• Title, Summary, Keyword: metformin

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High-Dose Metformin Plus Temozolomide Shows Increased Anti-tumor Effects in Glioblastoma In Vitro and In Vivo Compared with Monotherapy

  • Eun, Jung;Lim, Ji Hee;Hong, Yong Kil;Yang, Seung Ho
    • Cancer Research and Treatment
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    • v.50 no.4
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    • pp.1331-1342
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    • 2018
  • Purpose The purpose of the study is to investigate the efficacy of combined treatment with temozolomide (TMZ) and metformin for glioblastoma (GBM) in vitro and in vivo. Materials and Methods We investigated the efficacy of combined treatment with TMZ and metformin using cell viability and apoptosis assays. A GBM orthotopic mice model was established by inoculation of $5{\times}10^5$ U87 cells and treated with metformin, TMZ, and the combination for 4 weeks. Western blotting and immunofluorescence of tumor specimens were analyzed to investigate AMP-activated protein kinase (AMPK) and AKT pathway. Results The combination of TMZ and metformin showed higher cytotoxicity than single agents in U87, U251, and A172 cell lines. A combination of high-dose metformin and TMZ showed the highest apoptotic activity. The combination of TMZ and metformin enhanced AMPK phosphorylation and inhibited mammalian target of rapamycin phosphorylation, AKT phosphorylation, and p53 expression. The median survival of each group was 43.6, 55.2, 53.2, 65.2, and 71.3 days for control, metformin treatment (2 mg/25 g/day or 10 mg/25 g/day), TMZ treatment (15 mg/kg/day), combination treatment with low-dose metformin and TMZ, and combination treatment with high-dose metformin and TMZ, respectively. Expression of fatty acid synthase (FASN) was significantly decreased in tumor specimens treated with metformin and TMZ. Conclusion The combination of metformin and TMZ was superior to monotherapy using metformin or TMZ in terms of cell viability in vitro and survival in vivo. The combination of high-dose metformin and TMZ inhibited FASN expression in an orthotopic model. Inhibition of FASN might be a potential therapeutic target of GBM.

Drug Interaction of Metformin and Aspirin in Rabbits (메트포르민과 아스피린의 약물상호작용)

  • Choi, Jun Shik;Choi, In
    • Korean Journal of Clinical Pharmacy
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    • v.13 no.2
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    • pp.67-71
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    • 2003
  • The purpose of this study was to investigate the effect of aspirin (5, 10, 20 mg/kg) on the pharmacokinetics of metformin $(15\;mg/kg)$ in rabbits. The plasma concentration of metformin was decreased significantly (p<0.05) by co-administration of aspirin (10, 20 mg/kg) compared with control. Area under the plasma concentration-time curve (AUC) of metformin was decreased significantly (p<0.05) by co-administration of aspirin (10, 20mg/kg) compared with control. Relative bioavailability $(R.B\%)$ of metformin by co-administration was 79.3 (5 mg/kg), 57.5 (10 mg/kg) and 62.5 (20 mg/kg). Peak plasma concentration of metformin was significantly (p<0.05) decreased by co-administration of aspirin (10, 20 mg/kg) compared with control. The elimination rate constant $(K_{el})$ of metformin was increased by co-administration of aspirin (10, 20 mg/kg) compared with control. The terminal half-lifes $(t_{1/2})$ and mean resident time (MRT) of metformin by co-administration of aspirin (10, 20 mg/kg) were decreased significantly (p<0.05) compared with control. It is considered that the significantly decreased plasma concentration and AUC of metrormin is due to increase of elimination in urine acidified by co-administration of aspirin. The results suggest that the dosage of metformin should be adjusted when metformin is co-administered with aspirin in the clinical situation.

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Frequency of Inappropriate Metformin Use in Patients with Diabetes Mellitus (당뇨병환자에게 부적절하게 사용된 Metformin의 처방빈도 분석)

  • Sin, Hye-Yeon;Jung, Ki-Hwa
    • YAKHAK HOEJI
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    • v.54 no.6
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    • pp.455-460
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    • 2010
  • We evaluated the inappropriateness of metformin use in patients with type 2 diabetes and chronic medical conditions to identify the frequency of the prescription metformin in violation of the food and drug administration (FDA) black box warning. We reviewed medical records of 307 outpatients who received metformin at endocrinology department in a hospital setting between January 1, 2005 and August 30, 2009. Of the 307 outpatients, 25 discontinued treatment of metformin due to elevated serum creatinine level (Scr${\geq}$1.5 mg/dl in male, Scr${\geq}$1.4 mg/dl in female), cancers, and/or liver disease. 5 were lost to follow-up. 89 (29.0%) of the patients had cardiovascular disease, 54.1% for hypertension, 9.8% for liver disease, and 60 (20.8%) for chronic kidney disease. 12 patients (3.9%) with chronic kidney disease and/or elevated serum creatinine level, and 1 patient (0.3%) with lactic acidosis were contraindicated to metformin use. Metformin should be avoided in 7 outpatients (2.3%) with active hepatitis and 1 patient (2.6%) with liver cirrhosis. Of the 307 outpatients, 13 (4.2%) patients who received metformin at the first visit and 16 (8.7%) patients who received metformin at the last visit violated to black box warning. 8 (2.6%) of the patients were in precautionary conditions to metformin use. Adjusted mean difference of serum creatinine was -0.16 mg/dl [95% CI: -0.22 to -0.11 (p<0.05)] and adjusted mean difference of alanine aminotransferase was 4.46 IU/l [95% CI: 2.47 to 6.44 (p<0.05)] between the first visit and the last visit. Critical number of elderly patients who are at the high risks of drug-disease and drug-laboratory interaction is exposed to the inappropriate metformin use in violation of black box warning. The periodic evaluation of metformin use and monitoring prescription through drug utility review (DUR) system is needed to improve patients' safety and to reduce adverse drug events.

Pharmacokinetic and Pharmacodynamic Interaction between Metformin and (-)-Epigallocatechin-3-gallate

  • Ko, Jeong-Hyeon;Jang, Eun-Hee;Park, Chang-Shin;Kim, Hyoung-Kwang;Cho, Soon-Gu;Shin, Dong-Wun;Yi, Hyeon-Gyu;Kang, Ju-Hee
    • Molecular & Cellular Toxicology
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    • v.5 no.4
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    • pp.298-303
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    • 2009
  • (-)-Epigallocatechin-3-gallate (EGCG), a major flavonoid in green tea has multiple health benefits including chemoprevention, anti-inflammatory, anti-diabetic, and anti-obesity effects. In connection with these effects, EGCG can be a candidate to help the treatment of metabolic diseases. Metformin is a widely used anti-diabetic drug regulating cellular energy homeostasis via AMP-activated protein kinase (AMPK) activation. Therefore, the combination of metformin with EGCG may have additive or synergistic effects on treatment of type 2 diabetes. Nevertheless, there is no report for the pharmacokinetic and/or pharmacodynamic interaction of EGCG with metformin. Here, we evaluated the pharmacokinetic and pharmacodynamic interaction between metformin and EGCG in rats. Pharmacokinetics parameters of metformin were measured after oral administration of metformin in rats pre-treated with EGCG (10 mg/kg) or saline for 7 days. The results showed that there is no significant difference in pharmacokinetic parameters between saline control and EGCG-treated group. In addition, the hepatic AMPK activation by metformin in EGCG-treated rats was also similar to the control. The lack of additive effects of EGCG on AMPK activation or intracellular uptake of metformin was also evaluated in cells in the presence or absence of EGCG. Treatment of HepG2 cells with EGCG inhibited the metformin-induced AMPK activation. Combined results suggested that EGCG has no effect on the pharmacokinetics of metformin but may contribute to metformin action.

Metformin displays in vitro and in vivo antitumor effect against osteosarcoma

  • Ko, Yunmi;Choi, Aery;Lee, Minyoung;Lee, Jun Ah
    • Korean Journal of Pediatrics
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    • v.59 no.9
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    • pp.374-380
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    • 2016
  • Purpose: Patients with unresectable, relapsed, or refractory osteosarcoma need a novel therapeutic agent. Metformin is a biguanide derivative used in the treatment of type II diabetes, and is recently gaining attention in cancer research. Methods: We evaluated the effect of metformin against human osteosarcoma. Four osteosarcoma cell lines (KHOS/NP, HOS, MG-63, U-2 OS) were treated with metformin and cell proliferation was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell cycle progression and apoptosis were evaluated using flow cytometric analysis, and migration and wound healing assay were performed. Fourteen female Balb/c-nude mice received KHOS/NP cell grafts in their thigh, and were allowed access to metformin containing water (2 mg/mL) ad libitum. Tumor volume was measured every 3-4 days for a period of 4 weeks. Results: Metformin had a significant antiproliferative effect on human osteosarcoma cells. In particular, metformin inhibited the proliferation and migration of KHOS/NP cells by activation of AMP-activated protein kinase and consequent inhibition of the mammalian target of rapamycin pathway. It also inhibited the proliferation of cisplatin-resistant KHOS/NP clone cells. Analysis of KHOS/NP xenograft Balb/c-nude models indicated that metformin displayed potent in vivo antitumor effects. Conclusion: Further studies are necessary to explore metformin's therapeutic potential and the possibilities for its use as an adjuvant agent for osteosarcoma.

Metformin Inhibits Growth of Hepatocellular Carcinoma Cells by Inducing Apoptosis Via Mitochondrion-mediated Pathway

  • Xiong, Yu;Lu, Qing-Jun;Zhao, Jing;Wu, Guo-Yang
    • Asian Pacific Journal of Cancer Prevention
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    • v.13 no.7
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    • pp.3275-3279
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    • 2012
  • Recently, population-based studies of type 2 diabetes patients have provided evidence that metformin treatment is associated with a reduced cancer incidence and mortality, but its mode of action remains unclear. Here we report effects of metformin on hepatocellular carcinoma (HCC) Hep-G2 cells and details of molecular mechanisms of metformin activity. Our research indicates that metformin displays anticancer activity against HCC through inhibition of the mTOR translational pathway in an AMPK-independent manner, leading to G1 arrest in the cell-cycle and subsequent cell apoptosis through the mitochondrion-dependent pathway. Furthermore, we showed that metformin strongly attenuated colony formation and dramatically inhibited Hep-G2 tumor growth in vivo. In conclusion, our studies suggested that metformin might have potential as a cytotoxic drug in the prevention and treatment of HCC.

Effects of Metformin and Rosiglitazone in Overweight or Obese Women with Polycystic Ovarian Syndrome (과체중 및 비만 다낭성 난소 증후군 환자에서의 Metformin과 Rosiglitazone의 효용성)

  • Bai, Kwang Bum
    • Clinical and Experimental Reproductive Medicine
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    • v.32 no.4
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    • pp.347-352
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    • 2005
  • Objective: The purpose of this study was to evaluate and compare the effects of metformin and rosiglitazone in overweight or obese women with polycystic ovarian syndrome. Methods: Twenty Six overweight or obese patients with polycystic ovarian syndrome were randomly treated with either metformin (500 mg three times daily, n=13) or rosiglitazone (4 mg once daily, n=13) for 6 months. Hormonal studies were performed before and after treatment. Insulin resistances were calculated by computerized HOMA 2 Calculator v2.2. Results: Testosterone decreased while SHBG increased after 6 months treatment in both metformin and rosiglitazone treatment groups. Fasting glucose decreased after metformin or rosiglitazone treatment. HOMA insulin resistance improved after treatment with either drug. There was no differences in hormonal changes and insulin resistance between 2 treatment groups. Conclusions: This study shows that metformin and rosiglitazone are effective in improving insulin sensitivity and ameliorating hyperandrogenism in overweight/obese polycystic ovarian syndrome women.

Metformin May Improve the Prognosis of Patients with Pancreatic Cancer

  • Zhang, Jia-Wei;Sun, Qing
    • Asian Pacific Journal of Cancer Prevention
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    • v.16 no.9
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    • pp.3937-3940
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    • 2015
  • Background: Pancreatic cancer risk is increased in patients with type 2 diabetes, while being reduced by metformin treatment. However, it is unclear whether metformin could be associated with clinical outcomes of patients with pancreatic cancer and concurrent type 2 diabetes. Materials and Methods: A pooled analysis of 4 publications including 1,429 patients was performed to investigate the association of metformin and overall survival(OS) in patients with pancreatic cancer and concurrent type 2 diabetes. Results: A borderline significant relative survival benefit was found in metformin treated patients compared with non-metformin treated patients (hazard ratio 0.80; 95% CI: 0.62-1.03). Conclusions: These results suggest that further investigation is warranted of whether metformin may benefit the survival of patients with pancreatic cancer and concurrent type 2 diabetes.

Pharmacokinetic-Pharmacodynamic Modeling for the Relationship between Glucose-Lowering Effect and Plasma Concentration of Metformin in Volunteers

  • Lee, Shin-Hwa;Kwon, Kwang-il
    • Archives of Pharmacal Research
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    • v.27 no.7
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    • pp.806-810
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    • 2004
  • Metformin is a biguanide antihyperglycemic agent often used for the treatment of non-insulin dependent diabetics (NIDDM). In this study, the pharmacokinetics and pharmacodynamics of metformin were investigated in Korean healthy volunteers during a fasting state for over 10 h. In order to evaluate the amount of glucose-lowering effect of metformin, the plasma concentrations of glucose were measured for a period of 10 h followed by the administration of metformin (oral 500 mg) or placebo. In addition, the concentration of metformin in blood samples was determined by HPLC assay for the drug. All volunteers were consumed with 12 g of white sugar 10 minutes after drug intake to maintain initial plasma glucose concentration. The time courses of the plasma concentration of metformin and the glucose-lowering effect were analyzed by nonlinear regression analysis. The estimated $C_{max}$, $T_{max}$, $CL_{t}$/F (apparent clearance), V/F(apparent volume of distribution), and half-life of metformin were 1.42$\{pm}$0.07 $\mu\textrm{g}$/mL, 2.59$\{pm}$0.18h, 66.12$\{pm}$4.6 L/h, 26.63 L, and 1.54 h respectively. Since a significant counterclock-wise hysteresis was found for the metformin concentration in the plasma-effect relationship, indirect response model was used to evaluate pharmacodynamic parameters for metformin. The mean concentration at half-maximum inhibition $IC_{50}$, $k_{in}$, $k_{out}$ were 2.26 $\mu\textrm{g}$/mL, 83.26 $H^{-1}$, and 0.68 $H^{-1}$, respectively. Therefore, the pharmacokinetic-pharmacodynamic model may be useful in the description for the relationship between plasma concentration of metformin and its glucose-lowering effect.

The Effect of Metformin Therapy on Clomiphene Citrate-resistant Polycystic Ovarian Syndrome Women (클로미펜에 저항성을 보이는 다낭성 난소증후군 여성들에 대한 메트포민 치료의 효과)

  • Ko, Sang-Hyeon;Lee, Sang-Hoon
    • Clinical and Experimental Reproductive Medicine
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    • v.28 no.4
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    • pp.255-264
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    • 2001
  • Objective : This study was performed to investigate the effect of metformin therapy on ovulation induction & pregnancy rate in clomiphene citrate-resistant PCOS women. Method: This study used a randomized, single-blinded, case-controlled methods. Total study group consisted of 21 women who showed clomiphene citrate-resistant parttern on previous ovulation induction cycles. Patients of metformin group received metformin 500 mg three times daily, for 7 weeks. Control group received none. Metformin group was consisted of 10 women and control group was consisted of 11 women. Then clomiphene was administrated at daily 50 mg for 5 days to both groups. Clomiphene dosage was increased to daily 150 mg until ovulation was occurred. Before and After metformin treatment, blood samples for measurement of insulin, glucose, steroids were obtained. Results: In the metformin and control groups, 6 of 10 women (60%) and 2 of 11 women (18%) ovulated. And 4 of 10 women (40%) and 0 of 11 women (0%) conceived. Comparisons between the groups were significant. Conclusion: In PCOS women who are resistant to CC, metformin use increased the ovulation rate and pregnancy rate from CC treatment, significantly.

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