Keratomycosis due to Tintelnotia destructans refractory to common therapy treated successfully with systemic and local terbinafine in combination with polyhexamethylene biguanide.

Science.gov (United States)

Behrens-Baumann, Wolfgang J; Hofmüller, Wolfram; Tammer, Ina; Tintelnot, Kathrin

2018-04-28

To report on a wearer of rigid gas-permeable contact lenses with a keratomycosis due to Tintelnotia-a new genus of Phaeosphaeriaceae-treated with terbinafine and polyhexamethylene biguanide. Chart review of a patient with fungal keratitis treated additionally with systemic and topical terbinafine 0.25% after symptoms increased under conventional antimycotic therapy with voriconazole. Antifungal susceptibility had been tested in vitro. After starting an additional treatment with systemic and topical terbinafine, the severe corneal infection was sufficiently resolved. The drug was well tolerated without any neurological, dermatological or gastroenterological problems. Terbinafine revealed a marked in vitro antifungal activity of 0.12 µg/ml. The fungus was identified as Tintelnotia destructans. Terbinafine might be considered as a therapeutic option in severe cases of fungal keratitis refractory to common antifungal therapy.

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

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Albenones José de Mesquita

2007-09-01

Full Text Available

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

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

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

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

Determination of polyhexamethylene biguanide hydrochloride using photometric colloidal titration with crystal violet as a color indicator.

Science.gov (United States)

Masadome, Takashi; Miyanishi, Takaaki; Watanabe, Keita; Ueda, Hiroshi; Hattori, Toshiaki

2011-01-01

A solution of polyhexamethylene biguanide hydrochloride (PHMB-HCl) was titrated with a standard solution of potassium poly(vinyl sulfate) (PVSK) using crystal violet (CV) as an photometric indicator cation. The end point was detected by a sharp absorbance change due to an abrupt decrease in the concentration of CV. A linear relationship between the concentration of PHMB-HCl and the end-point volume of the titrant existed in the concentration range from 2 to 10 × 10(-6) eq mol L(-1). Back-titration was based on adding an excess amount of PVSK to a sample solution containing CV, which was titrated with a standard solution of poly(diallyldimethylammonium chloride) (PDADMAC). The calibration curve of the PHMB-HCl concentration to the end point volume of the titrant was also linear in the concentration range from 2 to 8 × 10(-6) eq mol L(-1). Both photometric titrations were applied to the determination of PHMB-HCl in a few contact-lens detergents. Back-titration showed a clear end point, but direct titration showed an unclear end point. The results of the back-titration of PHMB-HCl were compared with the content registered in its labels. 2011 © The Japan Society for Analytical Chemistry

The effect of the disulfideisomerase domain containing protein in the defense against polyhexamethylene biguanide of highly tolerant Acanthamoeba at the trophozoite stage

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Fu-Chin Huang

2016-12-01

Full Text Available Acanthamoeba castellanii is a free-living protozoan pathogen capable of causing a blinding keratitis and fatal granulomatous encephalitis. Current treatment generally involves an hourly application of polyhexamethylene biguanide (PHMB over a period of several days but this is not entirely effective against all strains/isolates. The tolerance mechanisms of PHMB in Acanthamoeba cells remain unclear. In this study, we found that the mRNA expression level of disulfideisomerase domain containing protein (PDI increased rapidly in surviving cells of the highly PHMB-tolerant Acanthamoeba castellanii strain, NCKH_D, during PHMB treatment, but not in the ATCC standard strain. After PDI-specific silencing, NCKH_D was found to be more vulnerable to PHMB treatment. The results described above show that PDI is an important gene for PHMB tolerance ability in a highly PHMB-tolerant strain of Acanthamoeba and provide a new insight for more efficient medicine development for Acanthamoeba keratitis.

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

INTRODUCTION: Newly diagnosed type 2 diabetes mellitus (T2DM) in patients with coronary artery disease (CAD) more than doubles the risk of death compared with otherwise matched glucose tolerant patients. The biguanide metformin is the drug of choice in treatment of T2DM and has shown to ameliorate...... cardiovascular morbidity in patients with T2DM and myocardial infarction (MI). The incretin hormone, glucagon-like peptide-1 (GLP-1) improves β-cell function, insulin sensitivity and causes weight loss and has been suggested to have beneficial effects on cardiac function. The GLP-1 receptor agonist (GLP-1RA......), liraglutide, is currently used for treatment of T2DM but its potential effect on cardiac function has not been investigated in detail. We hypothesised that liraglutide added to metformin backbone therapy in patients with CAD and newly diagnosed T2DM will improve β-cell function and left ventricular systolic...

Potentiometric titration of polyhexamethylene biguanide hydrochloride with potassium poly(vinyl sulfate) solution using a cationic surfactant-selective electrode.

Science.gov (United States)

Masadome, Takashi; Yamagishi, Yuichi; Takano, Masaki; Hattori, Toshiaki

2008-03-01

A potentiometric titration method using a cationic surfactant as an indicator cation and a plasticized poly(vinyl chloride) membrane electrode sensitive to the cationic surfactant is proposed for the determination of polyhexamethylene biguanide hydrochloride (PHMB-HCl), which is a cationic polyelectrolyte. A sample solution of PHMB-HCl containing an indicator cation (hexadecyltrimethylammonium ion, HTA) was titrated with a standard solution of an anionic polyelectrolyte, potassium poly(vinyl sulfate) (PVSK). The end-point was detected as a sharp potential change due to an abrupt decrease in the concentration of the indicator cation, HTA, which is caused by its association with PVSK. The effects of the concentrations of HTA ion and coexisting electrolytes in the sample solution on the degree of the potential change at the end-point were examined. A linear relationship between the concentration of PHMB-HCl and the end-point volume of the titrant exists in the concentration range from 2.0 x 10(-5) to 4.0 x 10(-4) M in the case that the concentration of HTA is 1.0 x 10(-5) M, and that from 1.0 x 10(-6) to 1.2 x 10(-5) M in the case that the concentration of HTA is 5.0 x 10(-6) M, respectively. The proposed method was applied to the determination of PHMB-HCl in some contact-lens detergents.

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

[Antagonistic action of prednisolone and buformin in the carbohydrate metabolism of healthy persons (author's transl)].

Science.gov (United States)

Bottermann, P; Schweigart, U; Ermler, R

1976-02-13

Intravenous glucose tolerance tests were performed and changes of blood glucose and insulin concentration were measured to examine whether the diabetogenic effect of glucocorticoides can be compensated by biguanides. Seven standard weight volunteers with a healthy metabolism were given prednisolone and buformin as well as a combination of both. In spite of the reactively higher insulin secretion after treatment with prednisolone the glucose tolerance was reduced. In contrast, treatment with biguanide improved the glucose tolerance while decreasing the insulin secretion. It was nearly possible to compensate the negative effect of prednisolone on the carbohydrate metabolism by biguanides. We, therefore, consider a preventive administration of biguanides to be effective in long term or high dosage administration of glucocorticoides.

Bactericidal and Anti-biofilm Effects of Polyhexamethylene Biguanide in Models of Intracellular and Biofilm of Staphylococcus aureus Isolated from Bovine Mastitis

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Nor F. Kamaruzzaman

2017-08-01

Full Text Available Staphylococcus aureus infection is a common cause of mastitis, reducing milk yield, affecting animal welfare and causing huge economic losses within the dairy industry. In addition to the problem of acquired drug resistance, bacterial invasion into udder cells and the formation of surface biofilms are believed to reduce antibiotic efficacy, leading to treatment failure. Here, we investigated the antimicrobial activities of enrofloxacin, an antibiotic that is commonly used in mastitis therapy and polyhexamethylene biguanide (PHMB, an antimicrobial polymer. The antimicrobial activities were tested against intracellular S. aureus in infected Mac-T cells (host cells. Also, fluorescein-tagged PHMB was used to study PHMB uptake and localization with S. aureus within the infected Mac-T cells. Anti-biofilm activities were tested by treating S. aureus biofilms and measuring effects on biofilm mass in vitro. Enrofloxacin and PHMB at 15 mg/L killed between 42 to 92 and 99.9% of intracellular S. aureus, respectively. PHMB-FITC entered and colocalized with the intracellular S. aureus, suggesting direct interaction of the drug with the bacteria inside the host cells. Enrofloxacin and PHMB at 15 mg/L reduced between 10 to 27% and 28 to 37% of biofilms’ mass, respectively. The half-maximal inhibitory concentrations (IC50 obtained from a cytotoxicity assay were 345 ± 91 and 21 ± 2 mg/L for enrofloxacin and PHMB, respectively; therefore, both compounds were tolerated by the host cells at high concentrations. These findings suggest that both antimicrobials are effective against intracellular S. aureus and can disrupt biofilm structures, with PHMB being more potent against intracellular S. aureus, highlighting the potential application of PHMB in mastitis therapy.

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.

Exceptionally High Proton and Lithium Cation Gas-Phase Basicity of the Anti-Diabetic Drug Metformin.

Science.gov (United States)

Raczyńska, Ewa D; Gal, Jean-François; Maria, Pierre-Charles; Michalec, Piotr; Zalewski, Marcin

2017-11-16

Substituted biguanides are known for their biological effect, and a few of them are used as drugs, the most prominent example being metformin (1,1-dimethylbiguanide, IUPAC name: N,N-dimethylimidodicarbonimidic diamide). Because of the presence of hydrogen atoms at the amino groups, biguanides exhibit a multiple tautomerism. This aspect of their structures was examined in detail for unsubstituted biguanide and metformin in the gas phase. At the density functional theory (DFT) level {essentially B3LYP/6-311+G(d,p)}, the most stable structures correspond to the conjugated, push-pull, system (NR 2 )(NH 2 )C═N-C(═NH)NH 2 (R = H, CH 3 ), further stabilized by an internal hydrogen bond. The structural and energetic aspects of protonation and lithium cation adduct formation of biguanide and metformin was examined at the same level of theory. The gas-phase protonation energetics reveal that the more stable tautomer is protonated at the terminal imino C═NH site, still with an internal hydrogen bond maintaining the structure of the neutral system. The calculated proton affinity and gas-phase basicity of the two molecules reach the domain of superbasicity. By contrast, the lithium cation prefers to bind the less stable, not fully conjugated, tautomer (NR 2 )C(═NH)-NH-C(═NH)NH 2 of biguanides, in which the two C═NH groups are separated by NH. This less stable form of biguanides binds Li + as a bidentate ligand, in agreement with what was reported in the literature for other metal cations in the solid phase. The quantitative assessment of resonance in biguanide, in metformin and in their protonated forms, using the HOMED and HOMA indices, reveals an increase in electron delocalization upon protonation. On the contrary, the most stable lithium cation adducts are less conjugated than the stable neutral biguanides, because the metal cation is better coordinated by the not-fully conjugated bidentate tautomer.

Dgroup: DG00113 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available n hydrochloride (JP17/USP) ... Antidiabetic agent ... DG01685 ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic... Unclassified ... DG02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic ATC code: A10BA02 Biganide antidiabetic

Drug: D00595 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D00595 Drug Buformin (USAN/INN) ... C6H15N5 D00595.gif ... Antidiabetic agent ... DG01685... ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Unclassified ... DG02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic

Drug: D04966 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D04966 Drug Metformin (USAN/INN) ... C4H11N5 D04966.gif ... Antidiabetic agent ... DG0168...5 ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Unclassified ... DG02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic

Dgroup: DG00114 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available ydrochloride (JP17) ... Antidiabetic agent ... DG01685 ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Unc...lassified ... DG02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic ATC code: A10BA03 Biganide antidiabetics AMPK (PRKAA) [HSA:5562 5563] [KO:K07198] ...

Metformin and phenformin block the peripheral antinociception induced by diclofenac and indomethacin on the formalin test.

Science.gov (United States)

Ortiz, Mario I

2012-01-02

Recent evidence has shown that systemic administration of sulfonylureas and biguanides block the diclofenac-induced antinociception, but not the effect produced by indomethacin. However, there are no reports about the peripheral interaction between analgesics and the biguanides metformin and phenformin. Therefore, this work was undertaken to determine whether glibenclamide and glipizide and the biguanides metformin and phenformin have any effect on the peripheral antinociception induced by diclofenac and indomethacin. Diclofenac and indomethacin were administered locally in the formalin-injured rat paw, and the antinociceptive effect was evaluated using the 1% formalin test. To determine whether peripheral antinociception induced by diclofenac or indomethacin was mediated by either the ATP-sensitive K(+) channels or biguanides-induced mechanisms, the effect of pretreatment with the appropriates vehicles or glibenclamide, glipizide, metformin and phenformin on the antinociceptive effect induced by local peripheral diclofenac and indomethacin was assessed. Local peripheral injections of diclofenac (50-200 μg/paw) and indomethacin (200-800 μg/paw) produced a dose-dependent antinociception during the second phase of the test. Local pretreatment with glibenclamide, glipizide, metformin and phenformin blocked the diclofenac-induced antinociception. On the other hand, the pretreatment with glibenclamide and glipizide did not prevent the local antinociception produced by indomethacin. Nonetheless, metformin and phenformin reversed the local antinociception induced by indomethacin. Data suggest that diclofenac could activate the K(+) channels and biguanides-dependent mechanisms to produce its peripheral antinociceptive effects in the formalin test. Likewise, a biguanides-dependent mechanism could be activated by indomethacin consecutively to generate its peripheral antinociceptive effect. Copyright © 2011 Elsevier Inc. All rights reserved.

Involvement of organic cation transporter 1 in the lactic acidosis caused bv metformin

NARCIS (Netherlands)

Wang, DS; Kusuhara, H; Kato, Y; Jonker, JW; Schinkel, AH; Sugiyama, Y

Biguanides are a class of drugs widely used as oral antihyperglycemic agents for the treatment of type 2 diabetes mellitus, but they are associated with lactic acidosis, a lethal side effect. We reported previously that biguanides are good substrates of rat organic cation transporter 1 (Oct1;

Drug: D00944 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D00944 Drug Metformin hydrochloride (JP17/USP); Glucophage (TN) ... C4H11N5. HCl D00944.gif ... Antidiabetic... agent ... DG01685 ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Unclassified ... DG...02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic Therapeutic category: 3962 ATC code: A10BA02 Chemical

Drug: D02206 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D02206 Drug Buformin hydrochloride (JP17); Dibetos-B (TN) ... C6H15N5. HCl D02206.gif ... Antidiabetic... agent ... DG01685 ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Unclassified ... DG02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic Therapeutic category: 3962 ATC code: A10BA03 Chemical group

Drug: D08352 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D08352 Drug Phenformin hydrochloride; Debei (TN) ... C10H15N5. HCl D08352.gif ... Antidiabetic... agent ... DG01685 ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Cyp substrate ... DG01644 ... CYP2D6... substrate Unclassified ... DG02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic ATC code: A10BA01 Chemical

Drug: D08351 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D08351 Drug Phenformin (BAN) ... C10H15N5 D08351.gif ... Antidiabetic agent ... DG01685 ... ...Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Cyp substrate ... DG01644 ... CYP2D6 substrate Unclassified ... ...DG02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic Same as: C07673 ATC code: A10BA01 Chemical group: D

Drug: D04103 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D04103 Drug Etoformin hydrochloride (USAN) ... C8H19N5. HCl D04103.gif ... Antidiabetic... agent ... DG01685 ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Unclassified ... DG02044 ... Hypoglycemics ... ... DG01684 ... Biguanide antidiabetic ... Biganides ... CAS: 53597-26-5 PubChem: 47206055 ChEMBL: CHEMBL2106592 LigandBox: D04103 NIKKAJI: J244.891B ...

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.

Dgroup: DG00112 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available DG00112 Chemical ... DGroup Phenformin ... D08351 ... Phenformin (BAN) D08352 ... Phenformin hydrochloride Antidiabeti...c agent ... DG01685 ... Insulin sensitizer ... DG01684 ... Biguanide antidiabetic Cyp substrat...e ... DG01644 ... CYP2D6 substrate Unclassified ... DG02044 ... Hypoglycemics ... DG01684 ... Biguanide antidiabetic ATC code...: A10BA01 Biganide antidiabetics AMPK (PRKAA) [HSA:5562 5563] [KO:K07198] Enzyme: CYP2D6 [HSA:1565] ...

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

OpenAIRE

Duque, Jorge Eduardo; Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá D.C.; López, Catalina; Grupo de Investigación en Terapia Regenerativa, Universidad de Caldas, Manizales; Cruz, Nataly; Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá D.C.; Samudio, Ismael; Grupo de Terapia Celular y Molecular, Pontificia Universidad Javeriana, Bogotá D.C.

2010-01-01

Metformin is a synthetic biguanide first described in the 1920´s as a side product of the synthesis of N,N-dimethylguanidine. Like other related biguanides, metformin displays antihyperglycemic properties, and has become the most widely prescribed oral antidiabetic medicine around the world. Intriguing recent evidence suggests that metformin has chemopreventive and direct antitumor properties, and several ongoing clinical studies around the world are using this agent alone or in combi...

Evaluation of a combination of sodium hypochlorite and polyhexamethylene biguanide as an egg wash for red-eared slider turtles (Trachemys scripta elegans) to suppress or eliminate Salmonella organisms on egg surfaces and in hatchlings.

Science.gov (United States)

Mitchell, Mark A; Adamson, Trinka W; Singleton, Charles B; Roundtree, Marlana K; Bauer, Rudy W; Acierno, Mark J

2007-02-01

To evaluate a combination of 2 nonantibiotic microbicide compounds, sodium hypochlorite (NaOCl) and polyhexamethylene biguanide (PHMB), as a treatment to suppress or eliminate Salmonella spp from red-eared slider (RES) turtle (Trachemys scripta elegans) eggs and hatchlings. 2,738 eggs from 8 turtle farms in Louisiana. Eggs were randomly sorted into 3 or, when sufficient eggs were available, 4 treatment groups as follows: control, pressure-differential egg treatment with NaOCl and gentamicin, NaOCl and PHMB bath treatment, and pressure-differential egg treatment with NaOCl and PHMB. Bacterial cultures were performed from specimens of eggs and hatchlings and evaluated for Salmonella spp. RES turtle eggs treated with NaOCl and PHMB as a bath (odds ratio [OR], 0.2 [95% confidence interval (CI), 0.1 to 0.3]) or as a pressure-differential dip (OR, 0.01 [95% CI, 0.001 to 0.07]) or with gentamicin as a pressure-differential dip (OR, 0.1 [95% CI, 0.06 to 0.2]) were significantly less likely to have Salmonella-positive culture results than control-group eggs. Concern over reptile-associated salmonellosis in children in the United States is so great that federal regulations prohibit the sale of turtles that are < 10.2 cm in length. Currently, turtle farms treat eggs with gentamicin solution. Although this has reduced Salmonella shedding, it has also resulted in antimicrobial resistance. Results of our study indicate that a combination of NaOCl and PHMB may be used to suppress or eliminate Salmonella spp on RES turtle eggs and in hatchlings.

Metformin in the treatment of polycystic ovary syndrome.

Science.gov (United States)

Motta, Dra Alicia Beatriz

2008-01-01

Polycystic ovary syndrome (PCOS) is one of the most frequent diseases that affects women in their reproductive age. The heterogeneity of PCOS makes not only the diagnosis but also the choice of an adequate treatment difficult. The biguanide, N, N' dimethyl-biguanide: Metformin is an antidiabetic drug that increases glucose utilization in insulin-sensitive tissues and is useful in the reduction of both insulin resistance and circulating androgens as well as restoring ovulation. However, metformin is being clinically used without a complete understanding of the mechanism involved. The present review explores some of the actions and efficacy of metformin in the treatment of PCOS during different reproductive periods.

Dgroup: DG01685 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available DG01685 DGroup Insulin sensitizer ... DG01684 ... Biguanide antidiabetic ... DG00112 ... Phen...litazar (USAN/INN) ... D09350 ... Indeglitazar (USAN) Antidiabetic agent ... Antidiabetics ...

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

Directory of Open Access Journals (Sweden)

Tatiane Karen Cabeça

2012-09-01

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

Understanding the benefit of metformin use in cancer treatment

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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.

Formation of the diuretic chlorazanil from the antimalarial drug proguanil--implications for sports drug testing.

Science.gov (United States)

Thevis, Mario; Geyer, Hans; Thomas, Andreas; Tretzel, Laura; Bailloux, Isabelle; Buisson, Corinne; Lasne, Francoise; Schaefer, Maximilian S; Kienbaum, Peter; Mueller-Stoever, Irmela; Schänzer, Wilhelm

2015-11-10

Chlorazanil (Ordipan, N-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine) is a diuretic agent and as such prohibited in sport according to the regulations of the World Anti-Doping Agency (WADA). Despite its introduction into clinical practice in the late 1950s, the worldwide very first two adverse analytical findings were registered only in 2014, being motive for an in-depth investigation of these cases. Both individuals denied the intake of the drug; however, the athletes did declare the use of the antimalarial prophylactic agent proguanil due to temporary residences in African countries. A structural similarity between chlorazanil and proguanil is given but no direct metabolic relation has been reported in the scientific literature. Moreover, chlorazanil has not been confirmed as a drug impurity of proguanil. Proguanil however is metabolized in humans to N-(4-chlorophenyl)-biguanide, which represents a chemical precursor in the synthesis of chlorazanil. In the presence of formic acid, formaldehyde, or formic acid esters, N-(4-chlorophenyl)-biguanide converts to chlorazanil. In order to probe for potential sources of the chlorazanil detected in the doping control samples, drug formulations containing proguanil and urine samples of individuals using proguanil as antimalarial drug were subjected to liquid chromatography-high resolution/high accuracy mass spectrometry. In addition, in vitro simulations with 4-chlorophenyl-biguanide and respective reactants were conducted in urine and resulting specimens analyzed for the presence of chlorazanil. While no chlorazanil was found in drug formulations, the urine samples of 2 out of 4 proguanil users returned findings for chlorazanil at low ng/mL levels, similar to the adverse analytical findings in the doping control samples. Further, in the presence of formaldehyde, formic acid and related esters, 4-chlorophenyl-biguanide was found to produce chlorazanil in human urine, suggesting that the detection of the obsolete diuretic

Assessing the Burden of Diabetes Mellitus in Emergency Departments in the United States: The National Hospital Ambulatory Medical Care Survey (NHAMCS)

Science.gov (United States)

Asao, Keiko; Kaminski, James; McEwen, Laura N.; Wu, Xiejian; Lee, Joyce M.; Herman, William H.

2014-01-01

Objective To evaluate the performance of three alternative methods to identify diabetes in patients visiting Emergency Departments (EDs), and to describe the characteristics of patients with diabetes who are not identified when the alternative methods are used. Research Design and Methods We used data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) 2009 and 2010. We assessed the sensitivity and specificity of using providers’ diagnoses and diabetes medications (both excluding and including biguanides) to identify diabetes compared to using the checkbox for diabetes as the gold standard. We examined the characteristics of patients whose diabetes was missed using multivariate Poisson regression models. Results The checkbox identified 5,567 ED visits by adult patients with diabetes. Compared to the checkbox, the sensitivity was 12.5% for providers’ diagnoses alone, 20.5% for providers’ diagnoses and diabetes medications excluding biguanides, and 21.5% for providers’ diagnoses and diabetes medications including biguanides. The specificity of all three of the alternative methods was >99%. Older patients were more likely to have diabetes not identified. Patients with self-payment, those who had glucose measured or received IV fluids in the ED, and those with more diagnosis codes and medications, were more likely to have diabetes identified. Conclusions NHAMCS's providers’ diagnosis codes and medication lists do not identify the majority of patients with diabetes visiting EDs. The newly introduced checkbox is helpful in measuring ED resource utilization by patients with diabetes. PMID:24680472

Use of thiazolidinediones and risk of bladder cancer

DEFF Research Database (Denmark)

Bazelier, Marloes T; de Vries, Frank; Vestergaard, Peter

2013-01-01

BACKGROUND: Pioglitazone, a drug for the treatment of type 2 diabetes mellitus has been associated with bladder cancer in observational studies. Diabetes mellitus itself has also been linked with bladder cancer. The objective was to estimate the risk of bladder cancer for diabetic patients using...... thialozidinediones (TZDs) compared with patients in other treatment stages of the disease. METHODS: We performed a population-based cohort study (1996-2007) in the Danish National Health Registers. Oral antidiabetic drug users (n=179,056) were matched 1:3 by sex and year of birth to non-users. Hazard ratios (HRs......) of bladder cancer were estimated using Cox proportional hazards models. Time-dependent adjustments were made for age, comorbidity, and drug use. Four different treatment stages were defined: current use of either a biguanide or a sulfonylureum (stage 1), current use of a biguanide and a sulfonylureum...

Enterobacteriaceae and Salmonella recovered from non-sanitized and sanitized broiler hatching eggs

Science.gov (United States)

Sanitizing hatching eggs may reduce the chances that a flock will become colonized with Salmonella and reduce the numbers of other microorganisms, such as Enterobacteriaceae, that can depress hatchability. An experiment was conducted to determine if a quaternary-biguanide sanitizer applied as foam ...

Polyhexanide - safety and efficacy as an antiseptic.

Science.gov (United States)

Fjeld, Hilde; Lingaas, Egil

2016-05-01

BACKGROUND Polyhexamethylene biguanide hydrochloride/polyhexanide/polyaminopropyl biguanide (PHMB) is used as a disinfectant and antiseptic. This article discusses the use of the substance as an antiseptic. We summarise published data on its antimicrobial effect in vitro and its clinical effect and safety when used on skin, wounds and mucosa.MATERIAL AND METHOD A literature search was conducted in PubMed for articles published in the last five years. Articles available as of June 2014 were considered.RESULTS Of 332 articles identified, 27 were included. In vitro studies have demonstrated an antimicrobial effect on Gram-negative bacteria, Gram-positive bacteria and Candida albicans. The clinical studies are small, not well controlled and frequently sponsored by industry. Few adverse effects from the substance were reported.INTERPRETATION Better designed, larger-scale clinical studies of effect and safety are needed in order to give recommendations on the use of polyhexanide on skin, wounds and mucosa.

Effects of Hyperglycemia and Iron Deficiency on Kidney and Heart Function in Type 2 Diabetes Disease

Directory of Open Access Journals (Sweden)

Belma Aščić-Buturović

2006-02-01

Full Text Available Untreated anemia can caused significant cardiac and kidney damage. The aim of this study was to investigate the efficiency of anemia and hyperglycemia treatment in type 2 diabetes and their impact on kidney and heart impairment. The study is clinical retrospective and prospective and it was conducted in Clinic of Endocrinology, Diabetes Mellitus and Metabolic Diseases, University Clinical Center of Sarajevo. Prior to the study all patients were taking oral hypoglycemic drugs included sulfonylureas and biguanides. These subjects were put on 2 times daily fix mix insulin and biguanides after lunch. Each day, subjects received Iron tab 1 x 100 mg/ day, and C vitamin 1 x 100 mg/day. The results of our study are showing that effective treatment of glycaemia and anemia in patients with diabetes, reduces blood pressure, urine albumin secretion and pulse rate, diminishing cardiovascular damage and improving kidney function.

Recent advances in the Management of Diabetes Mellitus | Sanusi ...

African Journals Online (AJOL)

Life style modi cation, oral hypoglycaemic agents, insulin therapy and islet cell transplantation are some of the approaches in the management of diabetes mellitus. Several classes of oral hypoglycemic agents like sulfonylureas, biguanides and alpha-glucosidase inhibitors are available for the treatment of type II diabetes ...

Hypoglycemic Effects of Clitoria ternatea Linn. (Fabaceae) in ...

African Journals Online (AJOL)

Erah

capable of reducing blood sugar level belong to two chemical classes - sulfonylureas and biguanides [3]. ... treatment of cancer, heart disease, diabetes mellitus, and high blood pressure [7]. Clitoria ternatea Linn ... was collected from the heart using a syringe, transferred to sodium fluoride bottles bottles, allowed to clot and ...

Dgroup: DG01684 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available DG01684 DGroup Biguanide antidiabetic -formin DG01684.gif DG00112 ... Phenformin ... D08... hydrochloride (JP17) ... D04103 ... Etoformin hydrochloride (USAN) Antidiabetic agen...t ... DG01685 ... Insulin sensitizer Unclassified ... DG02044 ... Hypoglycemics ATC code: A10BA Antidiabetics AMPK (PRKAA) [HSA:5562 5563] [KO:K07198] ...

Prescription of oral hypoglycemic agents for patients with type 2 diabetes mellitus: A retrospective cohort study using a Japanese hospital database.

Science.gov (United States)

Tanabe, Makito; Motonaga, Ryoko; Terawaki, Yuichi; Nomiyama, Takashi; Yanase, Toshihiko

2017-03-01

In treatment algorithms of type 2 diabetes mellitus in Western countries, biguanides are recommended as first-line agents. In Japan, various oral hypoglycemic agents (OHAs) are available, but prescription patterns are unclear. Data of 7,108 and 2,655 type 2 diabetes mellitus patients in study 1 and study 2, respectively, were extracted from the Medical Data Vision database (2008-2013). Cardiovascular disease history was not considered in study 1, but was in study 2. Initial choice of OHA, adherence to its use, effect on glycated hemoglobin levels for 2 years and the second choice of OHA were investigated. In study 1, α-glucosidase inhibitor, glinide and thiazolidinedione were preferentially medicated in relatively lower glycated hemoglobin cases compared with other OHAs. The two most prevalent first prescriptions of OHAs were biguanides and dipeptidyl peptidase-4 inhibitors, and the greatest adherence was for α-glucosidase inhibitors. In patients treated continuously with a single OHA for 2 years, improvement in glycated hemoglobin levels was greatest for dipeptidyl peptidase-4 inhibitors. As a second OHA added to the first OHA during the first 2 years, dipeptidyl peptidase-4 inhibitors were chosen most often, especially if a biguanide was the first OHA. In study 2, targeting patients with a cardiovascular disease history, a similar tendency to study 1 was observed in the first choice of OHA, adherence and the second choice of OHA. Even in Japanese type 2 diabetes mellitus patients, a Western algorithm seems to be respected to some degree. The OHA choice does not seem to be affected by a cardiovascular disease history. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Intracellular Delivery of siRNA by Polycationic Superparamagnetic Nanoparticles

Directory of Open Access Journals (Sweden)

Betzaida Castillo

2012-01-01

Full Text Available The siRNA transfection efficiency of nanoparticles (NPs, composed of a superparamagnetic iron oxide core modified with polycationic polymers (poly(hexamethylene biguanide or branched polyethyleneimine, were studied in CHO-K1 and HeLa cell lines. Both NPs demonstrated to be good siRNA transfection vehicles, but unmodified branched polyethyleneimine (25 kD was superior on both cell lines. However, application of an external magnetic field during transfection (magnetofection increased the efficiency of the superparamagnetic NPs. Furthermore, our results reveal that these NPs are less toxic towards CHO-K1 cell lines than the unmodified polycationic-branched polyethyleneimine (PEI. In general, the external magnetic field did not alter the cell’s viability nor it disrupted the cell membranes, except for the poly(hexamethylene biguanide-modified NP, where it was observed that in CHO-K1 cells application of the external magnetic field promoted membrane damage. This paper presents new polycationic superparamagnetic NPs as promising transfection vehicles for siRNA and demonstrates the advantages of magnetofection.

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.

Modelling of the Blood Plasma Species of Biguanide Derivatives ...

African Journals Online (AJOL)

NJD

99mTc-DMSA.5 According to the literature, 99mTc-BIG has promising practical and ..... data points approach a ZH value of 3 at lower pH values, con- firming that there .... In Mg(II)-ITB, the MLOH species are formed, where the pro- ton is lost ...

Evaluation of sanitizers efficiency over spore forming bacteria isolated from whole UHT milk

Directory of Open Access Journals (Sweden)

Edite Andrade Costa

2017-03-01

Full Text Available It is known that sporulated bacteria produce proteolytic and lipolytic thermoresistant enzymes associated with technological problems such as off-flavors, age gelation and bitter taste in milk and dairy products. Preventive measures to avoid contamination of milk must be taken in consideration, e.g., the employment of a certain type of sanitizing agent, its conditions of use, concentration, contact time and temperature. The aim of this work was to evaluate the sanitation efficiency of workers of the dairy industry in relation to sporulated bacteria isolated from UHT milk. The suspension test was used to evaluate the efficiency of solutions of sodium hypocholite, biguanide, peracetic acid and hydrogen peroxide against 18 strains of Bacillus sp. isolated from whole UHT milk. Although the biguanide resulted in significant decimal reduction, none of the sanitizing agents studied was effective under the evaluated conditions. The average decimal reduction values obtained were below 5 log cycles (99.999%. The effectiveness of the sanitizing agent is a primary factor in order to control the contaminations within the dairy industry. Thus, it is essential to define the ideal conditions of use of these agents.

Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis.

Directory of Open Access Journals (Sweden)

Takla Griss

2015-12-01

Full Text Available Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth through its actions on complex I of the mitochondrial electron transport chain (ETC. However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial-dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity.

Antimicrobial efficacy assessment of multi-use solution to disinfect hydrophilic contact lens, in vitro

OpenAIRE

Lui,Aline Cristina Fioravanti; Netto,Adamo Lui; Silva,Cely Barreto da; Hida,Richard; Mendes,Thais Sousa; Lui,Giovana Arlene Fioravanti; Gemperli,Daniela Barbosa; Vital,Enderson Dantas

2009-01-01

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)...

Avaliação da ação antimicrobiana de soluções multiuso para desinfecção de lentes de contato hidrofílicas, in vitro

OpenAIRE

Lui, Aline Cristina Fioravanti; Netto, Adamo Lui; Silva, Cely Barreto da; Hida, Richard; Mendes, Thais Sousa; Lui, Giovana Arlene Fioravanti; Gemperli, Daniela Barbosa; Vital, Enderson Dantas

2009-01-01

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)...

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.

METFORMIN: A REVIEW OF THE LITERATURE

OpenAIRE

Rodrigues Neto, Edilson Martins; Universidade Federal do Ceará- Dep Fisiologia e Farmacologia/ Faculdade Católica Rainha do Sertão; Marques, Lidia Audrey Rocha Valadas; Universidade Federal do Ceará - Dep Clínica Odontológica; Ferreira, Maria Augusta Drago; Universidade Federal do Ceará - Dep Farmácia; Lobo, Patricia Leal Dantas; Universidade Federal do Ceará- Curso de Odontologia Campus Sobral; Girão Junior, Francisco Josimar; Faculdade Católica Rainha do Sertão; Camarão, Gisela Costa; Universidade Federal do Ceará- Dep. Fisiologia e Farmacologia; Moraes, Maria Elisabete Amaral de; Universidade Federal do Ceará- Dep. Fisiologia e Farmacologia

2015-01-01

Metformin, commercialized under several trademarks and also as a generic medicine, is an oral anti-diabetic drug, belonging to the biguanide class. It is actually the first choice in the treatment of Type 2 diabetes mellitus (DM2) due to its toxicity and clinical efficaciousness. It extensive use requires a constant discussion on its characteristics and applications. Current paper is a bibliographical review comprising the application of metformin in DM2 treatment as its chemical, physical-ch...

Polycystic ovary syndrome and metformin in pregnancy

DEFF Research Database (Denmark)

Lilja, Anna E; Mathiesen, Elisabeth R

2006-01-01

UNLABELLED: The diagnostic criteria of polycystic ovary syndrome incorporate hyperandrogenism, polycystic ovaries, anovulation and irregular menstrual bleeding and the syndrome is a recognized reason behind infertility. The biguanide metformin has encouraging effects on several metabolic aspects...... of the syndrome, including insulin sensitivity, plasma glucose concentration and lipid profile. Moreover, metformin improves the ovarian function in women diagnosed with polycystic ovary syndrome. Hence, metformin is considered an agent for ovulation induction among these patients. However, even higher ovulation...

Metformin selectively targets redox control of complex I energy transduction

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Amy R. Cameron

2018-04-01

Full Text Available Many guanide-containing drugs are antihyperglycaemic but most exhibit toxicity, to the extent that only the biguanide metformin has enjoyed sustained clinical use. Here, we have isolated unique mitochondrial redox control properties of metformin that are likely to account for this difference. In primary hepatocytes and H4IIE hepatoma cells we found that antihyperglycaemic diguanides DG5-DG10 and the biguanide phenformin were up to 1000-fold more potent than metformin on cell signalling responses, gluconeogenic promoter expression and hepatocyte glucose production. Each drug inhibited cellular oxygen consumption similarly but there were marked differences in other respects. All diguanides and phenformin but not metformin inhibited NADH oxidation in submitochondrial particles, indicative of complex I inhibition, which also corresponded closely with dehydrogenase activity in living cells measured by WST-1. Consistent with these findings, in isolated mitochondria, DG8 but not metformin caused the NADH/NAD+ couple to become more reduced over time and mitochondrial deterioration ensued, suggesting direct inhibition of complex I and mitochondrial toxicity of DG8. In contrast, metformin exerted a selective oxidation of the mitochondrial NADH/NAD+ couple, without triggering mitochondrial deterioration. Together, our results suggest that metformin suppresses energy transduction by selectively inducing a state in complex I where redox and proton transfer domains are no longer efficiently coupled. Keywords: Diabetes, Metformin, Mitochondria, NADH, NAD+

Pharmacogenetics of Anti-Diabetes Drugs

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Johanna K. DiStefano

2010-08-01

Full Text Available A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D. In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs, meglitinides, α-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4 inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of ‘response’ can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for “individualized medicine” for patients with T2D.

The antimicrobial polymer PHMB enters cells and selectively condenses bacterial chromosomes

DEFF Research Database (Denmark)

Chindera, Kantaraja; Mahato, Manohar; Sharma, Ashwani Kumar

2016-01-01

To combat infection and antimicrobial resistance, it is helpful to elucidate drug mechanism(s) of action. Here we examined how the widely used antimicrobial polyhexamethylene biguanide (PHMB) kills bacteria selectively over host cells. Contrary to the accepted model of microbial membrane disrupti...... to bacterial and mammalian cellular DNA and selectively binds and condenses bacterial chromosomes. Because acquired resistance to PHMB has not been reported, selective chromosome condensation provides an unanticipated paradigm for antimicrobial action that may not succumb to resistance....

Time survivor study of Escherichia coli with polyhexamethylene biguanide on cotton

NARCIS (Netherlands)

Amrit, Usha Rashmi Bhaskara; Hendrix, Ron; Dutschk, Victoria; Warmoeskerken, Marijn

2013-01-01

Time survivor or time kill studies are commonly used to investigate the efficacy of antimicrobial agents in homogeneous solutions. Such a study was attempted via a textile treated with an antimicrobial agent. For this study, a finished undyed cotton fabric and a commercially available antimicrobial

Renoprotective effects of metformin.

Science.gov (United States)

Nasri, Running Hamid

2013-05-16

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.

Review on the efficacy, safety and clinical applications of polihexanide, a modern wound antiseptic.

Science.gov (United States)

Hübner, N-O; Kramer, A

2010-01-01

Infected wounds are still one of the great challenges in medicine. In the last decade, it has become increasingly clear that antimicrobial chemotherapy is limited by the spread of antimicrobial resistance. Fortunately, new, highly effective antiseptic substances with a broad antimicrobial spectrum are available, so local treatment is expected to get increasingly more important in wound therapy. This paper reviews the antiseptic agent polihexanide (polyhexamethylene biguanide, PHMB), one of the most promising substances available today, from a clinical point of view, focusing on efficacy, safety and clinical applications. Copyright © 2010 S. Karger AG, Basel.

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

[Trichological examinations in women suffering from diabetes mellitus].

Science.gov (United States)

Brzezińska-Wcisło, L; Bogdanowski, T; Koślacz, E; Hawrot, A

2000-01-01

The lack of data on the process of alopecia in women suffering from diabetes mellitus made us undertake research in this area. The aim of this paper was the assessment of the state of head hair in trichological and clinical examinations, and on the basis of questionnaire. 50 women (age 44-82 years) were included in the study. Alopecia in women with diabetes mellitus is diffuse, located on the apex of the head and basic hair loss lies in telogenic pathomechanism. The highest percentage of telogenic hair is found in women treated with biguanides, and the lowest one in female patients taking insulin.

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

Long-term safety and efficacy of a novel once-weekly oral trelagliptin as monotherapy or in combination with an existing oral antidiabetic drug in patients with type 2 diabetes mellitus: A 52-week open-label, phase 3 study.

Science.gov (United States)

Inagaki, Nobuya; Sano, Hiroki; Seki, Yoshifumi; Kuroda, Shingo; Kaku, Kohei

2016-09-01

Trelagliptin is a novel once-weekly oral dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus that was first approved in Japan. We evaluated long-term safety and efficacy of trelagliptin in Japanese patients with type 2 diabetes mellitus. This was a phase 3, multicenter, open-label study to evaluate long-term safety and efficacy of trelagliptin. Patients with type 2 diabetes mellitus inadequately controlled despite diet/exercise or treatment with one of the existing oral antidiabetic drugs along with diet/exercise received trelagliptin 100 mg orally once weekly for 52 weeks as monotherapy or combination therapies. The primary end-points were the safety variables, and the secondary end-points were glycosylated hemoglobin and fasting plasma glucose. A total of 680 patients received the following antidiabetic therapies: trelagliptin monotherapy (n = 248), combination with a sulfonylurea (n = 158), a glinide (n = 67), an α-glucosidase inhibitor (n = 65), a biguanide (n = 70), or a thiazolidinedione (n = 72). During the study, 79.8% of the patients experienced at least one adverse event for monotherapy, 87.3% for combination with a sulfonylurea, 77.6% for a glinide, 81.5% for an α-glucosidase inhibitor, 64.3% for a biguanide, and 84.7% for a thiazolidinedione, respectively. Most of the adverse events were mild or moderate. The change in glycosylated hemoglobin from baseline at the end of the treatment period was -0.74 to -0.25% for each therapy. Once-weekly oral trelagliptin provides well-tolerated long-term safety and efficacy in both monotherapy and combination therapies in Japanese patients with type 2 diabetes mellitus. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Risk of cardiovascular disease

DEFF Research Database (Denmark)

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

2014-01-01

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...

Effect of hypolipidemic drugs on basal and stimulated adenylate cyclase activity in tumor cells

International Nuclear Information System (INIS)

Bershtein, L.M.; Kovaleva, I.G.; Rozenberg, O.A.

1986-01-01

This paper studies adenylate cyclase acticvity in Ehrlich's ascites carcinoma (EAC) cells during administration of drugs with a hypolipidemic action. Seven to eight days before they were killed, male mice ingested the antidiabetic biguanide phenformin, and the phospholipid-containing preparation Essentiale in drinking water. The cAMP formed was isolated by chromatography on Silufol plates after incubation of the enzyme preparation with tritium-ATP, or was determined by the competitive binding method with protein. It is shown that despite the possible differences in the concrete mechanism of action of the hypolipidemic agents chosen for study on the cyclase system, the use of such agents, offers definite prospects for oriented modification of the hormone sensitivity of tumor cells

Characterizing clinical isolates of Acanthamoeba castellanii with high resistance to polyhexamethylene biguanide in Taiwan

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Fu-Chin Huang

2017-10-01

Conclusion: Our results confirm the existence of clinical isolates of A. castellanii with high resistance to PHMB in Taiwan and present the alternative drug tolerance of A. castellanii in addition to the transformation of pseudocyst/cyst.

Extreme Basicity of Biguanide Drugs in Aqueous Solutions: Ion Transfer Voltammetry and DFT Calculations

Czech Academy of Sciences Publication Activity Database

Langmaier, Jan; Pižl, Martin; Samec, Zdeněk; Záliš, Stanislav

2016-01-01

Roč. 120, č. 37 (2016), s. 7344-7350 ISSN 1089-5639 R&D Projects: GA ČR(CZ) GA15-03139S Institutional support: RVO:61388955 Keywords : voltammetry * Alkalinity * Complexation Subject RIV: CG - Electrochemistry Impact factor: 2.847, year: 2016

Synthesis of dimethyl-1,1 guanylguanidine-{sup 14}C-2,4 (dimethyl-1-1 biguanide) hydrochloride; Synthese du chlorhydrate de dimethyl-1,1 guanylguanidine {sup 14}C-2,4 (dimethyl-1-1 biguanide)

Energy Technology Data Exchange (ETDEWEB)

Herbert, M; Pichat, L [Commissariat a l' Energie Atomique, Saclay (France).Centre d' Etudes Nucleaires

1961-07-01

A description of the synthesis of dimethyl-1,1 guanylguanidine-{sup 14}C-2,4 hydrochloride passing through the {sup 14}C{sub 2} dicyandiamide. The overall yield with respect to Ba{sup 14}CO{sub 3} is 38 per cent. (author) [French] Description de la synthese du chlorhydrate de dimethyl-1,1 guanylguanidine {sup 14}C-2,4 par l'intermediaire de la dicyandiamide {sup 14}C{sub 2}. Le rendement global par rapport a {sup 14}CO{sub 3}Ba est de 38 pour cent. (auteur)

Mechanisms involved in metformin action in the treatment of polycystic ovary syndrome.

Science.gov (United States)

Motta, A B

2009-01-01

The N, N' dimethyl-biguanide : Metformin is an antidiabetic drug that increases glucose utilization in insulin-sensitive tissues. As Polycystic Ovary Syndrome (PCOS) and diabetes share some altered parameters-such as abnormal glucose: insulin ratio, altered lipidic metabolism and insulin-resistance syndrome- the use of metformin has become increasingly accepted and widespread in the treatment of PCOS. Currently, metformin is used to induce ovulation and during early pregnancy in PCOS patients, however, a complete knowledge of the metformin action has not been achieved yet. This review describes beyond the classical reproductive action of metformin and explores other benefits of the drug. In addition, the present work discusses the molecular mechanisms involved further than the classical pathway that involves the AMP-activated protein kinase.

OBESITY AS A RISK FACTOR FOR NON-ALCOHOLIC FATTY LIVER DISEASE

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O. A. Pavlenko

2015-01-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is a highly prevalent disorder associated with obesity and metabolic syndrome. The main pathophysiological factor of liver steatosis is insulin resistance that may lead to development of type 2 diabetes mellitus. Overcoming of insulin resistance by means of body weight reduction and administration of insulin sensitizers is considered to be a promising approach to NAFLD treatment. In accordance with the Russian guidelines on diagnostics and treatment of NAFLD, sibutramine is the drug of choice for medical treatment of obesity. As for insulin sensitizers, metformin (biguanide class is widely used for treatment of NAFLD in everyday clinical practice. Treatment of NAFLD as a component of metabolic syndrome should be multifactorial and aimed at different aspects of the disease pathophysiology. 

Cobalamin Deficiency in Elderly Patients: A Personal View

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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.

Metformin: A Hopeful Promise in Aging Research

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

2016-01-01

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

Effect of Luffa aegyptiaca (seeds) and Carissa edulis (leaves) extracts on blood glucose level of normal and streptozotocin diabetic rats.

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El-Fiky, F K; Abou-Karam, M A; Afify, E A

1996-01-01

The present study investigates the effect of oral administration of the ethanolic extracts of Luffa aegyptiaca (seeds) and Carissa edulis (leaves) on blood glucose levels both in normal and streptozotocin (STZ) diabetic rats. Treatment with both extracts significantly reduced the blood glucose level in STZ diabetic rats during the first three hours of treatment. L. aegyptiaca extract decreased blood glucose level with a potency similar to that of the biguanide, metformin. The total glycaemic areas were 589.61 +/- 45.62 mg/dl/3 h and 660.38 +/- 64.44 mg/dl/3 h for L. aegyptiaca and metformin, respectively, vs. 816.73 +/- 43.21 mg/dl/3 h for the control (P < 0.05). On the other hand, in normal rats, both treatments produced insignificant changes in blood glucose levels compared to glibenclamide treatment.

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 - others: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

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

Phosphorus and Calcium Metabolism in Postmenopausal Women with Diabetes Mellitus: Effects of the Type and Duration of the Disease, Time of Menopause and Body Mass

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M.L. Kyryliuk

2016-02-01

Full Text Available The article deals with the impact of diabetes mellitus (DM on the phosphorus and calcium metabolism in postmenopausal women, depending on the type and duration of the disease, duration of menopause, body mass and type of hypoglycemic therapy. The state of phosphorus and calcium metabolism in 86 women with type 1 DM (13 patients and type 2 DM (73 patients was studied. In all patients, the concentration of calcium and phosphorus in the blood was within normal limits. It was found that the concentration of ionized calcium, total calcium and inorganic phosphorus in the blood can not be the main criterion for the state of bone mineral density in postmenopausal women with DM. Sulfonylureas and insulin in combination with biguanides have no effect on the status of phosphorus and calcium metabolism in postmenopausal women with type 2 DM.

Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus

DEFF Research Database (Denmark)

Hermansen, Kjeld; Mortensen, Lene S

2007-01-01

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

Computational chemistry and metal-based radiopharmaceuticals

International Nuclear Information System (INIS)

Neves, M.; Fausto, R.

1998-01-01

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)

Gestational Diabetes Mellitus Management with Oral Hypoglycemic Agents

Science.gov (United States)

Ryu, Rachel J.; Hays, Karen E.; Hebert, Mary F.

2014-01-01

Oral hypoglycemic agents such as glyburide (second generation sulfonylurea) and metformin (biguanide) are attractive alternatives to insulin due to lower cost, ease of administration, and better patient adherence. The majority of evidence from retrospective and prospective studies suggests comparable efficacy and safety of oral hypoglycemic agents such as glyburide and metformin as compared to insulin when used in the treatment of women with gestational diabetes mellitus (GDM). Glyburide and metformin have altered pharmacokinetics during pregnancy and both agents cross the placenta. In this article, we review the efficacy, safety and dosage of oral hypoglycemic agents for the treatment of gestational diabetes mellitus. Additional research is needed to evaluate optimal dosage for glyburide and metformin during pregnancy. Comparative studies evaluating the effects of glyburide and metformin on long-term maternal and fetal outcomes are also needed. PMID:25315294

Antimocrobial Polymer

Science.gov (United States)

McDonald, William F.; Huang, Zhi-Heng; Wright, Stacy C.

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.

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

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.

The lysosome among targets of metformin: new anti-inflammatory uses for an old drug?

Science.gov (United States)

Lockwood, Thomas D

2010-05-01

Rheumatoid arthritis and type-2 diabetes exhibit progressive co-morbidity. Chloroquine (CQ) reportedly improves both. CQ inhibits lysosomal function in cultured cells at supra-therapeutic concentration; however, this is doubted as target mechanism. Some anti-diabetic biguanides are metal-interactive lysosomal inhibitors; and all bind Zn(2+). i) To bioassay the potency of CQ using (3)H-leucine release from perfused myocardial tissue. ii) To determine whether metformin (MET) is CQ-mimetic, and interactive with Zn(2+). Therapeutic CQ concentration (0.1 - 0.5 microM) clearly does cause lysosomal inhibition although delayed and submaximal. MET alone (10 microM) caused sub-maximal inhibition. Supra-physiological extracellular Zn(2+) (5 - 50 microM) alone increased tissue Zn(2+) content, and inhibited lysosomal proteolysis. Physiological equivalent Zn(2+) (approximately 1 microM) had no effect. MET (use as an anti-inflammatory agent are suggested. Guanidylguanidine is a practical pharmacophore for synthesis of future anti-lysosomal agents.

CLINICAL FEATURES, DIAGNOSIS, THE RESULTS OF THERAPEUTIC AND SURGICAL TREATMENT OF ACANTHAMOEBIC KERATITIS

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Evg. A. Kasparova

2017-01-01

Full Text Available Purpose: to describe our experience in Acanthamoeba keratitis diagnostics and treatment in the FGBNU Research Institute of eye diseases, Moscow.Patients and Methods. We observed 24 patients (25 eyes with the Acanthamoeba keratitis (AK. The age ranged from 18 to 47 years. All patients, except one, were contact lenses wearers. Clinical signs included superficial epithelial-stromal lesions in 8 patients (8 eyes, stromal forms of AK- in 16 patients (17 eyes, and mixed keratitis in 9 (9 eyes. We used confocal microscopy, conjunctival smearing and blood immunofluorescent analysis for HSV types I and II. 8 patients (8 eyes underwent penetrating keratoplasty (PKP and their corneal buttons were morphologically examined. AK treatment included 2 biguanid antiseptics — a PHMB ("Comfort-drops" — solution for contact lenses care and 0.025% solution of a chlorhexidini bigluconati, or "Vitabact" in frequent instillations. We also used Diflucan solution 0.2% instillations — 6–8 times a day in, and Orungal or Diflucan per os (200 mg once a day. Eye drops of aminoglycozide or fluorhinolon groups were added to the treatment as well. In the cases of mixed Acanthamoeba and HSV keratitis we used anti-herpetic medications (Poludan, Acyclovir.Results. Cysts were found with confocal microscopy in 66% examined patients, and in 75% of the corneal buttons after keratoplasty. 15 cases (60% healed with various intensity opacities. We removed corneal epithelium in 2 patients with poor effect of the medication treatment. 8 patients (8 eyes underwent PKP with transparent (2 patients and a semi-transparent engraftment (2 patients, in 4 cases (4 eyes AK recurrences had occurred, what required repeated surgery. Long persistence of Acanthamoeba cysts in the cornea after clinical recovery caused the admission of 2 antiseptic biguanids eye drops for 6–20 months in all patients. There were no recurrences in the group of patients during the observation period (range 1 to 6

Drug-class-specific changes in the volume and cost of antidiabetic medications in Poland between 2012 and 2015.

Science.gov (United States)

Śliwczyński, Andrzej; Brzozowska, Melania; Jacyna, Andrzej; Iltchev, Petre; Iwańczuk, Tymoteusz; Wierzba, Waldemar; Marczak, Michał; Orlewska, Katarzyna; Szymański, Piotr; Orlewska, Ewa

2017-01-01

to investigate the drug-class-specific changes in the volume and cost of antidiabetic medications in Poland in 2012-2015. This retrospective analysis was conducted based on the National Health Fund database covering an entire Polish population. The volume of antidiabetic medications is reported according to ATC/DDD methodology, costs-in current international dollars, based on purchasing power parity. During a 4-year observational period the number of patients, consumption of antidiabetic drugs and costs increased by 17%, 21% and 20%, respectively. Biguanides are the basic diabetes medication with a 39% market share. The insulin market is still dominated by human insulins, new antidiabetics (incretins, thiazolidinediones) are practically absent. Insulins had the largest share in diabetes medications expenditures (67% in 2015). The increase in antidiabetic medications costs over the analysed period of time was mainly caused by the increased use of insulin analogues. The observed tendencies correspond to the evidence-based HTA recommendations. The reimbursement status, the ratio of cost to clinical outcomes and data on the long-term safety have a deciding impact on how a drug is used.

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.

Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism.

Science.gov (United States)

Cuyàs, E; Fernández-Arroyo, S; Verdura, S; García, R Á-F; Stursa, J; Werner, L; Blanco-González, E; Montes-Bayón, M; Joven, J; Viollet, B; Neuzil, J; Menendez, J A

2018-02-15

The anti-diabetic biguanide metformin may exert health-promoting effects via metabolic regulation of the epigenome. Here we show that metformin promotes global DNA methylation in non-cancerous, cancer-prone and metastatic cancer cells by decreasing S-adenosylhomocysteine (SAH), a strong feedback inhibitor of S-adenosylmethionine (SAM)-dependent DNA methyltransferases, while promoting the accumulation of SAM, the universal methyl donor for cellular methylation. Using metformin and a mitochondria/complex I (mCI)-targeted analog of metformin (norMitoMet) in experimental pairs of wild-type and AMP-activated protein kinase (AMPK)-, serine hydroxymethyltransferase 2 (SHMT2)- and mCI-null cells, we provide evidence that metformin increases the SAM:SAH ratio-related methylation capacity by targeting the coupling between serine mitochondrial one-carbon flux and CI activity. By increasing the contribution of one-carbon units to the SAM from folate stores while decreasing SAH in response to AMPK-sensed energetic crisis, metformin can operate as a metabolo-epigenetic regulator capable of reprogramming one of the key conduits linking cellular metabolism to the DNA methylation machinery.

Visual outcome in Japanese patients with Acanthamoeba keratitis.

Science.gov (United States)

Yamazoe, K; Yamamoto, Y; Shimazaki-Den, S; Shimazaki, J

2012-04-01

To identify prognostic factors affecting visual outcome in Acanthamoeba keratitis (AK) treated with topical chlorhexidine gluconate (CHG). A total of 35 eyes in 34 patients with AK were treated with 0.02% topical CHG. Patients were divided into two groups according to the final visual outcome: Group 1, final visual acuity (VA) of 20/25 or greater (22 eyes); Group 2, less than 20/25 (13 eyes). We compared these groups and evaluated the effectiveness of topical CHG compared with outcomes in previous reports. Ring infiltrate was observed more often in Group 2 (4.5% vs 61.5%, OR 33.6, 95% confidence interval (CI) 3.4-333.9, PAK was significantly longer (24.9 days vs 48.4 days, OR 1.03, 95% CI 1.00-1.06, P = 0.04) and VA at initial examination (log MAR) significantly lower (0.47 vs 1.59, OR 25.5, 95% CI 3.4-186.7, PAK. Topical CHG was comparably effective to other treatments, including polyhexamethyl biguanide and propamidine isethionate.

Obesity, insulin resistance, and type 1 diabetes mellitus.

Science.gov (United States)

Polsky, Sarit; Ellis, Samuel L

2015-08-01

To summarize recent studies about obesity, insulin resistance, and type 1 diabetes mellitus (T1DM). Overweight and obesity continue to be prevalent among individuals with T1DM. Obesity rates appear to have reached a plateau among children with T1DM in some parts of the world. The risk for development of T1DM is increased by obesity and may occur at an earlier age among obese individuals with a predisposition. Obesity increases the risk for comorbidities among individuals with T1DM, especially metabolic syndrome, and microvascular and macrovascular diseases. Metformin, glucagon-like peptide-1 agonist therapy, sodium glucose cotransporter-2 inhibitor therapy, and bariatric surgery may be beneficial therapies for glucose control, comorbidity management, and obesity among adults with T1DM. Insulin resistance may be improved among obese individuals with T1DM by biguanides (metformin) and glucagon-like peptide-1 agonists (exenatide). We review the last 18 months of literature on obesity, insulin resistance, and T1DM to highlight new epidemiologic results and treatments.

A review of pioglitazone HCL and glimepiride in the treatment of type 2 diabetes.

Science.gov (United States)

Dorkhan, Mozhgan; Frid, Anders

2007-01-01

Type 2 diabetes (T2D) is a progressive disorder with a consistent and steady increase in glycosylated hemoglobin (HbA1c) over time associated with enhanced risk of micro- and macrovascular complications and a substantial reduction in life expectancy. There are three major pathophysiologic abnormalities associated with T2D: impaired insulin secretion, excessive hepatic glucose output, and insulin resistance in skeletal muscle, liver, and adipose tissue. These defects have been treated in clinical praxis by use of oral insulin secretagogues (sulfonylureas/ glinides) or insulin, biguanides, and thiazolidinediones (TZDs) respectively. Pioglitazone HCL is an insulin sensitizer in the TZD family and glimepiride is an insulin secretagogue in the SU family. This article reviews mechanisms of action and clinical data behind the use of these two commonly used oral hypoglycemic agents with documented efficacy and good safety profile of once-daily administration, alone or in combination with insulin or metformin, in the management of T2D in terms of glycemic and non-glycemic effects, tolerability and side effects, and impact on vascular health.

Utilization study of antidiabetic agents in a teaching hospital of Sikkim and adherence to current standard treatment guidelines.

Science.gov (United States)

Satpathy, Sushrut Varun; Datta, Supratim; Upreti, Binu

2016-01-01

Diabetes has gradually emerged as one of the most serious public health problems in our country. This underlines the need for timely disease detection and decisive therapeutic intervention. This prospective cross-sectional observational study aims at analyzing the utilization pattern of antidiabetic agents in a remote North-East Indian tertiary care teaching hospital in the perspective of current standard treatment guidelines. Diabetic patients receiving antidiabetic medication, both as outpatients and inpatients in our hospital over a period of 12 months (May 2013-May 2014), were included in this study. The data obtained were sorted and analyzed on the basis of gender, type of therapy, and hospital setting. A total of 310 patients were included in the study. Metformin was the single most frequently prescribed antidiabetic agent (66.8%) followed by the sulfonylureas group (37.4%). Insulin was prescribed in 23.2% of the patients. Combination antidiabetic drug therapy (65.1%) was used more frequently than monotherapy (34.8%). The use of biguanides (P standard treatment guidelines. Increased use of generic drugs is an area with scope for improvement.

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.

Directory of Open Access Journals (Sweden)

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.

High Pressure Laminates with Antimicrobial Properties

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Sandra Magina

2016-02-01

Full Text Available High-pressure laminates (HPLs are durable, resistant to environmental effects and good cost-benefit decorative surface composite materials with special properties tailored to meet market demand. In the present work, polyhexamethylene biguanide (PHMB was incorporated for the first time into melamine-formaldehyde resin (MF matrix on the outer layer of HPLs to provide them antimicrobial properties. Chemical binding of PHMB to resin matrix was detected on the surface of produced HPLs by attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR. Antimicrobial evaluation tests were carried out on the ensuing HPLs doped with PHMB against gram-positive Listeria innocua and gram-negative Escherichia coli bacteria. The results revealed that laminates prepared with 1.0 wt % PHMB in MF resin were bacteriostatic (i.e., inhibited the growth of microorganisms, whereas those prepared with 2.4 wt % PHMB in MF resin exhibited bactericidal activity (i.e., inactivated the inoculated microorganisms. The results herein reported disclose a promising strategy for the production of HPLs with antimicrobial activity without affecting basic intrinsic quality parameters of composite material.

[Mechanism of action of insulin sensitizer agents in the treatment of polycystic ovarian syndrome].

Science.gov (United States)

Galindo García, Carlos G; Vega Arias, Maria de Jesús; Hernández Marín, Imelda; Ayala, Aquiles R

2007-03-01

Polycystic ovarian disease (PCOD) is the most important endocrine abnormality that affects women in reproductive age. It is characterized by chronic anovulation and hyperandrogenemia probably secondary to insulin resistance. Hence insulin sensitizers agents had been used in PCOD. Metformin is a biguanide used in the treatment of PCOD via decrease of hepatic gluconeogenesis and insulinemia; improvement peripheral glucose utilization, oxidative glucose metabolism, nonoxidative glucose metabolism and intracellular glucose transport. Such effects, when this drug is administered alone during 3 to 6 months, increase sex hormone binding globulin (SHBG), reduce free androgens index and hirsutism, decrease insulin resistance, and regulate menses in 60 to 70% of cases. Thiazolidinodiones are drugs that decrease insulin resistance in the liver with hepatic glucose production. Their mechanism of action is through the peroxisome proliferator-activated receptors gamma (PPAR-gamma), that help to decrease plasmatic concentrations of free fatty acids, pre and postprandial glucose, insulin, triglycerides, increased HDL cholesterol and decreased LDL, menses return to normality, with improvement of ovulation and decreased hirsutism. It seems that by modulation and attenuation of insulin resistance, hypoglucemic agents such as metfomin and thiazolidinodiones can be used effectively to treat anovulation, infertility and hyperandrogenemia.

Antimicrobial activity of different disinfectants against cariogenic microorganisms

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Esra UZER CELIK

Full Text Available Abstract The aim of this study was to assess the in vitro antimicrobial effects of chlorhexidine digluconate (CHX, polyhexamethylene biguanide (PHBM, and octenidine dihydrochloride (OCT on cariogenic microorganisms by using their minimum inhibitory concentration (MIC and minimum bactericidal concentration (MBC. CHX, PHBM, and OCT were diluted in distilled water to the final test concentrations. Using the in-tube dilution method, Streptococcus mutans, Lactobacillus acidophilus, Lactobacillus rhamnosus, and Actinomyces viscosus were cultivated on blood agar and Mueller–Hinton broth (MHB at 37°C for 48 h. They were read using a spectrophotometer to detect MIC. To determine MBC, samples in the range of the turbidity threshold after 24 h were transferred onto blood agar and evaluated for growth after 24 h. Different MICs and MBCs were observed in all disinfectants against each microorganism. The lowest MIC and MBC against S. mutans (60 mg/L were obtained from PHBM. The lowest values against L. rhamnosus (15 mg/L, 30 mg/L, A. viscosus (30 mg/L, and L. acidophilus (15 mg/L, 30 mg/L were determined by OCT. PHBM and OCT have the potential to be replaced with CHX because they were effective against cariogenic microorganisms.

Vildagliptin , a DPP-4 inhibitor for the twice-daily treatment of type 2 diabetes mellitus with or without metformin.

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Forst, Thomas; Bramlage, Peter

2014-06-01

Dipeptidyl peptidase-4 inhibitors increase circulating levels of glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide regulating glucose-dependent insulin secretion. In addition, GLP-1 suppresses glucagon secretion, delays gastric emptying and increases satiety. The combination of vildagliptin with the biguanide metformin is of particular interest because of its complementary mode of action, addressing insulin resistance, alpha- and beta cell function in the islet of the pancreas. Because of the abundance of data supporting the use of vildagliptin alone and in combination with metformin, the present paper aims at giving an overview on the current evidence for its use in patients with type 2 diabetes mellitus. The data suggest that vildagliptin offers similar glycemic control compared to sulfonylureas and thiazolidinediones, while having the benefit of being associated with fewer cases of hypoglycemia and less body weight gain. There is increasing evidence that compared with sulfonylureas, vildagliptin has favorable effects on pancreatic alpha- and beta-cell function. Vildagliptin in combination with metformin, improve glycemic control with a favorable safety and tolerability profile, making it an attractive therapeutic option in patients where metformin monotherapy alone is not sufficient.

Simultaneous measurement of proguanil and its metabolites in human plasma and urine by reversed-phase high-performance liquid chromatography, and its preliminary application in relation to genetically determined S-mephenytoin 4'-hydroxylation status.

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Kusaka, M; Setiabudy, R; Chiba, K; Ishizaki, T

1996-02-01

A simple high-performance liquid chromatographic (HPLC) assay method was developed for the measurement of proguanil (PG) and its major metabolites, cycloguanil (CG) and 4-chlorophenyl-biguanide (CPB), in human plasma and urine. The assay allowed the simultaneous determination of all analytes in 1 ml of plasma or 0.1 ml of urine. The detection limits of PG, CG, and CPB, defined as the signal-to-noise ratio of 3, were 1 and 5 ng/ml for plasma and urine samples, respectively. Recoveries of the analytes and the internal standard (pyrimethamine) were > 62% from plasma and > 77% from urine. Intra-assay and interassay coefficients of variation for all analytes in plasma and urine were CG and CPB, which ranged from 10% to 15% at one or two concentrations among 4-5 concentrations studied. The clinical applicability of the method was assessed by the preliminary pharmacokinetic study of PG, CG, and CPB in six healthy volunteers with the individually known phenotypes (extensive and poor metabolizers) of S-mephenytoin 4'-hydroxylation, suggesting that individuals with a poor metabolizer phenotype of S-mephenytoin have a much lower capacity to bioactivate PG to CG compared with the extensive metabolizers.

Metformin in cancer.

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Mallik, Ritwika; Chowdhury, Tahseen A

2018-05-26

Metformin is a lipophilic biguanide which inhibits hepatic gluconeogenesis and improves peripheral utilization of glucose. It is the first line pharmacotherapy for glucose control in patients with Type 2 diabetes due to its safety, efficacy and tolerability. Metformin exhibits pleotropic effects, which may have beneficial effects on a variety of tissues independent of glucose control. A potential anti-tumourigenic effect of metformin may be mediated by its role in activating AMP-kinase, which in turn inhibits mammalian target of rapamycin (mTOR). Non-AMPK dependent protective pathways may include reduction of insulin, insulin-like growth factor-1, leptin, inflammatory pathways and potentiation of adiponectin, all of which may have a role in tumourigenesis. A role in inhibiting cancer stem cells is also postulated. A number of large scale observational and cohort studies suggest metformin is associated with a reduced risk of a number of cancers, although the data is not conclusive. Recent randomised studies reporting use of metformin in treatment of cancer have revealed mixed results, and the results of much larger randomised trials of metformin as an adjuvant therapy in breast and colorectal cancers are awaited. Copyright © 2018 Elsevier B.V. All rights reserved.

Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, and treatment with special focus on oral cobalamin therapy.

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Andrès, Emmanuel; Vidal-Alaball, Josep; Federici, Laure; Loukili, Noureddine Henoun; Zimmer, Jacques; Kaltenbach, Georges

2007-10-01

The aim of this work was to review the literature concerning cobalamin deficiency in elderly patients. Articles were identified through searches of PubMed-MEDLINE (January 1990 to June 2006), restricted to: English and French language, human subjects, elderly patients (>65 years), clinical trial, review and guidelines. Additional unpublished data from our cohort with cobalamin deficiency at the University Hospital of Strasbourg, France, were also considered. All of the papers and abstracts were reviewed by at least two senior researchers who selected the data used in the study. In elderly people, the main causes of cobalamin deficiency are pernicious anemia and food-cobalamin malabsorption. The recently identified food-cobalamin malabsorption syndrome is a disorder characterized by the inability to release cobalamin from food or from its binding proteins. This syndrome is usually the consequence of atrophic gastritis, related or not to Helicobacter pylori infection, and of the long-term ingestion of antacids and biguanides (in around 60% of the patients). Management of cobalamin deficiency has been well established with the use of cobalamin injections. However, new routes of cobalamin administration (oral and nasal) are currently being developed, especially the use of oral cobalamin therapy to treat food-cobalamin malabsorption.

Serotonin-mediated modulation of Na+/K+ pump current in rat hippocampal CA1 pyramidal neurons.

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Zhang, Li Nan; Su, Su Wen; Guo, Fang; Guo, Hui Cai; Shi, Xiao Lu; Li, Wen Ya; Liu, Xu; Wang, Yong Li

2012-01-19

The aim of this study was to investigate whether serotonin (5-hydroxytryptamine, 5-HT) can modulate Na+/K+ pump in rat hippocampal CA1 pyramidal neurons. 5-HT (0.1, 1 mM) showed Na+/K+ pump current (Ip) densities of 0.40 ± 0.04, 0.34 ± 0.03 pA/pF contrast to 0.63 ± 0.04 pA/pF of the control of 0.5 mM strophanthidin (Str), demonstrating 5-HT-induced inhibition of Ip in a dose-dependent manner in hippocampal CA1 pyramidal neurons. The effect was partly attenuated by ondasetron, a 5-HT3 receptor (5-HT3R) antagonist, not by WAY100635, a 5-HT1AR antagonist, while 1-(3-Chlorophenyl) biguanide hydrochloride (m-CPBG), a 5-HT3R specific agonist, mimicked the effect of 5-HT on Ip. 5-HT inhibits neuronal Na+/K+ pump activity via 5-HT3R in rat hippocampal CA1 pyramidal neurons. This discloses novel mechanisms for the function of 5-HT in learning and memory, which may be a useful target to benefit these patients with cognitive disorder.

Method for Bacterial Growth and Ammonia Production and Effect of Inhibitory Substances in Disposable Absorbent Hygiene Products.

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Forsgren-Brusk, Ulla; Yhlen, Birgitta; Blomqvist, Marie; Larsson, Peter

The purpose of this study was to evaluate a pragmatic laboratory method to provide a technique for developing incontinence products better able to reduce malodor when used in the clinical setting. Bacterial growth and bacterially formed ammonia in disposable absorbent incontinence products was measured by adding synthetic urine inoculated with bacteria to test samples cut from the crotch area of the product. The inhibitory effect's of low pH (4.5 and 4.9) and 3 antimicrobial substances-chlorhexidine, polyhexamethylene biguanide (PHMB), and thymol-at 2 concentrations each, were studied. From the initial inocula of 3.3 log colony-forming units per milliliter (cfu/mL) at baseline, the bacterial growth of the references increased to 5.0 to 6.0 log cfu/mL at 6 hours for Escherichia coli, Proteus mirabilis, and Enterococcus faecalis. At 12 hours there was a further increase to 7.0 to 8.9 log cfu/mL. Adjusting the pH of the superabsorbent in the incontinence product from 6.0 to pH 4.5 and pH 4.9 significantly (P disposable absorbent products to inhibit bacterial growth and ammonia production. This technique, we describe, provides a pragmatic method for assessing the odor-inhibiting capacity of specific incontinence products.

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

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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.

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

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Pragya Tiwari

2015-01-01

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

Protective effect of metformin on D-galactose-induced aging model in mice.

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Fatemi, Iman; Khaluoi, Amin; Kaeidi, Ayat; Shamsizadeh, Ali; Heydari, Sara; Allahtavakoli, Mohammad Aa

2018-01-01

Metformin (Met), an antidiabetic biguanide, reduces hyperglycemia via improving glucose utilization and reducing the gluconeogenesis. Met has been shown to exert neuroprotective, antioxidant and anti-inflammatory properties. The present study investigated the possible effect of Met on the D-galactose (D-gal)-induced aging in mice. Met (1 and 10 mg/kg/p.o.), was administrated daily in D-gal-received (500 mg/kg/p.o.) mice model of aging for six weeks. Anxiety-like behavior, cognitive function, and physical power were evaluated by the elevated plus-maze, novel object recognition task (NORT), and forced swimming capacity test, respectively. The brains were analyzed for the level of superoxide dismutase (SOD) and brain-derived neurotrophic factor (BDNF). Met decreased the anxiety-like behavior in D-gal-treated mice. Also, Met treated mice showed significantly improved learning and memory ability in NORT compared to the D-gal-treated mice. Furthermore, Met increased the physical power as well as the activity of SOD and BDNF level in D-gal-treated mice. Our results suggest that the use of Met can be an effective strategy for prevention and treatment of D-gal-induced aging in animal models. This effect seems to be mediated by attenuation of oxidative stress and enhancement of the neurotrophic factors.

The Effect of Sanggua Drink Extract on Insulin Resistance through the PI3K/AKT Signaling Pathway

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Yu Cai

2018-01-01

Full Text Available Treating type 2 diabetes mellitus (T2DM using thiazolidinediones and biguanides can present several challenges for patients. Sanggua Drink (SGD is a commonly used agent in traditional Chinese medicine, and it consists of Folium Mori, Fructus Momordicae Charantiae, Radix Puerariae Lobatae, and Rhizoma Dioscorea. The hypoglycemic effects and mechanisms of SGD extracts on insulin resistance in diabetic rats were investigated. SGD (1.24 g/kg orally was verified in T2DM rats induced by a high-fat diet and streptozotocin. The results showed that SGD treatment was observed to reduce fasting blood glucose, water and food intake, total cholesterol triglycerides, and LDL, OGTT, FINS, HOMA-IR, GHb, and MDA and increase hepatic glycogen, HDL, SOD, CAT, and GSH-Px in diabetic rats. Simultaneously, SGD treatment by T2DM showed significantly ameliorated pathological changes and reduced inflammation in the pancreas. Treatment was also observed to increase gene and protein expressions of InsR, IRS-2, PI3K, AKT, and Glut4 in the livers of diabetic treated rats. These results suggest that SGD extracts have hypoglycemic properties and may alleviate insulin resistance in T2DM rats through the PI3K/AKT pathway. Therefore, SGD appears to be a promising insulin sensitizer.

Effect of Liquid Crystalline Systems Containing Antimicrobial Compounds on Infectious Skin Bacteria.

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Souza, Carla; Watanabe, Evandro; Aires, Carolina Patrícia; Lara, Marilisa Guimarães

2017-08-01

This study aimed (i) to prepare liquid crystalline systems (LCS) of glyceryl monooleate (GMO) and water containing antibacterial compounds and (ii) to evaluate their potential as drug delivery systems for topical treatment of bacterial infections. Therefore, LCS containing CPC (cetylpyridinium chloride) (LCS/CPC) and PHMB (poly(hexamethylene biguanide) hydrochloride) (LCS/PHMB) were prepared and the liquid crystalline phases were identified by polarizing light microscopy 24 h and 7 days after preparation. The in vitro drug release profile and in vitro antibacterial activity of the systems were assessed using the double layer agar diffusion method against Staphylococcus aureus, methicillin-resistant S. aureus, Staphylococcus epidermidis, Escherichia coli, and Enterococcus faecalis. The interaction between GMO and the drugs was evaluated by a drug absorption study. Stable liquid crystalline systems containing CPC and PHMB were obtained. LCS/PHMB decreased the PHMB release rate and exerted strong antibacterial activity against all the investigated bacteria. In contrast, CPC interacted with GMO so strongly that it became attached to the system; the amount released was not sufficient to exert antibacterial activity. Therefore, the studied liquid crystalline systems were suitable to deliver PHMB, but not CPC. Accordingly, it was demonstrated that GMO interacts with each drug differently, which may interfere in the final efficiency of GMO/water LCS.

A review of pioglitazone HCL and glimepiride in the treatment of type 2 diabetes

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Mozhgan Dorkhan

2007-11-01

Full Text Available Mozhgan Dorkhan, Anders FridDepartment of Clinical Sciences, Division of Diabetes and Endocrinology, Lund University, Malmö University Hospital, SwedenAbstract: Type 2 diabetes (T2D is a progressive disorder with a consistent and steady increase in glycosylated hemoglobin (HbA1c over time associated with enhanced risk of micro- and macrovascular complications and a substantial reduction in life expectancy. There are three major pathophysiologic abnormalities associated with T2D: impaired insulin secretion, excessive hepatic glucose output, and insulin resistance in skeletal muscle, liver, and adipose tissue. These defects have been treated in clinical praxis by use of oral insulin secretagogues (sulfonylureas/glinides or insulin, biguanides, and thiazolidinediones (TZDs respectively. Pioglitazone HCL is an insulin sensitizer in the TZD family and glimepiride is an insulin secretagogue in the SU family. This article reviews mechanisms of action and clinical data behind the use of these two commonly used oral hypoglycemic agents with documented efficacy and good safety profile of once-daily administration, alone or in combination with insulin or metformin, in the management of T2D in terms of glycemic and non-glycemic effects, tolerability and side effects, and impact on vascular health.Keywords: pioglitazone, glimepiride, type 2 diabetes, thiazolidinediones, sulfonylureas

A central role for neuronal adenosine 5'-monophosphate-activated protein kinase in cancer-induced anorexia.

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Ropelle, Eduardo R; Pauli, José R; Zecchin, Karina G; Ueno, Mirian; de Souza, Cláudio T; Morari, Joseane; Faria, Marcel C; Velloso, Lício A; Saad, Mario J A; Carvalheira, José B C

2007-11-01

The pathogenesis of cancer anorexia is multifactorial and associated with disturbances of the central physiological mechanisms controlling food intake. However, the neurochemical mechanisms responsible for cancer-induced anorexia are unclear. Here we show that chronic infusion of 5-amino-4imidazolecarboxamide-riboside into the third cerebral ventricle and a chronic peripheral injection of 2 deoxy-d-glucose promotes hypothalamic AMP-activated protein kinase (AMPK) activation, increases food intake, and prolongs the survival of anorexic tumor-bearing (TB) rats. In parallel, the pharmacological activation of hypothalamic AMPK in TB animals markedly reduced the hypothalamic production of inducible nitric oxide synthase, IL-1beta, and TNF-alpha and modulated the expression of proopiomelanocortin, a hypothalamic neuropeptide that is involved in the control of energy homeostasis. Furthermore, the daily oral and intracerebroventricular treatment with biguanide antidiabetic drug metformin also induced AMPK phosphorylation in the central nervous system and increased food intake and life span in anorexic TB rats. Collectively, the findings of this study suggest that hypothalamic AMPK activation reverses cancer anorexia by inhibiting the production of proinflammatory molecules and controlling the neuropeptide expression in the hypothalamus, reflecting in a prolonged life span in TB rats. Thus, our data indicate that hypothalamic AMPK activation presents an attractive opportunity for the treatment of cancer-induced anorexia.

Synthesis of positively charged hybrid PHMB-stabilized silver nanoparticles: the search for a new type of active substances used in plant protection products

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Krutyakov, Yurii A.; Kudrinsky, Alexey A.; Gusev, Alexander A.; Zakharova, Olga V.; Klimov, Alexey I.; Yapryntsev, Alexey D.; Zherebin, Pavel M.; Shapoval, Olga A.; Lisichkin, Georgii V.

2017-07-01

Modern agriculture calls for a decrease in pesticide application, particularly in order to decrease the negative impact on the environment. Therefore the development of new active substances and plant protection products (PPP) to minimize the chemical load on ecosystems is a very important problem. Substances based on silver nanoparticles are a promising solution of this problem because of the fact that in correct doses such products significantly increase yields and decrease crop diseases while displaying low toxicity to humans and animals. In this paper we for the first time propose application of polymeric guanidine compounds with varying chain lengths (from 10 to 130 elementary links) for the design and synthesis of modified silver nanoparticles to be used as the basis of a new generation of PPP. Colloidal solutions of nanocrystalline silver containing 0.5 g l-1 of silver and 0.01-0.4 g l-1 of polyhexamethylene biguanide hydrochloride (PHMB) were obtained by reduction of silver nitrate with sodium borohydride in the presence of PHMB. The field experiment has shown that silver-containing solutions have a positive effect on agronomic properties of potato, wheat and apple. Also the increase in activity of such antioxidant system enzymes as peroxidase and catalase in the tissues of plants treated with nanosilver has been registered.

The Usage of Oral Anti Hyperglycemic Agent in Gestational Diabetes: Pros and Cons

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Bram Pradipta

2014-06-01

Full Text Available The prevalence of gestational diabetes mellitus (GDM  is increasing as the pregnant population becomes older and more obese. Fifteen percent of GDM patients require medical intervention. Insulin is still the drug of choice because it has not been implicated as a teratogen in human pregnancies.Insulin has its disadvantages such as the need for injections, the risk of hypoglycaemia, excessive weight gain and the costs. The use of oral anti hyperglicemic agent (OAHA, traditionally contraindicated, now can be considered as an alternative for insulin which can be beneficial in developing countries. From four groups of OAHA, sulfonylurea and biguanides can be used during pregnancy. Studies and randomized controlled trial (RCT have been done and most summarized that it does not increase any maternal and perinatal morbidity. Most data also show that thereare also no differences in glycemic control or pregnancy outcomes compared with insulin. There are conflicting data shows metformin increase prevalence of preeclampsia patient and perinatal morbidity. OAHA usage, although not yet recommended internationally, can be considered in GDMpatients with uncontrolled blood sugar levels that require medical intervention but can not use insulin. Wellconducted, prospective, controlled studies regarding itsfeasibility in pregnant women with diabetes are still needed.Keywords:oral antihyperglycemic agent, gestational, diabetes

Repurposing phenformin for the targeting of glioma stem cells and the treatment of glioblastoma

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Jiang, Wei; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Brodie, Ziv; Mikkelsen, Tom; Poisson, Laila; Shackelford, David B.; Brodie, Chaya

2016-01-01

Glioblastoma (GBM) is the most aggressive primary brain tumor with poor prognosis. Here, we studied the effects of phenformin, a mitochondrial complex I inhibitor and more potent chemical analog of the diabetes drug metformin on the inhibition of cell growth and induction of apoptosis of glioma stem cells (GSCs) using both in vitro and in vivo models. Phenformin inhibited the self-renewal of GSCs, decreased the expression of stemness and mesenchymal markers and increased the expression of miR-124, 137 and let-7. Silencing of let-7 abrogated phenformin effects on the self-renewal of GSCs via a pathway associated with inhibition of H19 and HMGA2 expression. Moreover, we demonstrate that phenformin inhibited tumor growth and prolonged the overall survival of mice orthotopically transplanted with GSCs. Combined treatments of phenformin and temozolomide exerted an increased antitumor effect on GSCs in vitro and in vivo. In addition, dichloroacetate, an inhibitor of the glycolysis enzyme pyruvate dehydrogenase kinase, that decreases lactic acidosis induced by biguanides, enhanced phenformin effects on the induction of cell death in GSCs and prolonged the survival of xenograft-bearing mice. Our results demonstrate for the first time that phenformin targets GSCs and can be efficiently combined with current therapies for GBM treatment and GSC eradication. PMID:27486821

NEW IN THE TREATMENT OF TYPE 2 DIABETES

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V. G. Kadzharyan

2014-02-01

Full Text Available Diabetes mellitus (DM is a major medical and social problem almost in all countries of the world. Currently, there are more and more various pharmacological agents that make management of the glycaemia in patients with type 2 diabetes extremely difficult. Therefore, when the physician is faced with the choice of glucose-lowering therapy, he should be clearly aware of all the options in contemporary treatment. 11 groups of hypoglycemic agents are used for the treatment of type 2 diabetes The biguanides. According to modern concepts, biguanides inhibit the oxidation of glucose by stimulating anaerobic glycolysis. Both in the consensus of ADA / EASD, and in the IDF recommendations metformin may be the drug of the choice for hypoglycemic therapy of diabetes type 2. Sulfonylurea derivatives: glibenclamide, glimepiride, gliquidone, Glipizide. They belong to a group of secretagogues, as their action is based on the ability to stimulate the secretion of insulin by ß-cells of the pancreas. Prandial glucose regulators. Meglitinides (repaglinide and nateglinide stimulate insulin secretion by ß-cells. Due to the rapid normalization of stimulated insulin level after taking the drugs the risk of hypoglycaemia between meals is minimized. Insulin sensitayzers. Thiazolidinediones (rosiglitazone, pioglitazone reduce insulin resistance of peripheral tissues by binding to receptors, activating peroxisome proliferation (PPARg in the nuclear membrane. Alpha-glucosidase inhibitors (acarbose, miglitol, voglibose competitively inhibits intestinal enzymes (α-glucosidase. It consequently slows carbohydrate absorption from foods and supply of glucose into the blood. Incretin mimetics. Analogues of glucagon-like peptide 1 (GLP-1 stimulate the biosynthesis and secretion of insulin, regulate food consumption, support ß-cells in a healthy state, suppress glucagon secretion, depending on the glucose levels, affect the rate of gastric emptying, stimulat proliferation of �

Diffusion of Antimicrobials Across Silicone Hydrogel Contact Lenses.

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Zambelli, Alison M; Brothers, Kimberly M; Hunt, Kristin M; Romanowski, Eric G; Nau, Amy C; Dhaliwal, Deepinder K; Shanks, Robert M Q

2015-09-01

To measure the diffusion of topical preparations of moxifloxacin, amphotericin B (AmB), and polyhexamethylene biguanide (PHMB) through silicone hydrogel (SH) contact lenses (CLs) in vitro. Using an in vitro model, the diffusion of three antimicrobials through SH CLs was measured. Diffused compounds were measured using a spectrophotometer at set time points over a period of 4 hr. The amount of each diffused antimicrobial was determined by comparing the experimental value with a standard curve. A biological assay was performed to validate the CL diffusion assay by testing antimicrobial activity of diffused material against lawns of susceptible bacteria (Staphylococcus epidermidis) and yeast (Saccharomyces cerevisiae). Experiments were repeated at least two times with a total of at least four independent replicates. Our data show detectable moxifloxacin and PHMB diffusion through SH CLs at 30 min, whereas AmB diffusion remained below the limit of detection within the 4-hr experimental period. In the biological assay, diffused moxifloxacin demonstrated microbial killing starting at 20 min on bacterial lawns, whereas PHMB and AmB failed to demonstrate killing on microbial lawns over the course of the 60-min experiment. In vitro diffusion assays demonstrate limited penetration of certain anti-infective agents through SH CLs. Further studies regarding the clinical benefit of using these agents along with bandage CL for corneal pathologic condition are warranted.

A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

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Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

2018-02-01

Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

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

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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. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

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

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Rebuma Firdessa

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

Antimicrobial-impregnated dressing combined with negative-pressure wound therapy increases split-thickness skin graft engraftment: a simple effective technique.

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Wu, Cheng-Chun; Chew, Khong-Yik; Chen, Chien-Chang; Kuo, Yur-Ren

2015-01-01

Immobilization and adequate surface contact to wounds are critical for skin graft take. Techniques such as the tie-over dressing, cotton bolster, and vacuum-assisted closure are used to address this, but each has its limitations. This study is designed to assess the effect of antimicrobial-impregnated dressing (AMD) combined with negative-pressure wound therapy (NPWT) on skin graft survival. Retrospective case-control study : Patients with chronic or contaminated wounds treated with split-thickness skin graft. A broad spectrum of wounds was included, from causes such as trauma, burns, chronic diabetic ulcers, and infection. Antimicrobial-impregnated dressing, which contains 0.2% polyhexamethylene biguanide, with NPWT MAIN OUTCOME MEASURE:: Success of skin graft : In the AMD group, all skin grafts achieved 100% take without secondary intervention. No infection or graft failure was observed in any patients, and no complications, such as hematoma or seroma formation, were noted, although in the control group partial loss of skin grafts was noted in 3 patients. Infection and inadequate immobilization were thought to be the main reasons. There were no hematoma or seroma formations in the control group. Use of an AMD dressing with NPWT after split-thickness skin grafting can be an effective method to ensure good graft to wound contact and enhances skin graft take in chronic and contaminated wounds.

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

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Soheila Riahinejad

2016-04-01

Full Text Available 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 randomly. All patients received metformin from the fifth day of menstrual cycle at a dose of 850 mg (one tablet daily for 3 months. Body mass index, Triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C, low-density lipoprotein cholesterol (LDL-C, fasting blood sugar and homocysteine levels were recorded at entry into the study and after 3 months treatment.Results: BMI, plasma Homocysteine concentrations and fasting blood sugar levels were significantly (p < 0.05 decreased after the treatment period. No significant changes were observed in the lipid profiles of patients. There was a weak negative correlation between homocysteine and LDL cholesterol serum levels (p = 0.04, r = -0.27.Conclusion: Treatment with metformin in PCOS women may lead to beneficial effects in terms of BMI, plasma homocysteine concentrations and fasting blood sugar with no remarkable effect on lipid profile. 

Evaluation of the efficacy of antibacterial medical gloves in the ICU setting.

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Kahar Bador, M; Rai, V; Yusof, M Y; Kwong, W K; Assadian, O

2015-07-01

Inappropriate use of medical gloves may support microbial transmission. New strategies could increase the safety of medical gloves without the risk of patient and surface contamination. To compare the efficacy of synthetic antibacterial nitrile medical gloves coated with polyhexamethylen-biguanid hydrochloride (PHMB) on the external surface with identical non-antibacterial medical gloves in reducing glove contamination after common patient care measures in an intensive care unit (ICU) setting. ICU staff wore either standard or antibacterial gloves during patient care activities. The number of bacteria on gloves was measured semi-quantitatively immediately after the performance of four clinical activities. There was a significant difference in mean bacterial growth [colony-forming units (cfu)] between control gloves and antibacterial gloves {60 [standard deviation (SD) 23] vs 16 (SD 23) cfu/glove imprint, P gloves had significantly less bacterial contamination compared with the control gloves (P = 0.011 and gloves showed lower bacterial contamination after changing linen compared with control gloves, the difference was not significant (P = 0.311). This study showed that use of antibacterial medical gloves significantly reduced bacterial contamination after typical patient care activities in 57% of the investigated clinical activities (P gloves may support reduction of cross-contamination in the ICU setting. Copyright © 2015 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

Effects of dual combinations of antifolates with atovaquone or dapsone on nucleotide levels in Plasmodium falciparum.

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Yeo, A E; Seymour, K K; Rieckmann, K H; Christopherson, R I

1997-04-04

The triazine antifolates, cycloguanil and 4,6-diamino-1,2-dihydro-2,2-dimethyl-1-[(2,4,5-trichlorophenoxy)propy loxy]-1,3,5-triazine hydrobromide (WR99210), and their parent biguanide compounds, proguanil and N-[3-(2,4,5-trichlorophenoxy)propyloxy]-n-(1-methylethyl)-imido dicarbonimidic-diamine hydrochloride (PS-15), were tested in combination with a series of antimalarial drugs for synergism against Plasmodium falciparum growing in erythrocytic culture. Four synergistic combinations were found: cycloguanil dapsone, WR99210-dapsone, proguanil-atovaquone, and PS-15-atovaquone. Cycloguanil-dapsone or WR99210-dapsone had a profound suppressive effect on the concentration of dTTP in parasites while that of dATP increased. Depletion of dTTP is consistent with cycloguanil or WR99210 inhibiting dihydrofolate reductase and dapsone inhibiting dihydropteroate synthase. For the combinations proguanil-atovaquone and PS-15-atovaquone, the levels of nucleoside triphosphates (NTPs) and dNTPs were generally suppressed, suggesting that inhibition is not through nucleotide pathways but probably through another metabolic mechanism(s). Combinations of two synergistic pairs of antimalarial drugs, (proguanil-atovaquone)-(cycloguanil-dapsone) and (PS-15-atovaquone)-(WR99210-dapsone), were tested, and it was found that NTPs and dNTPs decreased much more than for a single synergistic combination. Dual synergistic combinations could play an important role in the therapy of multidrug-resistant malaria, just as combination chemotherapy is used to treat cancer.

The phenomenon of the switching of estrogen effects and joker function of glucose: similarities and relation to age-associated pathology and approaches to correction.

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Berstein, Lev M; Tsyrlina, Evgenia V; Vasilyev, Dmitry A; Poroshina, Tatjana E; Kovalenko, Rina G

2005-12-01

Estrogens and glucose are characterized by a myriad of functions that can be reduced to a small number of principal actions. In aging there is a simultaneous increase in the prevalence of diseases connected with estrogen deficiency as well as with estrogenic excess and associated with the phenomenon of the switching of estrogen effects (PSEE). Estrogens possess hormonal and genotoxic properties. An increase in genotoxic effect (isolated or combined with a decrease in hormonal effect) can influence the course of age-associated diseases that, contrary to the situation with adaptive hypersensitivity to estrogens, may become less favorable or more aggressive. Inductors of PSEE include smoking, irradiation, and aging. Yet with "glycemic load" and the endocrine effect of glucose (the stimulation of insulin secretion), reactive oxygen species are formed in multiple sites, including adipose tissue. The ratio between hormonal and genotoxic effects reflects a "joker" function of glucose and can be conditioned by endogenous (perhaps including genetic) and exogenous factors. The shift in this glucose-associated ratio may selectively encourage some chronic non-communicable diseases. Several groups of treatments can be distinguished including alleviators of PSEE and insulin resistance syndrome (biguanides, glitazones, statins, modifiers of adipocytokines secretion, etc.) as well as other compounds aimed to optimally orchestrate the balance between endocrine and DNA-damaging effects of estrogens and glucose.

Therapeutic molecules against type 2 diabetes: What we have and what are we expecting?

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Kumar, Ashwini; Bharti, Sudhanshu Kumar; Kumar, Awanish

2017-10-01

World Health Organization (WHO) has identified diabetes as one of the fastest growing non-communicable diseases with 422 million patients around the world in 2014. Diabetes, a metabolic disease, is characterized primarily by hyperglycemia which results in various macrovascular and microvascular complications like cardiovascular disease and neuropathies which can significantly deteriorate the quality of life. The body either does not manufactures enough insulin (type 1 diabetes or T1DM) or becomes insensitive to physiologically secreted insulin or both (type 2 diabetes or T2DM). The majority of the diabetic population is affected by type 2 diabetes. Currently, hyperglycemia is treated by a broad range of molecules such as biguanides, sulfonylurea, insulin, thiazolidinediones, incretin mimetics, and DPP-4 inhibitors exerting different mechanisms. However, new drug classes have indeed come in the market such as SGLT-2 inhibitors and other are in the experimental stages such as GPR 40 agonists, GSK-3 inhibitors, GK activators and GPR21 inhibitors which definitely could be anticipated as safe and effective for diabetes therapy. This article reviews the general approach to currently approved therapies for type 2 diabetes and focusing on novel approaches that could be a panacea and might be useful in the future for diabetes patients. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Increased resistance of contact lens related bacterial biofilms to antimicrobial activity of soft contact lens care solutions

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Szczotka-Flynn, Loretta B.; Imamura, Yoshifumi; Chandra, Jyotsna; Yu, Changping; Mukherjee, Pranab K.; Pearlman, Eric; Ghannoum, Mahmoud A.

2014-01-01

PURPOSE To determine if clinical and reference strains of Pseudomonas aeruginosa, Serratia marcescens, and Staphylococcus aureus form biofilms on silicone hydrogel contact lenses, and ascertain antimicrobial activities of contact lens care solutions. METHODS Clinical and American Type Culture Collection (ATCC) reference strains of Pseudomonas aeruginosa, Serratia marcescens, and Staphylococcus aureus were incubated with lotrafilcon A lenses under conditions that facilitate biofilm formation. Biofilms were quantified by quantitative culturing (colony forming units, CFUs), and gross morphology and architecture were evaluated using scanning electron microscopy (SEM) and confocal microscopy. Susceptibilities of the planktonic and biofilm growth phases of the bacteria to five common multipurpose contact lens care solutions and one hydrogen peroxide care solution were assessed. RESULTS P. aeruginosa, S. marcescens, and S. aureus reference and clinical strains formed biofilms on lotrafilcon A silicone hydrogel contact lenses, as dense networks of cells arranged in multiple layers with visible extracellular matrix. The biofilms were resistant to commonly used biguanide preserved multipurpose care solutions. P. aeruginosa and S. aureus biofilms were susceptible to a hydrogen peroxide and a polyquaternium preserved care solution, whereas S. marcescens biofilm was resistant to a polyquaternium preserved care solution but susceptible to hydrogen peroxide disinfection. In contrast, the planktonic forms were always susceptible. CONCLUSIONS P. aeruginosa, S. marcescens, and S. aureus form biofilms on lotrafilcon A contact lenses, which in contrast to planktonic cells, are resistant to the antimicrobial activity of several soft contact lens care products. PMID:19654521

Effectiveness of basal-supported oral therapy (BOT) using insulin glargine in patients with poorly controlled type 2 diabetes.

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Suzuki, Daisuke; Umezono, Tomoya; Miyauchi, Masaaki; Kimura, Moritsugu; Yamamoto, Naoyuki; Tanaka, Eitaro; Kuriyama, Yusuke; Sato, Hiroki; Miyatake, Han; Kondo, Masumi; Toyoda, Masao; Fukagawa, Masafumi

2012-07-20

To determine the clinical usefulness of basal-supported oral therapy (BOT) using insulin glargine in Japanese patients with type 2 diabetes. We compared HbA1c levels, body weight, and insulin doses before the introduction of BOT and in the final month of the observation period in 122 patients with type 2 diabetes who received BOT with insulin glargine between October 2007 and July 2009. To exclude the possible effects of seasonal changes in glycemic control, 57 of the 122 patients were followed-up for one year and examined for changes in HbA1c levels, body weight, and insulin dose. Examination of all cases (n=122) showed a significant decrease in HbA1c (before BOT: 8.7±1.8, after: 7.1±1.1%), but no significant change in body weight (before: 63.1±16.1, after: 63.8±17.0 kg). The mean observation period was 10.5±6.4 months. Insulin doses were significantly increased during the study. HbA1c levels improved significantly in patients on non-insulin-secreting drugs (biguanide, α-glucosidase inhibitor and thiazolidine derivatives) than those on insulin-secreting drugs (SU agents and glinides). BOT with insulin glargine is a useful strategy that can achieve good glycemic control in clinical practice without causing serious hypoglycemia. The introduction of BOT before exhaustion of pancreatic β cells may increase its effectiveness.

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

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Venu Gopal Jonnalagadda

2014-05-01

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

[A clinical case of lactic acidosis development in a diabetic patient taking metformin].

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Cezur, Mustafa; Celmen, Nedim; Cetinbas, Riza; Badalov, Pavel; Erdemli, Ozcan

2009-01-01

Metformin is a biguanide. Due to its effects in decreasing the hepatic production of glucose and in increasing insulin sensitivity in peripheral tissues, such as adipose tissue and skeletal muscle, the agent is used in metabolic syndrome and type 2 diabetes mellitus and, in which insulin resistance is especially pronounced. Eighty-one-year old male patient was admitted to the emergency unit with sudden vertigo, tiredness, dyspnea, cyanosis, and lethargy. He had had type 2 diabetes mellitus for 10 years and was taking glargin 12 U/kg once daily and metformin (glucophage) 850 mg thrice daily. The patient showed no cooperation and orientation. Metabolic acidosis, hypoxemia, and hypercapnea were detected in arterial blood gases (ABG). The patient was transferred to an intensive care unit of the hospital; endotracheal intubation was applied and mechanic ventilation was started. On the following day, his ABG got better; he was disconnected and weaning was applied. Lung X-ray study revealed no signs of pneumonia or pulmonary edema. On the same day, extubation was ended and O2 was given by mask at a rate of 4 L/min. After the patient's vital signs, blood sugar, and lactate levels were stabilized; his treatment regimen was arranged again and the patient was discharged on day 4 of his admission. Dyspnea, acidosis, and hypoxia seen in the patient were thought to be due to lactic acidosis which may rarely occur when metformin is used.

Sensitive method for the quantitative determination of proguanil and its metabolites in rat blood and plasma by liquid chromatography-mass spectrometry.

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Leveque, Nathalie L; Charman, William N; Chiu, Francis C K

2006-01-18

A sensitive, simple and fast liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for the determination of proguanil (PG) and its metabolites, cycloguanil (CG) and 1-(4-chlorophenyl)biguanide (4CPB), was developed and validated over a concentration range of 1-2000 ng/mL using only 50 microL of blood or plasma. After a simple solvent precipitation procedure, the supernatant was analysed directly by HPLC-MS/MS. Separation was achieved using an ethyl-linked phenyl reverse phase column with polar endcapping with an acetonitrile-water-formic acid gradient. Mass spectrometry was performed using a triple quadrupole mass spectrometer operating in positive electrospray ionization mode. The elution of PG (254.07-->169.99), CG (252.12-->195.02) and 4CPB (212.06-->153.06) was monitored using selected reaction monitoring. The three compounds and the internal standard (chloroproguanil) were well separated by HPLC and no interfering peaks were detected at the usual concentrations found in blood and plasma. The limit of quantification of PG and CG was 1 ng/mL and 5 ng/mL for 4CPB in rat blood and plasma. The extraction efficiency of PG, CG and 4CPB from rat blood and plasma was higher than 73%. The intra- and inter-assay variability of PG, CG and 4CPB were within 12% and the accuracy within +/-5%. This new assay offers higher sensitivity and a much shorter run time over earlier methods.

Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners.

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Sarfstein, Rive; Friedman, Yael; Attias-Geva, Zohar; Fishman, Ami; Bruchim, Ilan; Werner, Haim

2013-01-01

Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.

Metformin and insulin receptors

International Nuclear Information System (INIS)

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

1984-01-01

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

Uso de la metformina en la diabetes mellitus tipo II Use of metformin to treat type 2 diabetes mellitus

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Yohana Salazar ÁLvarez

2011-03-01

Full Text Available Metformina es una biguanida eficaz en el control metabólico de la diabetes mellitus tipo II, no insulinodependiente cuando el control dietético falla. Dada su probada eficacia y actual accesibilidad en el mercado de medicamentos en Cuba, para ser utilizada a nivel primario de atención no solo en pacientes sintomáticos sino en la población en riesgo, se presenta este artículo cuyo propósito es actualizar a los especialistas de Medicina General Integral y Medicina Interna acerca de aspectos de interés relacionados con este medicamento, como: interacciones medicamentosas, enfermedades concomitantes, la biotransformación de la droga y los posibles efectos adversos que se pueden asociar a su uso. Se presentan consideraciones finales acerca del uso de esta droga.Metformin is an effective biguanide for the metabolic control of non-insulin dependent type 2 diabetes mellitus when the dietary control fails. Given its proven efficacy and present accessibility in the pharmaceutical market in Cuba -to be used at primary health care not only in symptomatic patients but in the population at risk-this article was presented to update the knowledge of the Family Medicine and Internal Medicine specialists about interesting aspects related to this drug, i.e, drug interactions, concomitant diseases, drug biotransformation and the possible adverse effects associated to its use. Final remarks on the use of this drug were stated.

Cellular and molecular mechanisms of metformin: an overview

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Viollet, Benoit; Guigas, Bruno; Sanz Garcia, Nieves; Leclerc, Jocelyne; Foretz, Marc; Andreelli, Fabrizio

2012-01-01

Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycemic agent now recommended as the first line oral therapy for type 2 diabetes (T2D). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory-chain complex 1. In addition, the resulting decrease in hepatic energy status activates the AMP-activated protein kinase (AMPK), a cellular metabolic sensor, providing a generally accepted mechanism for metformin action on hepatic gluconeogenic program. The demonstration that the respiratory-chain complex 1, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin was reported to restore ovarian function in polycystic ovary syndrome, reduce fatty liver and to lower microvascular and macrovascular complications associated with T2D. Its use was also recently suggested as an adjuvant treatment for cancer or gestational diabetes, and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent data from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D. PMID:22117616

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

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

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John M Stafford

2007-09-01

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

Biocompatibility index of antiseptic agents by parallel assessment of antimicrobial activity and cellular cytotoxicity.

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Müller, Gerald; Kramer, Axel

2008-06-01

To assess the suitability of an antiseptic agent, both the microbicidal activity and the cytotoxic effect must be taken into consideration to derive biocompatible antibacterial agents. We defined the biocompatibility index (BI) by measuring the antibacterial activity against the test organisms Escherichia coli and Staphylococcus aureus and, in parallel, the cytotoxicity on cultured murine fibroblasts. The antiseptic agents tested were benzalkonium chloride (BAC), cetylpyridinium chloride (CPC), chlorhexidine digluconate (CHX), mild silver protein (MSP), octenidine dihydrochloride (OCT), polyhexamethylene biguanide (PHMB), povidone iodine in solution [PVP-I(s)], povidone iodine in ointment [PVP-I(o)], silver nitrate (AgNO(3)), silver (I) sulfadiazine (SSD) and triclosan (TRI). Assays were carried out for 30 min of exposure at 37 degrees C in the presence of cell culture medium containing 10% fetal bovine serum. The resulting dimensionless BI was defined as the ratio of the concentration at which 50% of the murine fibroblasts are damaged and the microbicidal effect producing at least 3 log(10) (99.9%) reduction. The resulting rank ordering of BI for the ratio of fibroblast cytotoxicity to E. coli toxicity was OCT > PHMB > CHX > PVP-I(o) > PVP-I(s) > BAC > CPC > TRI > MSP and that to S. aureus was OCT > PHMB > CHX > CPC > PVP-I(o) > BAC > PVP(s) > TRI > MSP. OCT and PHMB were the most suitable agents with a BI greater than 1. The BI presented may be a useful tool to evaluate antiseptic agents for use in clinical practice.

PS-15: a potent, orally active antimalarial from a new class of folic acid antagonists.

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Canfield, C J; Milhous, W K; Ager, A L; Rossan, R N; Sweeney, T R; Lewis, N J; Jacobus, D P

1993-07-01

A new, orally-active inhibitor of dihydrofolic acid reductase (DHFR), PS-15 (N-(3-(2,4,5-trichlorophenoxy)propyloxy)-N'-(1-methylethyl)- imidocarbonimidic diamide hydrochloride), has significant activity against drug-resistant Plasmodium falciparum. It is not cross-resistant with other inhibitors of DHFR (e.g., pyrimethamine and cycloguanil). Although it bears similarities to proguanil, PS-15 represents a new antifolate class of drugs that we have named oxyguanils or hydroxylamine-derived biguanides. This compound displays intrinsic antimalarial activity and also is metabolized in vivo to WR99210, an extremely active triazine inhibitor of DHFR. When tested in vitro against drug-resistant clones of P. falciparum, PS-15 was more active than proguanil, and the putative metabolite, WR99210, was more active than the proguanil metabolite cycloguanil. The drug is also more active as well as less toxic than proguanil when administered orally to mice infected with P. berghei. When administered orally to Aotus monkeys infected with multidrug-resistant P. falciparum, PS-15 was more active than either proguanil or WR99210. In 1973, WR99210 underwent clinical trials for safety and tolerance in volunteers. The trials showed gastrointestinal intolerance and limited bioavailability; further development of the drug was abandoned. Because PS-15 has intrinsic antimalarial activity, is not cross-resistant with other DHFR inhibitors, and can be metabolized to WR99210 in vivo, oral administration of this new drug should circumvent the shortcomings and retain the advantages found with both proguanil and WR99210.

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

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

2015-12-07

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

The Effect of Tianmai Xiaoke Pian on Insulin Resistance through PI3-K/AKT Signal Pathway

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Nana Wang

2016-01-01

Full Text Available In the clinical setting, given the potential adverse effects of thiazolidinediones and biguanides, we often have difficulty in treatment that no other insulin sensitizers are available for use in type 2 diabetic mellitus (T2DM patients. Tianmai Xiaoke Pian (TMXKP is a traditional Chinese medicine tablet, which is comprised of chromium picolinate, Tianhuafen, Maidong, and Wuweizi. To understand its mechanism of action on insulin resistance, TMXKP (50 mg/kg orally was tested in T2DM rats (induced by a high-fat diet and streptozotocin. Eight weeks later, fasting blood glucose (FBG and oral glucose tolerance tests (OGTT were performed. Area under the curve (AUC and homeostatic model assessment of insulin resistance (HOMA-IR were calculated, and PI3-K/AKT signal pathway-related genes and proteins were tested by reverse transcription-polymerase chain reaction (RT-PCR and western blot analysis in muscle, adipose, and liver tissues, respectively. TMXKP significantly reduced FBG, OGTT, AUC, and HOMA-IR in diabetic rats P<0.05. Furthermore, we also observed that TMXKP could significantly decrease IRS-1, IRS-2, PI3-K p85α, and AKT2 gene expression and also IRS-1, IRS-2, PI3-K, AKT2, and p-AKT2 protein expression levels P<0.05 in diabetic rats. These findings confirm that TMXKP can alleviate insulin resistance in T2DM rats through the PI3K/AKT pathway. Thus TMXKP appears to be a promising insulin sensitizer.

Synergistic Effect of Rapamycin and Metformin Against Age-Dependent Oxidative Stress in Rat Erythrocytes.

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Singh, Abhishek Kumar; Garg, Geetika; Singh, Sandeep; Rizvi, Syed Ibrahim

2017-10-01

Erythrocytes are particularly vulnerable toward age-dependent oxidative stress-mediated damage. Caloric restriction mimetics (CRMs) may provide a novel strategy for the maintenance of redox balance as well as effective treatment of age-associated diseases. Herein, we have investigated the beneficial effect of cotreatment with CRM-candidate drugs, rapamycin (an immunosuppressant drug and inhibitor of mammalian target of rapamycin) and metformin (an antidiabetic biguanide and activator of adenosine monophosphate kinase), against aging-induced oxidative stress in erythrocytes and plasma of aging rats. Male Wistar rats of age 4 (young) and 24 months (old) were coexposed to rapamycin (0.5 mg/kg body weight [b.w.]) and metformin (300 mg/kg b.w.), and data were compared with the response of rats receiving an independent exposure to these chemicals at similar doses. The exposure of individual candidate drugs significantly reversed the age-dependent alterations in the endpoints associated with oxidative stress such as reactive oxygen species, ferric reducing ability of plasma, malondialdehyde, reduced glutathione, plasma membrane redox system, plasma protein carbonyl, and acetyl cholinesterase in erythrocytes and plasma of aging rats. However, the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of these age-dependent biomarkers of oxidative stress, suggesting a synergistic response. Thus, the findings open up further possibilities for the design of new combinatorial therapies to prevent oxidative stress- and age-associated health problems.

Involvement of spinal serotonin receptors in the regulation of intraspinal acetylcholine release.

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Kommalage, Mahinda; Höglund, A Urban

2005-02-21

Stimulation of spinal serotonin (5-HT) receptors results in analgesia and release of acetylcholine. We investigated the involvement of 5-HT1, 5-HT2, and 5-HT3 receptor subtypes in the regulation of spinal acetylcholine release. A spinal microdialysis probe was placed dorsally at about the C5 level in anaesthetized rats. The selective serotonin reuptake inhibitor citalopram was found to increase acetylcholine release when infused via the microdialysis probe. Several doses of the 5-HT receptor agonists 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT, 5-HT1A), 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (CP93129, 5-HT1B), alpha-methyl-5-hydroxytryptamine maleate (m5-HT, 5-HT2), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 5-HT2C), and 1-(m-chlorophenyl)-biguanide (5-HT3) were subsequently infused via the microdialysis probe. Only 8-OH-DPAT, CP93129, and m5-HT increased acetylcholine release dose dependently. The 5-HT1A receptor selective antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazine-1-yl)-2-phenylpropanamide hydrochloride and the 5-HT2A receptor selective antagonist ketanserin tartrate inhibited the 8-OH-DPAT and the m5-HT induced acetylcholine release. The results suggest that 5-HT1A and the 5-HT2A receptors are involved in the regulation of acetylcholine release in the spinal cord.

Evaluation of Protamine as a Disinfectant for Contact Lenses.

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Bandara, Mahesh K; Masoudi, Simin; Zhu, Hua; Bandara, Rani; Willcox, Mark D P

2016-11-01

To investigate the ability of protamine, alone or in combination with other antimicrobial agents, to kill bacteria and fungi associated with contact lens-related keratitis. The International Organization for Standardization 14729:2001 procedure was used to test the antimicrobial activity of solutions of protamine (23-228 μM) with and without polyhexamethylene biguanide (PHMB) and ethylenediamine tetra-acetic acid (EDTA). The recommended ISO panel of microbes along with six clinical isolates was tested. The effect of increasing sodium chloride concentration on the antimicrobial activity was also assessed. The cytotoxicity of the final protamine/EDTA/PHMB solution was measured using ISO 10993-5 standard assays. Protamine gave a dose-dependent antimicrobial effect, with the highest effect for most strains being at 228 μM (≥6 log reductions of viable bacteria and ≥1 log reduction of viable fungi). Addition of EDTA and PHMB increased the antimicrobial effect for all strains except Pseudomonas aeruginosa ATCC6538, which had optimum activity (≥6 log inhibition) even in protamine alone. The optimum antimicrobial activity of all microbes was achieved in 0.2% sodium chloride, but even in 0.8% sodium chloride, the activity met or exceeded the ISO standard (>3 log reductions for bacteria and >1 log reduction for fungi). None of the formulations was cytotoxic to mammalian cells. This study highlights the potential for protamine to be used for the development of effective multipurpose disinfection solutions. Further investigations such as stability, compatibility with contact lenses, and in vivo toxicity are warranted.

Phenformin-Induced Mitochondrial Dysfunction Sensitizes Hepatocellular Carcinoma for Dual Inhibition of mTOR.

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Veiga, Sonia Rosa; Ge, Xuemei; Mercer, Carol A; Hernández-Alvarez, María Isabel; Thomas, Hala Elnakat; Hernández-Losa, Javier; Ramón Y Cajal, Santiago; Zorzano, Antonio; Thomas, George; Kozma, Sara C

2018-04-24

Hepatocellular carcinoma (HCC) ranks second in cancer mortality and has limited therapeutic options. We recently described the synergistic effect of allosteric and ATP-site competitive inhibitors against the mammalian target of rapamycin (mTOR) for the treatment of HCC. However, such inhibitors induce glycemia and increase mitochondrial efficiency. Here we determined whether the mitochondrial complex I inhibitor Phenformin could reverse both side effects, impose an energetic-stress on cancer cells and suppress the growth of HCC. Human HCC cell lines were used in vitro to access the signaling and energetic impact of mTOR inhibitors and Phenformin, either alone or in combination. Next, the therapeutic utility of these drugs alone or in combination was investigated pre-clinically in human orthotopic tumors implanted in mice, by analyzing their impact on the tumor burden and overall survival. We found Phenformin caused mitochondrial dysfunction and fragmentation, inducing a compensatory shift to glycolysis. In contrast, dual inhibition of mTOR impaired cell growth and glycolysis, while increasing mitochondrial fusion and efficiency. In a mouse model of human HCC, dual inhibition of mTOR, together with Phenformin, was highly efficacious in controlling tumor burden. However, more striking, pretreatment with Phenformin sensitized tumors to dual inhibition of mTOR, leading to a dramatic improvement in survival. Treatment of HCC cells in vitro with the biguanide Phenformin causes a metabolic shift to glycolysis, mitochondrial dysfunction and fragmentation, and dramatically sensitizes orthotopic liver tumors to dual inhibition of mTOR. We therefore propose this therapeutic approach should be tested clinically in HCC. Copyright ©2018, American Association for Cancer Research.

Efficacy of structured education in patients with type 2 diabetes mellitus receiving insulin treatment.

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Guo, Xiao Hui; Ji, Li Nong; Lu, Ju Ming; Liu, Jie; Lou, Qing Qing; Liu, Jing; Shen, Li; Zhang, Ming Xia; Lv, Xiao Feng; Gu, Ming Jun

2014-07-01

The aim of the present study was to assess the efficacy of structured education in insulin-treated type 2 diabetes mellitus (T2DM) patients. In a 16-week open-label randomized controlled study, 1511 T2DM patients with inadequate responses to two or more oral antidiabetic drugs (OADs) for >3 months (HbA1c >7.5%) were randomized (1:1) to either an education group (structured diabetes education plus insulin therapy) or a control group (usual care plus insulin therapy). Both groups discontinued previous OADs (except biguanides and α-glucosidase inhibitors) and started twice daily injections of 30% soluble-70% isophane recombinant insulin. The primary endpoint was the change in HbA1c from baseline. Efficacy and safety data were analyzed for within- and between-group differences. Of the initial 1511 patients, 1289 completed the study (643 in the control group; 646 in the education group). At the end of the study, significant reductions in HbA1c versus baseline were evident in both groups, but the reduction was greater in the education group (2.16% vs. 2.08%; P patients in the education group achieved target HbA1c levels patients in the education group showed greater increments in scores and improvement in the Morisky Medication Adherence Scale (P education can promote the ability of patients to self-manage and their compliance with medications, thereby achieving better outcomes. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

Glucotoxicity promotes aberrant activation and mislocalization of Ras-related C3 botulinum toxin substrate 1 [Rac1] and metabolic dysfunction in pancreatic islet β-cells: reversal of such metabolic defects by metformin.

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Baidwan, Sartaj; Chekuri, Anil; Hynds, DiAnna L; Kowluru, Anjaneyulu

2017-11-01

Emerging evidence suggests that long-term exposure of insulin-secreting pancreatic β-cells to hyperglycemic (HG; glucotoxic) conditions promotes oxidative stress, which, in turn, leads to stress kinase activation, mitochondrial dysfunction, loss of nuclear structure and integrity and cell apoptosis. Original observations from our laboratory have proposed that Rac1 plays a key regulatory role in the generation of oxidative stress and downstream signaling events culminating in the onset of dysfunction of pancreatic β-cells under the duress of metabolic stress. However, precise molecular and cellular mechanisms underlying the metabolic roles of hyperactive Rac1 remain less understood. Using pharmacological and molecular biological approaches, we now report mistargetting of biologically-active Rac1 [GTP-bound conformation] to the nuclear compartment in clonal INS-1 cells, normal rat islets and human islets under HG conditions. Our findings also suggest that such a signaling step is independent of post-translational prenylation of Rac1. Evidence is also presented to highlight novel roles for sustained activation of Rac1 in HG-induced expression of Cluster of Differentiation 36 [CD36], a fatty acid transporter protein, which is implicated in cell apoptosis. Finally, our findings suggest that metformin, a biguanide anti-diabetic drug, at a clinically relevant concentration, prevents β-cell defects [Rac1 activation, nuclear association, CD36 expression, stress kinase and caspase-3 activation, and loss in metabolic viability] under the duress of glucotoxicity. Potential implications of these findings in the context of novel and direct regulation of islet β-cell function by metformin are discussed.

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.

Results of the State Diabetes Mellitus Register in Bukhara, Navoi, Khorezm Regions and the Republic of Karakalpakstan

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N.M. Alikhanova

2016-04-01

Full Text Available Introduction. Diabetes mellitus (DM is an important medical and social problem. The objective of the study — to analyze the adequacy of the diagnosis and treatment of patients based on the results of the register in the four regions of the Republic of Uzbekistan. Materials and Methods. Among 14 214 patients with DM from Bukhara, Navoi, Khorezm regions and the Republic of Karakalpakstan, the analysis of card-registers has been performed. Results. Analysis of the register data in the four regions of Uzbekistan showed a lack of work on the diagnosis, treatment and prevention of diabetes complications. There is a lack of diagnosis and registration of complications of diabetic nephropathy and diabetic retinopathy in Bukhara, Khorezm regions, the Republic of Karakalpakstan, the lack of diagnosis and detection of macroangiopathy in Bukhara, Navoi, Khorezm regions, the Republic of Karakalpakstan. There is almost no achievement of target levels of glycemia in all regions, the regimen of intensive insulin therapy, as well as biguanide drugs, are administered not enough among patients with type 2 DM in all regions, which leads to an increased risk of diabetes complications. Physicians are not aware of macrovascular diabetic complications and the treatment of hypertension, angiotensin converting enzyme inhibitors (especially in the Khorezm region and the Republic of Karakalpakstan contributing to the prevention of diabetes complications, and in particular diabetic nephropathy, are underprescribed. Conclusions. Analysis of the register data in the four regions of Uzbekistan showed a lack of work on the diagnosis, treatment and prevention of DM complications.

A murine model of type 2 diabetes mellitus developed using a combination of high fat diet and multiple low doses of streptozotocin treatment mimics the metabolic characteristics of type 2 diabetes mellitus in humans.

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Nath, Sayantan; Ghosh, Sankar Kumar; Choudhury, Yashmin

A murine model of type 2 diabetes mellitus was used to compare the antidiabetic effects of the dipeptidyl peptidase-4 (DPP4) inhibitor vildagliptin and biguanide, metformin. Swiss albino mice (n=20 males; n=25 females) were given high fat diet (HFD) ad libitum for 3weeks followed by low dose (40mgkg -1 body weight, bw daily) of streptozotocin (STZ) intraperitoneally five times from the 22nd day of treatment onwards, with HFD continued up to 26th day. Controls (n=15 males; n=15 females) were fed normal balanced diet without administration of STZ. Successful induction of diabetes mellitus was confirmed by testing for fasting blood glucose, intraperitoneal glucose tolerance and intraperitoneal insulin sensitivity. Diabetic mice were administered vildagliptin (10mgkg -1 bw daily) and metformin (50mgkg -1 bw daily) orally for 4weeks. Control, diabetic, vildagliptin and metformin-treated diabetic mice were evaluated for alterations in lipid profile using blood serum and histopathology and oxidative stress using tissues including liver, kidney and heart. Diabetic mice showed significant alterations in lipid profile, tissue histopathology, impaired glucose tolerance, lower insulin sensitivity and elevated lipid peroxidation and protein carbonylation, with depressed catalase activity, when compared to age and gender-matched controls. Metformin and vildagliptin ameliorated the abovementioned diabetic conditions, with vildagliptin found to be more effective. A murine model developed by the combination of HFD and multiple low dose of STZ mimics the metabolic characteristics of type 2 diabetes mellitus in humans, and may be useful for antidiabetic drug screening. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Rapid increase in the use of oral antidiabetic drugs in the United States, 1990-2001.

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Wysowski, Diane K; Armstrong, George; Governale, Laura

2003-06-01

To describe the use of oral antidiabetic drugs for management of type 2 diabetes in the U.S. from 1990 through 2001. Data on oral antidiabetic drugs were derived from two pharmaceutical marketing databases from IMS Health, the National Prescription Audit Plus and the National Disease and Therapeutic Index. In 1990, 23.4 million outpatient prescriptions of oral antidiabetic agents were dispensed. By 2001, this number had increased 3.9-fold, to 91.8 million prescriptions. Glipizide and glyburide, two sulfonylurea medications, accounted for approximately 77% of prescriptions of oral antidiabetic drugs in 1990 and 35.5% of prescriptions in 2001. By 2001, the biguanide metformin (approved in 1995) had captured approximately 33% of prescriptions, and the thiazolidinedione insulin sensitizers (rosiglitazone and pioglitazone marketed beginning in 1999) accounted for approximately 17% of market share. Compared with patients treated in 1990, those in 2001 were proportionately younger and they more often used oral antidiabetic drugs and insulin in combination. Internists and general and family practitioners were the primary prescribers of this class of drugs. Consistent with the reported increase in the prevalence of type 2 diabetes, the number of dispensed outpatient prescriptions of oral antidiabetic drugs increased rapidly between 1990 and 2001. This period was marked by an increase in the treatment of younger people and the use of oral antidiabetic drugs in combination. With the approval in the last decade of several new types of oral antidiabetic medications with different mechanisms of action, options for management of type 2 diabetes have expanded.

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

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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.

Repositioning of Verrucosidin, a Purported Inhibitor of Chaperone Protein GRP78, as an Inhibitor of Mitochondrial Electron Transport Chain Complex I

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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

Non-contact lens related Acanthamoeba keratitis

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Prashant Garg

2017-01-01

Full Text Available The purpose of the study is to describe epidemiology, clinical features, diagnosis, and treatment of Acanthamoeba keratitis (AK with special focus on the disease in nonusers of contact lenses (CLs. This study was a perspective based on authors' experience and review of published literature. AK accounts for 2% of microbiology-proven cases of keratitis. Trauma and exposure to contaminated water are the main predisposing factors for the disease. Association with CLs is seen only in small fraction of cases. Contrary to classical description experience in India suggests that out of proportion pain, ring infiltrate, and radial keratoneuritis are seen in less than a third of cases. Majority of cases present with diffuse infiltrate, mimicking herpes simplex or fungal keratitis. The diagnosis can be confirmed by microscopic examination of corneal scraping material and culture on nonnutrient agar with an overlay of Escherichia coli. Confocal microscopy can help diagnosis in patients with deep infiltrate; however, experience with technique and interpretation of images influences its true value. Primary treatment of the infection is biguanides with or without diamidines. Most patients respond to medical treatment. Corticosteroids play an important role in the management and can be used when indicated after due consideration to established protocols. Surgery is rarely needed in patients where definitive management is initiated within 3 weeks of onset of symptoms. Lamellar keratoplasty has been shown to have good outcome in cases needing surgery. Since the clinical features of AK in nonusers of CL are different, it will be important for ophthalmologists to be aware of the scenario wherein to suspect this infection. Medical treatment is successful if the disease is diagnosed early and management is initiated soon.

Comparative study of in vitro release and mucoadhesivity of gastric-compacts composed of multiple unit system/bilayered discs using direct compression of metformin hydrochloride

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Mitra Jelvehgari

2014-03-01

Full Text Available Introduction: Metformin is an oral anti-diabetic drug in the biguanide class. The goal of this study was to develop gastric-retentive MH discs in order to prolong the retention of drug in gastric mucosa.Methods:Two groups of metformin hydrochloride (MH mucoadhesive gastroretentive discs were prepared: (a bilayered discs prepared by direct compression of powders containing polymers as Carbopol 934P (CP, mucoadhesive polymer and ethylcellulose (EC, rotardant polymer, (b multiple unit system (microparticle discs prepared by the emulsification, solvent evaporation, and compression technique from microparticles using polymers CP and EC. Gastric-mucoadhesive compacts were evaluated by investigating their release pattern, swelling capacity, mucoadhesion property, surface pH, and in vitro gastro-retentive time. Discs formulation was subjected to disintegration and dissolution tests by placing in 0.1 M hydrochloric acid for 8 h. Results: The production yield showed F2 microparticles of 98.80%, mean particle size of 933.25 µm and loading efficiency of 98.44%. The results showed that prepared microparticle discs had slower release than bilayered discs (p>0.05. The bilayered discs exhibited very good percentage of mucoadhesion. The results also showed a significant higher retention of mucoadhesive bilayered discs in upper gastrointestinal tract (F´1, 1:2 ratio of CP:EC. Histopathological studies revealed no gastric mucosal damage.Conclusion: Mucoadhesive multiple unit system/bilayered discs interact with mucus of gastrointestinal tract and are considered to be localized or trapped at the adhesive site by retaining a dosage form at the site of action as well as improving in the intimacy of contact with underlying absorptive membrane to achieve a better therapeutic performance of anti-diabetic drug.

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

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Unadike, B.C.; Akpan, N.A.; Essien, I.O.

2010-01-01

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)

Metformin: Multi-faceted protection against cancer

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Cufí, Sílvia; Oliveras-Ferraros, Cristina; Bosch-Barrera, Joaquim; Joven, Jorge; Martin-Castillo, Begoña; Menendez, Javier A.

2011-01-01

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

Impact of lens case hygiene guidelines on contact lens case contamination.

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Wu, Yvonne T; Teng, Yuu Juan; Nicholas, Mary; Harmis, Najat; Zhu, Hua; Willcox, Mark D P; Stapleton, Fiona

2011-10-01

Lens case contamination is a risk factor for microbial keratitis. The effectiveness of manufacturers' lens case cleaning guidelines in limiting microbial contamination has not been evaluated in vivo. This study compared the effectiveness of manufacturers' guidelines and an alternative cleaning regimen. A randomized cross-over clinical trial with two phases (n = 40) was performed. Participants used the lens types of their choice in conjunction with the provided multipurpose solution (containing polyhexamethylene biguanide) for daily wear. In the manufacturers' guideline phase, cases were rinsed with multipurpose solution and air dried. In the alternative regimen phase, cases were rubbed, rinsed with solution, tissue wiped, and air-dried face down. The duration of each phase was 1 month. Lens cases were collected at the end of each phase for microbiological investigation. The levels of microbial contamination were compared, and compliance to both regimens was assessed. The case contamination rate was 82% (32/39) in the manufacturers' guideline group, compared with 72% (28/39) in the alternative regimen group. There were significantly fewer (p = 0.004) colony forming units (CFU) of bacteria from cases used by following the alternative regimen (CFU range of 0 to 10, and median of 12 CFU per well) compared with that of the manufacturer's guidelines (CFU range of 0 to 10, and median of 28 CFU per well). The compliance level between both guidelines was not significantly different (p > 0.05). The alternative guidelines are more effective in eliminating microbial contamination from lens cases than that of the current manufacturer's guideline. Simply incorporating rubbing and tissue-wiping steps in daily case hygiene reduces viable organism contamination.

Potential use of germicides in vase solutions for gladiolus ‘White Friendship’

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Maria Carolina Casares

2017-03-01

Full Text Available Gladiolus (Gladiolus x hortulanus is one of the most important crops for cut flowers worldwide, however having a short longevity. Usually, stems are harvested at the bud stage and need water and carbohydrates to support inflorescence development and to ensure flower quality. Vase solutions can supply these elements. However, sugars may benefit bacterial proliferation, which eventually can block xylem vessels. Bactericides potentially inhibit microorganism proliferation and new compounds are being tested constantly. This experiment was conducted to evaluate ‘White Friendship’ cut gladiolus performance in vase solutions with sodium dichloroisocyanurate dihydrate (Na-DCC, 8-hydroxyquinoline (8-HQ or polymeric biguanide (PB. Inflorescences harvested at commercial maturity were placed in distilled water with 4% w/v of sucrose plus the germicides and kept under ambient conditions. Vase life, inflorescence postharvest development, fresh mass, membrane stability index and water relations were evaluated. There were no visual symptoms of toxicity in the treatments. The highest values of vase life, fully-open flowers, fresh mass and water balance were obtained with the Na-DCC treatment. Inflorescences treated with 8-HQ exhibited the highest values of solution uptake and wilting flowers. PB had a limited effect in gladiolus postharvest since the obtained results were similar to the sucrose alone. There was no effect of germicides on membrane stability index and its reduction was due to flower senescence progress only. Vase solution with Na-DCC plus sucrose improved water balance, increased open flowers, reduced wilting of flowers and fresh mass loss. Therefore, vase solutions with sucrose 4% w/v and Na-DCC enhance postharvest quality of cut gladiolus inflorescences.

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

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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.

Oxidative cleavage of the octyl side chain of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045) in rat and dog liver preparations.

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Umehara, K; Kudo, S; Hirao, Y; Morita, S; Uchida, M; Odomi, M; Miyamoto, G

2000-08-01

The metabolism of 1-(3,4-dichlorobenzyl)-5-octylbiguanide (OPB-2045), a new potent biguanide antiseptic, was investigated using rat and dog liver preparations to elucidate the mechanism of OPB-2045 metabolite formation, in which the octyl side chain is reduced to four, five, or six carbon atoms. Chemical structures of metabolites were characterized by 1H NMR, fast atom bombardment/mass spectrometry, and liquid chromatography/electrospray ionization-tandem mass spectrometry. Three main metabolites were observed during incubation of OPB-2045 with rat liver S9: 2-octanol (M-1), 3-octanol (M-2), and 4-octanol (M-3). In the incubation of OPB-2045 with dog liver S9, eight metabolites were observed, seven of which being M-1, M-2, M-3, 2-octanone (M-4), threo-2,3-octandiol (M-5), erythro-2,3-octandiol (M-6), and 1,2-octandiol (M-7). M-5 and M-6 were further biotransformed to a ketol derivative and C-C bond cleavage metabolite (hexanoic acid derivative), an in vivo end product, in the incubation with dog liver microsomes. The reactions required NADPH as a cofactor and were significantly inhibited by the various inhibitors of cytochrome P450 (i.e., CO, n-octylamine, SKF 525-A, metyrapone, and alpha-naphthoflavone). The results indicate that the degraded products of OPB-2045 are produced by C-C bond cleavage after monohydroxylation, dihydroxylation, and ketol formation at the site of the octyl side chain with possible involvement of cytochrome P450 systems. This aliphatic C-C bond cleavage by sequential oxidative reactions may play an important role in the metabolism of other drugs or endogenous compounds that possess aliphatic chains.

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

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

2015-01-01

Olanexidine gluconate [1-(3,4-dichlorobenzyl)-5-octylbiguanide gluconate] (development code OPB-2045G) is a new monobiguanide compound with bactericidal activity. In this study, we assessed its spectrum of bactericidal activity and mechanism of action. The minimal bactericidal concentrations of the compound for 30-, 60-, and 180-s exposures were determined with the microdilution method using a neutralizer against 320 bacterial strains from culture collections and clinical isolates. Based on the results, the estimated bactericidal olanexidine concentrations with 180-s exposures were 869 μg/ml for Gram-positive cocci (155 strains), 109 μg/ml for Gram-positive bacilli (29 strains), and 434 μg/ml for Gram-negative bacteria (136 strains). Olanexidine was active against a wide range of bacteria, especially Gram-positive cocci, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, and had a spectrum of bactericidal activity comparable to that of commercial antiseptics, such as chlorhexidine and povidone-iodine. In vitro experiments exploring its mechanism of action indicated that olanexidine (i) interacts with the bacterial surface molecules, such as lipopolysaccharide and lipoteichoic acid, (ii) disrupts the cell membranes of liposomes, which are artificial bacterial membrane models, (iii) enhances the membrane permeability of Escherichia coli, (iv) disrupts the membrane integrity of S. aureus, and (v) denatures proteins at relatively high concentrations (≥160 μg/ml). These results indicate that olanexidine probably binds to the cell membrane, disrupts membrane integrity, and its bacteriostatic and bactericidal effects are caused by irreversible leakage of intracellular components. At relatively high concentrations, olanexidine aggregates cells by denaturing proteins. This mechanism differs slightly from that of a similar biguanide compound, chlorhexidine. PMID:25987609

Acute metformin intoxication: 2012 experience of Emergency Departement of Lodi, Italy.

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Acquistapace, Giulia; Rossi, Marco; Garbi, Mara; Cosci, Pablo; Canetta, Ciro; Manelli, Anna; Ricevuti, Giovanni

2014-10-01

Background: Metformin is a biguanide antihyperglycemic agent that decreases insulin resistance. It is removed through renal mechanisms and its clearance is reduced in renal failure. Metformin ingestion should always be considered in the differential diagnosis of any patient with metabolic acidosis and increased lactate level. Hemodialysis and continuous veno-venous hemofiltration (CVVH) are both efficient methods to treat metformin intoxication and correct metabolic abnormalities. Patient 1: A 63-year-old man with type 2 diabetes mellitus presented to emergency department (ED) of Lodi (Italy) for dyspnea. He also reported having diarrhea for 10 days. Initial investigations revealed metabolic acidosis with hyperlactatemia and hypoglycemia (54 mg/dL), metformin concentration was 41 μg/mL (normal value <4 μg/mL). His hemodynamic condition became rapidly unstable and hypotension worsened despite CVVH being performed. Death occurred in 24 h. Patient 2: A 76-year-old man with type 2 diabetes mellitus presented to ED of Lodi for dyspnea. He referred a recent surgery amputation of the left foot's fifth phalanx for osteomyelitis, in levofloxacin therapy. Initial investigations revealed metabolic acidosis with hyperlactatemia and severe hypoglycemia (20 mg/dL). Two hemodialysis sessions were performed with complete normalization of the serum concentration of metformin. In our two cases the genesis of metformin intoxication was clear, powered by acute renal failure, but less obvious was the etiology of acute renal damage responsible for metformin accumulation. Damage due to renal hypoperfusion or the direct toxic effect of metformin should be considered. Additionally, for the second patient, we can also hypothesize that interstitial nephritis was exacerbated by levofloxacin.

Effect of poly-hexamethylene biguanide hydrochloride (PHMB) treated non-sterile medical gloves upon the transmission of Streptococcus pyogenes, carbapenem-resistant E. coli, MRSA and Klebsiella pneumoniae from contact surfaces.

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Ali, S; Wilson, A P R

2017-08-17

Reduction of accidental contamination of the near-patient environment has potential to reduce acquisition of healthcare-associated infection(s). Although medical gloves should be removed when soiled or touching the environment, compliance is variable. The use of antimicrobial-impregnated medical gloves could reduce the horizontal-transfer of bacterial contamination between surfaces. Determine the activity of antimicrobial-impregnated gloves against common hospital pathogens: Streptococcus pyogenes, carbapenem-resistant E.coli (CREC), MRSA and ESBL-producing Klebsiella pneumoniae. Fingerpads (~1cm 2 ) of PHMB-treated and untreated gloves were inoculated with 10 μL (~10 4 colony-forming-units [cfu]) of test-bacteria prepared in heavy-soiling (0.5%BSA), blood or distilled-water (no-soiling) and sampled after 0.25, 1, 10 or 15 min contact-time. Donor surfaces (~1cm 2 computer-keys) contaminated with wet/dry inoculum were touched with the fingerpad of treated/untreated gloves and subsequently pressed onto recipient (uncontaminated) computer-keys. Approximately 4.50log 10 cfu of all bacteria persisted after 15 min on untreated gloves regardless of soil-type. In the absence of soiling, PHMB-treated gloves reduced surface-contamination by ~4.5log 10 cfu (>99.99%) within 10 min of contact-time but only ~2.5log 10 (>99.9%) and ~1.0log 10 reduction respectively when heavy-soiling or blood was present. Gloves became highly-contaminated (~4.52log 10 -4.91log 10 cfu) when handling recently-contaminated computer-keys. Untreated gloves contaminated "recipient" surfaces (~4.5log 10 cfu) while PHMB-treated gloves transferred fewer bacteria (2.4-3.6log 10 cfu). When surface contamination was dry, PHMB gloves transferred fewer bacteria (0.3-0.6log 10 cfu) to "recipient" surfaces than untreated gloves (1.0-1.9log 10 ; P gloves may be useful in preventing dissemination of organisms in the near-patient environment during routine care. However they are not a substitute for appropriate hand-hygiene procedures.

Familial diabetes is associated with reduced risk of cancer in diabetic patients: a possible role for metformin.

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Berstein, Lev M; Boyarkina, Marina P; Teslenko, Svetlana Yu

2012-06-01

Type 2 diabetes mellitus (DM2) is a risk factor of a number of malignancies. Therefore, it is important to identify factors linking DM2 and cancer within family units and how current treatment regimens influence the development of cancer in DM2 patients. The present case-controlled study was designed to assess DM2 prevalence among parents or siblings of (a) cancer patients who did not have diabetes (n = 77; age 59.3 ± 1.3 years) or (b) had overt (n = 197; 63.7 ± 0.6 years) or latent (n = 25; 61.5 ± 1.5 years) DM2 and (c) of female DM2 patients without cancer (n = 172; 61.7 ± 0.6 years). In the families of cancer-free DM2 women, DM2 was found to be significantly more frequent (30.8 ± 3.5%) than in families of cancer patients without diabetes (in all patients: 6.5 ± 2.8%; in female patients: 5.0 ± 3.4%). More importantly, DM2 in families of cancer-free DM2 women was more frequent than in the families of DM2 patients having mammary (9.5 ± 4.5%), endometrial (6.3 ± 4.1%) or any other cancer (in all: 15.2 ± 2.6%; in women: 12.9 ± 2.8%). Additionally, DM2 patients without cancer, who had parents or siblings with DM2, received biguanide metformin versus sulfonylurea derivatives more often than those with breast or endometrial cancer, either with or without family history of DM2. Our data indicate that familial DM2 may have a protective effect for some cancer types and that the type of anti-diabetes therapy may be a factor of influence in the associations observed.

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

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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

The diabetes medication Canagliflozin reduces cancer cell proliferation by inhibiting mitochondrial complex-I supported respiration

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Linda A. Villani

2016-10-01

Full Text Available Objective: The sodium-glucose transporter 2 (SGLT2 inhibitors Canagliflozin and Dapagliflozin are recently approved medications for type 2 diabetes. Recent studies indicate that SGLT2 inhibitors may inhibit the growth of some cancer cells but the mechanism(s remain unclear. Methods: Cellular proliferation and clonogenic survival were used to assess the sensitivity of prostate and lung cancer cell growth to the SGLT2 inhibitors. Oxygen consumption, extracellular acidification rate, cellular ATP, glucose uptake, lipogenesis, and phosphorylation of AMP-activated protein kinase (AMPK, acetyl-CoA carboxylase, and the p70S6 kinase were assessed. Overexpression of a protein that maintains complex-I supported mitochondrial respiration (NDI1 was used to establish the importance of this pathway for mediating the anti-proliferative effects of Canagliflozin. Results: Clinically achievable concentrations of Canagliflozin, but not Dapagliflozin, inhibit cellular proliferation and clonogenic survival of prostate and lung cancer cells alone and in combination with ionizing radiation and the chemotherapy Docetaxel. Canagliflozin reduced glucose uptake, mitochondrial complex-I supported respiration, ATP, and lipogenesis while increasing the activating phosphorylation of AMPK. The overexpression of NDI1 blocked the anti-proliferative effects of Canagliflozin indicating reductions in mitochondrial respiration are critical for anti-proliferative actions. Conclusion: These data indicate that like the biguanide metformin, Canagliflozin not only lowers blood glucose but also inhibits complex-I supported respiration and cellular proliferation in prostate and lung cancer cells. These observations support the initiation of studies evaluating the clinical efficacy of Canagliflozin on limiting tumorigenesis in pre-clinical animal models as well epidemiological studies on cancer incidence relative to other glucose lowering therapies in clinical populations. Keywords: AMP

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

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

2013-01-01

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

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.

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.

Predictors of mortality subsequent to a fracture in diabetes mellitus patients

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Jakob eStarup-Linde

2015-04-01

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

AMPK Signaling Involvement for the Repression of the IL-1β-Induced Group IIA Secretory Phospholipase A2 Expression in VSMCs.

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Khadija El Hadri

Full Text Available Secretory Phospholipase A2 of type IIA (sPLA2 IIA plays a crucial role in the production of lipid mediators by amplifying the neointimal inflammatory context of the vascular smooth muscle cells (VSMCs, especially during atherogenesis. Phenformin, a biguanide family member, by its anti-inflammatory properties presents potential for promoting beneficial effects upon vascular cells, however its impact upon the IL-1β-induced sPLA2 gene expression has not been deeply investigated so far. The present study was designed to determine the relationship between phenformin coupling AMP-activated protein kinase (AMPK function and the molecular mechanism by which the sPLA2 IIA expression was modulated in VSMCs. Here we find that 5-aminoimidazole-4-carboxamide-1-β-D-ribonucleotide (AICAR treatment strongly repressed IL-1β-induced sPLA2 expression at least at the transcriptional level. Our study reveals that phenformin elicited a dose-dependent inhibition of the sPLA2 IIA expression and transient overexpression experiments of constitutively active AMPK demonstrate clearly that AMPK signaling is involved in the transcriptional inhibition of sPLA2-IIA gene expression. Furthermore, although the expression of the transcriptional repressor B-cell lymphoma-6 protein (BCL-6 was markedly enhanced by phenformin and AICAR, the repression of sPLA2 gene occurs through a mechanism independent of BCL-6 DNA binding site. In addition we show that activation of AMPK limits IL-1β-induced NF-κB pathway activation. Our results indicate that BCL-6, once activated by AMPK, functions as a competitor of the IL-1β induced NF-κB transcription complex. Our findings provide insights on a new anti-inflammatory pathway linking phenformin, AMPK and molecular control of sPLA2 IIA gene expression in VSMCs.

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

Racial/ethnic disparities in prevalence and care of patients with type 2 diabetes mellitus.

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Ferdinand, Keith C; Nasser, Samar A

2015-05-01

As of 2012, nearly 10% of Americans had diabetes mellitus. People with diabetes are at approximately double the risk of premature death compared with those in the same age groups without the condition. While the prevalence of diabetes has risen across all racial/ethnic groups over the past 30 years, rates are higher in minority populations. The objective of this review article is to evaluate the prevalence of diabetes and disease-related comorbidities as well as the primary endpoints of clinical studies assessing glucose-lowering treatments in African Americans, Hispanics, and Asians. As part of our examination of this topic, we reviewed epidemiologic and outcome publications. Additionally, we performed a comprehensive literature search of clinical trials that evaluated glucose-lowering drugs in racial minority populations. For race/ethnicity, we used the terms African American, African, Hispanic, and Asian. We searched PubMed for clinical trial results from 1996 to 2015 using these terms by drug class and specific drug. Search results were filtered qualitatively. Overall, the majority of publications that fit our search criteria pertained to native Asian patient populations (i.e., Asian patients in Asian countries). Sulfonylureas; the α-glucosidase inhibitor, miglitol; the biguanide, metformin; and the thiazolidinedione, rosiglitazone have been evaluated in African American and Hispanic populations, as well as in Asians. The literature on other glucose-lowering drugs in non-white races/ethnicities is more limited. Clinical data are needed for guiding diabetes treatment among racial minority populations. A multi-faceted approach, including vigilant screening in at-risk populations, aggressive treatment, and culturally sensitive patient education, could help reduce the burden of diabetes on minority populations. To ensure optimal outcomes, educational programs that integrate culturally relevant approaches should highlight the importance of risk-factor control in

Effectiveness of various cleaning and disinfectant products on Clostridium difficile spores of PCR ribotypes 010, 014 and 027

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N. Kenters

2017-06-01

Full Text Available Abstract Background In healthcare facilities, Clostridium difficile infections spread by transmission of bacterial spores. Appropriate sporicidal disinfectants are needed to prevent development of clusters and outbreaks. In this study different cleaning/disinfecting wipes and sprays were tested for their efficacy against spores of distinctive C. difficile PCR ribotypes. Methods Four different products were tested; 1 hydrogen peroxide 1.5%; 2 glucoprotamin 1.5%; 3 a mixture of ethanol, propane and N-alkyl amino propyl glycine; and 4 a mixture of didecyldimonium chloride, benzalkonium chloride, polyaminopropyl, biguanide and dimenthicone as active ingredients. Tiles were contaminated with a test solution containing a concentration of 5x106CFU/ml spores of C. difficile strains belonging to PCR ribotypes 010, 014 or 027. The tiles were left to dry for an hour and then wiped or sprayed with one of the sprays or wipes as intended by the manufacturers. When products neutralized after 5 min, microbiological cultures and ATP measures were performed. Results Irrespective of the disinfection method, the microbial count log10 reduction of C. difficile PCR ribotype 010 was highest, followed by the reduction of C. difficile 014 and C. difficile 027. Overall, the wipes performed better than the sprays with the same active ingredient. On average, although not significantly, a difference in relative light units (RLU reduction between the wipes and sprays was found. The wipes had a higher RLU log10 reduction, but no significant difference for RLU reduction was observed between the different C. difficile strains (p = 0.16. Conclusion C. difficile spores of PCR ribotypes 014 and 027 strains are more difficult to eradicate than non-toxigenic PCR ribotype 010. In general, impregnated cleaning/disinfection wipes performed better than ready-to-use sprays. Wipes with hydrogen peroxide (1.5% showed the highest bactericidal activity.

Metformin and Its Sulfenamide Prodrugs Inhibit Human Cholinesterase Activity

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Magdalena Markowicz-Piasecka

2017-01-01

Full Text Available The results of epidemiological and pathophysiological studies suggest that type 2 diabetes mellitus (T2DM may predispose to Alzheimer’s disease (AD. The two conditions present similar glucose levels, insulin resistance, and biochemical etiologies such as inflammation and oxidative stress. The diabetic state also contributes to increased acetylcholinesterase (AChE activity, which is one of the factors leading to neurodegeneration in AD. The aim of this study was to assess in vitro the effects of metformin, phenformin, and metformin sulfenamide prodrugs on the activity of human AChE and butyrylcholinesterase (BuChE and establish the type of inhibition. Metformin inhibited 50% of the AChE activity at micromolar concentrations (2.35 μmol/mL, mixed type of inhibition and seemed to be selective towards AChE since it presented low anti-BuChE activity. The tested metformin prodrugs inhibited cholinesterases (ChE at nanomolar range and thus were more active than metformin or phenformin. The cyclohexyl sulfenamide prodrug demonstrated the highest activity towards both AChE (IC50 = 890 nmol/mL, noncompetitive inhibition and BuChE (IC50 = 28 nmol/mL, mixed type inhibition, while the octyl sulfenamide prodrug did not present anti-AChE activity, but exhibited mixed inhibition towards BuChE (IC50 = 184 nmol/mL. Therefore, these two bulkier prodrugs were concluded to be the most selective compounds for BuChE over AChE. In conclusion, it was demonstrated that biguanides present a novel class of inhibitors for AChE and BuChE and encourages further studies of these compounds for developing both selective and nonselective inhibitors of ChEs in the future.

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

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Kato, Haruo; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

2015-01-01

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

Clinical usage of hypolipidemic and antidiabetic drugs in the prevention and treatment of cancer.

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Berstein, Lev M

2005-06-28

Factors predisposing hormone-dependent tissues to the development of tumors coincide, at least partly, with hormonal-metabolic promoters (like insulin resistance, glucose intolerance, visceral obesity, etc.) of other main non-communicable diseases. This important knowledge poses the question of whether the same approach which is applied for prevention/treatment of a metabolic syndrome and the associated endocrine disorders might also be used in preventive and therapeutic oncology. Whereas an answer to this question remains controversial and is based mainly on experimental evidence, there is accumulating clinical data suggesting a practical significance of such a strategy, even though it is not to be considered as directly cytostatic. Among the many drugs under discussion, three groups of medicines (statins, antidiabetic biguanides, and thiazolidinediones) are the most attractive. The concept of metabolic rehabilitation is proposed and used practically in an adjuvant setting for the correction of the above-mentioned endocrine-metabolic disorders commonly found in cancer patients. The current use and aim of this approach is to improve the survival of patients and limit cancer progression. Nonetheless, it also appears potentially useful as a neoadjuvant therapy as well as a prophylactic treatment earlier in life for specific groups of people with hormone-associated enhanced oncological risk. It seems possible that certain hypolipidemic and antidiabetic medicines with pleiotropic effects might be combined with traditional antisteroid prevention/therapeutic approaches in routine clinical situations as well as for overcoming resistance to standard cancer hormonal therapies including receptor-negative cases. Characteristic at the end of the 20th and at the beginning of the 21st century is an epidemic of diabetes and obesity, which might further increase the incidence of certain cancers. This makes it timely to apply hypolipidemic and antidiabetic drugs (in combination

5-HT receptors as novel targets for optimizing pigmentary responses in dorsal skin melanophores of frog, Hoplobatrachus tigerinus

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Ali, Sharique A; Salim, Saima; Sahni, Tarandeep; Peter, Jaya; Ali, Ayesha S

2012-01-01

BACKGROUND AND PURPOSE Biochemical identification of 5-HT has revealed similar projection patterns across vertebrates. In CNS, 5-HT regulates major physiological functions but its peripheral functions are still emerging. The pharmacology of 5-HT is mediated by a diverse range of receptors that trigger different responses. Interestingly, 5-HT receptors have been detected in pigment cells indicating their role in skin pigmentation. Hence, we investigated the role of this monoaminergic system in amphibian pigment cells, melanophores, to further our understanding of its role in pigmentation biology together with its evolutionary significance. EXPERIMENTAL APPROACH Pharmacological profiling of 5-HT receptors was achieved using potent/selective agonists and antagonists. In vitro responses of melanophores were examined by Mean Melanophores Size Index assay. The melanophores of lower vertebrates are highly sensitive to external stimuli. The immediate cellular responses to drugs were defined in terms of pigment translocation within the cells. KEY RESULTS 5-HT exerted strong concentration-dependent pigment dispersion at threshold dose of 1 × 10−6 g·mL−1. Specific 5-HT1 and 5-HT2 receptor agonists, sumatriptan and myristicin. also induced dose-dependent dispersion. Yohimbine and metergoline synergistically antagonized sumatriptan-mediated dispersion, whereas trazodone partially blocked myristicin-induced dispersion. Conversely, 5-HT3 and 5-HT4 receptor agonists, 1 (3 chlorophenyl) biguanide (1,3 CPB) and 5-methoxytryptamine (5-MT), caused a dose-dependent pigment aggregation. The aggregatory effect of 1,3 CPB was completely blocked by ondansetron, whereas L-lysine partially blocked the effect of 5-MT. CONCLUSIONS AND IMPLICATIONS The results suggest that 5-HT-induced physiological effects are mediated via distinct classes of receptors, which possibly participate in the modulation of pigmentary responses in amphibian. PMID:21880033

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

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

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

2015-05-22

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

Systemic medication and intraocular pressure in a British population: the EPIC-Norfolk Eye Study.

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Khawaja, Anthony P; Chan, Michelle P Y; Broadway, David C; Garway-Heath, David F; Luben, Robert; Yip, Jennifer L Y; Hayat, Shabina; Wareham, Nicholas J; Khaw, Kay-Tee; Foster, Paul J

2014-08-01

To determine the association between systemic medication use and intraocular pressure (IOP) in a population of older British men and women. Population-based, cross-sectional study. We included 7093 participants from the European Prospective Investigation into Cancer-Norfolk Eye Study. Exclusion criteria were a history of glaucoma therapy (medical, laser, or surgical), IOP asymmetry between eyes of >5 mmHg, and missing data for any covariables. The mean age of participants was 68 years (range, 48-92) and 56% were women. We measured IOP using the Ocular Response Analyzer. Three readings were taken per eye and the best signal value of the Goldmann-correlated IOP value considered. Participants were asked to bring all their medications and related documentation to the health examination, and these were recorded by the research nurse using an electronic case record form. The medication classes examined were angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, α-blockers, β-blockers, calcium channel blockers, diuretics, nitrates, statins, insulin, biguanides, sulfonylureas, aspirin, and other nonsteroidal anti-inflammatory drugs. We examined associations between medication use and IOP using multivariable linear regression models adjusted for age, sex, and body mass index. Models containing diabetic medication were further adjusted for glycosylated hemoglobin levels. Mean IOP of the right and left eyes. Use of systemic β-blockers (-0.92 mmHg; 95% CI, -1.19, -0.65; Pnitrates (-0.63 mmHg; 95% CI, -1.12, -0.14; P = 0.011) were independently associated with lower IOP. The observed associations between statin or aspirin use with IOP were no longer significant after adjustment for β-blocker use. This is the first population-based study to demonstrate and quantify clinically significant differences in IOP among participants using systemic β-blockers or nitrates. Lower IOP observed in participants using statins or aspirin was explained by concurrent

[A clinical case of development of lactic acid acidosis in a diabetic patient taking metformin].

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Cesur, Mustafa; Cekmen, Nedum; Cetinbas, Riza R; Badalov, Pavel; Erdemli, Ozcan

2006-01-01

Metformin is a biguanide. Due to its effects in suppressing the hepatic production of endogenous glucose and in increasing insulin sensitivity in adipose tissue and skeletal muscle, the agent is used particularly in type 2 diabetes mellitus and metabolic syndrome, in which insulin resistance is especially pronounced. Lactic acidosis is one of the most important side effects of metformin. A male patient, born in 1923, was admitted to the emergency unit of our hospital for sudden vertigo, weakness, dyspnea, cyanosis, and lethargy. His history data showed that the patient had been suffering from type 2 diabetes mellitus for 10 years and taking Glargin (insulin), 12 U/kg, once daily and Glucophage (metformin), 850 mg thrice daily. The patient's general condition was fair; stupor, time and spatial orientation were absent. Analysis of arterial blood gases showed the presence of metabolic acidosis, hypokalemia, hypoxemia, and hypercapnia. Thereafter the patient was transferred to the intensive care unit of the hospital; intubated and connected to a T-bird ventilation apparatus. On the following day, an analysis of arterial blood gases indicated the proximity of the results to their physiological parameters. Ventilation was stopped; and monitoring of the patient continued by following the T-shape type of ventilation discontinuation. There were no X-ray signs of pneumonia or pulmonary edema. On the same day, the patient was extubated and oxygen inhalation in a dose of L/min was continued through a mask. On day 4 since therapy was initiated, the patient's vital signs, serum sugar and lactate levels became normal. By determining a new treatment regimen, the patient was discharged from the intensive care unit. Dyspnea, acidosis, and hypoxia developed in the patient resulted from lactic acidosis caused by the use of metformin. It should be remembered that dyspnea, acidosis, and hypoxia, which suddenly developed in metformin-treated patients with type 2 diabetes mellitus, may be

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

Metformin Mitigates Fibrosis and Glucose Intolerance Induced by Doxorubicin in Subcutaneous Adipose Tissue

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Luana A. Biondo

2018-05-01

Full Text Available Doxorubicin (DX is a chemotherapeutic drug that is used in clinical practice that promotes deleterious side effects in non-tumor tissues such as adipose tissue. We showed that DX leads to extensive damage in adipose tissue via a disruption in 5′-adenosine monophosphate-activated protein kinase (AMPK and PPAR-gamma signaling. Thus, we investigated whether co-treatment with the biguanide drug metformin (MET could prevent the side effects of DX through the activation of AMPK in adipose tissue. The goal of the present study was to verify the effects of DX and adjuvant MET treatment in subcutaneous adipose tissue (SAT and to determine whether MET could protect against chemotherapy-induced side effects. C57/BL6 mice received DX hydrochloride (2.5 mg/kg intraperitoneally 2 times per week for 2 weeks (DX, concomitantly or not, with MET administration (300 mg/kg oral daily (DX + MET. The control group (CTRL was pair-fed according to the food consumption of the DX group. After euthanasia, adipose tissue fat pads were collected, and SAT was extracted so that adipocytes could be isolated. Glucose uptake was then measured, and histological, gene, and protein analyses were performed. One-way analysis of variance was also performed, and significance was set to 5%. DX reduced retroperitoneal fat mass and epididymal pads and decreased glycemia. In cultured primary subcutaneous adipocytes, mice in the DX group had lower glucose uptake when stimulated with insulin compared with mice in the CTRL group. Adipocytes in the DX group exhibited a reduced area, perimeter, and diameter; decreased adiponectin secretion; and decreased fatty acid synthase gene expression. SAT from MET-treated mice also showed a reduction in collagen deposition. Treatment with MET prevented fibrosis and restored glucose uptake in SAT after insulin stimulation, yet the drug was unable to prevent other side effects of DX such as tissue loss and inflammatory response.

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

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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

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

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

2016-07-19

The incidence of type 2 diabetes in pregnancy is rising and rates of serious adverse maternal and fetal outcomes remain high. Metformin is a biguanide that is used as first-line treatment for non-pregnant patients with type 2 diabetes. We hypothesize that metformin use in pregnancy, as an adjunct to insulin, will decrease adverse outcomes by reducing maternal hyperglycemia, maternal insulin doses, maternal weight gain and gestational hypertension/pre-eclampsia. In addition, since metformin crosses the placenta, metformin treatment of the fetus may have a direct beneficial effect on neonatal outcomes. Our aim is to compare the effectiveness of the addition of metformin to insulin, to standard care (insulin plus placebo) in women with type 2 diabetes in pregnancy. The MiTy trial is a multi-centre randomized trial currently enrolling pregnant women with type 2 diabetes, who are on insulin, between the ages of 18-45, with a gestational age of 6 weeks 0 days to 22 weeks 6 days. In this randomized, double-masked, parallel placebo-controlled trial, after giving informed consent, women are randomized to receive either metformin 1,000 mg twice daily or placebo twice daily. A web-based block randomization system is used to assign women to metformin or placebo in a 1:1 ratio, stratified for site and body mass index. The primary outcome is a composite neonatal outcome of pregnancy loss, preterm birth, birth injury, moderate/severe respiratory distress, neonatal hypoglycemia, or neonatal intensive care unit admission longer than 24 h. Secondary outcomes are large for gestational age, cord blood gas pH pregnancy, and duration of hospital stays. The trial aims to enroll 500 participants. The results of this trial will inform endocrinologists, obstetricians, family doctors, and other healthcare professionals caring for women with type 2 diabetes in pregnancy, as to the benefits of adding metformin to insulin in this high risk population. ClinicalTrials.gov Identifier: no

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

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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.

Systemic Medication and Intraocular Pressure in a British Population

Science.gov (United States)

Khawaja, Anthony P.; Chan, Michelle P.Y.; Broadway, David C.; Garway-Heath, David F.; Luben, Robert; Yip, Jennifer L.Y.; Hayat, Shabina; Wareham, Nicholas J.; Khaw, Kay-Tee; Foster, Paul J.

2014-01-01

Objective To determine the association between systemic medication use and intraocular pressure (IOP) in a population of older British men and women. Design Population-based, cross-sectional study. Participants We included 7093 participants from the European Prospective Investigation into Cancer–Norfolk Eye Study. Exclusion criteria were a history of glaucoma therapy (medical, laser, or surgical), IOP asymmetry between eyes of >5 mmHg, and missing data for any covariables. The mean age of participants was 68 years (range, 48–92) and 56% were women. Methods We measured IOP using the Ocular Response Analyzer. Three readings were taken per eye and the best signal value of the Goldmann-correlated IOP value considered. Participants were asked to bring all their medications and related documentation to the health examination, and these were recorded by the research nurse using an electronic case record form. The medication classes examined were angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, α-blockers, β-blockers, calcium channel blockers, diuretics, nitrates, statins, insulin, biguanides, sulfonylureas, aspirin, and other nonsteroidal anti-inflammatory drugs. We examined associations between medication use and IOP using multivariable linear regression models adjusted for age, sex, and body mass index. Models containing diabetic medication were further adjusted for glycosylated hemoglobin levels. Main Outcome Measures Mean IOP of the right and left eyes. Results Use of systemic β-blockers (−0.92 mmHg; 95% CI, −1.19, −0.65; Pnitrates (−0.63 mmHg; 95% CI, −1.12, −0.14; P = 0.011) were independently associated with lower IOP. The observed associations between statin or aspirin use with IOP were no longer significant after adjustment for β-blocker use. Conclusions This is the first population-based study to demonstrate and quantify clinically significant differences in IOP among participants using systemic β-blockers or

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

Diabetes mellitus en el anciano, un problema frecuente Diabetes mellitus present in elderly, a common problem

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Marelys Yanes Quesada

2009-09-01

Full Text Available La presencia de diabetes mellitus en la población anciana es un problema de salud frecuente en la atención primaria. Es por ello que en el presente trabajo pretendemos revisar algunos elementos importantes de este tema. Esta entidad se presenta habitualmente en estos pacientes, oligosintomática o de manera atípica, y los objetivos terapéuticos dependen de la situación funcional del enfermo. En relación con el tratamiento no farmacológico, la educación, la dieta y el ejercicio físico constituyen los pilares básicos; y respecto a la terapéutica farmacológica, se deben evitar las sulfonilureas de acción prolongada y de gran potencia. Las biguanidas pueden ser usadas para mejorar la sensibilidad a la insulina, y los inhibidores de la alfa glucosidasa son los medicamentos de elección cuando predomina la hiperglucemia posprandial. Las tiazolidinedionas deben ser usadas con precaución en pacientes con riesgo cardiovascular, y el uso de insulina está indicado en circunstancias especiales. Siempre se debe tener presente el tratamiento de la comorbilidad, para así tratar integralmente al anciano con diabetes mellitus.Presence of diabetes mellitus in elderlies is a common health problem in primary care. Thus, the aim of present paper is to review some significant elements of this matter. This entity is habitually present in these patients in a olisymptomatic way of in a atypical form, and therapeutic objectives depend on functional status of patient. With regard to non-pharmacological treatment, the education, diet, and physical exercise are the main basis; and regarding the pharmacological therapeutics, sulfonylurea of lengthy action and very potent must to be avoided. Biguanides may be used to improve insulin-sensitivity, and a-glycosidase inhibitors are the choice drugs when there is a predominance of postprandial hyperglycemia. The thiazolidinediones must to be used with precaution in patients presenting with cardiovascular risk, and

Patient characteristics, diagnosis, and treatment of non-contact lens related Acanthamoeba keratitis.

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Sharma, S; Garg, P; Rao, G N

2000-10-01

To review the clinical characteristics, diagnosis, and visual outcome in patients with non-contact lens related Acanthamoeba keratitis and compare the findings with reported series of contact lens associated Acanthamoeba keratitis. Medical and microbiology records of 39 consecutive patients with a diagnosis of Acanthamoeba keratitis, at a tertiary eyecare centre in India between January 1996 and June 1998, were analysed retrospectively. A majority of the patients presented with poor visual acuity and large corneal stromal infiltrates (mean size 38.20 (SD 26. 18) mm). A predisposing factor was elicited in 19/39 (48.7%) patients (trauma 15, dirty water splash three, leaf juice one). None of the patients had worn contact lenses. Most patients (26/39 (66. 6%)) came from a low socioeconomic background. Complaint of severe pain was not a significant feature and radial keratoneuritis was seen in 1/39 (2.5%) patients. A ring infiltrate was present in 41.1% of cases. A clinical diagnosis of fungal keratitis was made in 45% of the patients before they were seen by us. However, all patients were diagnosed microbiologically at our institute based on demonstration of Acanthamoeba cysts in corneal scrapings (34/39) and/or culture of Acanthamoeba (34/39). Treatment with biguanides (PHMB, 15/38 (39.4%), PHMB with CHx, 23/38 (60.5%), one patient did not return for treatment) resulted in healing with scar formation in 27 out of 31(87.0%) followed up patients (mean time to healing 106.9 days). Overall visual outcome was poor with no statistical difference between cases diagnosed within 30 days (early) or 30 days after (late) start of symptoms. The visual outcome in cases requiring tissue adhesive (five) and keratoplasty (three) was also poor. This is thought to be the largest series of cases of Acanthamoeba keratitis in non-contact lens wearers. In such cases, the disease is advanced at presentation in most patients, pathognomonic clinical features are often not seen, disease

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

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Sabatini Mary E

2011-05-01

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

Occurrence of the antidiabetic drug Metformin and its ultimate transformation product Guanylurea in several compartments of the aquatic cycle.

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Trautwein, Christoph; Berset, Jean-Daniel; Wolschke, Hendrik; Kümmerer, Klaus

2014-09-01

In 2030, the World Health Organization estimates that more than 350 million people will be diagnosed with diabetes. Consequently, Metformin - the biguanide drug of choice orally administered for diabetes type II - is anticipated to see a spike in production. Unlike many pharmaceutical drugs, Metformin (Met) is not metabolized by humans but passes through the body unchanged. Entering aquatic compartments, such as in sewage, it can be bacterially transformed to the ultimate transformation product Guanylurea (Gua). Sampling over one week (n=5) from a Southern German sewage treatment plant revealed very high average (AV) concentrations in influent (AVMet=111,800ng/L, AVGua=1300ng/L) and effluent samples (AVMet=4800ng/L, AVGua=44,000ng/L). To provide a more complete picture of the distribution and potential persistence of these compounds in the German water cycle, a new, efficient and highly sensitive liquid chromatography mass spectrometric method with direct injection was used for the measurement of Metformin and Guanylurea in drinking, surface, sewage and seawater. Limits of quantification (LOQ) ranging from 2-10ng/L allowed the detection of Metformin and Guanylurea in different locations such as: Lake Constance (n=11: AVMet=102ng/L, AVGua=16ng/L), river Elbe (n=12: AVMet=472ng/L, AVGua=9ng/L), river Weser (n=6: AVMet=349ng/L, AVGua=137ng/L) and for the first time in marine North Sea water (n=14: AVMet=13ng/L, AVGua=11ng/L). Based on daily water discharges, Metformin loads of 15.2kg/d (Elbe) and 6.4kg/d (Weser) into the North Sea were calculated. Lake Constance is used to abstract potable water which is further purified to be used as drinking water. A first screening of two tap water samples contained 2ng/L and 61ng/L of Metformin, respectively. The results of this study suggest that Metformin and Guanylurea could be distributed over a large fraction of the world's potable water sources and oceans. With no natural degradation processes, these compounds can be easily

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

International Nuclear Information System (INIS)

Higurashi, Takuma; Fujisawa, Nobutaka; Uchiyama, Shiori; Ezuka, Akiko; Nagase, Hajime; Kessoku, Takaomi; Matsuhashi, Nobuyuki; Yamanaka, Shoji; Inayama, Yoshiaki; Morita, Satoshi; Nakajima, Atsushi; Takahashi, Hirokazu; Endo, Hiroki; Hosono, Kunihiro; Yamada, Eiji; Ohkubo, Hidenori; Sakai, Eiji; Uchiyama, Takashi; Hata, Yasuo

2012-01-01

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

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

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Loos, Julia A.; Cumino, Andrea C.

2015-01-01

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

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

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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

DIABETES MELLITUS IN PATIENTS WITH LIVER CIRRHOSIS: NEW TREATMENT OPTIONS

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L. Yu. Morgunov

2017-01-01

connection with the emergence of modern groups of hypoglycemic drugs, as well as new approaches to the treatment of type 2 diabetes, this concept has radically changed. Unfortunately, the issues of correction of carbohydrate metabolism in patients with cirrhosis of the liver are practically not covered in the world literature. This article deals with the correction of carbohydrate metabolism in patients with cirrhosis and hepatocellular insufficiency of insulin analogs, biguanides, drugs with incretin effect — dipeptidyl peptidase‑4 inhibitors, agonists of glucagon-like peptide‑1, inhibitors of sodium-glucose cotransporter 2 diabetes. Particular attention is paid to the development of hepatocellular insufficiency and portal hypertension in patients with cirrhosis and type 2 diabetes, as well as processes for their prevention and insulin alternative correction methods.

Current management of diabetes mellitus and future directions in care.

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Chatterjee, Sudesna; Davies, Melanie J

2015-11-01

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

Agentes farmacológicos actuales en el tratamiento de la diabetes mellitus no insulinodependiente

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Arturo Hernández-Yero

1997-12-01

Full Text Available Se plantea que debido a la heterogeneidad patogénica de la diabetes mellitus no insulinodependiente, se debe considerar que diferentes agentes farmacológicos serán necesarios para tratar con éxito la enfermedad, por lo cual se realiza una revisión bibliográfica de las líneas de tratamiento actuales y en perspectivas para esta compleja entidad. Las modalidades terapéuticas actuales incluyen 5 grupos de agentes esenciales: los inhibidores de las alfaglucosidasas intestinales, las sulfonilureas, las biguanidas, la insulina y el recién incorporado grupo de las tiazolidinedionas, que si se utilizan en los comienzos de la enfermedad o en pacientes con resistencia insulínica, pudieran retrasar o prevenir el desarrollo de ésta, y pueden interferir en la reducción progresiva de la función pancreática. Se expone un grupo importante de agentes farmacológicos, así como sus posibles mecanismos de acción, sobre los cuales se ha estado investigando, para ampliar e incrementar la terapéutica de la diabetes, entre los que se encuentran los análogos de la insulina, los agentes insulinomiméticos y los preparados orales de insulina, los agentes insulinotrópicos no sulfonilureas, los análogos de la amilina, los péptidos similares al glucagón, los antagonistas alfa-2 adrenérgicos, los moduladores del metabolismo de la glucosa y algunas sustancias de origen vegetal con posibles efectos hipoglucémicos.It is stated that due to the pathogenic heterogeneity of non insulin-dependent diabetes mellitus, it should be considered that different pharmacological agents will be necessary to treat this disease successfully. To this end, a bibliographical review of the present and prospective treatment lines for this complex disease is made. The current therapeutic modalities include 5 groups of esential agents: the inhibitors of the intestinal alphaglucosidases, the sulphonylureas, the biguanides, insulin, and the newly incorporated group of

Connectivity maps for biosimilar drug discovery in venoms: the case of Gila monster venom and the anti-diabetes drug Byetta®.

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Aramadhaka, Lavakumar Reddy; Prorock, Alyson; Dragulev, Bojan; Bao, Yongde; Fox, Jay W

2013-07-01

instances and negative correlation with 868 instances. Interestingly, the Gila monster venom and Byetta(®) both showed positive correlation with the anti-diabetic drugs troglitazone, of the thiazolidinedione class, and metformin, of the biguanide class, although Byetta(®) as a glucagon-like peptide-1 (GLP-1) agonist functions in a different manner than either of these two classes of anti-diabetic drugs. In summary, despite the fact that Gila monster venom contains a mixture of biologically active molecules, similarities in terms of perturbation of gene expression profiles on MCF7 cells were observed between the venom and the drug Byetta(®). Furthermore, using Connectivity Mapping the Gila monster venom was demonstrated to have nodes of positive correlation to several anti-diabetic drugs two of which were the same as observed with Byetta(®). Therefore, this study suggests that by using this approach novel drug activities heretofore unconsidered may be discovered in venoms using informatic tools and Connectivity Mapping. Copyright © 2013 Elsevier Ltd. All rights reserved.

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

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Nelson Maimone

2001-11-01

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

THE STUDY OF HYPOGLYCEMIC ACTIVITY OF 3-BENZYL-8-METHYLXANTHINE DERIVATIVES

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I. М. Bilay

2015-04-01

Full Text Available Diabetes mellitus is a chronic endocrine disease. It etiology is the impact of both endogenous (genetic and exogenous factors that cause absolute or relative shortage of insulin or not effective use of it, which in turn leads to disruption of all kinds of substances exchange. The study of this problem is actual due to the high prevalence of diabetes, chronic disease, the tendency to increase the number of patients, their high morbidity and mortality. Diabetes is characterized by high blood glucose levels, which eventually leads to various complications associated with many human systems damage. Hormones (insulin and its analogues and synthetic drugs (sulfonylureas, biguanides etc. are used For the treatment of diabetes, but their high toxicity, cumulativeness, various side effects (autoimmunization, cutaneous allergic reactions, disturbance of the micro flora of the digestive tract, and the formation of insulin resistance restrict the use of these drugs in clinical practice. On this aspect the attention of researchers is attracted to xanthine derivatives, which are known as substances with wide range of biological activities including hypoglycemic. Based on the above, the search and development of new drugs among new 3-R-substituted xanthine, which would have hypoglycemic effect and would be deprived of most side effects is an acute problem of modern medical and pharmaceutical sciences. The aim of this study was to investigate the hypoglycemic activity of newly synthesized derivatives of 3-benzyl-8-methylxanthine and establish certain patterns "structure-activity" relationship. Materials and methods As objects of study for hypoglycemic activity we used derivatives of 3-benzyl-8-methylxanthine synthesized at the Department of Biochemistry and LaboratoryDiagnostics ofZaporizhzhyaStateMedicalUniversity. Hypoglycemic action of xanthine derivatives evaluated by intraperitoneal glucose tolerance test, which was reproduced by injection to animals

Patrones de prescripción de antidiabéticos en un grupo de pacientes colombianos Antidiabetic drugs prescription patterns among a group of patients in Colombia

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Jorge Enrique Machado Alba

2007-08-01

prescribed from two to four. The medications prescribed were: biguanides (67.5%, sulphonylureas (64.9%, insulin (23.5%, and thiazolidinediones (0.1%. The most common oral combination-therapies were: glibenclamide and metformin (n = 2 847, metformin and insulin (n = 510, glibenclamide and insulin (n = 148, and metformin, insulin, and glibenclamide (n = 288. Of the total, 94.3% had comorbid conditions for which they had been prescribed medication: antihypertensive drugs (in 74.4% of the cases, anti-inflammatories (61.5%, hypolipemiants (45.5%, antiulcer medications (21.0%, psychoactive drugs (16.8%, antimicrobials (14.4%, asthma medication (5.3%, and salicylic acid (2.8%. Prescriptions for comorbid conditions were more common among women than men (95.6% vs. 92.7%, P < 0.001. Undertreatment with certain medications (metformin, thiazolidinediones, alpha-glucosidase inhibitors, and salicylic acid, and overtreatment with others (antiulcer drugs, probably exist. CONCLUSIONS: There are significant differences in oral therapies prescribed for diabetes across the 19 cities studied, but overall, prescription patterns are appropriate. Educational strategies should be developed to address those prescribing practices that are not appropriate, and the clinical results of the medications studied should be explored.

[The use of natural and synthetic hydrophilic polymers in the formulation of metformin hydrochloride tablets with different profile release].

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Kołodziejczyk, Michał Krzysztof; Kołodziejska, Justyna; Zgoda, Marian Mikołaj

2012-01-01

Metformin hydrochloride after buformin and phenformin belongs to the group of biguanid derivatives used as oral anti-diabetic drugs. The object of the study is the technological analysis and the potential effect of biodegradable macromolecular polymers on the technological and therapeutic parameters of oral anti-diabetic medicinal products with metformin hydrochloride: Siofor, Formetic, Glucophage, Metformax in doses of 500mg and 1000mg and Glucophage XR in a dose of 500 mg of modified release. Market therapeutic products containing 500 and 1000 mg of metformin hydrochloride in a normal formulation and 500 mg of metformin hydrochloride in a formulation of modified release were analyzed. Following research methods were used: technological analysis of tablets, study of disintegration time of tablets, evaluation of pharmaceutical availability of metformin hydrochloride from tested therapeutic products, mathematical and kinetic analysis of release profiles of metformin hydrochloride, statistical analysis of mean differences of release coefficients. The percentage of excipients in the XR formulation is higher and constitutes 50.5% of a tablet mass. However, in standard formulations the percentage is lower, between 5.5% and 12.76%. On the basis of the results of disintegration time studies, the analysed therapeutic products can be divided into two groups, regardless the dose. The first one are preparations with faster (not fast!) disintegration: Glucophage i Metformax. The second group are preparations with slower disintegration, more balanced in the aspect of a high dose of the biologically active substance: Formetic and Siofor. Products with a lower content of excipients (Metformax, Glucophage) disintegrate in a faster way. The disintegration rate of the products with a higher content of excipients (Formetic, Siofor) is slower. The appearance of metformin hydrochloride concentration in the gastrointestinal contents, balanced in time, caused by a slower disintegration

Métodos analíticos necesarios para el desarrollo de tabletas de metformina 500 mg Analytical methods needed for Metformin 500mg tablets development

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Caridad M. García Peña

2009-12-01

cada uno de los casos en el intervalo de concentraciones establecido.Metformin hydrochloride is a biguanide-derivative used in non-dependent insulin diabetes mellitus reducing the blood glucose concentration without increases insulin secretion, and it is considered a anti-hyperglycemia agent and not a hypoglycemia one. Technological development requires of a reliable analytical methods allowing drug quantification in different stages of research. The aim of present paper was the analytical method validation, reported in USA Pharmacopeia (USP 31,2008 by UV-spectrophotometry and the adaptation of abovementioned method reported in the same pharmacopeia, for analysis of compound related in determination of active principle in end product, by high-performance liquid chromatography validated for quality control and study of Metformin (500-mg tablets stability. In validated techniques by chromatographic spectrophtometric methods we determined performance parameter, specificity, linearity, accuracy, and precision. Calibration curves for each method was performed in intervals of 60to 140%, where they were linear with correlation coefficients equal to 0.9994 and 0.99903, respectively. Statistical test for interceptor and slope was considered as non-significant. We achieved recoveries of 100.01 and 99.1, respectively during interval of study concentrations, and the Cochran (G and Student's (t tests were not significant. Variation coefficients in studies of repetition were equal to 1.4 and 0.8, respectively for the 6 assayed replica, whereas in average precision analysis, Fischer and Student tests were not significant. Results allow concluding that both methods fulfill the established requirements as acceptable for each of cases during the concentration interval established.

This Issue at A Glance

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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

Phosphorus-calcium metabolism in postmenopausal women with diabetes mellitus = Фосфорно-кальцієвий обмін у постменопаузальних жінок, хворих на цукровий діабет

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M. L. Kyryliuk

2015-12-01

� In this work it was investigated the state of phosphorus-calcium metabolism in postmenopausal women with diabetes mellitus depending on the type of diabetes, length of menopause and diabetes, body weight, type of hypoglycemic therapy. It is shown that the concentration of ionized calcium, general calcium and inorganic phosphorus in the blood can not serve as the main marker of the state of bone mineral density in postmenopausal women with diabetes mellitus type 2 in in cases of absence of severe chronic renal failure and related comorbid pathology. It was found that sulfonylureas drugs and insulin in combination with biguanide not affect on performance of phosphorous-calcium metabolism in postmenopausal women with diabetes mellitus type 2.   Keywords: phosphorus-calcium metabolism, diabetes mellitus, menopause.   Kyryliuk Mykhailo - Prof, MD, PhD, DMSci, Head the Department of Neuroendocrinology and General Endocrinology http://lazarevich.at.ua/ Atanova Yana - MD, endocrinologist

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

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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

Evaluación de la calidad de la asistencia al paciente diabético en América Latina Evaluation of the quality of care for diabetic patients in Latin America

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Juan José Gagliardino

2001-11-01

%. Of the people with DM1, 20% of them had a body mass index < 19 kg/m², probably reflecting deficient metabolic control and inadequate insulin intake. The systematic checking of metabolic control, other cardiovascular risk factors, and chronic DM complications was inadequate in from 3% to 75% of the cases, depending on the specific aspect considered. According to various patient-therapy-education indicators, only some one-quarter to one-half of the studied patients could play an active, effective role in DM control and treatment. Of the persons with DM1, 50% of them were treated with a mixed dose of insulin (NPH + regular insulin, administered in two daily injections in 43% of the cases. Among the patients, 5% of them received one daily insulin injection, and 9% of them received three daily insulin injections. Of the people with DM2, 13% of them treated it only with diet and 14% just with insulin. Among the patients receiving drug treatment, the oral hypoglycemics most used in monotherapy were sulfonylureas (33%, biguanides (9%, and a combination of these two (14%. Fewer than half of the people with diabetes received drug therapy for the associated cardiovascular risk factors. The frequency of patients' macroangiopathic and microangiopathic complications increased with the duration of their disease. Comparing patients who had had diabetes for 5 years or less with those who had had the illness for more than 20 years, the frequency of renal insufficiency and of amputations was around 7 times as great in the latter group; for peripheral neuropathy, it was 2 times as great, and for stroke 1.6 times as great. Conclusions. These results show the need to improve the quality of care for diabetic patients in Latin America and the Caribbean, and that QUALIDIAB could help do this. Expanding the QUALIDIAB network will help to more accurately diagnose the quality of that care in the Americas, and it will facilitate interventions aimed at optimizing the care. This, in turn, will