Delving into the Latest Updates on Metformin Hydrochloride/Rosiglitazone Maleate with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Avandamet, Avandamet XR, Metformin Hydrochloride and Rosiglitazone Maleate

+ [5]

Target

PPARγ x PRKAB1

Action

agonists, activators

Mechanism

PPARγ agonists(Peroxisome proliferator-activated receptor γ agonists), PRKAB1 activators(Protein kinase AMP-activated non-catalytic subunit beta 1 activators)

Therapeutic Areas

Endocrinology and Metabolic Disease

Active Indication

Diabetes Mellitus, Type 2

Inactive Indication-

Originator Organization

GSK Plc

Active Organization

Glenmark Pharmaceuticals Ltd.GlaxoSmithKline Australia Pty Ltd.

Inactive Organization

GSK PlcSmithkline Beecham Plc

SB Pharmco Puerto Rico, Inc.

License Organization-

Drug Highest PhaseApproved

First Approval Date

United States (10 Oct 2002),

Diabetes Mellitus, Type 2

Regulation-

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Structure/Sequence

Molecular FormulaC26H35ClN8O7S

InChIKeyUABJPASVFPMIGE-KWZUVTIDSA-N

CAS Registry622402-70-4

BACKGROUNDRosiglitazone metformin adduct (RZM) is a novel compound, synthesized from rosiglitazone (Ros) and metformin (Met) combined at a molar mass ratio of 1:1. Met and Ros are widely used together for treating type 2 diabetes to improve drug effectiveness and reduce adverse drug reactions. Recent studies reported that both Met and Ros may possess antineoplastic properties in several cancers, including hepatocellular carcinoma (HCC). However, the effects of RZM in HCC and its underlying mechanisms remain unknown.METHODSRZM was synthesized from Ros and Met at an equal molar ratio and identified by infrared spectroscopy. MTS and colony formation assays were performed to detect proliferative repression of RZM, the mixture, Met and Ros, respectively. Tumorigenesis assay in vivo was used to confirm the anti-tumorigenesis potential of RZM and Met. Moreover, cellular apoptosis caused by RZM was analyzed by hoechst staining assay and flow cytometry. RT-qPCR and western blotting were performed to reveal mechanisms for the function of RZM.RESULTSBoth in vitro and in vivo data showed that low doses of RZM enhanced inhibitory effect on HCC cells growth compared with Met. Flow cytometry analysis confirmed that treatment with RZM at 1 mM for 48 h triggered HCC cells apoptosis. RT-qPCR and western blotting analyses showed that p21 was upregulated in response to 1 mM RZM treatment. Furthermore, RZM could increase AMPK activation compared with Met. The increased p21 expression induced by RZM treatment was attenuated by an AMPK inhibitor compound C.CONCLUSIONSAll these observations demonstrate that RZM increases the antiproliferative effect of Met in HCC via upregulating p21 expression in an AMPK-dependent manner. Our results suggest that RZM has the potential to be an adjuvant for HCC therapy.

07 Jan 2019·Molecular PharmaceuticsQ2 · MEDICINE

Three-Level Hepatotoxicity Prediction System Based on Adverse Hepatic Effects

Q2 · MEDICINE

Article

Author: Zhang, Lin ; Ouyang, Defang ; Fu, Li ; Cao, Qian ; Cao, Dong-Sheng ; Ye, Wen-Ling ; Zhang, Jin-Wei ; Cheng, Yan ; Wei, Hui ; Liu, Lu ; Deng, Zhen-Ke

Hepatotoxicity is a major cause of drug withdrawal from the market. To reduce the drug attrition induced by hepatotoxicity, an accurate and efficient hepatotoxicity prediction system must be constructed. In the present study, we constructed a three-level hepatotoxicity prediction system based on different levels of adverse hepatic effects (AHEs) combined with machine learning, using (1) an end point, hepatotoxicity; (2) four hepatotoxicity severity degrees; and (3) specific AHEs. After collecting and curing 15 873 compound-AHE pairs associated with 2017 compounds and 403 AHEs, we constructed 27 models with three end point levels with the random forest algorithm, and obtained accuracies ranging from 67.0 to 78.2% and the area under receiver operating characteristic curves (AUCs) of 0.715-0.875. The 27 models were fully integrated into a tiered hepatotoxicity prediction system. The existence of hepatotoxicity existence, severity degree, and potential AHEs for a given compound could be inferred simultaneously and systematically. Thus, the tiered hepatotoxicity prediction system allows researchers to have significant confidence in confirming compound hepatotoxicity, analyzing hepatotoxicity from multiple perspectives, obtaining warnings for the potential hepatotoxicity severity, and even rapidly selecting the proper in vitro experiments for hepatotoxicity verification. We also applied three external sets (11 drugs or candidates that failed in clinical trials or were withdrawn from the market, the PharmGKB (offsides) database, and an herbal hepatotoxicity data set) to test and validate the prediction ability of our system. Furthermore, the hepatotoxicity prediction system was adapted into a flow framework based on the Konstanz Information Miner, which was made available for researchers.

20 May 2015·Chinese Medical JournalQ3 · MEDICINE

Efficacy and Safety of Avandamet or Uptitrated Metformin Treatment in Patients with Type 2 Diabetes Inadequately Controlled with Metformin Alone

Q3 · MEDICINE

ArticleOA

Author: Ying-Li Chen ; Jia-Jun Zhao ; Wei Gu ; Xiao-Ling Cai ; Jin-Kui Yang ; Cheng-Jiang Li ; Zhong-Yan Shan ; Hua-Zhang Yang ; Hao-Ming Tian ; Li-Nong Ji ; Tian-Pei Hong ; Ming-Cai Qiu ; Yao-Ming Xue

BACKGROUNDAt present, China has listed the compound tablet containing a fixed dose of rosiglitazone and metformin, Avandamet, which may improve patient compliance. The aim of this study was to evaluate the efficacy and safety of Avandamet or uptitrated metformin treatment in patients with type 2 diabetes inadequately controlled with metformin alone.METHODSThis study was a 48-week, multicenter, randomized, open-labeled, active-controlled trial. Patients with inadequate glycaemic control (glycated hemoglobin [HbA1c] 7.5-9.5%) receiving a stable dose of metformin (≥1500 mg) were recruited from 21 centers in China (from 19 November, 2009 to 15 March, 2011). The primary objective was to compare the proportion of patients who reached the target of HbA1c ≤7% between Avandamet and metformin treatment.RESULTSAt week 48, 83.33% of patients reached the target of HbA1c ≤7% in Avandamet treatment and 70.00% in uptitrated metformin treatment, with significantly difference between groups. The target of HbA1c ≤6.5% was reached in 66.03% of patients in Avandamet treatment and 46.88% in uptitrated metformin treatment. The target of fasting plasma glucose (FPG) ≤6.1 mmol/L was reached in 26.97% of patients in Avandamet treatment and 19.33% in uptitrated metformin treatment. The target of FPG ≤7.0 mmol/L was reached in 63.16% of patients in Avandamet treatment and 43.33% in uptitrated metformin treatment. Fasting insulin decreased 3.24 ± 0.98 μU/ml from baseline in Avandamet treatment and 0.72 ± 1.10 μU/ml in uptitrated metformin treatment. Overall adverse event (AE) rates and serious AE rates were similar between groups. Hypoglycaemia occurred rarely in both groups.CONCLUSIONSCompared with uptitrated metformin, Avandamet treatment provided significant improvements in key parameters of glycemic control and was generally well tolerated.REGISTRATION NUMBERChiCTR-TRC-13003776.

100 Deals associated with Metformin Hydrochloride/Rosiglitazone Maleate

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	A10BD03	-

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	India	Glenmark Pharmaceuticals Ltd.	22 Jan 2004

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Preclinical	United States	SB Pharmco Puerto Rico, Inc.	10 Oct 2002

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00131664 (AVALANCHE, CTgov)	Phase 3	Diabetes Mellitus, Type 2	391	Amaryl (Avandia and Amaryl)	cdgsajouuc(dojiqdsvcl) = udfllgxbqn igijhefiml (limbkhgunv, kxqrwjpkva - ixjtvbfcqt) View more	-	17 Apr 2013
				Avandamet (Avandamet)	cdgsajouuc(dojiqdsvcl) = gsnzqgvqzs igijhefiml (limbkhgunv, rszwzctiev - fxubyohjvd) View more
NCT01332071 (CTgov)	Phase 1	Diabetes Mellitus, Type 2	26	Rosiglitazone Maleate (Test Product)	zfwxmupvny(fvffnvxfnz) = naxvxbzska wvexablyfu (cdmbfgxytx, dfaywckudv - mdwpzhdycf) View more	-	08 Apr 2011
				Rosiglitazone Maleate (Reference Product)	zfwxmupvny(fvffnvxfnz) = omsnfxkmyv wvexablyfu (cdmbfgxytx, zuvqejsbsz - vkcrwgfadj) View more