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Sushant B Jadhav, Rahul M Mane, Kalyanraman L Narayanan, Popatrao N Bhosale
A novel, stability indicating, reverse phase high-performance liquid chromatography (RP-HPLC) method was developed to determine the S-isomer of linagliptin (LGP) in linagliptin and metformin hydrochloride (MET HCl) tablets (LGP-MET HCl) by implementing design of experiment (DoE), i.e., two-level, full factorial design (2³ + 3 centre points = 11 experiments) to understand the critical method parameters (CMP) and its relation with the critical method attribute (CMA), and to ensure robustness of the method. The separation of the S-isomer, LGP and MET HCl in the presence of their impurities was achieved on Chiralpak(®) IA-3 (Amylose tris (3, 5-dimethylphenylcarbamate), immobilized on 3 µm silica gel) stationary phase (250 × 4...
October 17, 2016: Scientia Pharmaceutica
Francisco J Tinahones, Baptist Gallwitz, Matias Nordaby, Sophia Götz, Mario Maldonado-Lutomirsky, Hans J Woerle, Uli C Broedl
AIM: To evaluate the efficacy and safety of linagliptin versus placebo as add-on to empagliflozin and metformin in patients with type 2 diabetes. MATERIALS AND METHODS: Patients with inadequate glycaemic control despite stable-dose metformin received open-label empagliflozin 10 mg (study 1) or 25 mg (study 2) as add-on therapy for 16 weeks. Subsequently, those with HbA1c ≥7.0 and ≤10.5% (>53 and ≤91 mmol/mol) (N = 482) were randomized to 24 weeks' double-blind, double-dummy treatment with linagliptin 5 mg or placebo in study 1, or linagliptin 5 mg or placebo in study 2; all patients continued treatment with metformin and empagliflozin 10 mg (study 1) or metformin and empagliflozin 25 mg (study 2)...
October 20, 2016: Diabetes, Obesity & Metabolism
Seol Ju Moon, Sun-Young Kim, Cheol-Hee Lim, Hwan Bong Jang, Min-Gul Kim, Ji-Young Jeon
We investigated botanical drug-pharmaceutical drug interactions between DW1029 (a botanical extract of Morus alba linne root bark and Puerariae radix) and metformin, losartan, and linagliptin in the steady state. Three studies were conducted as a randomized, open-label, two-period, two-treatment, multiple-dose, two-way crossover designs. Eligible subjects received metformin (500 mg twice daily), losartan (50 mg once daily), or linagliptin (5 mg once daily) with DW1029M (300 mg × 2T twice daily) every 12 h on days 1 through 6 and a single dose in the morning of day 7...
October 14, 2016: Clinical Pharmacology in Drug Development
Norbert J Tripolt, Felix Aberer, Regina Riedl, Barbara Hutz, Jasmin Url, Gudrun Dimsity, Andreas Meinitzer, Tatjana Stojakovic, Ronald Hödl, Marianne Brodmann, Franz Hafner, Harald Sourij
BACKGROUND: Patients with type 2 diabetes (T2DM) are at increased risk for macrovascular events as well as for microvascular complications. There is evidence that in patients with coronary artery disease (CAD), about 35 % suffer from manifest T2DM. Early glucose-lowering intervention in subjects with T2DM has been demonstrated to be beneficial in terms of cardiovascular risk reduction. But thus far, no data are available regarding investigating the impact of linagliptin treatment in patients with early diabetes on cardiovascular endpoints or surrogate parameters...
October 13, 2016: Trials
Yoshio Fujitani, Shimpei Fujimoto, Kiyohito Takahashi, Hiroaki Satoh, Takahisa Hirose, Toru Hiyoshi, Masumi Ai, Yosuke Okada, Masahiko Gosho, Tomoya Mita, Hirotaka Watada
AIMS: To compare the efficacy on glycemic parameters between a 12-week administration of once-daily linagliptin and thrice-daily voglibose in Japanese patients with type 2 diabetes. METHODS: In a multi-center, randomized, parallel-group study, 382 patients with diabetes were randomized to the linagliptin group (n=192) or the voglibose group (n=190). A meal tolerance test was performed at weeks 0 and 12. Primary outcomes were the change from baseline to week 12 in serum glucose levels at 2h during the meal tolerance test, HbA1c levels, and serum fasting glucose levels, which were compared between the 2 groups...
September 22, 2016: Diabetes Research and Clinical Practice
Jayasankar Kosaraju, R M Damian Holsinger, Lixia Guo, Kin Yip Tam
Glucagon-like peptide-1 (GLP-1) is an incretin hormone shown to be active in the treatment of type-2 diabetes (T2D) and has also been shown as efficacious in Alzheimer's disease (AD). Dipeptidyl peptidase-4 (DPP-4), an enzyme that is expressed in numerous cells, rapidly inactivates endogenous GLP-1. Therefore, DPP-4 inhibition is employed as a therapeutic avenue to increase GLP-1 levels in the management of T2D. The effectiveness of DPP-4 inhibitors in the treatment of AD has been reported in various animal models of AD...
October 3, 2016: Molecular Neurobiology
Stuart A Ross, A Enrique Caballero, Stefano Del Prato, Baptist Gallwitz, Diane Lewis-D'Agostino, Zelie Bailes, Sandra Thiemann, Sanjay Patel, Hans-Juergen Woerle, Maximilian von Eynatten
OBJECTIVES: Few studies of oral glucose-lowering drugs exist in newly diagnosed type 2 diabetes (T2D) patients with marked hyperglycemia, and insulin is often proposed as initial treatment. We evaluated the oral initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in this population. METHODS: We performed a pre-specified subgroup analysis of a randomized study in which newly diagnosed T2D patients with glycated hemoglobin A1c (HbA1c) 8...
September 29, 2016: Postgraduate Medicine
Dmitri A Pissarnitski, Zhiqiang Zhao, David Cole, Wen-Lian Wu, Martin Domalski, John W Clader, Giovanna Scapin, Johannes Voigt, Aileen Soriano, Theresa Kelly, Mary Ann Powles, Zuliang Yao, Duane A Burnett
Molecular modeling of unbound tricyclic guanine scaffolds indicated that they can serve as effective bioisosteric replacements of xanthines. This notion was further confirmed by a combination of X-ray crystallography and SAR studies, indicating that tricyclic guanine DPP4 inhibitors mimic the binding mode of xanthine inhibitors, exemplified by linagliptin. Realization of the bioisosteric relationship between these scaffolds potentially will lead to a wider application of cyclic guanines as xanthine replacements in drug discovery programs for a variety of biological targets...
November 1, 2016: Bioorganic & Medicinal Chemistry
Yuichiro Ueda, Hiroki Ishii, Taisuke Kitano, Mitsutoshi Shindo, Haruhisa Miyazawa, Kiyonori Ito, Keiji Hirai, Yoshio Kaku, Honami Mori, Taro Hoshino, Susumu Ookawara, Masafumi Kakei, Kaoru Tabei, Yoshiyuki Morishita
BACKGROUND: We investigated the effects and safety of linagliptin as an add-on therapy in patients with advanced-stage diabetic nephropathy (DMN) taking renin-angiotensin-aldosterone system (RAAS) blockers. METHOD: Twenty advanced-stage DMN patients (estimated glomerular filtration rate (eGFR): 24.5 ± 13.4 mL/min/1.73 m(2)) taking RAAS blockers were administered 5 mg/day linagliptin for 52 weeks. Changes in glucose and lipid metabolism and renal function were evaluated...
2016: Drug Target Insights
Yu S Gavrilova, N P Bgatova, V V Klimontov, I Yu Ischenko, S V Michurina, N E Myakina, E L Zavyalov
Effect of the dipeptidyl peptidase-4 inhibitor linagliptin on structural manifestations of diabetic nephropathy was studied in BKS.Cg-Dock7m+/+Leprdb/J mice (experimental model of type 2 diabetes mellitus). Linagliptin (10 mg/kg per day) or vehicle was administered by gavage over 8 weeks. Mesangial expansion, thickening of the basement membrane in glomerular capillaries and proximal tubules, and retraction of cytopodia were less pronounced in mice receiving linagliptin. The protective effect of linagliptin on the kidney structure was not associated with its hypoglycemic action...
August 2016: Bulletin of Experimental Biology and Medicine
Christian Ott, Iris Kistner, Mirjam Keller, Stefanie Friedrich, Carsten Willam, Peter Bramlage, Roland E Schmieder
AIMS/HYPOTHESIS: Endothelial dysfunction predicts cardiovascular damage and renal involvement. Animal experiments and human studies indicate an increased nitric oxide (NO) activity and endothelial NO synthase (NOS) expression in the early stage of type 2 diabetes. The aim of the study was to assess the effect of linagliptin on the endothelial function of the renal vasculature. METHODS: In this randomised, double-blind, parallel-group, investigator-initiated trial, 62 patients with type 2 diabetes were randomly assigned (by computer-generated random code) to receive linagliptin 5 mg (n = 30) or placebo (n = 32) for 4 weeks...
September 1, 2016: Diabetologia
Dimitrios Baltzis, Jody R Dushay, Jordan Loader, Jim Wu, Robert L Greenman, Matthieu Roustit, Aristidis Veves
CONTEXT: The dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, possesses pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties in animals, independent of its glucose-lowering properties. While large randomized clinical trials are being conducted to better evaluate the efficacy and safety of linagliptin on cardiovascular outcomes, little is known about its effects on vascular function in humans. OBJECTIVE: To evaluate the effect of linagliptin on surrogates of vascular and mitochondrial function...
September 1, 2016: Journal of Clinical Endocrinology and Metabolism
Gang Li, Yi Huan, Baokun Yuan, Jin Wang, Qian Jiang, Ziyun Lin, Zhufang Shen, Haihong Huang
A series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 was discovered through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Systematic optimization of general structure 5 led to the identification of compound 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Compound 20i may serve as a tool compound for further design of anti-diabetic drugs targeting both DPP-IV and GPR119...
August 13, 2016: European Journal of Medicinal Chemistry
Katsuhito Mori, Masanori Emoto, Tetsuo Shoji, Masaaki Inaba
OBJECTIVE: Focusing on efficacy and tolerability, we compared linagliptin monotherapy with voglibose monotherapy in patients with type 2 diabetes undergoing hemodialysis (HD). RESEARCH DESIGN AND METHODS: In this multicenter, randomized, open-label, parallel-group, active-controlled study, 78 patients were randomized (1:1) to receive a 12-week treatment with 5 mg linagliptin once daily or 0.2 mg voglibose three times a day. To assess whether linagliptin was superior to voglibose, the primary efficacy end point was the change in glycated hemoglobin (HbA1c) level between baseline and week 12...
2016: BMJ Open Diabetes Research & Care
Amanda M Farr, John J Sheehan, Brian M Davis, David M Smith
BACKGROUND: Adherence and persistence to antidiabetes medications are important to control blood glucose levels among individuals with type 2 diabetes mellitus (T2D). OBJECTIVES: The objective of this study was to compare adherence and persistence over a 12-month period between patients initiating saxagliptin and patients initiating linagliptin, two dipeptidyl peptidase-4 inhibitors. METHODS: This retrospective cohort study was conducted in MarketScan(®) Commercial and Medicare Supplemental claims databases...
2016: Patient Preference and Adherence
Yiwen Huang, Xiaoqing He, Taizhi Wu, Fuli Zhang
Linagliptin, a xanthine derivative, is a highly potent, selective, long-acting and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. During the process development of linagliptin, five new process-related impurities were detected by high performance liquid chromatography (HPLC). All these impurities were identified, synthesized, and subsequently characterized by their respective spectral data (MS, HRMS, ¹H-NMR, (13)C-NMR and IR) as described in this article. The identification of these impurities should be useful for quality control and the validation of the analytical method in the manufacture of linagliptin...
2016: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Takuo Nagai, Shigehiro Doi, Ayumu Nakashima, Taisuke Irifuku, Kensuke Sasaki, Toshinori Ueno, Takao Masaki
Recent studies have reported increases of methylglyoxal (MGO) in peritoneal dialysis patients, and that MGO-mediated inflammation plays an important role in the development of peritoneal fibrosis through production of transforming growth factor-β1 (TGF-β1). Linagliptin, a dipeptidyl peptidase-4 inhibitor, exerts anti-inflammatory effects independent of blood glucose levels. In this study, we examined whether linagliptin suppresses MGO-induced peritoneal fibrosis in mice. Male C57/BL6 mice were divided into three groups: control, MGO injection plus saline, and MGO injection plus linagliptin (n = 6 per group)...
2016: PloS One
Se Hee Park, Joo Young Nam, Eugene Han, Yong-Ho Lee, Byung-Wan Lee, Beom Seok Kim, Bong-Soo Cha, Chul Sik Kim, Eun Seok Kang
Hyperglycemia is associated with increased mortality and morbidity in patients with type 2 diabetes mellitus (T2DM) who are undergoing dialysis. Although dipeptidyl peptidase-4 (DPP-4) inhibitors have been widely used in end-stage renal disease (ESRD) patients with T2DM, there are few studies on their efficacy in this population. We studied the effect of 3 different DPP-4 inhibitors on metabolic parameters in ESRD patients with T2DM.Two hundred ESRD patients with T2DM who were treated with DPP-4 inhibitors (sitagliptin, vildagliptin, or linagliptin) were enrolled and analyzed retrospectively...
August 2016: Medicine (Baltimore)
Merlin C Thomas, Päivi M Paldánius, Rajeev Ayyagari, Siew Hwa Ong, Per-Henrik Groop
INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the management of patients with type 2 diabetes mellitus (T2DM) and renal impairment (RI). A systematic literature review was performed to compare the efficacy and safety of DPP-4 inhibitors in patients with T2DM and RI. METHODS: We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials (cut-off, June 2015) to identify ≥12-week, randomized, placebo-controlled trials on DPP-4 inhibitors in ≥50 patients with T2DM and RI...
September 2016: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Nobuya Inagaki, Wayne H-H Sheu, David R Owens, Susanne Crowe, Amit Bhandari, Yan Gong, Sanjay Patel
AIMS: Liver disease is highly prevalent among people with type 2 diabetes mellitus (T2DM). We evaluated the dipeptidyl peptidase-4 inhibitor linagliptin in subjects with T2DM and hepatic disorders. METHODS: Data were pooled from 17 randomized, double-blind, placebo-controlled clinical trials of linagliptin in T2DM subjects that included individuals with self-reported history of hepatic disorders at baseline. The primary endpoint was change in HbA1c from baseline to week 24...
November 2016: Journal of Diabetes and its Complications
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