Tuning smart microgel swelling and responsive behavior through strong and weak polyelectrolyte pair assembly.

The layer-by-layer (LbL) assembly of polyelectrolyte pairs on temperature and pH-sensitive cross-linked poly(N-isopropylacrylamide)-co-(methacrylic acid), poly(NIPAAm-co-MAA), microgels enabled a fine-tuning of the gel swelling and responsive behavior according to the mobility of the assembled polyelectrolyte (PE) pair and the composition of the outermost layer. Microbeads with well-defined morphology were initially prepared by synthesis in supercritical carbon dioxide. Upon LbL assembly of polyelectrolytes, interactions between the multilayers and the soft porous microgel led to differences in swelling and thermoresponsive behavior. For the weak PE pairs, namely poly(L-lysine)/poly(L-glutamic acid) and poly(allylamine hydrochloride)/poly(acrylic acid), polycation-terminated microgels were less swollen and more thermoresponsive than native microgel, whereas polyanion-terminated microgels were more swollen and not significantly responsive to temperature, in a quasi-reversible process with consecutive PE assembly. For the strong PE pair, poly(diallyldimethylammonium chloride)/poly(sodium styrene sulfonate), the differences among polycation and polyanion-terminated microgels are not sustained after the first PE bilayer due to extensive ionic cross-linking between the polyelectrolytes. The tendencies across the explored systems became less noteworthy in solutions with larger ionic strength due to overall charge shielding of the polyelectrolytes and microgel. ATR FT-IR studies correlated the swelling and responsive behavior after LbL assembly on the microgels with the extent of H-bonding and alternating charge distribution within the gel. Thus, the proposed LbL strategy may be a simple and flexible way to engineer smart microgels in terms of size, surface chemistry, overall charge and permeability.

Formulation of spray dried enzymes for dry powder inhalers: An integrated methodology.

One of the main challenges when developing a spray dried formulation of an inhalable enzyme is the generation of a safe and effective aerosol, able to reach the lungs, while preserving protein function and structural levels of the biologic. Hence, an appropriate excipient selection based on enzyme stabilization, inhalation precedence and spray drying (SD) process development is required to meet this balance. Herein, an integrated methodology is presented to expedite the selection of the best dry powder inhaler excipient system to formulate three model enzymes of increasing molecular mass and structural complexity belonging to the oxidoreductase class and often implicated in oxidative stress: superoxide dismutase, glucose oxidase and catalase. Three non-reducing sugars and four amino acids were screened using High Throughput Isothermal Denaturation Fluorimetry (HT-ITDF) for a stabilizing effect on the enzymes quaternary structure. For each tested enzyme, the sugar and amino acid showcasing a stabilizing effect, were spray dried together at fixed process conditions for three different ratios, to assess which formulation would then display the best aerodynamic performance. After SD, using the selected conditions, all powders displayed 65-85% of fine particle fraction (FPF) whilst each enzyme kept the oligomeric state. The present integrated methodology proved to be successful, allowing to narrow down 36 potential formulations (three sugars × four amino acids × three ratios) to only one for each enzyme, within few hours, while requiring a µg range of sample amount.

Valorization of Brewery Waste through Polyhydroxyalkanoates Production Supported by a Metabolic Specialized Microbiome.

Raw brewers' spent grain (BSG), a by-product of beer production and produced at a large scale, presents a composition that has been shown to have potential as feedstock for several biological processes, such as polyhydroxyalkanoates (PHAs) production. Although the high interest in the PHA production from waste, the bioconversion of BSG into PHA using microbial mixed cultures (MMC) has not yet been explored. This study explored the feasibility to produce PHA from BSG through the enrichment of a mixed microbial culture in PHA-storing organisms. The increase in organic loading rate (OLR) was shown to have only a slight influence on the process performance, although a high selectivity in PHA-storing microorganisms accumulation was reached. The culture was enriched on various PHA-storing microorganisms, such as bacteria belonging to the Meganema, Carnobacterium, Leucobacter, and Paracocccus genera. The enrichment process led to specialization of the microbiome, but the high diversity in PHA-storing microorganisms could have contributed to the process stability and efficiency, allowing for achieving a maximum PHA content of 35.2 ± 5.5 wt.% (VSS basis) and a yield of 0.61 ± 0.09 CmmolPHA/CmmolVFA in the accumulation assays. Overall, the production of PHA from fermented BSG is a feasible process confirming the valorization potential of the feedstock through the production of added-value products.

Dry powder inhaler formulation comparison: Study of the role of particle deposition pattern and dissolution.

The composition, morphology and dissolution profile of particles and micro-sized agglomerates delivered upon inhalation may have a significant impact on the product clinical effect. However, although several efforts are ongoing, a methodology that considers deposition structures and dissolution performance evaluation in a biorelevant set-up is not yet standardized. The goal of this work is to apply a collection and dissolution methodology able to discriminate dry powder inhaler (DPI) formulations in terms of deposition structures and dissolution profile in vitro. Hence, Fluticasone Propionate (FP) engineered particles and formulated products (used as a case study) were collected employing a breath simulator and characterized regarding (i) aerodynamic particle size distribution; (ii) deposited microstructures; and (iii) dissolution/absorption profiles using the DissolvIt® bio-relevant dissolution equipment. The results indicated that the particle engineering technology had an impact on the generated and deposited microstructures, here associated to the differences on surface properties of jet milled and wet polished particles quantified by the specific surface area. Differences on surface properties modulate particle interactions, resulting in agglomerates of drug substance and excipient upon actuation with significant different morphologies, observed by microscope, as well as quantified by Marple cascade impactor. These observations allow for a further understanding of the DPI aerosolization and deposition mechanisms. The dissolution and absorption assessment indicates that the presence of lactose may accelerate the drug substance dissolution kinetics, and the FP dissolution can be significantly enhanced when formulated as a spray-dried dispersion particle. Ultimately, the results suggest dissolution testing can be an essential tool to both optimize an innovator DPI and de-risk generics development.

Integrating human stem cell expansion and neuronal differentiation in bioreactors.

BACKGROUND: Human stem cells are cellular resources with outstanding potential for cell therapy. However, for the fulfillment of this application, major challenges remain to be met. Of paramount importance is the development of robust systems for in vitro stem cell expansion and differentiation. In this work, we successfully developed an efficient scalable bioprocess for the fast production of human neurons. RESULTS: The expansion of undifferentiated human embryonal carcinoma stem cells (NTera2/cl.D1 cell line) as 3D-aggregates was firstly optimized in spinner vessel. The media exchange operation mode with an inoculum concentration of 4 x 10(5) cell/mL was the most efficient strategy tested, with a 4.6-fold increase in cell concentration achieved in 5 days. These results were validated in a bioreactor where similar profile and metabolic performance were obtained. Furthermore, characterization of the expanded population by immunofluorescence microscopy and flow cytometry showed that NT2 cells maintained their stem cell characteristics along the bioreactor culture time.Finally, the neuronal differentiation step was integrated in the bioreactor process, by addition of retinoic acid when cells were in the middle of the exponential phase. Neurosphere composition was monitored and neuronal differentiation efficiency evaluated along the culture time. The results show that, for bioreactor cultures, we were able to increase significantly the neuronal differentiation efficiency by 10-fold while reducing drastically, by 30%, the time required for the differentiation process. CONCLUSION: The culture systems developed herein are robust and represent one-step-forward towards the development of integrated bioprocesses, bridging stem cell expansion and differentiation in fully controlled bioreactors.

Transcutaneous Electrical Stimulation, Interferential Current and Photobiomodulation May Lead to the Recurrence of Breast Cancer in Rats? / Estimulação Elétrica Transcutânea, Corrente Interferencial e Fotobiomodulação podem levar à Recorrência do Câncer de Mama em Ratas? / ¿La Estimulación Eléctrica Transcutánea, la Corriente Interferencial y la Fotobiomodulación pueden Provocar la Recurrencia del Cáncer de Mama en Ratas?

Introduction: Transcutaneous electrical nerve stimulation (TENS), interferential current therapy (IFC) and photobiomodulation therapy (PBMT) have been used in the management of cancer-related pain in adults. However, there are still some controversy regarding the effects of this therapy on tumor cells that may remain after cancer treatment. Objective: To evaluate the risk of recurrence of breast cancer in rats when using TENS, IFC or PBMT. Method: An experimental, randomized, controlled and cross-sectional study. With 90 days of age, 7,12-dimetylbenz(a)anthracene (7,12-DMBA) was administered to rats by gastric gavage to induce mammary cancer. After 120 days the mammary glands of the rats belonging to the group with mammary cancer were removed. Results: 39 female Sprague-Dawley rats were studied: 9 rats without induction of mammary carcinoma; 9 rats with induction of mammary carcinoma and without surgery; 9 rats with induction of mammary carcinoma with surgery and placebo application of TENS, IFC, PBMT; 9 rats with induction of mammary carcinoma, surgery and the application of TENS, IFC and PBMT. Conclusion: This study demonstrated that there was local recurrence of tumors in rats that were stimulated with TENS or IFC, however no evidence of local recurrence with PBMT

Introdução: Estimulação elétrica nervosa transcutânea (TENS), corrente interferencial (IFC) e fotobiomodulação (PBMT) são usadas no tratamento da dor relacionada ao câncer em adultos. No entanto, ainda existem algumas controvérsias sobre os efeitos dessa terapia nas células tumorais que podem permanecer após o tratamento do câncer. Objetivo: Avaliar o risco de recorrência de câncer de mama em ratos ao usar TENS, IFC ou PBMT. Método: Estudo experimental, randomizado, controlado e transversal. Com 90 dias de idade, 7,12-dimetilbenz(a)antraceno (7,12-DMBA) foi administrado em ratos por gavagem gástrica para induzir câncer mamário. Após 120 dias, as glândulas mamárias das ratas pertencentes ao grupo com câncer mamário foram retiradas. Resultados: Foram estudados 39 ratos-fêmeas Sprague-Dawley: nove ratos sem indução de carcinoma mamário; nove ratos com indução de carcinoma mamário e sem cirurgia; nove ratos com indução de carcinoma mamário com cirurgia e placebo, aplicação de TENS, IFC, PBMT; nove ratos com indução de carcinoma mamário, cirurgia e aplicação de TENS, IFC e PBMT. Conclusão: Este estudo demonstrou que houve recorrência local de tumores em ratos que foram estimulados com TENS ou IFC, no entanto, nenhuma evidência de recorrência local com PBMT

Introducción: Estimulación nerviosa eléctrica transcutánea (TENS), interferencial corriente (IFC) y la terapia de fotobiomodulación (PBMT) en el tratamiento del dolor relacionado con el cáncer en adultos. Sin embargo, todavía quedan algunas controversias sobre los efectos de esta terapia en las células tumorales que pueden permanecer después del tratamiento del cáncer. Objetivo: Evaluar el riesgo de recurrencia del cáncer de mama en ratos cuando se usa TENS, IFC o PBMT. Método: Estudio experimental, aleatorizado, controlado y transversal. Con 90 días de edad, se administró 7,12-dimetilbenz(a)antraceno (7,12-DMBA) a ratos por sonda gástrica para inducir cáncer de mama. Después de 120 días, las glándulas mamarias de las ratas pertenecientes al grupo con cáncer de mama fueron extraídas. Resultados: Se estudiaron 39 ratos-hembras Sprague-Dawley: nueve ratos sin inducción de carcinoma de mama; nueve ratos con inducción de carcinoma mamario y sin cirugía; nueve ratos con inducción de carcinoma mamario con cirugía y placebo aplicación de TENS, IFC, PBMT; nueve ratos con inducción de carcinoma mamario, cirugía y la aplicación de TENS, IFC y PBMT. Conclusión: Este estudio demostró que hubo recurrencia local de tumores en ratos que fueron estimulados con TENS o IFC, sin embargo, no hay evidencia de recurrencia local con PBMT

Transcutaneous Electrical Stimulation, Interferential Current and Photobiomodulation May Lead to the Recurrence of Breast Cancer in Rats? / Estimulação Elétrica Transcutânea, Corrente Interferencial e Fotobiomodulação podem levar à Recorrência do Câncer de Mama em Ratas? / ¿La Estimulación Eléctrica Transcutánea, la Corriente Interferencial y la Fotobiomodulación pueden Provocar la Recurrencia del Cáncer de Mama en Ratas?

Introduction: Transcutaneous electrical nerve stimulation (TENS), interferential current therapy (IFC) and photobiomodulation therapy (PBMT) have been used in the management of cancer-related pain in adults. However, there are still some controversy regarding the effects of this therapy on tumor cells that may remain after cancer treatment. Objective: To evaluate the risk of recurrence of breast cancer in rats when using TENS, IFC or PBMT. Method: An experimental, randomized, controlled and cross-sectional study. With 90 days of age, 7,12-dimetylbenz(a)anthracene (7,12-DMBA) was administered to rats by gastric gavage to induce mammary cancer. After 120 days the mammary glands of the rats belonging to the group with mammary cancer were removed. Results: 39 female Sprague-Dawley rats were studied: 9 rats without induction of mammary carcinoma; 9 rats with induction of mammary carcinoma and without surgery; 9 rats with induction of mammary carcinoma with surgery and placebo application of TENS, IFC, PBMT; 9 rats with induction of mammary carcinoma, surgery and the application of TENS, IFC and PBMT. Conclusion: This study demonstrated that there was local recurrence of tumors in rats that were stimulated with TENS or IFC, however no evidence of local recurrence with PBMT

Introdução: Estimulação elétrica nervosa transcutânea (TENS), corrente interferencial (IFC) e fotobiomodulação (PBMT) são usadas no tratamento da dor relacionada ao câncer em adultos. No entanto, ainda existem algumas controvérsias sobre os efeitos dessa terapia nas células tumorais que podem permanecer após o tratamento do câncer. Objetivo: Avaliar o risco de recorrência de câncer de mama em ratos ao usar TENS, IFC ou PBMT. Método: Estudo experimental, randomizado, controlado e transversal. Com 90 dias de idade, 7,12-dimetilbenz(a)antraceno (7,12-DMBA) foi administrado em ratos por gavagem gástrica para induzir câncer mamário. Após 120 dias, as glândulas mamárias das ratas pertencentes ao grupo com câncer mamário foram retiradas. Resultados: Foram estudados 39 ratos-fêmeas Sprague-Dawley: nove ratos sem indução de carcinoma mamário; nove ratos com indução de carcinoma mamário e sem cirurgia; nove ratos com indução de carcinoma mamário com cirurgia e placebo, aplicação de TENS, IFC, PBMT; nove ratos com indução de carcinoma mamário, cirurgia e aplicação de TENS, IFC e PBMT. Conclusão: Este estudo demonstrou que houve recorrência local de tumores em ratos que foram estimulados com TENS ou IFC, no entanto, nenhuma evidência de recorrência local com PBMT

Introducción: Estimulación nerviosa eléctrica transcutánea (TENS), interferencial corriente (IFC) y la terapia de fotobiomodulación (PBMT) en el tratamiento del dolor relacionado con el cáncer en adultos. Sin embargo, todavía quedan algunas controversias sobre los efectos de esta terapia en las células tumorales que pueden permanecer después del tratamiento del cáncer. Objetivo: Evaluar el riesgo de recurrencia del cáncer de mama en ratos cuando se usa TENS, IFC o PBMT. Método: Estudio experimental, aleatorizado, controlado y transversal. Con 90 días de edad, se administró 7,12-dimetilbenz(a)antraceno (7,12-DMBA) a ratos por sonda gástrica para inducir cáncer de mama. Después de 120 días, las glándulas mamarias de las ratas pertenecientes al grupo con cáncer de mama fueron extraídas. Resultados: Se estudiaron 39 ratos-hembras Sprague-Dawley: nueve ratos sin inducción de carcinoma de mama; nueve ratos con inducción de carcinoma mamario y sin cirugía; nueve ratos con inducción de carcinoma mamario con cirugía y placebo aplicación de TENS, IFC, PBMT; nueve ratos con inducción de carcinoma mamario, cirugía y la aplicación de TENS, IFC y PBMT. Conclusión: Este estudio demostró que hubo recurrencia local de tumores en ratos que fueron estimulados con TENS o IFC, sin embargo, no hay evidencia de recurrencia local con PBMT

Doença inflamatória intestinal com eritema nodoso como manifestação inicial ­ dois casos clínicos / Inflammatory bowel disease with erythema nodosum as the initial manifestation ­ two clinical cases

OBJETIVOS: Descrever dois casos de doença inflamatória intestinal cujo diagnóstico foi precedido pelo surgimento de eritema nodoso e alertar para essa manifestação extraintestinal como forma de apresentação inicial da doença. DESCRIÇÃO DOS CASOS: Dois adolescentes de 12 e 15 anos recorreram ao serviço de urgência de Pediatria por eritema nodoso acompanhado de anorexia e perda de peso. Os exames auxiliares de diagnóstico disponíveis foram sugestivos de doença crônica inflamatória e a ecografia abdominal sugestiva de doença inflamatória intestinal. O diagnóstico de doença de Crohn foi confirmado após realização de endoscopia digestiva alta e colonoscopia total com biópsias. CONCLUSÕES: O eritema nodoso pode ser a forma de apresentação de doenças potencialmente graves com terapêuticas bem estabelecidas e implicações prognósticas. Na criança ou adolescente com eritema nodoso o índice de suspeição de doença inflamatória intestinal deve ser elevado, embora devam ser considerados outros diagnósticos diferenciais. A importância do diagnóstico precoce na doença inflamatória intestinal em idade pediátrica consiste na oportunidade terapêutica e nas complicações específicas dessa faixa etária, como déficit de crescimento, que ocorre mais frequentemente na doença de Crohn.

AIMS: To describe two cases of inflammatory bowel disease whose diagnosis was preceded by the appearance of erythema nodosum and to alert to this extra-intestinal manifestation as the initial presentation of the disease. CASES DESCRIPTION: Two adolescents of 12 and 15 years of age were referred to the pediatrics emergency department because of erythema nodosum accompanied by anorexia and weight loss. The available diagnostic tests were suggestive of chronic inflammatory disease and the abdominal ultrasound was suggestive of inflammatory bowel disease. The diagnosis of Crohn's disease was confirmed after completion of upper digestive endoscopy and total colonoscopy with biopsies. CONCLUSIONS: Erythema nodosum may be the form of presentation of potentially serious diseases with well established therapies and prognostic implications. In children or adolescents with erythema nodosum, the index of suspicion of inflammatory bowel disease should be high, although other differential diagnoses should be considered. The importance of early diagnosis of inflammatory bowel disease in pediatric age refers to the therapeutic opportunity and specific complications in this age group, as growth disturbance, which occurs more frequently in Crohn's disease.

Effects of metformin on QT and QTc interval dispersion of diabetic rats.

BACKGROUND: Several drugs can cause prolonged QT interval, as well as prolonged QT dispersion (QTd) in electrocardiographic (EKG) recordings. QTd may be a potentially sensitive marker of increased risk of cardiac arrhythmias and sudden cardiac death. Metformin is an effective antihyperglycemic agent used in the treatment of diabetes. However, studies have correlated dose-dependent effects of metformin on glycemia and cardiovascular risk markers. OBJECTIVE: To evaluate the dose-response effects of metformin on QT and QTd of diabetic rats. METHODS: Male Wistar rats were distributed in five groups: non-treated control (C), non-treated diabetics (D), diabetics treated with metmorfin at the doses of 3.5, 30 and 74 microg/kg/bw (DM 3.5, DM 30 and DM 74). Diabetes was induced by an alloxan injection (40 mg/kg, IV). EKG was recorded (days 1, 15 and 30) using four electrodes inserted into the subcutaneous layer of the paws. Both RR and QT intervals were measured, and then corrected QT and QT dispersion values were calculated. RESULTS: The DM 3.5 and DM 30 groups showed a significant reduction of glycemia (p< 0.05) when compared with the high dose (DM 74). Rats of the DM 74 group presented prolonged QTc, QTd and QTcd intervals, whereas rats of the DM 3.5 and DM 30 groups presented less prolonged intervals. CONCLUSION: Metformin at high doses provided greater dispersion of the QT interval probably because of the increased ventricular repolarization inhomogeneity, whereas at low doses decreased QT intervals were observed in diabetic rats.

Modelo experimental de carcinoma mamário em ratas induzidas com 7, 12-dimetilbenz(a)antraceno / Induction of experimental mammary carcinogenesis in rats with 7, 12-dimethylbenz(a)anthracene

Objetivo: Testar um modelo experimental de indução de carcinogênese em raras Sprague-Dawley. Métodos: Foram estudadas 30 ratas fêmeas virgens Sprague-Dawley, induzidas ao carcinogênese mamário. Com 50 dias de vida, foi injectado 7,12-dimerilbenz(a)antrace no ventre por gavage. Com 12 semanas, as glândulas mamárias foram examinadas, assim como os tecidos cerebrais, pulmonares, ossos do fêmur e fígado. Resultados: Doze semanas após a injeção de DMBA, 85% das ratas apresentaram pelo menos um tumor mamário visível. Conclusão: O modelo experimental de carcinoma mamário induzido por DMBA mostrou-se efetivo e de fácil reprodução.

Objective: To test an experimental model of chemical mammary carcinogenesis induction in Sprague-Dawley rats. Methods: Thirty virgin Sprague-Dawley female rats, aged 50 days, received 20 mg of 7,12-dimethyLbenz(a)anthracene (DMBA) intragastrically by gavage. At 12 week their mammary glands were examined. Brain, Liver, bone and Lung tissue were also analyzed. Results: Twelve weeks after DMBA injection, 85% rats presented at Least one breast tumor. Conclusion: This experimental animal model of chemical mammary induced carcinogenesis is feasible and can be used in further experiments on the role of tumorigenic biomodulator substances.

Os efeitos da metformina sobre a dispersão do intervalo QT e QTc de ratos diabéticos / Effects of metformin on QT and QTc interval dispersion of diabetic rats

FUNDAMENTO: Diversos fármacos podem causar aumento do intervalo QT, bem como da sua dispersão (QTd) em registros eletrocardiográficos (ECG). O QTd pode ser um marcador potencialmente sensível ao aumento do risco de arritmias cardíacas e morte súbita cardíaca. Metformina é uma substância de eficácia anti-hiperglicêmica utilizada no tratamento do diabete. Entretanto, estudos têm relacionado efeitos dose-dependentes da metformina sobre a glicemia e marcadores de riscos cardiovasculares. OBJETIVO: Avaliar os efeitos dose-resposta da metformina sobre o QT e QTd de ratos diabéticos. MÉTODOS: Ratos Wistar machos foram distribuídos em cinco grupos: controle não-tratado (C), diabético não-tratado (D), diabéticos tratados com metformina nas doses 3,5, 30 e 74 µg/kg/pc (DM 3,5, DM 30 e DM 74). O diabete foi induzido por uma injeção de aloxana (40 mg/kg, i.v.). O ECG foi registrado (1º, 15º e 30º dias) através de quatro eletrodos inseridos na camada subcutânea das patas. Ambos os intervalos, RR e QT, foram medidos, e então os valores do QT corrigido e da dispersão de QT foram calculados. RESULTADOS: Os grupos DM 3,5 e DM 30 mostraram significativa redução da glicemia (p< 0,05) quando comparados à alta dose (DM 74). Ratos do grupo DM 74 apresentaram aumento dos intervalos QTc, QTd e QTcd, enquanto os ratos dos grupos DM 3,5 e DM 30 apresentaram menor prolongamento desses intervalos. CONCLUSÃO: A metformina em altas doses proporcionou maior dispersão do intervalo QT, em razão, provavelmente, do aumento da não-homogeneidade do processo de repolarização ventricular, enquanto em baixas doses houve diminuição do intervalo QT em ratos diabéticos.

BACKGROUND: Several drugs can cause prolonged QT interval, as well as prolonged QT dispersion (QTd) in electrocardiographic (EKG) recordings. QTd may be a potentially sensitive marker of increased risk of cardiac arrhythmias and sudden cardiac death. Metformin is an effective antihyperglycemic agent used in the treatment of diabetes. However, studies have correlated dose-dependent effects of metformin on glycemia and cardiovascular risk markers. OBJECTIVE: To evaluate the dose-response effects of metformin on QT and QTd of diabetic rats. METHODS: Male Wistar rats were distributed in five groups: non-treated control (C), non-treated diabetics (D), diabetics treated with metmorfin at the doses of 3.5, 30 and 74 µg/kg/bw (DM 3.5, DM 30 and DM 74). Diabetes was induced by an alloxan injection (40 mg/kg, IV). EKG was recorded (days 1, 15 and 30) using four electrodes inserted into the subcutaneous layer of the paws. Both RR and QT intervals were measured, and then corrected QT and QT dispersion values were calculated. RESULTS: The DM 3.5 and DM 30 groups showed a significant reduction of glycemia (p< 0.05) when compared with the high dose (DM 74). Rats of the DM 74 group presented prolonged QTc, QTd and QTcd intervals, whereas rats of the DM 3.5 and DM 30 groups presented less prolonged intervals. CONCLUSION: Metformin at high doses provided greater dispersion of the QT interval probably because of the increased ventricular repolarization inhomogeneity, whereas at low doses decreased QT intervals were observed in diabetic rats.

Metformina interage com o treinamento físico diminuindo a glicemia e aumentando o armazenamento de glicogênio em ratos diabéticos / Metformin interacts with physical training decreasing glycemia and increasing glycogen supply in diabetic rats

INTRODUÇÃO: Assim como em humanos, ratos diabéticos apresentam baixas quantidades de glicogênio. Entretanto, treinamento ou medicamentos podem causar diminuição da glicemia e melhorar o controle metabólico. Metformina aumenta o glicogênio enquanto diminui a glicemia em ratos normais estressados por exercício. OBJETIVO: Investigar se exercício regular e metformina melhoram o metabolismo de ratos diabéticos. MÉTODOS: Ratos Wistar diabéticos por aloxana tratados com metformina (DTM) ou não (DT) foram treinados. O treinamento consistiu de 20 sessões de 30 min de duração, cinco dias por semana. Ratos diabéticos sedentários foram usados como controle (SD e SDM). Metformina (5,6µg/ml) foi dada na água de beber. Após 48h de repouso, a glicose (mg/dl) e a insulina (ng/mL) foram medidas no plasma e o glicogênio (mg/100mg de tecido molhado) no fígado, sóleo e gastrocnêmio. RESULTADOS: A glicemia diminuiu de 435 ± 15 para 230 ± 20 no grupo DSM, para 143 ± 8,1 no grupo DT e para 138 ± 19mg/dl no grupo DTM. O grupo DSM teve proporcional aumento de glicogênio hepático de 1,69 ± 0.22 para 3,53 ± 0.24 e o treinamento aumentou para 3,36 ± 0,16mg/100mg. A metformina induziu aumento proporcional nos músculos sóleo de 0,21 ± 0,008 para 0,42 ± 0,03 e no gastrocnêmio, de 0,33 ± 0,02 para 0,46 ± 0,03, enquanto que o treinamento aumentou apenas no gastrocnêmio para 0,53 ± 0,03. Uma grande interação foi observada no fígado (o glicogênio aumentou para 6,48 ± 0,34). CONCLUSÃO: Pequenas doses orais de metformina e/ou treinamento restituíram parcialmente a glicemia e promoveram aumento de glicogênio em tecidos de ratos diabéticos. A associação com o programa de exercício foi benéfica, ajudando a diminuir a glicemia e a aumentar o armazenamento de glicogênio no fígado de ratos diabéticos.

INTRODUCTION: Like in humans, lower amounts of glycogen are present in tissues of diabetic rats. However, training or drugs that lower glycemia can improve the metabolic control. Metformin increased glycogen while decreased glycemia in normal rats stressed by exercise. OBJECTIVE: In this work we investigated if regular exercise and metformin effects improve the metabolism of diabetic rats. METHODS: Alloxan diabetic Wistar rats treated with metformin (DTM) or not (DT) were trained. Training consisted of 20 sessions of 30 min, 5 days a week. Sedentary diabetic rats served as control (SD and SDM). Metformin (5.6 µg/g) was given in the drinking water. After 48 h resting, glucose (mg/dl) and insulin (ng/mL) was measured in plasma and glycogen (mg/100 mg of wet tissue) in liver, soleus and gastrocnemius. RESULTS: Glycemia decreased in DM group from 435±15 to 230±20, in DT group to 143±8.1 and in DTM group to 138±19 mg/dl. DM group had proportional increase in the hepatic glycogen from 1.69±0.22 to 3.53±0.24, and the training increased to 3.36 ± 0.16 mg/100 mg. Metformin induced the same proportional increase in the muscles (soleus from 0.21±0.008 to 0.42±0.03 and gastrocnemius from 0.33±0.02 to 0.46±0.03), while the training promoted increase on gastrocnemius to 0,53 ± 0,03, only. A high interaction was observed in liver (glycogen increased to 6.48±0.34). CONCLUSION: Very small oral doses of metformin and/or, partially restored glycemia in diabetic rats and decreased glycogen in tissues. Its association with an exercise program was beneficial, helping lower glycemia further and increase glycogen stores on liver of diabetic rats.