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Concept: Biguanide


Metformin (N,N-dimethylbiguanide), buformin (1-butylbiguanide) and phenformin (1-phenethylbiguanide) are anti-diabetic biguanide drugs, expected to having anti-cancer effect. The mechanism of anti-cancer effect by these drugs is not completely understood. In this study, we demonstrated that these drugs dramatically enhanced oxidative DNA damage under oxidative condition. Metformin, buformin and phenformin enhanced generation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in isolated DNA reacted with hydrogen peroxide (H2O2) and Cu(II), although these drugs did not form 8-oxodG in the absence of H2O2 or Cu(II). An electron paramagnetic resonance (EPR) study, utilizing alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide as spin trapping agents, showed that nitrogen-centered radicals were generated from biguanides in the presence of Cu(II) and H2O2, and that these radicals were decreased by the addition of DNA. These results suggest that biguanides enhance Cu(II)/H2O2 -mediated 8-oxodG generation via nitrogen-centered radical formation. The enhancing effect on oxidative DNA damage may play a role on anti-cancer activity.

Concepts: Buformin, Oxidative stress, Hydrogen peroxide, Anti-diabetic drug, Oxygen, Phenformin, Biguanide, Metformin


The biguanides are a family of drugs with diverse clinical applications. Metformin, a widely used anti-hyperglycemic biguanide, suppresses mitochondrial respiration by inhibiting respiratory complex I. Phenformin, a related anti-hyperglycemic biguanide, also inhibits respiration, but proguanil, which is widely used for the prevention of malaria, does not. The molecular structures of phenformin and proguanil are closely related and both inhibit isolated complex I. Proguanil does not inhibit respiration in cells and mitochondria because it is unable to access complex I. The molecular features that determine which biguanides accumulate in mitochondria, enabling them to inhibit complex I in vivo, are not known.

Concepts: Atovaquone, Inhibitor, Oxygen, Guanidines, Biguanide, Phenformin, Metformin, Cellular respiration


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

Concepts: Biguanide, Phenformin, Nitrosamine, Metformin, Cancer, Oncology, Carcinogen, Benzene


Debridement and control of bacterial load are key-points of wound care. The aim of this study is to evaluate the effectiveness of autolytic debridement and management of bacterial load (bioburden) of an occlusive hydro-active dressing impregnated with polyhexamethylene biguanide (PHMB).

Concepts: Control, Guanidines, Biguanide, PAPB


Polyhexamethylene biguanide (PHMB), an amphiphilic polymeric biocide, increased liver tumor incidence in male and female rats at 1000 and 1500 mg/l in drinking water, but not at 500 mg/l in previous studies. In another study, PHMB administered in diet at 4000 mg/kg was negative for hepatocellular tumors. The present studies evaluated bioavailability and distribution of PHMB administered in drinking water and diet and possible modes of action (MOA). PHMB in drinking water was unpalatable during the first 3 days, resulting in markedly decreased food consumption and decreased body weight. Ki-67 labeling index was increased in hepatocytes and endothelial cells dose responsively with PHMB administered in drinking water but not diet. Vitamin E had no effect on this. There was no cytotoxicity by histopathology or serum enzymes, and no increase in cytokines TNFα, IL-1α or NF-κB. Focal iron deposition in sinusoidal lining cells was detected. Microarray analyses were non-contributory. No effect on CAR or PPARα activation was detected. 14C-PHMB administered at 500, 1000, or 1500 mg/L in the drinking water or 4000 mg/kg in the diet was nearly completely absorbed and excreted in urine, with some fecal excretion. The hypothesized MOA for liver tumors induced by PHMB in drinking water is: 1) severe dehydration and starvation because of unpalatability, followed by ingestion with rapid absorption and urinary excretion; 2) increased hepatocyte proliferation; and 3) induction of hepatocellular foci and tumors. The PHMB-induced rat hepatocellular tumors are unlikely to pose a human cancer risk. However, the actual MOA has not been determined.

Concepts: Hepatocyte, Biguanide, Cancer, Bile, PAPB, Liver, Nutrition, Dehydration


A new salting-out assisted liquid-liquid extraction (SALLE) sample preparation method for the determination of the polar anti-diabetic biguanide drugs (metformin, buformin and phenformin) in blood plasma, urine and lake water samples were developed. The SALLE was performed by mixing samples (plasma (0.2mL), urine or lake water (1.0mL)) with acetonitrile (0.4mL for plasma, 0.5mL for urine or lake water), sodium hydroxide powder was then added for the phase separation. The effects of type of salting-out reagent, type of extraction solvent, volumes of acetonitrile and sample, amount of sodium hydroxide, vortexing and centrifugation times on the extraction efficiency were investigated. The upper layer, containing the biguanides, was directly injected into a HPLC unit using ZIC-HILIC column (150mm×2.1mm×3.5μm) and was detected at 236nm. The method was validated and calibration curves were linear with r2>0.99 over the range of 20-2000μgL-1 for plasma and 5-2000μgL-1 for urine and lake water samples. The limits of detection were in the range (3.8-5.6)μgL-1, (0.8-1.5)μgL-1 and (0.3-0.8)μgL-1 for plasma, urine and lake water, respectively. The accuracies in the three matrices were within 87.3-103%, 87.4-109%, 82.2-109% of the nominal concentration for metformin, buformin and phenformin, respectively. The relative standard deviation for inter- and intra -day precision were in the range of 1.0-17% for all analytes in the three matrices.

Concepts: Ethanol, Buformin, Sodium hydroxide, Anti-diabetic drug, Sodium, Phenformin, Metformin, Biguanide


New 1-arylamidebiguanide hydrochloride salts were synthesized via reaction of hydrazide derivatives with dicyandiamide in acidic medium. The structure of the obtained derivatives was characterized by spectroscopic and elemental analysis tools. The anti-diabetic properties of the synthesized compounds were determined. Oral treatment of hyperglycemic rats with the synthesized biguanide derivatives showed a significant decrease of the elevated glucose in comparison with the anti-diabetic standard drug, metformin. The effects of the synthesized biguanide derivatives on the diabetic properties regarding liver function enzyme activities (AST, ALT, and ALP), lipid profiles (TC, TG, and TL), lipid peroxide, and nitrous oxide as well as histopathological characteristics were investigated and discussed.

Concepts: Biguanide, Obesity, Metformin, Glucose, Insulin resistance, Insulin, Diabetes mellitus, Diabetes mellitus type 2


Biguanides are strong bases (pKa > 10), their protonated forms bind anions and may therefore act as receptors for anions. We report on easy-to-make anion receptors and fluorescence-based sensors utilizing the biguanide moieties that respond to the presence of anions with a change in fluorescence. The observed changes in fluorescence are anion-specific and even though the biguanide receptors are cross-reactive, these sensors may be used to identify various anions (halides, carboxylates, phosphates). Paper-based analytical arrays were used to assess the discriminatory ability of the sensors in the qualitative and quantitative analysis of multiple anions.

Concepts: Change, ACT, Biguanide, Ion, Polyatomic ion, Electron, Scientific method, Qualitative research


The anti-diabetic biguanide drugs metformin (METF) and phenformin (PHEN) may have anti-cancer effects. Biguanides suppress plasma growth factors, but nonetheless, the view that these mitochondrial inhibitors accumulate in tumor tissue to an extent that leads to severe energetic stress or alleviation of hypoxia-induced radioresistance is gaining ground. Our cell studies confirm that biguanides inhibits cell proliferation by targeting respiration, but only at highly suprapharmacological concentrations due to low drug retention. Biodistribution/PET studies of (11)C-labeled metformin ((11)C-METF) revealed that plasma bioavailability remained well below concentrations with metabolic/anti-proliferative in vitro effects, following a high oral dose. Intraperitoneal administration resulted in higher drug concentrations, which affected metabolism in normal organs with high METF uptake (e.g., kidneys), but tumor drug retention peaked at low levels comparable to plasma levels and hypoxia was unaffected. Prolonged intraperitoneal treatment reduced tumor growth in two tumor models, however, the response did not reflect in vitro drug sensitivity, and tumor metabolism and hypoxia was unaffected. Our results do not support that direct inhibition of tumor cell respiration is responsible for reduced tumor growth, but future studies using (11)C-METF-PET are warranted, preferably in neoplasia’s originating from tissue with high drug transport capacity, to investigate the controversial idea of direct targeting.

Concepts: Oxygen, Biguanide, Phenformin, Mitochondrion, Carbon dioxide, Enzyme inhibitor, Adenosine triphosphate, Cellular respiration


Metformin is the most commonly prescribed treatment for Type II diabetes and related disorders, however molecular insights into its mode(s) of action have been limited by an absence of structural data. Structural considerations along with an increasing body of literature demonstrating its effects on one-carbon metabolism suggest the possibility of folate mimicry and anti-folate activity. Motivated by increasing recognition that anti-diabetic biguanides may act directly upon the gut microbiome, we have determined structures of the complexes formed between the anti-diabetic biguanides: phenformin, buformin, and metformin and E. coli dihydrofolate reductase (ecDHFR) based on NMR, crystallographic and molecular modeling studies. Inter-ligand Overhauser effects indicate that metformin can form ternary complexes with p-aminobenzoyl-L-glutamate (pABG) as well as other ligands that occupy the region of the folate binding site that interacts with pABG, however DHFR inhibition is not cooperative. The biguanides inhibit the activity of ecDHFR competitively, with Ki ~ 20 mM (metformin) or 0.2 mM (phenformin). This inhibition may be significant at concentrations present in the gut of treated individuals, and inhibition of intestinal mucosal cells may also occur if accumulated levels are sufficient. Perturbation of folate homeostasis can alter the pyridine nucleotide redox ratios that regulate cellular metabolism.

Concepts: Anti-diabetic drug, Dihydrofolic acid, Metabolism, Phenformin, Enzyme, Biguanide, Diabetes mellitus type 2, Metformin