-01

    In the last decades, molecular techniques have gradually been adopted for the rapid confirmation of results obtained through gold standard methods. However, international organisations discourage their use in routine laboratory investigations for rabies post-mortem diagnosis, as they may lead to false positive results due to cross-contamination. Cleaning and disinfection are essential to prevent cross-contamination of samples in the laboratory environment. The present study evaluated the efficacy of selected disinfectants on rabies-contaminated necropsy equipment under organic challenge using a carrier-based test. The occurrence of detectable Rabies virus (RABV) antigen, viable virus and RNA was assessed through the gold standard Fluorescent Antibody Test, the Rabies Tissue Culture Infection Test and molecular techniques, respectively. None of the tested disinfectants proved to be effective under label conditions. Off label disinfection protocols were found effective for oxidizing agents and phenolic, only. Biguanide and quaternary ammonium compound were both ineffective under all tested conditions. Overall, discordant results were obtained when different diagnostic tests were compared, which means that in the presence of organic contamination common disinfectants may not be effective enough on viable RABV or RNA. Our results indicate that an effective disinfection protocol should be carefully validated to guarantee staff safety and reliability of results. PMID:27091100

  12. 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

  13. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. Antimicrobial dressing efficacy against mature Pseudomonas aeruginosa biofilm on porcine skin explants.

    Science.gov (United States)

    Phillips, Priscilla L; Yang, Qingping; Davis, Stephen; Sampson, Edith M; Azeke, John I; Hamad, Afifa; Schultz, Gregory S

    2015-08-01

    An ex vivo porcine skin explant biofilm model that preserves key properties of biofilm attached to skin at different levels of maturity (0-3 days) was used to assess the efficacy of commercially available antimicrobial dressings and topical treatments. Assays were also performed on the subpopulation of antibiotic tolerant biofilm generated by 24 hours of pre-treatment with gentamicin (120× minimal inhibitory concentration) prior to agent exposure. Five types of antimicrobial agents (iodine, silver, polyhexamethylene biguanide, honey and ethanol) and four types of moisture dressings (cotton gauze, sodium carboxymethylcellulose fibre, calcium alginate fibre and cadexomer beads) were assessed. Time-release silver gel and cadexomer iodine dressings were the most effective in reducing mature biofilm [between 5 and 7 logarithmic (log) of 7-log total], whereas all other dressing formulations reduced biofilm between 0·3 and 2 log in 24 or 72 hours with a single exposure. Similar results were found after 24-hour exposure to silver release dressings using an in vivo pig burn wound model, demonstrating correlation between the ex vivo and in vivo models. Results of this study indicate that commonly used microbicidal wound dressings vary widely in their ability to kill mature biofilm and the efficacy is influenced by time of exposure, number of applications, moisture level and agent formulation (sustained release). PMID:24028432

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

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    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

  2. Enhanced spontaneous thrombolysis: a new therapeutic challenge.

    Science.gov (United States)

    Kovacs, I B; Gorog, D A; Yamamoto, J

    2006-06-01

    Spontaneous thrombolysis is an endogenous protective mechanism against lasting arterial thrombotic occlusion, which is implicated in the pathogenesis of myocardial infarction and acute coronary events. Novel therapies for coronary heart disease (CHD) targeting atherosclerosis and thrombosis, together with cardiovascular prevention programs targeting risk-factors and lifestyle provide evidence that CHD is preventable. Although reduced fibrinolytic activity is a recognized risk-factor for ischemic cardiovascular events, it has so far been neglected. Our knowledge of the fibrinolytic effect of drugs commonly used for CHD such as antiplatelet agents (aspirin, ticlopidine, clopidogrel), anti-diabetic biguanides (phenformin, metformin) or anti-hypertensive drugs is scanty and conflicting. This is mainly due to the lack of a global test of spontaneous thrombolysis, as opposed to fibrinolysis of plasma or whole blood, i.e. the assessment of various activators and inhibitors of the fibrinolytic system. A recently described technique allows the measurement of spontaneous thrombolysis, that is, lysis of an autologous platelet-rich thrombus in the absence of added plasminogen activators. Early results suggest that this test may have significant clinical potential both in identifying those at risk of fatal cardiac events and in finding new therapeutic avenues or lifestyles to improve spontaneous thrombolytic activity. PMID:16683213

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

    Directory of Open Access Journals (Sweden)

    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.

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

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    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

  5. 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

  6. 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%.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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. PMID:25702883

  12. Energy disruptors: rising stars in anticancer therapy?

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    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

  13. 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

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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.

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

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    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

  2. 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.

  3. 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

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

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    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

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

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    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

  6. 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.

  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.

    Science.gov (United States)

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  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

    Directory of Open Access Journals (Sweden)

    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. 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

  17. 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

  18. Fatal hemolytic anemia associated with metformin: A case report

    Directory of Open Access Journals (Sweden)

    Packer Clifford D

    2008-09-01

    Full Text Available Abstract Introduction Metformin is a widely prescribed biguanide antidiabetic drug that has been implicated as a cause of hemolytic anemia in three previous case reports. We report a case of rapidly fatal hemolysis that was temporally associated with the initiation of metformin treatment for diabetes. Clinicians need to be aware of this rare but potentially serious side effect of metformin. Case presentation A 56-year-old Caucasian man with type 2 diabetes mellitus was started on metformin to improve glycemic control. Shortly afterwards, he developed progressive fatigue, exertional dyspnea, cranberry-colored urine and jaundice. Laboratory studies showed severe hemolysis, with a drop in hemoglobin from 14.7 to 6.6 g/dl over 4 days, markedly elevated lactate dehydrogenase, bilirubin and reticulocyte counts, and a low haptoglobin level. A peripheral blood smear showed no schistocytes, and a direct Coombs test was positive for anti-IgG and negative for anti-C3. Despite corticosteroid treatment and transfusion of packed red blood cells, the patient developed increasing dyspnea, hypotension, further decline in hemoglobin to 3.3 g/dl, and fatal cardiorespiratory arrest 12 hours after admission. Conclusion The serologic findings in this case suggest an autoimmune hemolytic anemia, caused either by a drug-induced autoantibody or a warm autoantibody. Based on the temporal association with metformin and the lack of other clear precipitating causes, we propose that metformin-induced hemolysis with a drug-induced autoantibody is a strong possibility. This mechanism differs from a previously described case with a possible antibody to the erythrocyte-drug complex. It has been shown, however, that hemolysis may occur via multiple mechanisms from the same drug. Clinicians should consider the possibility of metformin-associated immune hemolytic anemia in patients with otherwise unexplained hemolysis.

  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. 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.

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

    International Nuclear Information System (INIS)

    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

  2. FORMULATION AND EVALUATION OF EFFERVECENT FLOATING TABLETS OF ANTIDIABETIC DRUG

    Directory of Open Access Journals (Sweden)

    Anshuman Keshari

    2015-11-01

    Full Text Available The aim present investigation is Formulation and Evaluation of Effervescent Floating Tablets of antidiabetic drug. Gastric retention are such systems, which increase the gastric retention time of the dosage forms at the stomach and upper part of the small intestine and suitable for the drug having site-specific absorption from the above sites. The Metformin HCl an orally administered biguanide of BCS class-3 High solubility and low permeability, which is widely use in the management of and the type-II diabetes, is an oral anti- hyperglycemic agent, shows incomplete absorption from the gastrointestinal tract and from the gastrointestinal track and absolute bioavailability is 50-60%with relatively short plasma half-life of 1.5-4.5 hours. It was using different polymers studying of deferent factors affecting the floating behavior of the prepare tablets was of our goals and important target in this part. Gastro-retentive tablets of Metformin HCl were prepared by wet granulation method using HPMC K200M (Hydroxylpropyl methyl cellulose micro crystalline cellulose PH 101, sodium bicarbonate, HPMC K100 (LV, Magnesium stearate, colloidal silicon dioxide. In this formulation HPMC K 200 M was using different concentration. The Gastro-retentive tablet of Metformin HCl was evaluation of compression blend Angle of repose, Bulk density, tapped density, Drug compressibility study, Drug release rate, floating lag time etc. Result of our present study suggests that gastro-retentive tablets of Metformin HCl can be successfully designed to develop sustained release drug delivery which can reduce dosing frequency.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

    Science.gov (United States)

    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

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

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    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. 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

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

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    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.

  10. Comparative Virucidal Efficacy of Seven Disinfectants Against Murine Norovirus and Feline Calicivirus, Surrogates of Human Norovirus.

    Science.gov (United States)

    Zonta, William; Mauroy, Axel; Farnir, Frederic; Thiry, Etienne

    2016-03-01

    Human noroviruses (HuNoV) are the leading cause of acute non-bacterial gastroenteritis in humans and can be transmitted either by person-to-person contact or by consumption of contaminated food. A knowledge of an efficient disinfection for both hands and food-contact surfaces is helpful for the food sector and provides precious information for public health. The aim of this study was to evaluate the effect of seven disinfectants belonging to different groups of biocides (alcohol, halogen, oxidizing agents, quaternary ammonium compounds, aldehyde and biguanide) on infectious viral titre and on genomic copy number. Due to the absence of a cell culture system for HuNoV, two HuNoV surrogates, such as murine norovirus and feline calicivirus, were used and the tests were performed in suspension, on gloves and on stainless steel discs. When, as criteria of efficacy, a log reduction >3 of the infectious viral titre on both surrogates and in the three tests is used, the most efficacious disinfectants in this study appear to be biocidal products B, C and D, representing the halogens, the oxidizing agents group and a mix of QAC, alcohol and aldehyde, respectively. In addition, these three disinfectants also elicited a significant effect on genomic copy number for both surrogate viruses and in all three tests. The results of this study demonstrate that a halogen compound, oxidizing agents and a mix of QAC, alcohol and aldehyde are advisable for HuNoV disinfection of either potentially contaminated surfaces or materials in contact with foodstuffs. PMID:26445948

  11. 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)

  12. 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.

  13. 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.

  14. 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

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

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    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

  16. 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.

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    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

  17. 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.

  18. 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

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    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

  19. 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

  20. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  2. [Exploring an optimal approach to the use of oral hypoglycemic agents based on CGM results: implications for combination therapy with oral hypoglycemic agents].

    Science.gov (United States)

    Mori, Yutaka

    2011-08-01

    In the treatment of type 2 diabetes aimed at prevention of cardiovascular events impacting the prognosis of affected patients, it is critically important not only to lower HbAlc values but to find a way to improve postprandial hyperglycemia without causing hypoglycemia thus minimizing drastic glycemic variations or to maintain favorable glycemic control with daily glycemic variations in mind. In other words, it is no longer adequate to emphasize quantitative reductions in HbAlc as in conventional therapeutic approaches but qualitative glycemic control that takes daily glycemic variations into account is becoming of increasing importance to the management of type 2 diabetes. On the other hand, the 6 oral hypoglycemic agent (OHA) classes currently available for clinical use, i.e., biguanides (BGs), thiazolidinediones (TZDs), alpha-glucosidase inhibitors, sulfonylureas (SUs), fast-acting insulin secretagogues (glinides) and DPP-4 inhibitors, appear to vary from class to class or even from agent from agent within a class in regard to their impact on daily glycemic variations. In our CMG-based study of their impact on glycemic variations, it was demonstrated that BGs and TZDs improve hyperglycemia during nighttime and before breakfast more effectively than they do postprandial glycemic excursions; that, of the insulin secretagogues, glinides reduce daily glycemic variations as do alpha-glucosidase inhibitors, while SUs do not affect them very much; and that DPP-4 inhibitors lower not only mean glucose levels which are deemed equivalent to HbAlc values but also narrow the range of glycemic variations. Thus, OHAs can be broadly classified into those that primarily reduce 24-hour mean glucose levels as equivalent to HbAlc values and those that primarily narrow the range of glycemic variations. Therefore, with either of these agents as monotherapy, it is next to impossible to achieve reductions in HbAlc with a narrow range of glycemic variations, and combination therapy

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

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

    Directory of Open Access Journals (Sweden)

    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

  10. 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

  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. Anagliptin in the treatment of type 2 diabetes: safety, efficacy, and patient acceptability

    Directory of Open Access Journals (Sweden)

    Nishio S

    2015-03-01

    Full Text Available Shinya Nishio, Mariko Abe, Hiroyuki ItoDepartment of Diabetes, Metabolism and Kidney Disease, Edogawa Hospital Higashikoiwa, Edogawa-ku, Tokyo, JapanAbstract: Anagliptin is a novel dipeptidyl peptidase-4 inhibitor that has been available in Japan since 2012. Because anagliptin is not generally used in countries other than Japan, there are only a small number of reports investigating the effects of anagliptin. In the present article, we review the safety and efficacy of anagliptin according to data obtained from preclinical trials and postmarketing studies. The usual dose of anagliptin is 200 mg daily, and increases in the dose up to 400 mg daily have been approved in cases in which the blood glucose–lowering effect is insufficient. In a Phase II trial, the reduction in the HbA1c values from baseline after 12 weeks monotherapy with 200 mg and 400 mg of daily anagliptin was 0.75%±0.50% and 0.82%±0.46%, respectively, and more than 40% of the subjects receiving anagliptin at a dose of 200 mg or 400 mg daily achieved an HbA1c level below 6.9%. Furthermore, the levels of HbA1c, fasting blood glucose, and postprandial blood glucose were significantly decreased at 52 weeks compared with the baseline values in a Phase III trial investigating the effects of anagliptin included in combination therapy with other oral antidiabetic agents. In a pooled analysis of Phase II and Phase II/III trials, the goal achievement rates for an HbA1c level below 7.0% at 12 weeks were 40.3%, 39.4%, 30.0%, and 34.8% in the patients treated with anagliptin combined with α-glucosidase inhibitors, thiazolidinediones, sulfonylureas, and biguanides, respectively. Meanwhile, the serum lipid concentrations significantly improved after the administration of anagliptin in a pooled analysis of Phase III trials, and no serious adverse effects have been reported in preclinical trials. Therefore, the use of anagliptin in patients with type 2 diabetes is considered to be safe and

  13. Antihyperglycemic, antihyperlipidemic, anti-inflammatory and adenosine deaminase–lowering effects of garlic in patients with type 2 diabetes mellitus with obesity

    Directory of Open Access Journals (Sweden)

    Kumar R

    2013-01-01

    Full Text Available Rahat Kumar,1 Simran Chhatwal,1 Sahiba Arora,2 Sita Sharma,3 Jaswinder Singh,1 Narinder Singh,1 Vikram Bhandari,1 Ashok Khurana41Department of Pharmacology, 2Department of Biochemistry, 3Department of Obstetrics and Gynecology, 4Department of Medicine, Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar, IndiaIntroduction: Type 2 diabetes mellitus is a chronic disorder characterized by chronic hyperglycemia, with long term macrovascular and microvascular complications. The treatment is lifestyle management, exercise, weight control, and antihyperglycemic drugs such as sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and meglitinide. Recently, a direct association between high levels of C-reactive protein and serum adenosine deaminase levels in patients with uncontrolled diabetes with long-term complications has been seen. This study was conducted to assess the antihyperglycemic, lipid-lowering, anti-inflammatory, and improving glycemic control of garlic in type 2 diabetes patients with obesity.Materials and methods: This was an open-label, prospective, comparative study, conducted on 60 patients having type 2 diabetes mellitus and obesity. The patients were divided into two groups of 30 each, of either sex. Group 1 was given metformin tablets, 500 mg twice a day (BD/three times a day (TDS, after meals, and group 2 was given metformin tablets, 500 mg BD/TDS, after meals, along with garlic (Allium sativum capsules, 250 mg BD. Patients were routinely investigated for fasting and postprandial blood glucose, glycosylated hemoglobin (HbA1c, serum adenosine deaminase levels and lipid profile (serum cholesterol, high-density lipoprotein cholesterol, triglycerides and low-density lipoprotein cholesterol at the start of the study. Patients were followed up for 12 weeks, with monitoring of fasting and postprandial blood glucose at 2 week intervals, and monitoring of the other parameters at the end of study

  14. Caloric restriction.

    Science.gov (United States)

    Speakman, John R; Mitchell, Sharon E

    2011-06-01

    generalized shift from carbohydrate to fat metabolism. Four pathways have been implicated in mediating the CR effect. These are the insulin like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the adenosine monophosphate (AMP) activated protein kinase (AMPK) pathway and the target of rapamycin (TOR) pathway. These different pathways may interact and may all play important roles mediating different aspects of the response. Exactly how they generate the health benefits remains open for debate, however CR results in reduced oxidative stress and enhanced autophagy, both of which could be essential components of the beneficial effects. Most data about the effects of CR in mammals comes from work on rodents. There is limited work on non-human primates that shows promising effects and one randomized controlled trial in humans where physiological markers of the CR response are consistent with the responses in mice and rats. There are also populations of humans voluntarily restricting themselves. Humans on long term restriction report similar negative side effects to those observed in animals - perpetual hunger, reduced body temperature leading to a feeling of being cold, and diminished libido. Considerable effort has been directed in recent years to find drugs that mimic the CR response. Promising candidates are those that intersect with the critical signaling pathways identified above and include biguanides such as metformin that target the insulin signaling pathway, stilbenes (e.g. resveratrol) that affect sirtuin activity and drugs such as rapamycin that interact with mTOR signaling. Whether it will ever be possible to find drugs that capture the health benefits of CR without the negative side-effects remains unclear. Moreover, even if such drugs are developed how the current licensing system for drug use in western societies would cope with them may be a further obstacle to their use. PMID:21840335

  15. Formulation and Evaluation of Sitagliptin Phosphate and Metformin Hydrochloride Trilayered tablets

    Directory of Open Access Journals (Sweden)

    Prathima Srinivas Maringanti

    2013-04-01

    Full Text Available Sitagliptin phosphate when used alone is an oral anti hyperglycemic drug of the dipeptidyl peptidase-4 (DPP-4 inhibitor class. It is available as tablets under trade name JANUVIA. Metformin hydrochloride is used alone in the form of biguanide anti hyperglycemic agent for treating non-insulin-dependent diabetes mellitus (NIDDM and is available as both conventional and sustained release tablets. The objective of the present study was to develop a trilayered tablet of immediate release Sitagliptin phosphate layer and sustained release Metformin Hydrochloride layer. Apart from the aesthetic appeal this trilayered tablet is expected to improve glucose tolerance in patients with the type 2 diabetes by lowering both basal and postprandial plasma glucose, reducing the dose, reducing frequency of administration and dose related gastrointestinal side effects of metformin and improve its bioavailability thus improving the patient compliance. Metformin Hydrochloride has biological half-life of nearly 6 hours. An attempt was made to sustain its release by using two different polymers in two layers. Preformulation studies including drug excipient compatibility studies were conducted for both drugs. Different formulations of sustained release Metformin HCl tablets were prepared by using a combination of hydrophilic polymers like HPMC K100, HPMC K4M, HPMC K15 M, pH sensitive polymer Carbopol 971P, retarding polymer Ethyl cellulose and Low substituted hydroxy propyl cellulose. Sitagliptin immediate release formulations were prepared using cross povidone, croscarmellose sodium and sodium starch glycolate as super disintegrants. The tablets were evaluated for all physico chemical parameters like angle of repose, bulk density, tapped density, Hausners ratio and carr’s index. Based on the invitro dissolution data the formulations SF6, MF9 and MF8 were found to be the optimized formulations for Sitagliptin phosphate and Metformin Hydrochloride formulations

  16. 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

  17. [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

  18. 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

  19. 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

  20. 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