Metformin administration in prevention of colorectal polyps in type 2 diabetes mellitus patients

BACKGROUND Colorectal polyps are frequently observed in patients with type 2 diabetes mellitus(DM),posing a significant risk for colorectal cancer.Metformin,a widely prescribed biguanidine drug for type 2 DM,has been suggested to have potential chemoprophylactic effects against various cancers.AIM To explore the correlation between colorectal polyps and metformin use in type 2 DM patients.METHODS Type 2 DM patients were categorized into polyp and non-polyp groups.Following this,all patients were categorized into the type 2 DM-metformin,type 2 DM-non-metformin,and non-type 2 DM groups.Based on the baseline colonoscopy results,we performed pairwise comparisons of the incidence of colorectal polyps among the three groups.Additionally,we analyzed the relationship between colorectal polyps and the duration of metformin use and between the size and number of polyps and metformin use.Simultaneously,we focused on the specific pathological types of polyps and analyzed their relationship with metformin use.Finally,we compared the incidence of polyps between metformin and non-metformin groups according to the interval colonoscopy results.RESULTS The rate of metformin use in patients with colorectal polyps was 0.502 times that of patients without colorectal polyps[odds ratio(OR)=0.502,95%confidence interval(CI):0.365-0.689;P<0.001].The incidence of colorectal polyps did not differ significantly between the type 2 DM-metformin and non-type 2 DM groups(P>0.05).Furthermore,the correlations between the duration of metformin use and the incidence of colorectal polyps and between the size and number of polyps and metformin use were not statistically significant(P>0.05).Metformin use did not affect the incidence of colorectal polyps during interval colonoscopy(P>0.05).CONCLUSION Metformin use and colorectal polyp incidence in type 2 DM patients showed a negative correlation,independent of the hypoglycemic effect of metformin.

Megestrol acetate plus metformin for fertility-sparing treatment of atypical endometrial hyperplasia and early-stage endometrial adenocarcinoma: a prospective study

Objective To evaluate the efficacy of medroxyprogesterone acetate(MA)plus metformin as the primary fertility-sparing treatment for atypical endometrial hyperplasia(AEH)and early-stage grade 1 endometrial adenocarcinoma(G1 EAC)and the recurrence rate after treatment.Methods Sixty patients(aged 20-42 years)with AEH and/or grade 1 EAC limited to the endometrium were enrolled prospectively and randomized into two groups(n=30)to receive oral MA treatment at the daily dose of 160 mg(control)or MA plus oral metformin(850 mg,twice a day)for at least 6 months.The treatment could extend to 12 months until a complete response(CR)was achieved,and follow-up hysteroscopy and curettage were performed every 3 months.For all the patients who achieved CR,endometrial expressions of IGFBP-rP1,p-Akt and p-AMPK were detected immunohistochemically.Results A total of 58 patients completed the treatment.After 9 months of treatment,23(76.7%)patients in the combined treatment group and 20(71.4%)in the control group achieved CR;two patients in the control group achieved CR after converting to the combined treatment.The recurrence rate did not differ significantly between the control group and combined treatment group(30.0%vs 22.7%,P>0.05).Ten(35.7%)patients in the control group experienced significant weight gain of 5.7±6.1 kg,while none of the patients receiving the combined treatment exhibited significant body weight changes.Compared with the control group,the patients receiving the combined treatment showed enhanced endometrial expressions of IGFBP-rP1 and p-AMPK with lowered p-Akt expression.Conclusion Metformin combined with MA may provide an effective option for fertility-sparing treatment of AEH and grade 1 stage IA EAC,and the clinical benefits of metformin for controlling MA-induced weight gain and promoting endometrial expressions of IGFBP-rP1 and p-AMPK while inhibiting p-Akt expression warrants further study.

Effect of vildagliptin as add-on therapy to a low-dose metformin

AIM:To evaluate the efficacy and safety of the addition of vildagliptin to low-dose metformin and compare it to an uptitration of metformin in type 2 diabetes mellitus(T2DM) patients who have inadequate control with metformin monotherapy.METHODS:Eligible patients were randomized to receive vildagliptin 100 mg qd or metformin(500 mg qd for 2 wk and then 500 mg bid) added to open label me tformin 500 mg bid for the 24 wk.The primary endpoi nt was baseline to endpoint hemoglobin A1c(HbA1c) change.RESULTS:The adjusted mean change from baseline in HbA1c at the 24th wk was-0.51% in the vildagliptin/metformin group(mean baseline HbA1c:7.4%) and-0.37% in the metformin monothera py group(mean baseline HbA1c:7.3%).The mean diffe rence was-0.14% with 95% Confidence Interval(-0.24%,-0.05%).As non-inf e riority(margin of 0.4%) was achieved,a test for superiority was performed.This test showed statistically significant superiority of the combination over monotherapy group(P = 0.002).Gastrointestinal(GI) adverse events were signif icantly more frequent in the metformin group than the combin ation group(21.0% vs 15.4%,P = 0.032).CONCLUSION:In patients with T2DM inadequately controlled with metformin up to 1000 mg daily,the addition of vildagliptin 100 mg daily achieved larger HbA1c reduction with fewer GI events than with increa sing the metformin dose.

基于ADE优化的IPMSM全速域无传感器控制

为了实现内置式永磁同步电机(IPMSM)全速域的无传感器控制和切换速域的平滑过渡,提出了一种基于自适应差分进化(ADE)算法优化的复合控制方法。分别在零低速域、中高速域采用旋转高频电压注入法和滑模观测器法来对电机转速和转子位置进行估算,并在切换速域采用基于ADE算法的权重系数优化法来实现上述两种控制方法的平滑切换,从而实现IPMSM全速域无传感器控制。仿真结果表明:提出的复合控制方法能够实现电机全速域的无感控制和切换速域的平滑过渡,且具有良好的稳定性。

Effects of co-administration of methanol leaf extract of Catharanthus roseus on the hypoglycemic activity of metformin and glibenclamide in rats

Objective:To investigate the interacting effects of co-administration of methanol leaf extract of Catharanthus roseus（C.roseus） on the hypoglycemic activity of metformin as well as glibenclamide using experimental rats.Methods:Phytochemical analysis as well as acute toxicity and lethality(LD50) test were carried out on its methanol leaf extract.The alloxan model for experimental induction of diabetes in rats was employed.Six groups comprising five rats each were used.GroupsⅡ,ⅢandⅣreceived 250 mg/kg of extract,100 mg/kg of metformin and 1 mg/kg of glibenclamide respectively,while V and VI were administered metformin-extract and glibenclamide-extract combinations respectively at doses as above.Group I served as negative control and received only distilled water.All administration was done once daily for seven days. Fasting blood glucose was determined at 2,12,24,72 and 168 h using a glucometer.One-way ANOVA with post-hoc tests was used to assess for significant difference due to administration of drug alone and with co-administration of drug and extract.Results:The LD50 was 2 121.32 mg/kg. The phytochemical studies indicated the presence of saponins,tannins,alkaloids,phlotatannins, flavonoids,triterpenoids,reducing sugars,anthraquinones and glycosides.All medicaments significantly reduced blood glucose levels when compared with control alone（P【0.05） with the highest percentage reduction in blood glucose（64.86%） exhibited by metformin-extract combination.Conclusions:The leaf extract of C.roseus significandy increases the hypoglycemic effect of metformin.

儿童维生素AD滴剂,这样吃才对

众所周知,维生素A、D对孩子的生长发育至关重要。而补充维生素A、D,最好选择专门的维生素AD制剂,比如维生素AD滴剂。但许多家长对其又不甚了解,有诸多疑问。以下,笔者将一一进行解答。

ADS-B信号在对流层大气波导中的传播性能

对流层大气环境存在特殊大气结构“大气波导”,可形成电波超视距传播或产生雷达盲区等。目前,通过雷达、GNSS信号等可以对大气波导进行一定程度的反演探测,但均存在一定的不足。ADS-B信号具有应用范围广、信号密度大、实时性高等特点,为此提出利用ADS-B信号受到不同大气环境影响后能量损耗不同的特点对ADS-B信号与对流层大气环境关联性进行分析研究。以武汉地区ADS-B信号数据为例,基于抛物方程传播理论对路径损耗进行仿真分析,并进行了实验验证。结果表明:ADS-B接收信号与仿真结果存在线性相关性并给出线性表述,为后续利用ADS-B信号反演大气波导提供参考依据。

Research advances on how metformin improves memory impairment in “chemobrain”

Cognitive impairment caused by chemotherapy,referred to as“chemobrain,”is observed in approximately 70% of cancer survivors.However,it is not completely understood how chemotherapy induces cognitive dysfunction,and clinical treatment strategies for this problem are lacking.Metformin,used as a first-line treatment for type 2 diabetes mellitus,is reported to reduce the effects of chemobrain.Recently,several studies have examined the effect of metformin in rescuing chemobrain.This review discusses recent clinical/preclinical studies that addressed some mechanisms of chemobrain and evaluates the effect of metformin in rescuing chemobrain and its potential mechanisms of action.

星基ADS-B系统空天链路的建模与仿真

星基广播式自动相关监视(ADS-B,automatic dependent surveillance-broadcast)系统是一种新型的航空器监视技术,在未来空中交通管理系统中具有广阔的应用前景。为了深入研究星基ADS-B系统中航空器到卫星的空天链路通信性能,将专业软件Matlab和STK(system tool kit)有效联合,构建符合国际标准的星基ADS-B空天链路完整模型;通过离散事件动态交互模拟ADS-B消息的发送与接收全过程,最后统计得出体现星基ADS-B空天链路通信性能的消息识别概率(POI,possibility of identify)、消息检测概率(POD,possibility of detective)、信号接收功率、信号冲突概率、卫星覆盖范围等指标。仿真结果表明,随着区域内航空器数量上升,POI、POD下降,消息冲突概率上升。

Metformin promotes angiogenesis and functional recovery in aged mice after spinal cord injury by adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway

Treatment with metformin can lead to the recovery of pleiotropic biological activities after spinal cord injury.However,its effect on spinal cord injury in aged mice remains unclear.Considering the essential role of angiogenesis during the regeneration process,we hypothesized that metformin activates the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway in endothelial cells,thereby promoting microvascular regeneration in aged mice after spinal cord injury.In this study,we established young and aged mouse models of contusive spinal cord injury using a modified Allen method.We found that aging hindered the recovery of neurological function and the formation of blood vessels in the spinal cord.Treatment with metformin promoted spinal cord microvascular endothelial cell migration and blood vessel formation in vitro.Furthermore,intraperitoneal injection of metformin in an in vivo model promoted endothelial cell proliferation and increased the density of new blood vessels in the spinal cord,thereby improving neurological function.The role of metformin was reversed by compound C,an adenosine monophosphate-activated protein kinase inhibitor,both in vivo and in vitro,suggesting that the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway likely regulates metformin-mediated angiogenesis after spinal cord injury.These findings suggest that metformin promotes vascular regeneration in the injured spinal cord by activating the adenosine monophosphate-activated protein kinase/endothelial nitric oxide synthase pathway,thereby improving the neurological function of aged mice after spinal cord injury.

Facile Synthetic Design and Characterization of Curcumin-Metformin Adduct： Potential Insights into the Role of This Conjugate in Diseases of Aging

Recently, the anti-glycation and anticancer properties of curcumin longa and okra seed extract were studied alone and also in combination with the well-established drug metformin. The combined effect of curcumin with metformin and metformin with okra seed extract was found to be highly efficacious in inhibiting Advanced Glycation End-products （AGEs）. In order to understand the mechanistic implications of curcumin combined with metformin and its enhanced anti-glycation activity, a Curcumin-Metformin Adduct was chemically synthesized. This adduct was fully characterized by thin-layer chromatography, Nano Drop spectrophotometry and electrospray-ionization mass spectrometry. The adduct may be helpful not only in elucidating the mechanism of anti-glycation and anti-cancer activities but also in studying the role of curcumin in binding of AI3-oligomers and disaggregating fibrillar formation in Alzheimer＇s disease.

基于迁移学习-元学习的ADS-B攻击分类研究

准确分类通航领域ADS-B攻击类型,采取预防攻击措施,对保障通航运行安全性具有重要意义。针对通航领域ADS-B攻击数据样本少,提出一种基于迁移学习-元学习的ADS-B攻击分类模型。该模型将迁移学习与深度卷积自编码器相结合,建立ADS-B攻击特征提取模型,提取数据样本的攻击有效特征表示,并运用元学习策略在特征空间中实现ADS-B攻击准确分类。实例研究表明,基于迁移学习-元学习的攻击分类模型可有效分类小样本ADS-B攻击,且正确率在95%以上。

Continuous melt granulation to develop high drug loaded sustained release tablet of Metformin HCl

The present work explores the application of melt granulation technology to develop a high drug loaded sustained release matrix tablet of Metformin HCl using hydroxypropylcellulose(HPC) as a hydrophilic binder and stearic acid as an extrusion aid for producing cohesive granules. This novel approach allowed the use of a minimum number of excipients to reduce the tablet size, and to enhance compressibility of the drug. This also offered a cost effective method owing to the elimination of a ‘drying step’ prevalent in wet granulation method.Moreover, this research also focuses on resolving the processability issues associated with the use of HPC Nisso-H at high drug loading. The thermal lubricants were screened for this purpose and evaluated for their impact on extrudability, granule and tablet characteristics. Stearic acid was selected as the thermal lubricant, which not only contributed to the inhibition of burst release, but also improved the flow property of the granules.The developed matrix tablet(75% drug loading) resulted in 670 mg of weight for 500 mg dose strength and showed sustained drug release over 10 h. When compared, with conventional granulation techniques, it was observed that, under identical compression force, the tablet prepared by MG exhibited superior compactibility along with tablet hardness and optimal drug release profile. FTIR suggested nonexistence of chemical interaction between the drug and the other excipients while XRD and DSC analysis revealed the crystalline state of the drug.Furthermore, the results obtained from Raman spectroscopy proved the uniform distribution of the Metformin HCl and polymer in the final dosage form. This technology leads to the manufacture of sustained release matrix formulation with reduced tablet size of a high dose,highly water soluble drug otherwise difficult to process using standard batch-granulation.

Statins and Metformin Use Is Associated with Lower PSA Levels in Prostate Cancer Patients Presenting for Radiation Therapy

Background: A possible association between the level of prostate specific antigen (PSA) and the use of some commonly prescribed medications has been reported in recent studies. Most of these studies were carried out in general populations of men who were screened for prostate cancer using the PSA test. We reported on the association between the initial PSA level and the use of statins, metformin and alpha-blockers in patients who were diagnosed with prostate cancer and presented for radiation therapy. Methods: Three hundred and eighty one patients treated between the years of 2000-2005 and 2009-2012 were included in this retrospective study. The information about statin, metformin and alpha-blockers use was recorded immediately prior to treatment. Differences in PSA levels prior to treatment by medication status were estimated using univariate and multivariate linear regression on log PSA values. Results: Compared with men who were not on these medications, the PSA level at presentation was 20% lower for statin users (p = 0.002) and 33% lower for metformin users (p = 0.004). We did not observe statistically significant associations between the use of statins or metformin and cancer stage, National Comprehensive Cancer Network (NCCN) risk score, or therapy outcome. A statistically significant association between the NCCN risk score and the use of alpha-blockers was observed (p = 0.002). Conclusions: We found that statins and metformin were associated with lower PSA levels in prostate cancer patients to an extent that could influence management decisions. We found no statistically significant associations between the use of these medications and treatment outcomes.

基于多时间特征融合网络的ADS-B实采信号分离

不同于以往单天线广播式自动相关监视(Automatic Dependent Surveillance-Broadcast,ADS-B)信号分离中利用仿真的ADS-B信号制作数据集,将单天线接收的真实飞机发射的ADS-B原始信号通过调整信号起始时间以及功率并人为增加噪声来制作数据集。为了提高信号分离的时域波形精度,提出一种多分辨率多时间特征融合重采样(Multi-Temporal fusion Resampling of Multi-Resolution Features,MTRM-RF)网络,通过卷积将信号转化成不同采样率的信号并分别使用多层堆叠逐渐膨胀的一维卷积提取不同时间间隔的特征,以获得更多的时间信息。对多种基于深度学习的语音分离网络进行比较发现,MTRM-RF网络能够有效地融合ADS-B信号的不同采样率、不同时间间隔采样点的特征进行训练。并且随着训练集数据量的增加,分离信号的平均解码正确率达到88.39%,证明该网络可有效分离单天线实采的ADS-B交织信号。

Metformin and pancreatic neuroendocrine tumors:A systematic review and meta-analysis

BACKGROUND Most patients with advanced pancreatic neuroendocrine tumors(pNETs)die due to tumor progression.Therefore,identifying new therapies with low toxicity and good tolerability to use concomitantly with the established pNET treatment is relevant.In this perspective,metformin is emerging as a molecule of interest.Retrospective studies have described metformin,a widely used agent for the treatment of patients with type 2 diabetes mellitus(T2DM),to be effective in modulating different tumor-related events,including cancer incidence,recurrence and survival by inhibiting mTOR phosphorylation.This systematic review evaluates the role of T2DM and metformin in the insurgence and post-treatment outcomes in patients with pNET.AIM To systematically analyze and summarize evidence related to the diagnostic and prognostic value of T2DM and metformin for predicting the insurgence and posttreatment outcomes of pNET.METHODS A systematic review of the published literature was undertaken,focusing on the role of T2DM and metformin in insurgence and prognosis of pNET,measured through outcomes of tumor-free survival(TFS),overall survival and progression free survival.RESULTS A total of 13 studies(5674 patients)were included in this review.Analysis of 809 pNET cases from five retrospective studies(low study heterogeneity with I^(2)=0%)confirms the correlation between T2DM and insurgence of pNET(OR=2.13,95%CI=1.56-4.55;P<0.001).The pooled data from 1174 pNET patients showed the correlation between T2DM and post-treatment TFS in pNET patients(hazard ratio=1.84,95%CI=0.78-2.90;P<0.001).The study heterogeneity was intermediate,with I^(2)=51%.A few studies limited the possibility of performing pooled analysis in the setting of metformin;therefore,results were heterogeneous,with no statistical relevance to the use of this drug in the diagnosis and prognosis of pNET.CONCLUSION T2DM represents a risk factor for the insurgence of pNET and is a significant predictor of poor post-treatment TFS of pNET patients.Unfortunately,a few studies with heterogeneous results limited the possibility of exploring the effect of metformin in the diagnosis and prognosis of pNET.

Marked Improvement in Glycemic Control with Exenatide on Addition to Metformin, Sulfonylurea and Insulin Glargine in Type 2 Diabetes Mellitus, a Real World Experience

Background: The major effect of Exenatide is attributed to lowering of post-prandial glycemia, whereas insulin glargine mainly improves fasting glycemia [FPG]. Objective: Therefore, we assessed effect of Exenatide administration at 6 months and for at 1 year on glycemic control, lipids, body weight [BW], daily insulin dose and hypoglycemic events. Methods: Records of 164 subjects, 126 men and 38 women administered Exenatide between January 2011 and December 2013 are included in this report. Exenatide was initiated at 5 mcg subcutaneously twice daily [BID] in obese subjects, BMI > 30 kg/m2, with C-peptide > 1 ng/d, and HbA1c 7.5% - 9.5%, while receiving daily metformin 2000 mg, Sulfonylurea Glimepiride 8 mg and insulin Glargine [GLAR]. Exclusion criteria were creatinine > 1.5 mg/dL and liver enzymes > 2.5 times upper limit of normal. Indices of glycemic control include fasting plasma glucose levels and HbA1c. Lipids include serum concentrations of total, LDL and HDL cholesterol. Other endpoints are body weight, daily insulin dose and number of hypoglycemic events per patient during 4 weeks prior to initiation of Exenatide, at 6 months and 1 year of therapy. Results: In 37 subjects, Exenatide was discontinued within 1 - 3 weeks;29 due to onset of nausea and vomiting. Seven of these also complained of abdominal pain and in these, serum amylase and lipase were elevated indicating presence of acute pancreatitis. One subject discontinued because of chest pain. Fasting plasma Glucose remained unchanged following Exenatide administration. However, HbA1c declined significantly denoting improvement in overall glycemic control without significant changes in body weight, daily insulin dose and hypoglycemic events. Lipid panel improved as well. Conclusion: Exenatide may be an appropriate adjuvant option in obese subjects with Type 2 diabetes mellitus with lack of desirable glycemic control while receiving therapy with Metformin, Glimepiride, and insulin Glargine. Moreover, improvement in glycemic control is likely to be secondary to lowering of post prandial hyperglycemia induced by Exenatide.

Mechanism Based Pharmacokinetic Pharmacodynamic Modeling of Vildagliptin as an Add-on to Metformin for Subjects with Type 2 Diabetes

Various drugs are used to maintain normoglycemia in subjects with type 2 diabetes mellitus.The combination of the drugs from different classes in one single tablet may enhance the effectiveness of the anti-diabetic drugs.To investigate the impact of combining drugs on the glucose regulation of subjects with type 2 diabetes,we propose a pharmacokinetic/pharmacodynamics(PK/PD)mathematical modeling approach for a combination of metformin and vildagliptin drugs.In the proposed modeling approach,two separate PK models representing oral administration of metformin and vildagliptin for diabetic subjects are interconnected to a PD model comprising a detailed compartmental physiological model representing the regulatory effect of insulin,incretins and glucagon hormones on glucose concentration in a human body.The impact of doses of individual drugs and their combination on the blood glucose concentration of a group of type 2 diabetic subjects is investigated.It is indicated that while administration of individual drugs reduces the blood glucose levels,since they have separate mechanisms of action,combining them synergizes lowering the blood glucose levels.

Effectiveness of Telmisartan as an Adjunct to Metformin in Treating Type II Diabetes Mellitus in Rats

The monitoring reports of most patients with type II diabetes mellitus (T2DM) revealed that monotherapy with metformin could not achieve long-term glycemic control. Thus, we designed this study aiming to investigate the effect of telmisartan, a unique AT1 receptor antagonist and a partial agonist of peroxisome-proliferator activated receptor gamma (PPARγ), individually and as an adjunct to metformin, on a rat model that simulates the metabolic characteristics of human T2DM. Adult male Wistar rats were fed high-fat, high-fructose diet (HFFD) for 8 weeks followed by a single low dose of streptozotocin (STZ) (35 mg/kg/day, i.p.) rendering them diabetic and insulin resistant. The effectiveness of both drugs and their combination was tested by assessing the changes in the levels of serum glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR) index, lipid profile and adiponectin. In addition, the level of reduced glutathione (GSH) in the liver, was investigated. Results showed that the addition of telmisartan to metformin successfully restored serum glucose back to normal levels and corrected the altered serum total cholesterol (TC), triglycerides (TG) and adiponectin, emphasizing the potential role of telmisartan as an adjunct to metformin.

Promising use of metformin in treating neurological disorders:biomarker-guided therapies

Neurological disorders are a diverse group of conditions that affect the nervous system and include neurodegenerative diseases(Alzheimer’s disease,multiple sclerosis,Parkinson’s disease,Huntington’s disease),cerebrovascular conditions(stroke),and neurodevelopmental disorders(autism spectrum disorder).Although they affect millions of individuals around the world,only a limited number of effective treatment options are available today.Since most neurological disorders express mitochondria-related metabolic perturbations,metformin,a biguanide type II antidiabetic drug,has attracted a lot of attention to be repurposed to treat neurological disorders by correcting their perturbed energy metabolism.However,controversial research emerges regarding the beneficial/detrimental effects of metformin on these neurological disorders.Given that most neurological disorders have complex etiology in their pathophysiology and are influenced by various risk factors such as aging,lifestyle,genetics,and environment,it is important to identify perturbed molecular functions that can be targeted by metformin in these neurological disorders.These molecules can then be used as biomarkers to stratify subpopulations of patients who show distinct molecular/pathological properties and can respond to metformin treatment,ultimately developing targeted therapy.In this review,we will discuss mitochondria-related metabolic perturbations and impaired molecular pathways in these neurological disorders and how these can be used as biomarkers to guide metformin-responsive treatment for the targeted therapy to treat neurological disorders.