Background: Two-thirds of U.S. adult women are overweight or obese. High body mass index (BMI) and adult weight gain are risk factors for a number of chronic diseases, including postmenopausal breast cancer. The higher postmenopausal breast cancer risk in women with elevated BMI is likely to be attributable to related metabolic disturbances including altered circulating sex steroid hormones and adipokines, elevated pro-inflammatory cytokines, and insulin resistance. Metformin is a widely used antidiabetic drug that has demonstrated favorable effects on metabolic disturbances and as such may lead to lower breast cancer risk in obese women. Further, the anti-proliferative effects of metformin suggest it may decrease breast density, an accepted biomarker of breast cancer risk. Methods/design: This is a Phase II randomized, double-blind, placebo-controlled trial of metformin in overweight/obese premenopausal women who have elements of metabolic syndrome. Eligible participants will be randomized to receive metformin 850 mg BID (n=75) or placebo (n=75) for 12 months. The primary endpoint is change in breast density, based on magnetic resonance imaging (MRI) acquired fat-water features. Secondary outcomes include changes in serum insulin levels, serum insulin-like growth factor (IGF)-1 to insulin-like growth factor binding protein (IGFBP)-3 ratio, serum IGF-2 levels, serum testosterone levels, serum leptin to adiponectin ratio, body weight, and waist circumference. Exploratory outcomes include changes in metabolomic profiles in plasma and nipple aspirate fluid. Changes in tissue architecture as well as cellular and molecular targets in breast tissue collected in a subgroup of participants will also be explored. Discussion: The study will evaluate whether metformin can result in favorable changes in breast density, select proteins and hormones, products of body metabolism, and body weight and composition. The study should help determine the potential breast cancer preventive activity of metformin in a growing population at risk for multiple diseases.

The modulation of the electron transport during ischemia-reperfusion has been shown to be protective. We hypothesized that metformin, a Complex I inhibitor, may exhibit characteristics of a pharmacological agent that could achieve long-term therapeutic intervention against ischemia-reperfusion injury. Mitochondria were harvested from adult male mice and incubated with or without metformin at 30oC for 15 minutes, while being shaken at 300 rpm. Metformin decreased Complex I oxidative phosphorylation and Complex I activity. However, metformin also increased injury and decreased the maximum membrane potential. Even though there was a decrease in maximum membrane potential, the proton motive force (PMF) was still intact as the ADP/O ratio was not affected. In conclusion, metformin does exhibit some characteristics of a drug that could achieve long-term therapeutic benefit against ischemia-reperfusion.

Class of 2006 Abstract / Objectives: To determine if Polycystic Ovarian Syndrome (PCOS) patients treated with lifestyle changes and metformin resulted in ovulation after six months of treatment. Methods: A retrospective chart review of initial patient visits at an infertility clinic were obtained. Patients that were given a diagnosis of PCOS were further reviewed for age at initial diagnosis, weight, height, ovarian cysts, lifestyle recommendations (diet, exercise, and vitamin use), metformin recommendations and usage, and if ovulation occurred after six months of treatment. Results: A total of 1011 charts were reviewed. At the initial office visit, 206 (20.38%) of these patients were classified as having PCOS. Of PCOS patients, 113 (54.85%) patients ovulated after six months of treatment. In the average initial weight, ovulators averaged slightly less weight than did non-ovulators (171.77 pounds ± 44.26 vs. 188.65 pounds ± 51.37, p=0.0121). This also follows true for the initial BMI of ovulators vs. non-ovulators (29.53 kg/m2 ± 10.14 vs. 32.69 kg/m2 ± 13.03, p=0.0521). There was a significant difference in metformin use between ovulators and non-ovulators (90.27% vs. 73.12%, p=0.0024). More ovulators were found to continue metformin treatment as compared to non-ovulators. Conclusions: In this specific infertility clinic setting, 20.3% of patients were diagnosed with PCOS at the initial office visit. Of these PCOS patients, treatment with lifestyle changes and metformin use resulted in 55% of patients achieving ovulation at six months. This study shows that weight loss, through lifestyle modification and metformin treatment, increases this population’s chances of ovulation within six months of therapy.

ABSTRACT Metformin is the most common drug used against type 2 diabetes mellitus. However, it was only recently shown, in human and rat hepatocytes, that metformin-like 5-aminoimidazole-4-carboximide ribonucleoside (AICAR), acts via activation of the AMP-activated protein kinase (AMPK), an enzyme that plays a central role in lipid metabolism. Although it is well known that metformin is used in the treatment of type 2 diabetes and results in significant fat loss, no study has investigated the effects of this drug on adipocytes. In this report I studied the effects of metformin on the formation of fat deposits in mouse 3T3-L1 preadipocytes, as well as its effects on the activation of AMPK in these cells. Our results suggested that metformin significantly inhibits the transformation of pre-adipocytes into adipocytes. This is achieved via the inhibition of intracellular lipid accumulation during adipogenesis. In addition to its inhibition of intracellular lipid accumulation, metformin induced a significant increase in the phosphorylation of AMPK. It has been shown that AMPK activation with AICAR results in the inhibition of the nuclear factor-κB (NF-κB) induced gene expression. Since NF-κB is the key nuclear factor used by HIV-1 during the initiation of its gene transcription, I investigated the possibility of inhibiting HIV-1 replication in U1 cells with metformin and AICAR. I observed that AICAR and metformin inhibit HIV-1 replication in U1 cells. This inhibition wasparalleled by the accumulation of NF-κB in the cytoplasm of AICAR and metformin treated cells, and at the same time by a significant decrease in the concentration of this nuclear factor in the nucleus of these cells. However, I failed to observe any phosphorylation of AMPK by metformin and AICAR in U1 cells. In conclusion, metformin inhibits adipogenesis in mouse adipocytes and this inhibition is likely to take place via the activation of AMPK. AICAR and metformin have inhibitory properties against HIV-1 replication. However, this inhibition does not seem to be by the activation of AMPK.

Heart failure is a devastating disease which despite significant advances in therapy over the past two decades still results in a poor prognosis. Metabolic dysregulation is associated with heart failure; however, it remains unclear whether isoproterenol exerts deleterious effects through altered metabolic regulation. Whether metformin, a metabolic modulator, prevents isoproterenol-induced heart failure is unknown. The aim of this study was to determine whether metformin prevents functional and metabolic changes seen in the isoproterenol model of heart failure. Male Sprague-Dawley rats were administered isoproterenol and metformin for seven months. Thereafter, cardiac dimensions, metabolic gene expression and myocardial structural changes were assessed. Chronic administration of isoproterenol induced left ventricular dilatation and pump dysfunction and mitochondrial structural derangement. No changes were seen in metabolic gene expression. However, co-administration of metformin prevented isoproterenol-induced heart failure and retained mitochondrial structural arrangement. Therefore, cardiac dilatation and pump dysfunction induced by chronic administration of isoproterenol can be prevented by co-administering metformin.

Um crescente número de estudos tem associado diabetes mellitus a risco aumentado para o desenvolvimento de câncer e ao aumento da mortalidade específica por câncer. Por outro lado, diversos estudos sugerem que a metformina pode estar associada à redução do risco de desenvolvimento e de morte relacionada ao câncer em pacientes com diabetes mellitus. Diversas evidências disponíveis na literatura sugerem o papel da metformina como uma droga antineoplásica. No entanto, o mecanismo envolvido neste efeito benéfico da metformina não é totalmente compreendido. Apesar das evidências, alguns autores discordam quanto ao papel da metformina na redução do risco de câncer em pacientes com diabetes mellitus. Assim, o presente estudo objetivou identificar o perfil dos pacientes com diabetes mellitus que desenvolveram neoplasias e verificar a relação entre o uso de metformina e a presença de neoplasias em indivíduos com diagnóstico prévio de diabetes mellitus. Trata-se de um estudo caso-controle, onde foram selecionados 510 prontuários de pacientes de ambos os sexos, com idade acima de 35 anos que passaram por internações no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, no período de 2002 a 2012, com diagnóstico de diabetes mellitus, classificadas segundo CID-10 com os códigos de E10 a E14, e pacientes com diagnóstico de neoplasias malignas classificadas nos seguintes códigos do CID-10: C00-C75; C76 a C80; C97; D00 a D09; D37 a D48. Foram formados dois grupos na proporção de 1:2, sendo o grupo de casos com diagnóstico de diabetes mellitus e Neoplasias (170 prontuários) e o grupo controle com diagnóstico de diabetes mellitus sem neoplasias (340 prontuários). Os prontuários foram analisados quanto às variáveis sociodemográficas e clínico-epidemiológicas. Os resultados do presente estudo mostraram medianas de idade significativamente maiores no grupo de casos (portadores de diabetes mellitus e neoplasia), assim como maior ocorrência de óbitos, tabagismo e uso de metformina prévio. O tempo de uso de metformina, a dose de insulina NPH utilizada nos últimos 12 meses e a presença de obesidade foram significativamente maiores entre os pacientes com diabetes mellitus sem neoplasia (grupo controle). O estudo sugere a necessidade de mais estudos para avaliar o papel da metformina na ocorrência de neoplasias em pacientes com diabetes mellitus pré-existente / An increasing number of studies have associated diabetes mellitus with an increased risk for the development of cancer and increased specific cancer mortality. Furthermore, several studies suggest that metformin may be associated with reduced risk for developing cancer and cancer-related death in patients with diabetes mellitus. Several available evidence in the literature suggests the role of metformin as an anticancer drug. However, the mechanism involved in this beneficial effect of metformin is not fully understood. Despite the evidence, there are conflicting data on the role of metformin in reducing the risk of cancer in patients with diabetes mellitus. Thus, this study aimed to identify the profile of patients with diabetes mellitus who developed cancer and to investigate the relationship between the use of metformin and the occurrence of malignancies in patients with a previous diagnosis of diabetes mellitus. This is a case-control study where we selected 510 medical records of patients of both sexes, aged 35 years and over who have undergone hospitalization at the Hospital of Ribeirão Preto Medical School, University of São Paulo, in the 2002-2012 period, with diagnosis of diabetes mellitus, categorized by ICD-10 codes E10 to E14, and patients with diagnosis of malignancies classified by the following ICD-10 codes: C00-C75; C76 to C80; C97; D00 to D09; D37 to D48. Two groups were formed, at the proportion 1: 2, one composed by patients with diabetes mellitus and neoplasms, considered the group of cases (170 records) and another group by patients with diabetes mellitus, considered the control group (340 records). The medical records were analyzed regarding to sociodemographic and clinical-epidemiological variables. The results of this study showed significantly higher median age in the case group (patients with diabetes mellitus and cancer), as well as the occurrence of deaths, smoking, previous use of metformin. Length of metformin use, NPH insulin dose used in the last 12 months and the presence of obesity were significantly higher among patients with diabetes mellitus without cancer (controls). The study suggests the necessity of other studies to clarify the real role of metformin in the occurrence of tumors in patients with pre-existing diabetes mellitus

Epidemiology studies have found that type 2 diabetics treated with metformin are at a lower risk for developing cancer. It was speculated that the lowered risk might be attributed metformin's indirect physiological effect of lowering blood insulin levels, which is the opposite of many other antidiabetic drugs. However, further study of metformin's mechanism of action at the cellular level helped develop an understanding of its effect on the individual cell. This helped show why, mechanistically, it makes sense to use metformin for the treatment of cancer. As an activator of AMP-activated protein kinase (AMPK) via inhibition of complex 1 of the mitochondrial electron transport chain, metformin causes suppression of tumor growth and cell cycle arrest by acting on the mTOR pathway and cyclin/CDKs, respectively. Metformin has been most extensively studied in breast cancer, showing great efficacy in numerous breast cancer cell lines that include ER positive, HER2 positive, and triple negative breast cancer cell lines. This compilation of data and results of metformin's efficacy in various cancer subtypes will help push metformin forward as a new chemotherapeutic for breast cancer, and eventually for other cancer types as well.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. / Background Obesity, insulin resistance and type 2 diabetes mellitus (T2DM) have been associated with endometrial cancer (EC). In this systematic review and meta-analysis we evaluated the effect of metformin on clinical outcomes in patients with EC and insulin resistance or T2DM. Methods Four research databases were searched for original articles published in all languages up to 30 October 2016. Outcomes of interest were overall mortality (OM), cancer-specific mortality, disease progression, and metastases. We performed a random effect meta-analysis of adjusted effects expressed as hazard ratios (HR); heterogeneity among studies was described with the I2 statistic. Results Of the 290 retrieved citations, 6 retrospective cohort studies in women with EC (n = 4723) met the inclusion criteria, and 8.9% to 23.8% were treated with metformin; OM data was available from 5 studies. In 4 studies of EC patients (n = 4132), metformin use was associated with a significant reduction in OM in comparison with not using metformin (adjusted HR [aHR] 0.64, 95% CI 0.45–0.89, p = 0.009). In three studies evaluating patients with EC and T2DM (n = 2637), metformin use was associated with a significant reduction in OM (aHR 0.50, 95%CI 0.34–0.74, p = 0.0006). There was low to moderate heterogeneity of adjusted effects across studies. There was no information about the effect of metformin on cancer-specific mortality, disease progression, or metastases. Conclusions Metformin treatment is associated with a significant reduction in OM irrespective of diabetes status in patients with EC. The survival benefit suggests that diabetes screening and maintenance of good glycemic control may improve outcomes in EC. / Revisión por pares

A dissolução de um fármaco a partir de uma forma farmacêutica (FF) sólida oral é um pré-requisito para que o mesmo seja absorvido pelo organismo e cumpra seus efeitos terapêuticos. O ensaio de dissolução de medicamentos permite avaliar a quantidade de princípio ativo que é liberado a partir de sua FF, mimetizando in vitro o processo que ocorre no trato gastrointestinal (TGI). O DDDPlus® é o único programa de computador dedicado exclusivamente a simular ensaios de dissolução. O objetivo deste trabalho foi avaliar a capacidade do programa de computador DDDPlus® em fornecer perfis de dissolução in silico de comprimidos matriciais contendo metformina semelhantes aos perfis de dissolução in vitro e avaliar a possibilidade de substituir a comparação de perfis de dissolução in vitro de diferentes formulações de comprimidos matriciais contendo metformina pela comparação de perfis de dissolução in silico fornecidos pelo DDDPlus®.Para tanto, um planejamento estatístico foi realizado para obtenção de perfis de dissolução, variando a velocidade das pás e o uso do sinker. Os perfis de dissolução de 3 formulações teste (T1, T2 e T3) de comprimidos de liberação modificada por matriz polimérica contendo metformina foram comparadas pelos métodos de eficiência de dissolução (ED), tempo médio de dissolução (TMD), fator de diferença (f2) e fator de semelhança (f1). Os resultados indicaram o uso do sinker como fator determinante para a ED e TMD. Assim, o método que utilizava o sinker e a velocidade das pás de 50RPM foi utilizado para avaliar 4 produtos comercializados no Brasil. No DDDPlus® os ensaios de dissolução in vitro das formulações T1, T2 e T3 foram otimizadas para a obtenção das constantes de calibração (CC), as CC foram utilizadas para simular os ensaios de dissolução de T1, T2 e T3 em velocidades de 25 e 50RPM. Os perfis de dissolução simulados foram comparados aos perfis observados, resultando em valores de R2. Valores de R2 acima de 0,90 foram obtidos para todas as simulações realizadas utilizando CC de ensaios in vitro que utilizaram sinker, indicando o potencial do programa em auxiliar o desenvolvimento de novas formulações. Valores de R2 abaixo de 0,70 foram obtidos após a simulação de ensaios utilizando CC de ensaios in vitro que não utilizavam o sinker, indicando que o programa de computador não previu a adesão do comprimido ao fundo da cuba de dissolução durante o ensaio. Os perfis de dissolução simulados das formulações T1, T2 e T3 foram comparadas por f1 e f2 com os perfis de dissolução dos produtos do mercado. Tais comparações concluíram que o software não é indicado como substituto dos ensaios in vitro quando se almeja comparar perfis de dissolução. / Dissolution of a drug from an oral solid pharmaceutical form (FF) is a prerequisite for it to be absorbed by the body and to fulfill its therapeutic effects. in vitroDrug dissolution assay allows the amount of active principle released from a FF and mimics the in vivo the process that occurs in the gastrointestinal tract (TGI). DDDPlus® is the only computer program dedicated exclusively to simulating dissolution testing. The objective of this work was to evaluate the ability of DDDPlus® software to provide in silico dissolution profiles of matrix tablets containing metformin similar to in vitro dissolution profiles and to evaluate the possibility of replacing in vitro dissolution profiles comparison of different formulations of matrix tablets containing metformin for a comparison of in silico dissolution profiles provided by DDDPlus®. For this purpose, a statistical design was used, varying agitation speed and the use of sinker to obtain dissolution profiles for 3 test formulations (T1, T2 and T3) of polymer matrix-modified release tablets containing metformin. Dissolution profiles were compared by means of dissolution efficiency (ED), mean dissolution time (TMD), difference factor (f2) and similarity factor (f1). The results indicated the use of sinker as a determinant factor for ED and TMD. Thus, the method that used sinker and agitation speed of 50RPM was used to evaluate 4 products commercialized in Brazil. in vitro dissolution tests of the T1, T2 and T3 formulations were optimized using In DDDPlus® to obtain the calibration constants (CC), which were used to simulate dissolution profiles of T1, T2 and T3 at speeds of 25 and 50RPM. in silico dissolution profiles were compared to in vitro dissolution profiles, resulting in R2 values. R2 values above 0.90 were obtained for all simulations performed using CC from in vitro assays using sinker, indicating the potential of the program to assist the development of new formulations. R2 values below 0.70 were obtained after the simulation of assays using CC from in vitro assays that did not use the sinker, indicating that the computer program did not predict adhesion of the tablet to the bottom of the dissolution cell during the assay. The simulated dissolution profiles of the T1, T2 and T3 formulations were compared by f1 and f2 with the dissolution profiles of the market products. Such comparisons concluded that the software is not indicated as a substitute for in vitro assays when comparing dissolution profiles is desired.

A dissolução de um fármaco a partir de uma forma farmacêutica (FF) sólida oral é um pré-requisito para que o mesmo seja absorvido pelo organismo e cumpra seus efeitos terapêuticos. O ensaio de dissolução de medicamentos permite avaliar a quantidade de princípio ativo que é liberado a partir de sua FF, mimetizando in vitro o processo que ocorre no trato gastrointestinal (TGI). O DDDPlus® é o único programa de computador dedicado exclusivamente a simular ensaios de dissolução. O objetivo deste trabalho foi avaliar a capacidade do programa de computador DDDPlus® em fornecer perfis de dissolução in silico de comprimidos matriciais contendo metformina semelhantes aos perfis de dissolução in vitro e avaliar a possibilidade de substituir a comparação de perfis de dissolução in vitro de diferentes formulações de comprimidos matriciais contendo metformina pela comparação de perfis de dissolução in silico fornecidos pelo DDDPlus®.Para tanto, um planejamento estatístico foi realizado para obtenção de perfis de dissolução, variando a velocidade das pás e o uso do sinker. Os perfis de dissolução de 3 formulações teste (T1, T2 e T3) de comprimidos de liberação modificada por matriz polimérica contendo metformina foram comparadas pelos métodos de eficiência de dissolução (ED), tempo médio de dissolução (TMD), fator de diferença (f2) e fator de semelhança (f1). Os resultados indicaram o uso do sinker como fator determinante para a ED e TMD. Assim, o método que utilizava o sinker e a velocidade das pás de 50RPM foi utilizado para avaliar 4 produtos comercializados no Brasil. No DDDPlus® os ensaios de dissolução in vitro das formulações T1, T2 e T3 foram otimizadas para a obtenção das constantes de calibração (CC), as CC foram utilizadas para simular os ensaios de dissolução de T1, T2 e T3 em velocidades de 25 e 50RPM. Os perfis de dissolução simulados foram comparados aos perfis observados, resultando em valores de R2. Valores de R2 acima de 0,90 foram obtidos para todas as simulações realizadas utilizando CC de ensaios in vitro que utilizaram sinker, indicando o potencial do programa em auxiliar o desenvolvimento de novas formulações. Valores de R2 abaixo de 0,70 foram obtidos após a simulação de ensaios utilizando CC de ensaios in vitro que não utilizavam o sinker, indicando que o programa de computador não previu a adesão do comprimido ao fundo da cuba de dissolução durante o ensaio. Os perfis de dissolução simulados das formulações T1, T2 e T3 foram comparadas por f1 e f2 com os perfis de dissolução dos produtos do mercado. Tais comparações concluíram que o software não é indicado como substituto dos ensaios in vitro quando se almeja comparar perfis de dissolução. / Dissolution of a drug from an oral solid pharmaceutical form (FF) is a prerequisite for it to be absorbed by the body and to fulfill its therapeutic effects. in vitroDrug dissolution assay allows the amount of active principle released from a FF and mimics the in vivo the process that occurs in the gastrointestinal tract (TGI). DDDPlus® is the only computer program dedicated exclusively to simulating dissolution testing. The objective of this work was to evaluate the ability of DDDPlus® software to provide in silico dissolution profiles of matrix tablets containing metformin similar to in vitro dissolution profiles and to evaluate the possibility of replacing in vitro dissolution profiles comparison of different formulations of matrix tablets containing metformin for a comparison of in silico dissolution profiles provided by DDDPlus®. For this purpose, a statistical design was used, varying agitation speed and the use of sinker to obtain dissolution profiles for 3 test formulations (T1, T2 and T3) of polymer matrix-modified release tablets containing metformin. Dissolution profiles were compared by means of dissolution efficiency (ED), mean dissolution time (TMD), difference factor (f2) and similarity factor (f1). The results indicated the use of sinker as a determinant factor for ED and TMD. Thus, the method that used sinker and agitation speed of 50RPM was used to evaluate 4 products commercialized in Brazil. in vitro dissolution tests of the T1, T2 and T3 formulations were optimized using In DDDPlus® to obtain the calibration constants (CC), which were used to simulate dissolution profiles of T1, T2 and T3 at speeds of 25 and 50RPM. in silico dissolution profiles were compared to in vitro dissolution profiles, resulting in R2 values. R2 values above 0.90 were obtained for all simulations performed using CC from in vitro assays using sinker, indicating the potential of the program to assist the development of new formulations. R2 values below 0.70 were obtained after the simulation of assays using CC from in vitro assays that did not use the sinker, indicating that the computer program did not predict adhesion of the tablet to the bottom of the dissolution cell during the assay. The simulated dissolution profiles of the T1, T2 and T3 formulations were compared by f1 and f2 with the dissolution profiles of the market products. Such comparisons concluded that the software is not indicated as a substitute for in vitro assays when comparing dissolution profiles is desired.