The development and benefits of metformin in various diseases / 医学前沿

Metformin has been used for the treatment of type II diabetes mellitus for decades due to its safety, low cost, and outstanding hypoglycemic effect clinically. The mechanisms underlying these benefits are complex and still not fully understood. Inhibition of mitochondrial respiratory-chain complex I is the most described downstream mechanism of metformin, leading to reduced ATP production and activation of AMP-activated protein kinase (AMPK). Meanwhile, many novel targets of metformin have been gradually discovered. In recent years, multiple pre-clinical and clinical studies are committed to extend the indications of metformin in addition to diabetes. Herein, we summarized the benefits of metformin in four types of diseases, including metabolic associated diseases, cancer, aging and age-related diseases, neurological disorders. We comprehensively discussed the pharmacokinetic properties and the mechanisms of action, treatment strategies, the clinical application, the potential risk of metformin in various diseases. This review provides a brief summary of the benefits and concerns of metformin, aiming to interest scientists to consider and explore the common and specific mechanisms and guiding for the further research. Although there have been countless studies of metformin, longitudinal research in each field is still much warranted.

The mechanism of drug interactions of a selected antiarrhythmic drug with metformin, in different animal models

ABSTRACT This study was carried out to understand the influence of a selected antiarrhythmic drug on the pharmacodynamics and pharmacokinetics of an antidiabetic drug in animal models. Pharmacodynamic and pharmacokinetic responses were determined by measurements of blood glucose and serum insulin and serum metformin to drug interactions between disopyramide and metformin. Single dose and multi dose studies showed that the maximum blood glucose reductions in normal and diabetic rats were at the 6th hour, and in rabbits at the 3rd hour. Glucose-insulin homeostasis was evaluated to assess the safety and effectiveness of the combination. There was a marginal increase in the pharmacokinetic parameters of metformin with multiple dose treatments of disopyramide but no significant changes in kinetic parameters between single and multiple dose studies, compared to metformine alone. There may be a possibility of disopyramide and metformin interaction at the excretion stage, or an additive pharmacodynamic action. This study validates the drug interaction in two dissimilar species, which indicates more probability of its occurrence in humans.

Formulation of a modified release metformin. HCl matrix tablet: influence of some hydrophilic polymers on release rate and in-vitro evaluation / A formulação de uma matriz de libertação modificada de comprimido de metformin.HCl: influência de alguns polímeros hidrofílicos sobre a taxa de libertação e de avaliação in-vitro

Metformin hydrochloride is an antidiabetic agent which improves glucose tolerance in patients with type 2 diabetes and reduces basal plasma levels of glucose. In this study, a simplex centroid experimental design with 69 runs was used to select the best combination of some hydrophilic polymers that rendered a 24 h in-vitro release profile of metformin.HCl. The Korsmeyer-Peppas model was used to model the dissolution profiles since it presented the best fit to the experimental data. Further, a cubic model predicted the best formulation of metformin.HCl containing polyvinyl pyrrolidone, ethyl cellulose, hydroxypropyl methyl cellulose, carrageenan, sodium alginate, and gum arabic at 6.26, 68.7, 6.26, 6.26, 6.26 and 6.26 percent levels, respectively. The validation runs confirmed the accuracy of the cubic model with six components for predicting the best set of components which rendered a once-a-day modified release hydrophilic matrix tablet in compliance with the USP specifications.

O cloridrato de metformina é um agente antidiabético que melhora a tolerância à glicose em pacientes com diabetes tipo 2 e reduz os níveis plasmáticos basais de glicose. Neste estudo, um projeto experimental do tipo "centróide simplex" com 69 tomadas foi usado para selecionar a melhor combinação de alguns polímeros hidrofílicos que gerou um perfil de liberação da metformina.HCl de 24 horas. O modelo Korsmeyer-Peppas foi usado para modelar os perfis de dissolução, uma vez que apresentou os melhores ajustes aos dados experimentais. Além disso, um modelo cúbico previu a melhor formulação de metformina.HCl sendo aquela contendo polivinilpirrolidona, etilcelulose, hidroxipropilmetil celulose, carragena, alginato de sódio e goma arábica nos níveis 6.26, 68.7, 6.26, 6.26, 6.26 e 6.26 por cento, respectivamente. As corridas de validação confirmaram a precisão do modelo cúbico com os seis componentes para prever o melhor conjunto de componentes que originou uma libertação do tipo "uma vez ao dia" em conformidade com as especificações da USP, a partir de comprimidos matriciais.

Pharmaceutical evaluation of metformin HCI products available in the Jordanian market

Five brands of metformin HCI tablets that are commercially available in the Jordanian market were subjected to analysis according to the British Pharmacopoea [2007] monograph. The tested criteria of the preparations included identification, assay and dissolution performance. The obtained results indicated that all of the examined products were in accordance with the pharmacopeal specifications. However, dissolution profile comparisons, which are not required by British Pharmacopoa, revealed potentially serious differences in the performance of the studied products. According to similarity factor calculations, only one generic products was found to have similar dissolution profile to the originator [similarity factor [74.3]. The other products showed similarity factors less than 50. Therefore only one generic can be said to be exchangeable with the originator. Further investigation might be conducted to confirm such results

Metformina e diabetes melito tipo 2: passado, presente e farmacogenética / Metformin and type 2 diabetes mellitus: past, present and pharmacogenetics

O diabetes melito tipo 2 (DM2) é uma desordem heterogênea caracterizada por resistência à insulina e diminuição progressiva de sua secreção, o que resulta em hiperglicemia. Inevitavelmente, pacientes com DM2 necessitam controlar seus níveis glicêmicos com mudanças no estilo de vida e terapia farmacológica. Entre os fármacos mais prescritos para o tratamento do DM2, encontra-se a metformina, um anti-hiperglicemiante oral pertencente à classe das biguanidas. A resposta terapêutica a este fármaco apresenta uma considerável variação interindividual e depende da atuação de produtos protéicos de vários genes. Por este motivo, a farmacogenética tem emergido como uma ciência capaz de explicar porque há tanta variabilidade na resposta farmacológica, como aquela relacionada à terapia com metformina. Alguns genes candidatos a predizerem a resposta a esse fármaco já tiveram variantes avaliadas. Entre eles, os genes SLC22A1, SLC22A2 e SLC47A1, que codificam os transportadores de cátions orgânicos responsáveis pela entrada e saída da metformina no fígado e rins. Além destes, outros genes, como os que codificam as subunidades da proteína quinase ativada por adenosina monofosfato (AMPK) tem emergido com importantes candidatos a predizerem a resposta à metformina. De qualquer forma, a farmacogenética desta droga está dando seus primeiros passos e serão necessários mais estudos, em diferentes populações, para elucidar outros fatores genéticos que estão envolvidos na sua resposta. Além disso, modelos poligênicos capazes de avaliar a eficácia da metformina em pacientes individuais devem ser criados.

Diabetes mellitus type 2 (DM2) is a heterogeneous disorder characterized by insulin resistance and progressive decrease in secretion, resulting in hyperglycemia. Inevitably, patients with type 2 diabetes need to control their glucose levels with changes in lifestyle and pharmacologic therapy. Among the most prescribed drugs for the treatment of type 2 diabetes, is metformin, an oral anti-hyperglycaemic that belongs to biguanide class. Therapeutic response to this drug has considerable interindividual variation and depends on the activity of protein products of several genes. For this reason, pharmacogenetics has emerged as a science able to explain why there is so much variability in pharmacologic response, as that related to metformin therapy. Some candidate genes to predict the response to this drug had variants evaluated already. Among them, the genes SLC22A1, SLC22A2 and SLC47A1, which encode the organic cation transporters responsible for the entry and exit of metformin in the liver and kidneys. In addition, other genes, such as those that encode the subunits of protein kinase activated by adenosine monophosphate (AMPK) have emerged as important candidates to predict the response to metformin. Anyway, the pharmacogenetics of this drug is in its firsts studies and will require further investigation in different populations, to elucidate other genetic factors involved in the response. In addition, polygenic models capable of evaluating the effectiveness of metformin in individual patients should be created.

Effect of binders on 500mg metformin hydrochloride tablets produced by wet granulation

Metformin hydrochloride (MH) is an oral hypoglycemic agent and a high-dose drug that has poor flow and compression properties. In this study, the feasibility of developing adequate, low cost 500mg tablets of metformin hydrochloride by wet granulation was tested with several binders (Starch / PVP K30®; Starch1500® /PVP K30®, PVP K30® and PVP K90®) in a simple tablet press of the type used in small pharmaceutical laboratories. The drug powder was tested for ability to flow, by determining Carr?s Index (CI) and the Hausner ratio (HR). Differential scanning calorimetry and thermogravimetric analysis were carried out on isolated MH and 1:1 (w/w) binary mixtures with the excipients. The size distribution, friability, flow properties and drug content of the granules were analyzed, as were the hardness, friability, disintegration, dissolution and uniformity of the dosage form. The drug powder showed CI > 22% and HR > 1.25, characteristic of a poor flow powder, and no significant incompatibilities with the excipients. All the granules showed adequate flow properties and were suitable for pressing into tablets, all of which complied with pharmacopeial specifications. The starch /PVP K30® and starch 1500®/PVP K30® mixtures were best for producing 500 mg MH tablets.

Cloridrato de metformina é um fármaco hipoglicemiante oral que apresenta propriedades pobres de fluxo e compressibilidade. Este trabalho teve como objetivo o desenvolvimento de comprimidos de baixo custo,após granulação por via úmida, contendo 500 mg de cloridrato de metformina e diferentes aglutinantes (F1-amido / PVP K30®; F2- Starch 1500® / PVP K30®, F3-PVP K30®, F4- PVP K90®) em máquinas de compressão de baixo desempenho usadas em laboratórios farmacêuticos de pequeno porte. As propriedades defluxo do fármaco foram analisadas através do índice de Carr (IC) e fator de Hausner (FH). Cloridrato de metformina e suas misturas binárias com os excipientes na relação 1:1 (m/m) foram analisadas por calorimetria diferencial por varredura e análise termogravimétrica. Os granulados foram analisados quanto a distribuição granulométrica, friabilidade, propriedades de fluxo e teor e os comprimidos em relação à dureza, friabilidade, desintegração, dissolução e uniformidade de conteúdo.O cloridrato de metformina apresentou IC > 22% e FH> 1,25, característicos de fluxo pobre e não apresentou incompatibilidades com os outros excipientes. Todos os granulados demonstraram adequadas propriedades de fluxo e facilidade no processo de compressão. Os comprimidos apresentaram conformidade com as especificações farmacopeicas. As misturas amido / PVPK30® e Starch 1500® / PVP K30® foram mais adequadas para produzir comprimidos de cloridrato de metformina 500 mg.

aspirin alter the pharmacokinetic of metformin?

The main goal to study the pharmacokinetics of Metformin is to help physicans to determine the accurate dose of Metformin that enable them to have good glycemic control in patient with type II diabetes mellitus. Many medicines alter the pharmacokinetics of Metformin and that make modifying of the dose necessary. To study the interaction between Metformin and another medicines which are commonly used together. We choose to study the interaction between the Aspirin and Metformin, in patients with type II diabetes mellitus. Fifteen male volunteers [25-40 years] received oral Metformin [500 mg] every 12 hours for 4 days, Aspirin [325 mg] every 12 hours in combination of oral Metformin [500 mg] every 12 hours for 4 days. Plasma samples were collected on day 4 of each regimen. The result showed that coadministration of Metformin and Aspirin had no significant effects on the steady state pharmacokinetics [AUC: 0-12 h, C[max], T[max] or T[1/2]] of Metformin in patient with type II diabetes mellitus

Insulinorresistencia: generalidades e implicancias clínicas / Insulin resistance generalties and clinical approach

La insulinorresistencia, es la base fisiopatológica de múltiples enfermedades de alta prevalencia, entre las que se destacan: la obesidad androide, la intolerancia a la glucosa, la diabetes mellitus, la hipertensión arterial y la dislipidemia. Además, se presenta en otras situaciones patológicas frecuentes, entre otras, diabetes gestacional, ovario poliquístico y en sujetos pequeños para la edad gestacional. Finalmente, está presente en una serie de condiciones fisiológicas y patológicas poco frecuentes o muy excepcionales, ya sea de origen genético, congénitas o adquiridas. Quizás más que por su prevalencia, el principal problema reside en, que esta condición puede permanecer desconocida y el daño metabólico puede ocurrir mucho antes que un exámen fortuito o el cuadro florido de una diabetes 2 nos lleve finalmente a su diagnóstico. El propósito de esta revisión es dar una orientación diagnóstica práctica de este síndrome tanto desde el punto de vista clínico como de las metodologías actualmente en uso

Desenvolvimento e avaliação biofarmacotécnica de comprimidos de liberação controlada de cloridrato de metformina empregando meio de dissolução com variação gradual de pH / Development and biopharmaceutical evaluation of controlled release tablets of metformin hydrochloride using dissolution medium with gradual pH variation

Quatro formulações de comprimidos de liberação controlada contendo 850 mg de cloridrato de metformina foram preparadas variando-se as quantidades do polímero hidroxipropilmetilcelulose (HPMC K100) e de ácido esteárico. Estas preparações foram submetidas a ensaios de dissolução sob as seguintes condições experimentais: equipamento utilizado: aparelho de dissolução com seis cubas; meios de dissolução: meio com variação gradual de pH (1,3 a 7,5) e água desgaseificada; volume do meio de dissolução: 1000 mL; sistema de agitação: pá; velocidade de agitação: 100 rpm; temperatura: 37,0ñ0,5 ºC; volume de coleta e reposição do meio: 10 mL, nos intervalos de tempo de 10, 30, 60, 90, 120, 180, 240, 300 e 360 minutos. O fármaco foi quantificado por espectrofotometria no ultravioleta a 233 nm...

Desenvolvimento de comprimidos de cloridrato de metformina de liberação convencional e modificada: influência dos excipientes sobre o perfil de dissolução e avaliação termoanalítica / Development of metformin hydrochloride tablets of modified and conventional release: the excipients influence about the aspect of dissolution and thermoanalytical evaluation

Comprimidos de cloridrato de metformina de 850 mg, provenientes de dois laboratórios A e B (três lotes de cada) foram submetidos a ensaios de peso médio, dureza, friabilidade, desintegração, teste e perfil de dissolução, ensaios termoanalítico DSC e TG/DTG, seguindo-se metodologia descrita pela Farmacopéia Britânica/1993. A quantificação do fármaco foi realizada por espectrofotometria no UV a 233nm. Os resultados indicaram que dois lotes do laboratório B estavam em desacordo com as especificações por apresentarem dureza de 2,57(0,98) e 2,89(0,62) Kgf, inferior ao mínimo exigido pela Farmacopéia Brasileira 4ª ed. Todos os lotes do laboratório A, além de revelarem dureza (D) irregular (D=22,99(1,49); 8,64(0,99) e 19,02(2,36) Kgf, não cumpriram com os requisitos em relação ao teor de fármaco que estava, aproximadamente, 22 por cento abaixo do mínimo exigido, considerando-se a forma do sal expressa no rótulo e a bula dos produtos...

Efecto de la metformina sobre la resistencia insulínica en mujeres obesas y obesas hiperandrogénicas / Effects of metformin on insulin resistance in obese and hyperandrogenic women

Background: Metformin is a biguanide often used in obese diabetics that improves tissue sensitivity to insulin. Aim:To assess the effects of metformin on tissue insulin sensitivity in obese and byperandrogenic women. Patients and methods: Eight obese and eight obese and eight and hyperandrogenic women received metformin 850 mg orally during 12 weeks. Before and at the end of the treatment period, an insulin tolerance test to measure insulin sensitivity was performed and blood was drawn to measure sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS), testosterone, triglycerides, total and HDL cholesterol. The free androgen index was calculated for each sample. Results: After metformin treatment, the insulin sensitivity index improved from 0.38 (0.05-0.5) to 0.43 (0.25-0.59) in obese and hyperandrogenic women. SHBG increased and total cholesterol and triglycerides decreased significantly in both groups. No other significant changes were observed. Conclusions: Metformin has a favorable effect on tissue sensitivity to insulin, SHBG and serum lipids in obese and hyperandrogenic women

El retorno de las Biguanidas: metformin / The return of biguanidas: metformin

Presentamos un breve resumen histórico y enfatizamos la importancia del uso del metformin, en el tratamiento de diabetes no insulino - dependiente basada en la experiencia europea y canadiense. Recomendamos la dosis de 500 mg debido a que se ha demostrado que la incidencia de acidosis láctica es pequeña, se consigue un buen cumplimiento de la dosis y puede ser combinado con otros antidiabéticos orales.