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Pandya S, Vekaria HJ. Analytical Methods for Estimating Metformin Hydrochloride, Pioglitazone and Teneligliptin in Diabetes Management: a Comprehensive Review. J Chromatogr Sci 2025; 63:bmaf013. [PMID: 40037341 DOI: 10.1093/chromsci/bmaf013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 12/06/2024] [Accepted: 02/11/2025] [Indexed: 03/06/2025]
Abstract
Diabetes mellitus remains a global health challenge, with a growing need for effective therapies. Metformin, Pioglitazone and Teneligliptin are widely prescribed medications for diabetes management. Accurate and precise estimation of these drugs is essential to ensure optimal therapeutic efficacy while minimizing side effects. This comprehensive review examines a multitude of analytical methods employed for the quantification of Metformin, Pioglitazone and Teneligliptin individually as well as in combine pharmaceutical dosage form focusing on their strengths, limitations and applicability within the realm of diabetes treatment. The choice of analytical method depends on various factors, such as the specific formulation, sample matrix complexity and the required sensitivity and quantification range. This review encompasses a wide range of analytical techniques, including spectroscopic methods (ultraviolet-visible, Fourier transform infrared and nuclear magnetic resonance spectroscopy), chromatographic methods (high-performance liquid chromatography, ultra-high performance liquid chromatography, and gas chromatography, high-performance thin-layer chromatography, liquid chromatography-tandem mass spectrometry), electrochemical approaches and emerging technologies like mass spectrometry and biosensors. Additionally, it delves into the intricacies of method development and validation, sample preparation and the importance of stability-indicating methods. Recent advancements in sample extraction and preparation techniques are explored to enhance sensitivity and accuracy. By offering a comprehensive assessment of the analytical methods used for the estimation of Metformin, Pioglitazone and Teneligliptin for diabetes treatment, this review serves as a valuable resource for researchers, clinicians and pharmaceutical scientists. It aids in selecting the most suitable analytical method for specific applications, contributing to the continuous improvement of diabetes management and treatment.
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Affiliation(s)
- Sejal Pandya
- Department of Pharmaceutical Quality Assurance, School of Pharmacy, RK University, Bhavnagar Highway Kasturbadham, Rajkot-360020, Gujarat, India
| | - Hitesh J Vekaria
- Department of Pharmaceutical Quality Assurance, School of Pharmacy, RK University, Bhavnagar Highway Kasturbadham, Rajkot-360020, Gujarat, India
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Čermáková K, Šimková A, Wichterle F, Kryštůfek R, Staňurová J, Vaníčková Z, Bušek P, Konvalinka J, Šácha P. Sensitive quantification of fibroblast activation protein and high-throughput screening for inhibition by FDA-approved compounds. Eur J Med Chem 2024; 280:116948. [PMID: 39437576 DOI: 10.1016/j.ejmech.2024.116948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 09/29/2024] [Accepted: 10/06/2024] [Indexed: 10/25/2024]
Abstract
Fibroblast activation protein (FAP) has been extensively studied as a cancer biomarker for decades. Recently, small-molecule FAP inhibitors have been widely adopted as a targeting moiety of experimental theranostic radiotracers. Here we present a fast qPCR-based analytical method allowing FAP inhibition screening in a high-throughput regime. To identify clinically relevant compounds that might interfere with FAP-targeted approaches, we focused on a library of FDA-approved drugs. Using the DNA-linked Inhibitor Antibody Assay (DIANA), we tested a library of 2667 compounds within just a few hours and identified numerous FDA-approved drugs as novel FAP inhibitors. Among these, prodrugs of cephalosporin antibiotics and reverse transcriptase inhibitors, along with one elastase inhibitor, were the most potent FAP inhibitors in our dataset. In addition, by employing FAP DIANA in the quantification mode, we were able to determine FAP concentrations in human plasma samples. Together, our work expands the repertoire of FAP inhibitors, analyzes the potential interference of co-administered drugs with FAP-targeting strategies, and presents a sensitive and low-consumption ELISA alternative for FAP quantification with a detection limit of 50 pg/ml.
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Affiliation(s)
- Kateřina Čermáková
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic; First Faculty of Medicine, Charles University, Kateřinská 32, 121 08 Prague 2, Czech Republic
| | - Adéla Šimková
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic; Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic
| | - Filip Wichterle
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic; Department of Genetics and Microbiology, Faculty of Science, Charles University, Viničná 5, 128 44 Prague 2, Czech Republic
| | - Robin Kryštůfek
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic; Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic
| | - Jana Staňurová
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic
| | - Zdislava Vaníčková
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, U Nemocnice 5, 128 53 Prague 2, Czech Republic
| | - Petr Bušek
- Laboratory of Cancer Cell Biology, Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, U Nemocnice 5, 128 53 Prague 2, Czech Republic
| | - Jan Konvalinka
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic; Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic.
| | - Pavel Šácha
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo náměstí 2, 166 10 Prague 6, Czech Republic.
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Al Madhoun A. Teneligliptin: A potential therapeutic approach for diabetic cardiomyopathy. World J Diabetes 2024; 15:1654-1658. [PMID: 39192857 PMCID: PMC11346098 DOI: 10.4239/wjd.v15.i8.1654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 05/14/2024] [Accepted: 06/12/2024] [Indexed: 07/25/2024] Open
Abstract
In this editorial, we comment on the article by Zhang et al. Diabetes mellitus is a chronic disorder associated with several complications like cardiomyopathy, neuropathy, and retinopathy. Diabetes prevalence is increasing worldwide. Multiple diabetes medications are prescribed based on individual patients' needs. However, the exact mechanisms by which many of these drugs exert their pro-tective effects remain unclear. Zhang et al elucidates molecular mechanisms undelaying cardioprotective effect of the dipeptidyl peptidase-IV inhibitor, teneligliptin. Briefly, teneligliptin alleviates the activation of NOD-like receptor protein 3 inflammasome, a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Suppression of NOD-like receptor protein 3 inflammasome activity reduces the expression of cytokines, oxygen radicals and inflammation. These findings highlight teneligliptin as an anti-diabetic cardioprotective reagent.
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Affiliation(s)
- Ashraf Al Madhoun
- Department of Genetics and Bioinformatics, Dasman Diabetes Institute, Dasman 15400, Kuwait
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Shao DW, Zhao LJ, Sun JF. Synthesis and clinical application of representative small-molecule dipeptidyl Peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus (T2DM). Eur J Med Chem 2024; 272:116464. [PMID: 38704940 DOI: 10.1016/j.ejmech.2024.116464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 04/27/2024] [Accepted: 04/28/2024] [Indexed: 05/07/2024]
Abstract
Diabetes mellitus is a chronic metabolic disorder characterized by high blood glucose levels, which can cause many diseases, including osteoporosis, fractures, arthritis, and foot complications. The inhibitors of dipeptidyl peptidase-4 (DPP-4), an enzyme involved in glucose metabolism regulation, are essential for managing Type 2 Diabetes Mellitus (T2DM). The inhibition of DPP-4 has become a promising treatment approach for T2DM because it can increase levels of active glucagon-like peptide-1 (GLP-1), leading to improved insulin secretion in response to glucose and reduced release of glucagon. The review commences by elucidating the role of DPP-4 in glucose homeostasis and its significance in T2DM pathophysiology. Furthermore, it presents the mechanism of action, preclinical pharmacodynamics, clinical efficacy, and toxicity profiles of small-molecule DPP-4 inhibitors across various clinical stages. This comprehensive review provides valuable insights into the synthesis and clinical application of DPP-4 inhibitors, serving as an invaluable resource for researchers, clinicians, and pharmaceutical professionals interested in diabetes therapeutics and drug development.
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Affiliation(s)
- Dong-Wei Shao
- First People's Hospital of Shangqiu, Henan Province, Shangqiu, 476100, China.
| | - Li-Jie Zhao
- The Rogel Cancer Center, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, United States.
| | - Jin-Feng Sun
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of Education, Yanbian University, College of Pharmacy, Yanji, Jilin, 133002, China; Rega Institute for Medical Research, Medicinal Chemistry, KU Leuven, Herestraat 49-Box 1041, 3000, Leuven, Belgium.
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Sakaguchi K, Okiyama Y, Tanaka S. In Silico Search for Drug Candidates Targeting the PAX8-PPARγ Fusion Protein in Thyroid Cancer. Int J Mol Sci 2024; 25:5347. [PMID: 38791384 PMCID: PMC11121424 DOI: 10.3390/ijms25105347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 05/05/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
The PAX8/PPARγ rearrangement, producing the PAX8-PPARγ fusion protein (PPFP), is thought to play an essential role in the oncogenesis of thyroid follicular tumors. To identify PPFP-targeted drug candidates and establish an early standard of care for thyroid tumors, we performed ensemble-docking-based compound screening. Specifically, we investigated the pocket structure that should be adopted to search for a promising ligand compound for the PPFP; the position of the ligand-binding pocket on the PPARγ side of the PPFP is similar to that of PPARγ; however, the shape is slightly different between them due to environmental factors. We developed a method for selecting a PPFP structure with a relevant pocket and high prediction accuracy for ligand binding. This method was validated using PPARγ, whose structure and activity values are known for many compounds. Then, we performed docking calculations to the PPFP for 97 drug or drug-like compounds registered in the DrugBank database with a thiazolidine backbone, which is one of the characteristics of ligands that bind well to PPARγ. Furthermore, the binding affinities of promising ligand candidates were estimated more reliably using the molecular mechanics Poisson-Boltzmann surface area method. Thus, we propose promising drug candidates for the PPFP with a thiazolidine backbone.
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Affiliation(s)
| | - Yoshio Okiyama
- Graduate School of System Informatics, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan
| | - Shigenori Tanaka
- Graduate School of System Informatics, Kobe University, 1-1 Rokkodai, Nada-ku, Kobe 657-8501, Japan
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Kanjariya DC, Naik HN, Sherashiya MJ, Naliapara YT, Ahmad I, Patel H, Rajani D, Jauhari S. α-Amylase and mycobacterium-TB H37Rv antagonistic efficacy of novel pyrazole-coumarin hybrids: an in vitro and in silico investigation. J Biomol Struct Dyn 2023; 42:12788-12805. [PMID: 37904535 DOI: 10.1080/07391102.2023.2273436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 10/15/2023] [Indexed: 11/01/2023]
Abstract
The present investigation of minutiae to acquire structural information of the novel pyrazole-coumarin hybrids (PC1-PC10) synthesized using ultrasound methods and characterized using different spectroscopic techniques: mass, 1H-NMR, 13 C-NMR and IR spectroscopy, and theoretically explored using the DFT approach with a B3LYP/6-311G (d, p) basis set, and there in vitro, antagonistic efficacy against α-amylase and mycobacterium-TB H37Rv are described in this article. Pyrazole-coumarin hybrids (PC1-PC10) showed α-amylase inhibition ranging from IC50 (0.32-0.58 mM) when compared with acarbose (IC50 = 0.34 mM). Similarly, Mycobacterium-TB H37Rv strain inhibition screening showed MIC values ranging from 62.5 to 1000 µg/mL when compared with rifampicin and isoniazid MIC = 0.25 and 0.20 µg/mL, respectively. Molecular docking and MD simulation studies were performed to determine the active sites and rationalize the activities of the active compounds. To investigate the binding conformation and dynamics responsible for their activity, the three most active compounds (PC1, PC3 and PC6) were docked into the porcine pancreatic α-amylase active site (PDB ID:1OSE), and mycobacterium-TB H37Rv active site (PDB ID: 4TZK). The binding interactions between PC1, PC3, and PC6 with α-amylase were like those responsible for inhibiting α-amylase by acarbose. Also, the mycobacterium-TB H37Rv inhibiting responsible residues were compared with standard isoniazid and rifampicin.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Dilip C Kanjariya
- Department of Chemistry, Sardar Vallabhbhai National Institute of Technology, Surat, India
| | - Hem N Naik
- Department of Chemistry, Sardar Vallabhbhai National Institute of Technology, Surat, India
| | | | | | - Iqrar Ahmad
- Department of Pharmaceutical Chemistry, Prof. Ravindra Nikam College of Pharmacy, Dhule, India
| | - Harun Patel
- Department of Pharmaceutical Chemistry, Division of Computer Aided Drug Design, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, India
| | - Dhanji Rajani
- Microcare Laboratory and Tuberculosis Research Center, Surat, India
| | - Smita Jauhari
- Department of Chemistry, Sardar Vallabhbhai National Institute of Technology, Surat, India
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Li Q, Deng X, Xu YJ, Dong L. Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants. J Med Chem 2023; 66:11593-11631. [PMID: 37647598 DOI: 10.1021/acs.jmedchem.3c00412] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
Considerable effort has been made to achieve less frequent dosing in the development of DPP-4 inhibitors. Enthusiasm for long-acting DPP-4 inhibitors is based on the promise that such agents with less frequent dosing regimens are associated with improved patient adherence, but the rational design of long-acting DPP-4 inhibitors remains a major challenge. In this Perspective, the development of long-acting DPP-4 inhibitors is comprehensively summarized to highlight the evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades. The determinants for long duration of action are then examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical pharmacokinetic and pharmacodynamic profiles. More importantly, several possible approaches for the rational design of long-acting drugs are discussed. We hope that this information will facilitate the design and development of safer and more effective long-acting DPP-4 inhibitors and other oral drugs.
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Affiliation(s)
- Qing Li
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Xiaoyan Deng
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Yan-Jun Xu
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, China
| | - Lin Dong
- West China School of Pharmacy, Sichuan University, Chengdu 610041, China
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Nabil Shabaan S, Saleh Alshehri F, Fadel AL‐Rasheed J, El‐Sebaey SA, Husseiny EM. Synthesis and Exploration of New Imidazo[4,5‐c]Pyrazoles as Potent α‐Amylase Inhibitors. ChemistrySelect 2023; 8. [DOI: 10.1002/slct.202204757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/23/2023] [Indexed: 01/04/2025]
Abstract
AbstractTo identify new leads of small molecules as α‐amylase inhibitors, the current research is focused on the assessment of imidazopyrazoles. Hence, a set of novel imidazo[4,5‐c]pyrazoles was synthesized via simple versatile straightforward synthetic routes and was estimated for their in vitro α‐amylase inhibition activity. The findings revealed that diphenylaminomethyl and phenylcarbamodithioate derivatives elicited potent α‐amylase inhibition activities with IC50 values of 0.071 and 0.083 μM, respectively that were comparable to acarbose (IC50 0.060 μM). Molecular docking and in silico studies were performed for the most active derivatives and demonstrated that docked compounds have good binding affinities toward α‐amylase with binding free energies that are very similar to that of acarbose. Furthermore, these compounds demonstrated not only significant biological activity but also noteworthy physicochemical properties, drug‐likeness, and good pharmacokinetics. As a result, such compounds offered a robust opportunity for further development and optimization of the imidazopyrazole scaffold for the potential management of Type II Diabetes Mellitus.
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Affiliation(s)
- Sara Nabil Shabaan
- Department of Chemistry Faculty of Science (Girls) Al-Azhar University Nasr City, Cairo 11754 Egypt
- Department of Chemistry College of Science Imam Abdulrahman Bin Faisal University P.O. Box 1982 Dammam 31441 Saudi Arabia
| | - Fawzia Saleh Alshehri
- Department of Chemistry College of Science Imam Abdulrahman Bin Faisal University P.O. Box 1982 Dammam 31441 Saudi Arabia
- Basic & Applied Scientific Research Center Imam Abdulrahman Bin Faisal University P.O. Box 1982 Dammam 31441 Saudi Arabia
| | - Jinan Fadel AL‐Rasheed
- Department of Chemistry College of Science Imam Abdulrahman Bin Faisal University P.O. Box 1982 Dammam 31441 Saudi Arabia
| | - Samiha A. El‐Sebaey
- Department of Pharmaceutical Organic Chemistry Faculty of Pharmacy (Girls) Al-Azhar University 11754> Nasr City, Cairo Egypt
| | - Ebtehal M. Husseiny
- Department of Pharmaceutical Organic Chemistry Faculty of Pharmacy (Girls) Al-Azhar University 11754> Nasr City, Cairo Egypt
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Singh H, Singh J, Bhangu RK, Singla M, Singh J, Javid F. Potential approaches using teneligliptin for the treatment of type 2 diabetes mellitus: current status and future prospects. Expert Rev Clin Pharmacol 2023; 16:49-59. [PMID: 36567479 DOI: 10.1080/17512433.2023.2163386] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Based on pharmacological properties and results from clinical studies, teneligliptin has a great potential to be used as an alternate-day therapy and also the daily dose can be reduced to 10 mg. Clinical data also suggest its excellent efficacy and safety among older subjects. AREAS COVERED We have reviewed and discussed potential approaches using teneligliptin for the treatment of type 2 diabetes mellitus (T2DM) including alternate-day therapy and reduction of dose from 20 mg to 10 mg per day. We have also discussed the potential of teneligliptin to address the needs of older patients with T2DM. EXPERT OPINION It is an excellent option for use in older patients as studies in the geriatric population have shown encouraging results. Teneligliptin has a desirable pharmacokinetic profile that makes it a potential drug for use on an alternate-day basis. Teneligliptin has shown anti-diabetic efficacy even at a dose of 10 mg. These approaches may improve treatment satisfaction and patient compliance and can lower the cost; however, it is crucial to identify the subset of T2DM patients who can obtain maximum benefits. To verify these effects, large clinical investigations need to be planned and robust clinical evidence should be generated.
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Affiliation(s)
- Harmanjit Singh
- Department of Pharmacology, Government Medical College & Hospital, Chandigarh, India
| | - Jasbir Singh
- Department of Pharmacology, Government Medical College & Rajindra Hospital, Patiala, India
| | - Ravneet Kaur Bhangu
- Department of General Medicine, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Mandeep Singla
- Department of Medicine, Government Medical College & Hospital, Chandigarh, India
| | - Jagjit Singh
- Department of Pharmacology, Government Medical College & Hospital, Chandigarh, India
| | - Farideh Javid
- Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Queensgate, Huddersfield, UK
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Kopp KO, Glotfelty EJ, Li Y, Greig NH. Glucagon-like peptide-1 (GLP-1) receptor agonists and neuroinflammation: Implications for neurodegenerative disease treatment. Pharmacol Res 2022; 186:106550. [PMID: 36372278 PMCID: PMC9712272 DOI: 10.1016/j.phrs.2022.106550] [Citation(s) in RCA: 107] [Impact Index Per Article: 35.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 11/03/2022] [Accepted: 11/06/2022] [Indexed: 11/13/2022]
Abstract
Chronic, excessive neuroinflammation is a key feature of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, neuroinflammatory pathways have yet to be effectively targeted in clinical treatments for such diseases. Interestingly, increased inflammation and neurodegenerative disease risk have been associated with type 2 diabetes mellitus (T2DM) and insulin resistance (IR), suggesting that treatments that mitigate T2DM pathology may be successful in treating neuroinflammatory and neurodegenerative pathology as well. Glucagon-like peptide-1 (GLP-1) is an incretin hormone that promotes healthy insulin signaling, regulates blood sugar levels, and suppresses appetite. Consequently, numerous GLP-1 receptor (GLP-1R) stimulating drugs have been developed and approved by the US Food and Drug Administration (FDA) and related global regulatory authorities for the treatment of T2DM. Furthermore, GLP-1R stimulating drugs have been associated with anti-inflammatory, neurotrophic, and neuroprotective properties in neurodegenerative disorder preclinical models, and hence hold promise for repurposing as a treatment for neurodegenerative diseases. In this review, we discuss incretin signaling, neuroinflammatory pathways, and the intersections between neuroinflammation, brain IR, and neurodegenerative diseases, with a focus on AD and PD. We additionally overview current FDA-approved incretin receptor stimulating drugs and agents in development, including unimolecular single, dual, and triple receptor agonists, and highlight those in clinical trials for neurodegenerative disease treatment. We propose that repurposing already-approved GLP-1R agonists for the treatment of neurodegenerative diseases may be a safe, efficacious, and cost-effective strategy for ameliorating AD and PD pathology by quelling neuroinflammation.
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Affiliation(s)
- Katherine O Kopp
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States.
| | - Elliot J Glotfelty
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Yazhou Li
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States
| | - Nigel H Greig
- Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, MD 21224, United States.
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The antidiabetic drug teneligliptin induces vasodilation via activation of PKG, Kv channels, and SERCA pumps in aortic smooth muscle. Eur J Pharmacol 2022; 935:175305. [DOI: 10.1016/j.ejphar.2022.175305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 09/23/2022] [Accepted: 09/26/2022] [Indexed: 11/23/2022]
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Saboo B, Erande S, Unnikrishnan AG. A prospective multicentre open label study to assess effect of Teneligliptin on glycemic control through parameters of time in range (TIR) Metric using continuous glucose monitoring (TOP-TIR study). Diabetes Metab Syndr 2022; 16:102394. [PMID: 35078097 DOI: 10.1016/j.dsx.2022.102394] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 01/06/2022] [Accepted: 01/08/2022] [Indexed: 01/20/2023]
Abstract
BACKGROUND AND AIMS Continuous glucose monitoring (CGM) has been effective in assessing glycemic variability in diabetic patients. This study aims at assessing the effect of Teneligliptin using ambulatory glucose profile (AGP) indicators. METHODS A prospective, multicentre, open label study enrolling 59 type 2 diabetes patients between 18 and 65 years age was done between November 2020-May 2021. Patients were administered Teneligliptin 20 mg once daily, in addition to Metformin. The study included pre-treatment and two post-treatment phases. The data on time in range (TIR) and other AGP indicators of glycemic variability were obtained on each patient in all the three study phases and analysed to understand the effect of Teneligliptin on glycemic variability. Safety evaluation was done based on vital and biochemical parameters. RESULTS The percent TIR in post-treatment phase I was significantly higher than the pre-treatment phase (p < 0.0001), and was maintained till the end of phase II (p = 0.037). There was significant lowering of time above range (≥180 mg/dL) in the phase I (p = 0.003), which was maintained in phase II (p = 0.043), suggesting better control over hyperglycemic state. The reduction in mean glucose level in phase I and II was also significant compared to baseline (p = 0.003 and p = 0.023 respectively). The glucose variability percent and glucose management indicator also showed significant lowering in both the phases. CONCLUSIONS Teneligliptin addition to patients uncontrolled on Metformin monotherapy significantly reduced glycemic variability, as well showed significant glycemic improvement. Since this study was a single arm study, a comparative study with other DPP-4 inhibitors is needed.
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Affiliation(s)
| | - Suhas Erande
- Akshay Hospital, Department of Medicine, Pune, India.
| | - A G Unnikrishnan
- Chellaram Diabetes Institute, Department of Endocrinology, Pune, India.
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Seetharaman R, Pawar S, Advani M. One hundred years since insulin discovery: An update on current and future perspectives for pharmacotherapy of diabetes mellitus. Br J Clin Pharmacol 2022; 88:1598-1612. [PMID: 34608666 DOI: 10.1111/bcp.15100] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 09/02/2021] [Accepted: 09/26/2021] [Indexed: 12/30/2022] Open
Abstract
Diabetes mellitus was considered a fatal malady until the discovery, extraction and commercial availability of insulins. Numerous other classes of drugs ranging from sulfonylureas to sodium-glucose co-transporter-2 inhibitors were then marketed. However, with the prevalence of diabetes mellitus increasing every year, many more drugs and therapies are under investigation. This review article aimed to summarize the significant developments in the pharmacotherapy of diabetes mellitus and outline the progress made by the recent advances, 100 years since insulins were first extracted successfully. Insulin analogues and insulin delivery pumps have further improved glycaemic control in diabetes mellitus. Cardiovascular and renal outcome trials have changed the landscape of diabetology, with some of these drugs also efficacious in nondiabetics. Newer drug delivery systems are being evaluated to improve the efficacy and reduce the dosing frequency and adverse effects of antidiabetics. Some newer drugs with novel mechanisms of action targeting type 1 and type 2 diabetes have also shown promise in recent clinical trials. These drugs include dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1-agonists, glucokinase activators, anti-CD3 monoclonal antibodies and glimins. Their efficacy needs to be evaluated in larger studies.
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Affiliation(s)
- Rajmohan Seetharaman
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College & General Hospital, Sion, Mumbai, India
| | - Sudhir Pawar
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College & General Hospital, Sion, Mumbai, India
| | - Manjari Advani
- Department of Pharmacology, Lokmanya Tilak Municipal Medical College & General Hospital, Sion, Mumbai, India
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14
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Sharma A, Virmani T, Sharma A, Chhabra V, Kumar G, Pathak K, Alhalmi A. Potential Effect of DPP-4 Inhibitors Towards Hepatic Diseases and Associated Glucose Intolerance. Diabetes Metab Syndr Obes 2022; 15:1845-1864. [PMID: 35733643 PMCID: PMC9208633 DOI: 10.2147/dmso.s369712] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 06/10/2022] [Indexed: 11/23/2022] Open
Abstract
Dipeptidyl-peptidase-4 (DPP-4) is an enzyme having various properties and physiological roles in lipid accumulation, resistance to anticancer agents, and immune stimulation. DPP-4 includes membrane-bound peptidases and is a kind of enzyme that cleaves alanine or proline-containing peptides such as incretins, chemokines, and appetite-suppressing hormones (neuropeptide) at their N-terminal dipeptides. DPP-4 plays a role in the final breakdown of peptides produced by other endo and exo-peptidases from nutritious proteins and their absorption in these tissues. DPP-4 enzyme activity has different modes of action on glucose metabolism, hunger regulation, gastrointestinal motility, immune system function, inflammation, and pain regulation. According to the literature survey, as DPP-4 levels increase in individuals with liver conditions, up-regulation of hepatic DPP-4 expression is likely to be the cause of glucose intolerance or insulin resistance. This review majorly focuses on the cleavage of alanine or proline-containing peptides such as incretins by the DPP-4 and its resulting conditions like glucose intolerance and cause of DPP-4 level elevation due to some liver conditions. Thus, we have discussed the various effects of DPP-4 on the liver diseases like hepatitis C, non-alcoholic fatty liver, hepatic regeneration and stem cell, hepatocellular carcinoma, and the impact of elevated DPP-4 levels in association with liver diseases as a cause of glucose intolerance and their treatment drug of choices. In addition, the effect of DPP-4 inhibitors on obesity and their negative aspects are also discussed in brief.
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Affiliation(s)
- Ashwani Sharma
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Tarun Virmani
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Anjali Sharma
- Freelancer, Pharmacovigilance Expert, Uttar Pradesh, India
| | - Vaishnavi Chhabra
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Girish Kumar
- School of Pharmaceutical Sciences, MVN University, Palwal, Haryana, 121105, India
| | - Kamla Pathak
- Faculty of Pharmacy, Uttar Pradesh University of Medical Sciences, Uttar Pradesh, 206130, India
| | - Abdulsalam Alhalmi
- Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen
- Correspondence: Abdulsalam Alhalmi, Department of Pharmaceutical Science, College of Pharmacy, Aden University, Aden, Yemen, Email
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15
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Chen Y, Qie X, Quan W, Zeng M, Qin F, Chen J, Adhikari B, He Z. Omnifarious fruit polyphenols: an omnipotent strategy to prevent and intervene diabetes and related complication? Crit Rev Food Sci Nutr 2021:1-37. [PMID: 34792409 DOI: 10.1080/10408398.2021.2000932] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Diabetes mellitus is a metabolic syndrome which cannot be cured. Recently, considerable interest has been focused on food ingredients to prevent and intervene in complications of diabetes. Polyphenolic compounds are one of the bioactive phytochemical constituents with various biological activities, which have drawn increasing interest in human health. Fruits are part of the polyphenol sources in daily food consumption. Fruit-derived polyphenols possess the anti-diabetic activity that has already been proved either from in vitro studies or in vivo studies. The mechanisms of fruit polyphenols in treating diabetes and related complications are under discussion. This is a comprehensive review on polyphenols from the edible parts of fruits, including those from citrus, berries, apples, cherries, mangoes, mangosteens, pomegranates, and other fruits regarding their potential benefits in preventing and treating diabetes mellitus. The signal pathways of characteristic polyphenols derived from fruits in reducing high blood glucose and intervening hyperglycemia-induced diabetic complications were summarized.
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Affiliation(s)
- Yao Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Xuejiao Qie
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Wei Quan
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Maomao Zeng
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Fang Qin
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Jie Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
| | - Benu Adhikari
- School of Science, RMIT University, Melbourne, Victoria, Australia
| | - Zhiyong He
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, Jiangsu, China.,International Joint Laboratory on Food Safety, Jiangnan University, Wuxi, Jiangsu, China
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16
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Kim HJ, Kim YS, Lee CB, Choi MG, Chang HJ, Kim SK, Yu JM, Kim TH, Lee JH, Ahn KJ, Min KW, Kyung EJ, Kim YK, Lee KW. Efficacy and Safety of Switching to Teneligliptin in Patients with Type 2 Diabetes Inadequately Controlled with Dipeptidyl Peptidase-4 Inhibitors: 52-Week Results from a Prospective Observational Study. Diabetes Ther 2021; 12:2907-2920. [PMID: 34536208 PMCID: PMC8519978 DOI: 10.1007/s13300-021-01148-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 08/25/2021] [Indexed: 11/24/2022] Open
Abstract
INTRODUCTION The aim of this study was to assess the efficacy and safety of switching to teneligliptin from other dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes mellitus (T2DM) inadequately controlled despite treatment with a stable dose of other DPP-4 inhibitors. METHODS Patients with glycosylated hemoglobin (HbA1c) ≥ 7% despite taking DPP-4 inhibitors other than teneligliptin, with or without other antidiabetic agents, for at least 3 months were enrolled in this study. Patients on DPP-4 inhibitors administered prior to participation in this study were switched to 20 mg teneligliptin once daily and the dose was maintained for the 52-week study period. The primary endpoint was the change in HbA1c at week 12. Fasting plasma glucose (FPG) and the blood lipid profile were also evaluated. Adverse events were monitored for safety assessment. RESULTS At weeks 12, 24, and 52, the HbA1c values significantly decreased by - 0.39, - 0.44, and - 0.52%, respectively, compared to the baseline value (p < 0.0001); in addition, 56.3, 60.3, and 62.3% of patients, respectively, achieved decreases in HbA1c of at least 0.3%, and 40.1, 46.5, and 52.4% of patients, respectively, achieved decreases in HbA1c of at least 0.5%. The proportion of the patient population achieving HbA1c < 7.0% increased throughout the study period, reaching 30.4, 35.4, and 36.9% at weeks 12, 24, and 52, respectively; at these same time points, the percentage of patients achieving HbA1c < 6.5% increased to 9.5, 11.9, and 13.2% of the total study population. FPG levels and lipid parameters were also significantly decreased after teneligliptin treatment. There were no significant safety concerns. CONCLUSION Our results suggest the significant glucose-lowering effect of teneligliptin after switching from other DPP-4 inhibitors in patients with T2DM. The improvement in glycemic control was maintained for up to 52 weeks without safety concerns.
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Affiliation(s)
- Hae Jin Kim
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Woncheon-dong, Yeongtong-gu, Suwon, 443-721, South Korea
| | - Young Sik Kim
- Department of Family Medicine, University of Ulsan College of Medicine, Seoul, South Korea
| | - Chang Beom Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Guri, South Korea
| | - Moon-Gi Choi
- Department of Internal Medicine, College of Medicine, Hallym University, Chuncheon, South Korea
| | - Hyuk-Jae Chang
- Department of Cardiology, Yonsei University College of Medicine, Seoul, South Korea
| | - Soo Kyoung Kim
- Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, South Korea
| | - Jae Myung Yu
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, South Korea
| | - Tae Ho Kim
- Department of Internal Medicine, Seoul Medical Center, Seoul, South Korea
| | - Ji Hyun Lee
- Department of Internal Medicine, Catholic University of Daegu, Daegu, South Korea
| | - Kyu Jeung Ahn
- Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, Seoul, South Korea
| | - Kyung Wan Min
- Department of Internal Medicine, Eulji University School of Medicine, Seoul, South Korea
| | | | | | - Kwan Woo Lee
- Department of Endocrinology and Metabolism, Ajou University School of Medicine, San 5, Woncheon-dong, Yeongtong-gu, Suwon, 443-721, South Korea.
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Mori T, Nagata T, Nagata M, Fujimoto K, Fujino Y, Mori K. Diabetes severity measured by treatment control status and number of anti-diabetic drugs affects presenteeism among workers with type 2 diabetes. BMC Public Health 2021; 21:1865. [PMID: 34654398 PMCID: PMC8520264 DOI: 10.1186/s12889-021-11913-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 10/01/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The number of people with diabetes is increasing and resulting in major economic losses. Presenteeism accounts for the majority of economic losses, so measures against presenteeism are important. This study investigated the relationship between severity of type 2 diabetes and presenteeism. METHODS A cross-sectional study was conducted among workers over 40 years of age. Participants were classified as normal group or diabetic treatment group using their medical examination results and health insurance claims data. Diabetic treatment groups were described by degree of treatment control: Good (HbA1c < 7%), Intermediate (7% ≤ HbA1c < 8%), and Poor (8% ≤ HbA1c). Therapy type was also divided into monotherapy and combination therapy. Logistic regression analysis was performed to predict presenteeism loss using the Quantity and Quality method. RESULTS Data on 13,271 workers were analyzed. Presenteeism loss was significantly higher in all treatment control groups compared with the normal group, particularly for the intermediate and poor control groups. The monotherapy group did not differ from the normal group, but presenteeism loss was significantly higher in the combination therapy group than the normal group. CONCLUSIONS Presenteeism loss in workers with diabetes may be affected by diabetes severity, and even if treatment control were good, presenteeism loss could occur when the number of anti-diabetic drugs was high. Therefore, it is important to provide early intervention and continuous support as a preventive measure against not only diabetes and diabetes-related complications but also presenteeism.
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Affiliation(s)
- Takahiro Mori
- Department of Occupational Health Practice and Management, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka Yahatanishi-ku, Kitakyushu, Fukuoka, Japan.
| | - Tomohisa Nagata
- Department of Occupational Health Practice and Management, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka Yahatanishi-ku, Kitakyushu, Fukuoka, Japan
| | - Masako Nagata
- Department of Occupational Health Practice and Management, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka Yahatanishi-ku, Kitakyushu, Fukuoka, Japan
- Data Science Center for Occupational Health, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka Yahatanishi-ku, Kitakyushu, Fukuoka, Japan
| | - Kenji Fujimoto
- Data Science Center for Occupational Health, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka Yahatanishi-ku, Kitakyushu, Fukuoka, Japan
| | - Yoshihisa Fujino
- Department of Environmental Epidemiology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka Yahatanishi-ku, Kitakyushu, Fukuoka, Japan
| | - Koji Mori
- Department of Occupational Health Practice and Management, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan, 1-1 Iseigaoka Yahatanishi-ku, Kitakyushu, Fukuoka, Japan
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18
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Saboo B, Ghosh S, Tiwaskar M, Chawla R. QTc prolongation Safety and Effectiveness of Teneligliptin in Indian patients with type 2 Diabetes Mellitus: A real world study (QSET 2). Diabetes Metab Syndr 2021; 15:102264. [PMID: 34488059 DOI: 10.1016/j.dsx.2021.102264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 08/24/2021] [Accepted: 08/26/2021] [Indexed: 11/29/2022]
Abstract
AIMS To evaluate the safety with respect to QTc prolongation and effectiveness of Teneligliptin in Indian Type 2 Diabetes Mellitus (T2DM) patients. METHODS Retrospective data of T2DM patients on teneligliptin 20 mg or 40 mg once daily as a monotherapy or add-on therapy and having ECG records (before and after teneligliptin initiation) was collected. Safety was evaluated by change in QTc interval and effectiveness was evaluated by changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and haemoglobin A1C (HbA1c) from baseline to 12-weeks. RESULTS There was no significant change in mean QTc interval from baseline [418.68 milli seconds (ms) to 419 ms; mean change +0.33 ms; P = 0.1023] to follow up visit (mean duration 91 days). There was a significant reduction from baseline to 12 weeks in FPG [173.1 mg/dl (9.61 mmol/L) to 128.4 mg/dl (7.12 mmol/L), mean change - 44.64 mg/dl (2.47 mmol/L), P ≤ 0.001], PPG [242.5 mg/dl (13.46 mmol/L) to 176.5 mg/dl (9.79 mmol/L), mean change - 65.93 mg/dl (3.66 mmol/L), P ≤ 0.001], and HbA1c [8.2% (66 mmol/mol) to 7.2% (55 mmol/mol), mean change - 1.00% (10.9 mmol/mol), P ≤ 0.001]. CONCLUSION Teneligliptin did not cause QTc interval prolongation and was significantly effective in improving glycemic control.
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Affiliation(s)
- Banshi Saboo
- Diabetes Care and Hormone Clinic, Ahmedabad, Gujarat, India.
| | - Sujoy Ghosh
- FICP Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research, Kolkata, West Bengal, India.
| | | | - Rajeev Chawla
- North Delhi Diabetes Centre, Rohini, New Delhi, India.
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19
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Ji L, Li L, Ma J, Li X, Li D, Meng B, Lu W, Sun J, Liu Y, Takayanagi G, Wang Y. Efficacy and safety of teneligliptin added to metformin in Chinese patients with type 2 diabetes mellitus inadequately controlled with metformin: A phase 3, randomized, double-blind, placebo-controlled study. Endocrinol Diabetes Metab 2021; 4:e00222. [PMID: 33855222 PMCID: PMC8029565 DOI: 10.1002/edm2.222] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 12/09/2020] [Accepted: 12/19/2020] [Indexed: 11/11/2022] Open
Abstract
INTRODUCTION We evaluated the efficacy and safety of teneligliptin compared with placebo when added to metformin therapy in Chinese patients with type 2 diabetes inadequately controlled with metformin monotherapy. METHODS This multicentre, randomized, double-blind, placebo-controlled, parallel-group study enrolled type 2 diabetes patients with glycosylated haemoglobin (HbA1c) 7.0%-<10.0% and fasting plasma glucose (FPG) <270 mg/dl, receiving a stable metformin dose ≥1000 mg/day. Teneligliptin 20 mg or placebo was administered orally once daily (qd) before breakfast for 24 weeks. The primary efficacy end-point was change in HbA1c from baseline to Week 24. Safety end-points included the incidence of adverse events (AEs). RESULTS The least square mean (LSM) change from baseline (standard error [SE]) was -0.72 (0.07) (95% confidence intervals [CI], -0.87, -0.58) for teneligliptin and -0.01 (0.07) (95% CI, -0.16, 0.13) for placebo. The differences (LSM ± SE) between the placebo and teneligliptin groups in HbA1c and FPG were -0.71% ± 0.11% (p < .0001) and -16.5 ± 4.7 mg/dl (p = .0005), respectively. Teneligliptin yielded significant changes in HbA1c (-0.81%; p < .0001) and FPG (-22.2 mg/dl; p < .0001) at Week 12. At Week 24, more patients achieved HbA1c <7.0% with teneligliptin (41.7%) compared with placebo (16.1%; p < .0001). Treatment-emergent AE incidence was similar with teneligliptin (58.9%) and placebo (68.3%); upper respiratory tract infection, hyperuricaemia and hyperlipidaemia were the most common AEs. CONCLUSIONS Teneligliptin 20 mg qd for 24 weeks added to ongoing metformin treatment significantly decreased HbA1c and FPG levels compared with placebo in Chinese type 2 diabetes patients. The combination was safe and tolerable.
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Affiliation(s)
- Linong Ji
- Peking University People's HospitalBeijingChina
| | - Ling Li
- Shengjing Hospital of China Medical UniversityLiaoningChina
| | - Jianhua Ma
- Nanjing First HospitalNanjingJiangsuChina
| | | | - Dongmei Li
- Inner Mongolia People’s HospitalInner MongoliaChina
| | - Bangzhu Meng
- The Affiliated Hospital of Inner Mongolia University for NationalitiesInner MongoliaChina
| | - Weiping Lu
- Huai'an First People’s HospitalNanjing Medical UniversityNanjingJiangsuChina
| | - Jiao Sun
- Huadong Hospital Affiliated to Fudan UniversityShanghaiChina
| | - Yanmei Liu
- Yancheng City No.1 People's HospitalJiangsuChina
| | - Gen Takayanagi
- Mitsubishi Tanabe Pharma Development America, Inc.Jersey CityNJUSA
| | - Yi Wang
- Mitsubishi Tanabe Pharma Development (Beijing) Co., Ltd.BeijingChina
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20
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Ji L, Ma J, Lu W, Liu J, Zeng J, Yang J, Li W, Zhang X, Xiao X, Takayanagi G, Wang Y. Phase III, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of teneligliptin monotherapy in Chinese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. J Diabetes Investig 2021; 12:537-545. [PMID: 32810383 PMCID: PMC8015819 DOI: 10.1111/jdi.13389] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 08/03/2020] [Accepted: 08/12/2020] [Indexed: 11/29/2022] Open
Abstract
AIMS/INTRODUCTION Although the efficacy of teneligliptin, a highly selective dipeptidyl peptidase-4 inhibitor, has been amply studied for the treatment of type 2 diabetes, no clinical trials of teneligliptin have been carried out in China. We evaluated the efficacy and safety of teneligliptin monotherapy compared with a placebo in Chinese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. MATERIALS AND METHODS This multicenter, randomized, double-blind, placebo-controlled, parallel-group study, carried out at 42 sites, enrolled type 2 diabetes patients with glycosylated hemoglobin 7.0 to <10.0% and fasting blood glucose <270 mg/dL. Patients were randomly assigned, in a 1:1 ratio, to treatment with 20 mg teneligliptin or a placebo (n = 127, each) administered orally once daily before breakfast for 24 weeks. Change in glycosylated hemoglobin from baseline to week 24 was the primary efficacy end-point. Safety was assessed by the incidence of adverse events and adverse drug reactions. RESULTS The least square mean (LSM) change in glycosylated hemoglobin from baseline to week 24 was -0.95% with teneligliptin versus -0.14% with a placebo, yielding an LSM difference (teneligliptin vs placebo) of -0.80% (P < 0.0001). For the secondary end-point, from baseline to week 24, the LSM change in fasting blood glucose was -21.9 mg/dL with teneligliptin versus -1.4 mg/dL with a placebo, yielding an LSM difference (teneligliptin vs placebo) of -20.5 mg/dL (P < 0.0001). The adverse event and adverse drug reaction incidence rates, including hypoglycemia, were similar in both groups. CONCLUSIONS At 24 weeks, teneligliptin was generally well tolerated and effective in Chinese patients with type 2 diabetes mellitus inadequately controlled with diet and exercise.
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Affiliation(s)
- Linong Ji
- Peking University People’s HospitalBeijingChina
| | - Jianhua Ma
- Nanjing First HospitalNanjingJiangsuChina
| | - Weiping Lu
- Huai’an First People’s HospitalHuaianJiangsuChina
| | - Jingdong Liu
- Jiangxi Province People’s HospitalNanchangJiangxiChina
| | | | | | - Wei Li
- The Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsuChina
| | | | - Xinhua Xiao
- The First Affiliated HospitalUniversity of South ChinaHengyangHunanChina
| | - Gen Takayanagi
- Mitsubishi Tanabe Pharma Development America, Inc.Jersey CityNew JerseyUSA
| | - Yi Wang
- Mitsubishi Tanabe Pharma Development (Beijing) Co., Ltd.BeijingChina
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21
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Han E, Lee M, Lee YH, Kim HS, Lee BW, Cha BS, Kang ES. Effect of Switching from Linagliptin to Teneligliptin Dipeptidyl Peptidase-4 Inhibitors in Older Patients with Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2020; 13:4113-4121. [PMID: 33173319 PMCID: PMC7646502 DOI: 10.2147/dmso.s267994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 10/06/2020] [Indexed: 12/31/2022] Open
Abstract
INTRODUCTION Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed for type 2 diabetes (T2D) and their glycemic control effects are well studied. However, information regarding the effects of switching DPP-4 inhibitors is limited, especially in older patients. RESEARCH DESIGN AND METHODS We investigated whether switching from linagliptin to teneligliptin decreases blood glucose in older (≥65 years) T2D patients. In total, 164 patients with T2D who switched from linagliptin to teneligliptin for >12 weeks were included and the primary outcome was glycemic changes. RESULTS Switching from linagliptin to teneligliptin ameliorated fasting blood glucose (148.1 ± 47.1 to 139.6 ± 43.4 mg/dL), glycated hemoglobin (HbA1c; 7.9 ± 1.3 to 7.5 ± 1.2%), and postprandial blood glucose (224.8 ± 77.4 to 205.8 ± 70.8 mg/dL) levels (all P < 0.05). Low-density lipoprotein cholesterol concentration was reduced while liver and kidney functions were maintained. Subgroup analysis showed that glucose control improved more in patients with uncontrolled hyperglycemia (HbA1c > 8.0%) and chronic kidney disease (estimated glomerular filtration rate <90 mL/min/1.73m2). Multiple logistic analysis indicated higher baseline HbA1c was the strongest predictor of teneligliptin switching response. CONCLUSION Switching from linagliptin to teneligliptin helps maintain kidney function and reduce blood glucose safely in older patients with T2D.
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Affiliation(s)
- Eugene Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Minyoung Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong-ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Hospital Diabetes Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hye Soon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Byung-wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Hospital Diabetes Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bong-Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Hospital Diabetes Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
- Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
- Severance Hospital Diabetes Center, Yonsei University College of Medicine, Seoul, Republic of Korea
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22
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Ghosh S, Tiwaskar M, Chawla R, Jaggi S, Asirvatham A, Panikar V. Teneligliptin Real-World Effectiveness Assessment in Patients with Type 2 Diabetes Mellitus in India: A Retrospective Analysis (TREAT-INDIA 2). Diabetes Ther 2020; 11:2257-2268. [PMID: 32779100 PMCID: PMC7509012 DOI: 10.1007/s13300-020-00880-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Indexed: 10/29/2022] Open
Abstract
INTRODUCTION Teneligliptin is an antidiabetic medication that has been approved for the management of type 2 diabetes mellitus (T2DM) in Japan, South Korea and India. It is one of the most commonly prescribed antihyperglycaemic agents. The aim of this study was to assess the effectiveness of teneligliptin in improving glycemic control amongst Indian patients with T2DM in a real-world setting. METHODS This was a retrospective observational study in which a predesigned structured proforma was used to collect information from hospital records of 18 medical centres across India. All participating centres were established primary care hospitals with adequate record keeping, a pre-determined condition in the study design. Data were collected during the period of January 2019 to June 2019. Data extracted from patient records, including glycaemic parameters, concomitant drugs, drug dosage and duration, were collated. The effectiveness of teneligliptin was assessed by analyzing the mean change in glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and post-prandial plasma glucose (PPG) at 12 weeks after initiation of teneligliptin. RESULTS Data from 10,623 patients were available for analysis. The mean age of the enrolled patients was 51.86 ± 11.76 years. At 12 weeks after initiation of teneligliptin as monotherapy or add-on to other medications (combination therapy), the patients showed a signficant decrease from baseline in mean HbA1c, FPG and PPG. Mean HbA1c dropped from 8.66 ± 1.15% at baseline to 7.67 ± 1.28% at 12 weeks (71 ± 12.6 to 60 ± 14 mmol/mol), with a difference of - 0.99% (95% confidence interval [CI] 0.96-1.02) or - 10.8 (95% CI 10.5-11.1) mmol/mol (p < 0.0001). The mean reductions in FPG and PPG were 43.12 mg/dL (2.39 mmol/L) and 87.73 mg/dL (4.87 mmol/L) (both p < 0.0001) respectively. HbA1c (%) reductions with teneligliptin when used as add-on to metformin, add-on to metformin + sulfonylurea combination and add-on to metformin + sulfonylurea + alpha glucosidase inhibitor combination were 0.76% (8.3 mmol/mol), 1.24% (13.6 mmol/mol) and 1.04% (11.4 mmol/mol), respectively. Teneligliptin also significantly reduced HbA1c (1.13% or 12.4 mmol/mol, p < 0.0001) in patients with impaired renal function, without worsening the estimated glomerular filtration rate. Teneligliptin consistently reduced HbA1c across all three age categories tested-by 1% (10.9 mmol/mol) in patients aged < 60 years, by 1.15% (12.6 mmol/mol) in patients aged 60-75 years and by 0.88% (9.6 mmol/mol) in patients aged > 75 years. CONCLUSION Teneligliptin significantly improved glycaemic parameters in Indian patients with T2DM when prescribed either as monotherapy or as an add-on to one or more other commonly prescribed antihyperglycaemic agents.
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Affiliation(s)
- Sujoy Ghosh
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research, Kolkata, India.
| | | | | | | | | | - Vijay Panikar
- Endocrinology, Diabetes and Metabolism, Lilavati Hospital and Research Centre, Mumbai, India
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Chandra A, Rathod R, Ali F, Prakash A, Kumar R, Singh GN. Development and Validation of a Rapid and Sensitive Method for the Simultaneous Estimation of Gemigliptin and Teneligliptin in Bulk and Dosage Forms by Using Liquid Chromatography-tandem Mass Spectrometry. CURR PHARM ANAL 2020. [DOI: 10.2174/1573412915666190523112754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background:
A simple and sensitive ultra-performance liquid chromatography-mass
spectrometry method was developed and validated to measure the concentrations of gemigliptin
(GEM) and teneligliptin (TEN) using pioglitazone (PIO) as an internal standard.
Methods:
Chromatographic separation of two gliptins was achieved on a C-18 (100 mm X 2.1
mm, 2.7 μm) column using a mobile phase consisting of formic acid in water (0.1 % v/ v): acetonitrile
in gradient elution. Electrospray ionization (ESI) source was operated in positive mode (ionization).
Targeted MS-MS mode on a quadrupole time of flight (Q-TOF) mass spectrometer was
used to quantify the drugs utilizing the mass transitions of 490.1 (m/z), 427.2 (m/z) and 357.1
(m/z) for GEM, TEN and PIO, respectively.
Results:
As per ICH Q2R1 guidelines, a detailed validation of the method was carried out and the
standard curves were found to be linear between the concentration ranges of 509.8-1529.4 ng mL-1
and 510.6-1531.7 ng mL-1 for GEM and TEN, respectively. Precision and accuracy results were
found to be within the acceptable limits. The mean recovery was found to be 98.8± 0.76 % (GEM)
and 98.6 ±0.98 % (TEN), respectively.
Conclusions:
The optimized validated UPLC-QTOF (MS-MS) method offered the advantage of
shorter analytical times and higher sensitivity and selectivity to the nanogram level.
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Affiliation(s)
- Amrish Chandra
- Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India
| | - Ramji Rathod
- Amity Institute of Pharmacy, Amity University, Noida, Uttar Pradesh, India
| | - Faraat Ali
- Pharmaceutical Chemistry Division, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Govt. of India, Sector-23, Rajnagar, Ghaziabad, Uttar Pradesh-201002, India
| | - Anuj Prakash
- Pharmaceutical Chemistry Division, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Govt. of India, Sector-23, Rajnagar, Ghaziabad, Uttar Pradesh-201002, India
| | - Robin Kumar
- Pharmaceutical Chemistry Division, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Govt. of India, Sector-23, Rajnagar, Ghaziabad, Uttar Pradesh-201002, India
| | - Gyanendra Nath Singh
- Pharmaceutical Chemistry Division, Indian Pharmacopoeia Commission, Ministry of Health and Family Welfare, Govt. of India, Sector-23, Rajnagar, Ghaziabad, Uttar Pradesh-201002, India
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Syngle A, Chahal S, Vohra K. Efficacy and tolerability of DPP4 inhibitor, teneligliptin, on autonomic and peripheral neuropathy in type 2 diabetes: an open label, pilot study. Neurol Sci 2020; 42:1429-1436. [PMID: 32803534 DOI: 10.1007/s10072-020-04681-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 08/08/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Diabetic neuropathy increases risk of cardiovascular disease, peripheral artery disease, foot amputation and overall mortality. Not only hyperglycaemia induced nerve damage is harder to repair using currently approved medications, but also, the use of these agents is often limited by the extent of pain relief provided and side effects. METHODOLOGY In this prospective, open-label, pilot study, 20 type-2 diabetes mellitus patients (male/female=13/7, mean age- 56.1±8.04 years), meeting inclusion/exclusion criteria, were treated with dipeptidyl peptidase-4 (DPP-4) inhibitor, Teneligliptin, 20mg once a day for three months. Efficacy parameters: Sudomotor function (Sudoscan score); parasympathetic dysfunction assessed using Ewing's criteria i.e. heart rate response to -standing (HRS), -valsalva (HRV) and -deep breath (HRD); sympathetic dysfunction assessed as blood pressure response to -standing (BPS) and -handgrip (BPH); ankle brachial index (ABI), vibration perception threshold (VPT), C-reactive protein, glycemic profile and health related quality of life (HRQoL); and, tolerability parameters: complete blood count, liver function tests, serum creatinine, thyroid stimulating hormone, QT- interval and serum vitamin B12 levels, were measured. RESULTS There was no statistical difference in BMI, SBP, DBP, HRD, BPH and all safety parameters. After 12 weeks treatment, there was improvement in HRS (p<0.01) and HRV (p<0.01), but not in HRD (p=0.12). BPS was significantly lowered (p <0.01), but not the BPH (p =0.06). Sudoscan score was increased, while VPT was significantly decreased (both p<0.01). CONCLUSION Teneligliptin not only improves the glycemic status but also improves sudomotor function, peripheral and autonomic neuropathy, and reduces vascular inflammation in type 2 diabetes.
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Affiliation(s)
- Ashit Syngle
- Healing Touch City Clinic, # 547, Sector 16-D, Chandigarh, India.,Fortis Multi Specialty Hospital, Mohali, Punjab, India
| | - Simran Chahal
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
| | - Kanchan Vohra
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
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Chawla R, Madhu SV, Makkar BM, Ghosh S, Saboo B, Kalra S, On behalf of RSSDI-ESI Consensus
Group. RSSDI-ESI Clinical Practice Recommendations for the Management
of Type 2 Diabetes Mellitus 2020. Int J Diabetes Dev Ctries 2020. [PMCID: PMC7371966 DOI: 10.1007/s13410-020-00819-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Rajeev Chawla
- North Delhi Diabetes Centre Rohini, New Delhi, India
| | - S. V. Madhu
- Centre for Diabetes, Endocrinology & Metabolism, UCMS-GTB Hospital, Delhi, India
| | - B. M. Makkar
- Dr Makkar’s Diabetes & Obesity Centre Paschim Vihar, New Delhi, India
| | - Sujoy Ghosh
- Department of Endocrinology & Metabolism, Institute of Post Graduate Medical Education & Research, Kolkata, West Bengal India
| | - Banshi Saboo
- DiaCare - A Complete Diabetes Care Centre, Ahmedabad, India
| | - Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, Haryana India
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Vetapalem R, Yejella RP, Atmakuri LR. Development and Validation of a Stability Indicating RP-HPLC Method for Simultaneous Estimation of Teneligliptin and Metformin. Turk J Pharm Sci 2020; 17:141-147. [PMID: 32454773 DOI: 10.4274/tjps.galenos.2018.16768] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 12/06/2018] [Indexed: 12/01/2022]
Abstract
Objectives The main objective of the present work is to develop a simple, precise, specific and stability method indicating reverse phase high performance liquid chromatography method for simultaneous estimation of teneligliptin and metformin in bulk and tablet dosage form. Materials and Methods The analysis was performed with a Kromasil C18 column (250×4.6 mm, 5 μm) at 30°C using buffer: acetonitrile: methanol (65:25:10, v/v/v) as mobile phase. The detection was carried out with a flow rate of 1.0 mL/min at 254 nm. Results The retention time of teneligliptin and metformin was 2.842 min and 2.017 min, respectively. The linearity range was 5-30 μg/mL for teneligliptin and 125-750 μg/mL for metformin. The forced degradation studies were performed as per the guidelines of the The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use under acidic, alkaline, oxidative, thermal, photostability, and neutral conditions. Conclusion This method was successfully validated for all the parameters and could detect the the correct amounts of active drug substance in formulations that are available in the market. This developed method in the present study could be successfully employed for the simultaneous estimation of teneligliptin and metformin in bulk and tablet dosage form.
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Affiliation(s)
- Rajani Vetapalem
- Acharya Nagarjuna University, Department of Biotechnology, Nagarjuna Nagar, India
| | - Rajendra Prasad Yejella
- University College of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Andhra University, Visakhapatnam, India
| | - Lakshmana Rao Atmakuri
- Vallabhaneni Venkatadri Institute of Pharmaceutical Sciences, Department of Pharmaceutical Analysis, Gudlavalleru, India
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Zhang L, Yuan W, Kong X, Zhang B. Teneligliptin protects against ischemia/reperfusion-induced endothelial permeability in vivo and in vitro. RSC Adv 2020; 10:3765-3774. [PMID: 35492650 PMCID: PMC9048428 DOI: 10.1039/c9ra08810e] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 01/09/2020] [Indexed: 12/13/2022] Open
Abstract
Ischemic stroke is a leading cause of disability and mortality worldwide, especially among the elderly population. Ischemia and reperfusion cause damage to cells and initiate an acute inflammatory response, which leads to cerebral endothelial dysfunction, increased endothelial permeability, and potentially permanent disability. Teneligliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has been used almost exclusively in the treatment of type 2 diabetes mellitus. However, it is still unknown whether teneligliptin possesses a protective effect in brain endothelial dysfunction in the context of ischemic stroke. In the present work, we demonstrate the potential of teneligliptin treatment to protect against ischemia/reperfusion-induced damage using a series of both in vivo and in vitro experiments. Our key findings are that administration of teneligliptin could reduce brain infarct volume, ameliorate neurological damage, and improve brain permeability by increasing the expression of the tight junction protein occludin in middle cerebral artery occlusion (MCAO) mice models. Importantly, teneligliptin displayed a robust protective effect against oxygen–glucose deprivation/reperfusion (OGD/R)-induced cell death of primary human brain microvascular endothelial cells (HBMVECs) in vitro. Notably, teneligliptin prevented OGD/R-induced increased endothelial monolayer permeability in HBMVECs by increasing the expression of occludin, which was mediated by the ERK5/KLF2 signaling pathway. These findings suggest that teneligliptin might serve as a potential therapeutic agent for the treatment of stroke Ischemic stroke is a leading cause of disability and mortality worldwide, especially among the elderly population.![]()
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Affiliation(s)
- Lei Zhang
- Department of Neurology, The First Affiliated Hospital of Xi'an Medical University No. 48 Fenghao West Road, Lianhu District Xi'an Shaanxi province China +86-29-84277356 +86-29-84277356.,Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University Xi'an China
| | - Weiqiong Yuan
- Department of General Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China
| | - Xiangli Kong
- Department of Neurology, The First Affiliated Hospital of Xi'an Medical University No. 48 Fenghao West Road, Lianhu District Xi'an Shaanxi province China +86-29-84277356 +86-29-84277356.,Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University Xi'an China
| | - Bei Zhang
- Department of Neurology, The First Affiliated Hospital of Xi'an Medical University No. 48 Fenghao West Road, Lianhu District Xi'an Shaanxi province China +86-29-84277356 +86-29-84277356.,Shaanxi Key Laboratory of Brain Disorders, Xi'an Medical University Xi'an China
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Chawla R, Madhu SV, Makkar BM, Ghosh S, Saboo B, Kalra S, On behalf of the RSSDI-ESI Consensus Group. RSSDI-ESI Clinical Practice Recommendations for the Management of Type 2 Diabetes Mellitus 2020. Indian J Endocrinol Metab 2020; 24:1-122. [PMID: 32699774 PMCID: PMC7328526 DOI: 10.4103/ijem.ijem_225_20] [Citation(s) in RCA: 69] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Rajeev Chawla
- North Delhi Diabetes Centre, Rohini, New Delhi, India
| | - S. V. Madhu
- Centre for Diabetes, Endocrinology and Metabolism, UCMS-GTB Hospital, New Delhi, India
| | - B. M. Makkar
- Dr. Makkar's Diabetes and Obesity Centre, Paschim Vihar, New Delhi, India
| | - Sujoy Ghosh
- Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
| | - Banshi Saboo
- DiaCare - A Complete Diabetes Care Centre, Ahmedabad, Gujarat, India
| | - Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal, Haryana, India
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Surendran S, Sapkal R, Paul D, Nanjappan S. Effect of resveratrol on dipeptidyl peptidase-4 inhibitors pharmacokinetics: An in vitro and in vivo approach. Chem Biol Interact 2019; 315:108909. [PMID: 31786186 DOI: 10.1016/j.cbi.2019.108909] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 11/06/2019] [Accepted: 11/25/2019] [Indexed: 12/26/2022]
Abstract
Diabetes mellitus (DM) is a metabolic disorder with hyperglycemia being its hallmark symptom. The secondary symptom of DM is oxidative stress, which leads to the generation of free radicals. Diabetic nephropathy and neuropathy is the long-term effect of oxidative stress caused in DM, which leads to damage of kidneys and neurons respectively. Resveratrol (RES) is a phytochemical, found to be effective in the treatment of diabetic nephropathy and neuropathy. Due to its antioxidant property, it reduces the oxidative stress caused by DM. Dipeptidyl peptidase-4 (DPP-4) inhibitors are used for the treatment of type 2 DM. In vitro and in vivo data depicted that the metabolism of alogliptin (ALO), saxagliptin (SAX) and sitagliptin (SIT) were decreased in presence of RES while metabolism of teneligliptin (TEN) was not affected in presence of RES. The results show that the alteration of the pharmacokinetics of ALO, SAX and SIT was due to inhibition of CYP P450 by RES. Thus, there was a significant pharmacokinetic interaction between RES-ALO, RES-SAX and RES-SIT. Hence, a dose reduction is required when RES therapy is taken in combination with ALO, SAX and SIT as there is an increase in drug exposure, which might lead to toxicity.
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Affiliation(s)
- Shruti Surendran
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Rekha Sapkal
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - David Paul
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India
| | - Satheeshkumar Nanjappan
- Drug Metabolism and Interactions Research Lab, Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, 500037, India.
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Deng X, Wang N, Meng L, Zhou S, Huang J, Xing J, He L, Jiang W, Li Q. Optimization of the benzamide fragment targeting the S 2' site leads to potent dipeptidyl peptidase-IV inhibitors. Bioorg Chem 2019; 94:103366. [PMID: 31640932 DOI: 10.1016/j.bioorg.2019.103366] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 09/06/2019] [Accepted: 10/13/2019] [Indexed: 02/07/2023]
Abstract
Our recently successful identification of benzoic acid-based DPP-4 inhibitors spurs the further quest for in-depth structure-activity relationships (SAR) study in S2' site DPP-4. Thus novel benzamide fragments were designed to target the S2' site to compromise lipophilicity and improve oral activity. Exploring SAR by introduction of a variety of amide and halogen on benzene ring led to identification of several compounds, exerting moderated to excellent DPP-4 activities, in which 4'-chlorine substituted methyl amide 17g showed most potent DPP-4 activity with the IC50 value of 1.6 nM. Its activity was superior to reference alogliptin. Docking study ideally verified and interpreted the obtained SAR of designed compounds. As a continuation, DPP-8/9 assays revealed the designed compounds exhibited good selectivity over DPP-8 and DPP-9. Subsequent cell-based test indicated compound 17g displayed low toxicity toward the LO2 cell line up to 100 μM. In vivo evaluation showed compound 17g robustly improved the glucose tolerance in normal mice. Importantly, 17g exhibited reasonable pharmacokinetic (PK) profiles for oral delivery. Overall, compound 17g has the potential to a safe and efficacious DPP-4 inhibitor for T2DM treatment.
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Affiliation(s)
- Xiaoyan Deng
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China
| | - Na Wang
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China
| | - Liuwei Meng
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China
| | - Siru Zhou
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China
| | - Junli Huang
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China
| | - Junhao Xing
- Department of Organic Chemistry and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
| | - Linhong He
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China
| | - Weizhe Jiang
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China.
| | - Qing Li
- Pharmaceutical College, Guangxi Medical University, Nanning 530021, China.
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An Integrated In Silico and In Vitro Assays of Dipeptidyl Peptidase-4 and α-Glucosidase Inhibition by Stellasterol from Ganoderma australe. Sci Pharm 2019. [DOI: 10.3390/scipharm87030021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Background: Ganoderma fungus is rich in terpenoids. These compounds are known for their anti-hyperglycemic activities. However, the study of terpenoids as the secondary metabolite from Ganoderma as a dipeptidyl peptidase-4 (DPP-4) inhibitor remains unexplored. In addition, we examined the α-glucosidase inhibition activity. Objective: This study aimed to isolate the major terpenoid from non-laccate Ganoderma and examined its inhibitor activity on DPP-4 and α-glucosidase enzymes, and its interaction. Methods: The compound was isolated using column chromatography from Ganoderma australe. The structure of the isolated compound was confirmed by 1H and 13C nuclear magnetic resonance spectroscopy, while the inhibitory activity was evaluated using an enzymatic assay. The interaction of the isolated compound with DPP-4 and α-glucosidase enzymes was investigated using an in silico study. Results: The isolated compound was identified as stellasterol; IC50 values for DPP-4 and α-glucosidase inhibitor were 427.39 µM and 314.54 µM, respectively. This study revealed that the inhibitory effect of stellasterol on DPP-4 enzyme is through hydrophobic interaction, while the α-glucosidase enzyme is due to the interaction with six amino acids of the enzyme. Conclusion: Stellasterol is the major component of the steroid from G. australe. Enzyme inhibitory assay and in silico study suggest that stellasterol may contribute antidiabetic activity with a mechanism closer to acarbose rather than to sitagliptin.
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Park JW, Kim KA, Choi YJ, Yoon SH, Park JY. Effect of glimepiride on the pharmacokinetics of teneligliptin in healthy Korean subjects. J Clin Pharm Ther 2019; 44:720-725. [PMID: 31094010 DOI: 10.1111/jcpt.12848] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/15/2019] [Accepted: 04/24/2019] [Indexed: 12/15/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Teneligliptin is a DPP-4 inhibitor used for the treatment of type 2 diabetes mellitus, commonly prescribed in combination with glimepiride. Teneligliptin is metabolized by CYP3A4, and glimepiride might be partly metabolized by CYP3A4. The aim of the study was to investigate the possible effect of glimepiride on the pharmacokinetics of teneligliptin in healthy subjects. METHODS A repeated dose, open-label, fixed-sequence study was conducted in 26 healthy subjects. All participants were administered 20 mg teneligliptin daily for 6 days. On day 7, 4 mg glimepiride was administered together with 20 mg teneligliptin. Plasma teneligliptin concentrations were measured at a steady state, and its pharmacokinetic characteristics were compared without and with glimepiride. RESULTS AND DISCUSSION No statistically significant difference was found in the effect of glimepiride on teneligliptin pharmacokinetics. The steady-state Cmax,ss values of teneligliptin without and with glimepiride were 207.01 ng/mL and 202.15 ng/mL, respectively. Its AUCτ values at steady-state without and with glimepiride were 1527.8 ng · h/mL and 1578.6 ng · h/mL, respectively. The point estimation of geometric mean ratios (GMR) and the 90% confidence interval for both Cmax,ss and AUCτ were within the equivalence range of 0.8-1.25. The results of the present study revealed that glimepiride did not cause pharmacokinetic interaction with teneligliptin in humans. WHAT IS NEW AND CONCLUSION Glimepiride did not affect the pharmacokinetic characteristics of teneligliptin in healthy subjects.
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Affiliation(s)
- Jin-Woo Park
- Department of Clinical Pharmacology and Toxicology, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Korea
| | - Kyoung-Ah Kim
- Department of Clinical Pharmacology and Toxicology, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Korea
| | | | | | - Ji-Young Park
- Department of Clinical Pharmacology and Toxicology, Korea University College of Medicine, Korea University Anam Hospital, Seoul, Korea
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Kitada M, Ogura Y, Nitta K, Fujii M, Kanasaki K, Konishi K, Iida Y, Nakagawa A, Koya D. Effect of switching to teneligliptin from other dipeptidyl peptidase-4 inhibitors on glucose control and renoprotection in type 2 diabetes patients with diabetic kidney disease. J Diabetes Investig 2019; 10:706-713. [PMID: 30136384 PMCID: PMC6497591 DOI: 10.1111/jdi.12917] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 08/02/2018] [Accepted: 08/08/2018] [Indexed: 12/22/2022] Open
Abstract
AIMS/INTRODUCTION The objective of the present study was to elucidate the effect of switching to teneligliptin from other dipeptidyl peptidase-4 (DPP-4) inhibitors on glucose control and renoprotection in type 2 diabetes mellitus patients with diabetic kidney disease. MATERIALS AND METHODS The present study was a single-arm, open-label, observational study. A total of 23 patients, who had urinary albumin/creatinine ratios (UACR) ≥30 mg/gCr in their first urine in the early morning, and received other DPP-4 inhibitors and renin-angiotensin system inhibitors, switched to teneligliptin 20 mg/day. After switching to teneligliptin for 24 weeks, we evaluated changes in glycated hemoglobin (HbA1c), fasting plasma glucose levels, plasma DPP-4 activity and UACR. RESULTS HbA1c, fasting plasma glucose and UACR values showed no significant change after 24 weeks compared with baseline. However, plasma DPP-4 activity was significantly reduced after 24 weeks (0.57 ± 0.26 nmol/min/mL, P = 0.012, vs baseline), compared with baseline (1.49 ± 1.73 nmol/min/mL), and there was a positive relationship between the change rate of plasma DPP-4 activity (Δ%DPP-4) for 24 weeks and the levels of plasma DPP-4 activity (r = -0.5997, P = 0.0025) and fasting plasma glucose (r = -0.4235, P = 0.0440) at baseline. Additionally, the Δ%DPP-4 for 24 weeks was significantly correlated to the change rate of UACR (r = 0.556, P = 0.0059). However, there was no relationship between Δ%DPP-4 and ΔHbA1c (amount of HbA1c change). CONCLUSIONS Switching to teneligliptin from other DPP-4 inhibitors for 24 weeks reduces plasma DPP-4 activity, which is associated with a reduction in albuminuria, independent of the change in glucose levels, in type 2 diabetes mellitus patients with diabetic kidney disease.
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Affiliation(s)
- Munehiro Kitada
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaIshikawaJapan
- Division of Anticipatory Molecular Food Science and TechnologyMedical Research InstituteKanazawa Medical UniversityUchinadaIshikawaJapan
| | - Yoshio Ogura
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaIshikawaJapan
| | - Kyoko Nitta
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaIshikawaJapan
| | - Mizue Fujii
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaIshikawaJapan
| | - Keizo Kanasaki
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaIshikawaJapan
| | - Kazunori Konishi
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaIshikawaJapan
| | - Yasuo Iida
- Division of MathematicsDepartment of General Education‐Natural SciencesKanazawa Medical UniversityUchinadaIshikawaJapan
| | - Atsushi Nakagawa
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaIshikawaJapan
| | - Daisuke Koya
- Department of Diabetology and EndocrinologyKanazawa Medical UniversityUchinadaIshikawaJapan
- Division of Anticipatory Molecular Food Science and TechnologyMedical Research InstituteKanazawa Medical UniversityUchinadaIshikawaJapan
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Maideen NMP. Drug interactions of dipeptidyl peptidase 4 inhibitors involving CYP enzymes and P-gp efflux pump. World J Meta-Anal 2019; 7:156-161. [DOI: 10.13105/wjma.v7.i4.156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/21/2019] [Accepted: 04/23/2019] [Indexed: 02/06/2023] Open
Abstract
Dipeptidyl peptidase 4 (DPP4) inhibitors are oral antidiabetic drugs approved to manage type 2 diabetes mellitus. Saxagliptin is a substrate of CYP3A4/5 enzymes while other DPP4 inhibitors such as sitagliptin, linagliptin, gemigliptin and teneligliptin are weak substrates of CYP3A4. DPP4 inhibitors have also been identified as substrates of P-gp. Hence, the drugs inhibiting or inducing CYP3A4/5 enzymes and/or P-gp can alter the pharmacokinetics of DPP4 inhibitors. This review is aimed to identify the drugs interacting with DPP4 inhibitors. The plasma concentrations of saxagliptin have been reported to be increased significantly by the concomitant administration of ketoconazole or diltiazem while no significant interactions between various DPP4 inhibitors and drugs like warfarin, digoxin or cyclosporine have been identified.
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Glotfelty EJ, Delgado TE, Tovar-y-Romo LB, Luo Y, Hoffer BJ, Olson L, Karlsson TE, Mattson MP, Harvey BK, Tweedie D, Li Y, Greig NH. Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury. ACS Pharmacol Transl Sci 2019; 2:66-91. [PMID: 31396586 PMCID: PMC6687335 DOI: 10.1021/acsptsci.9b00003] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Indexed: 12/17/2022]
Abstract
Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short- and long-term disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with highest prevalence among younger and older populations. Increased public interest in the long-term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many incretin-based therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI.
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Affiliation(s)
- Elliot J. Glotfelty
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
- Department
of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Thomas E. Delgado
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
| | - Luis B. Tovar-y-Romo
- Division
of Neuroscience, Institute of Cellular Physiology, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Yu Luo
- Department
of Molecular Genetics, University of Cincinnati, Cincinnati, Ohio 45221, United States
| | - Barry J. Hoffer
- Department
of Neurosurgery, Case Western Reserve University
School of Medicine, Cleveland, Ohio 44106, United States
| | - Lars Olson
- Department
of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | | | - Mark P. Mattson
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
| | - Brandon K. Harvey
- Molecular
Mechanisms of Cellular Stress and Inflammation Unit, Integrative Neuroscience
Department, National Institute on Drug Abuse,
National Institutes of Health, Baltimore, Maryland 21224, United States
| | - David Tweedie
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
| | - Yazhou Li
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
| | - Nigel H. Greig
- Translational
Gerontology Branch, and Laboratory of Neurosciences, Intramural
Research Program, National Institute on
Aging, National Institutes of Health, Baltimore, Maryland 21224, United States
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Dipeptidyl dipeptidase-4 inhibitor recovered ischemia through an increase in vasculogenic endothelial progenitor cells and regeneration-associated cells in diet-induced obese mice. PLoS One 2019; 14:e0205477. [PMID: 30889182 PMCID: PMC6424405 DOI: 10.1371/journal.pone.0205477] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Accepted: 02/18/2019] [Indexed: 01/21/2023] Open
Abstract
Metabolic syndrome (MS), overlapping type 2 diabetes, hyperlipidemia, and/or hypertension, owing to high-fat diet, poses risk for cardiovascular disease. A critical feature associated with such risk is the functional impairment of endothelial progenitor cells (EPCs). Dipeptidyl dipeptidase-4 inhibitors (DPP-4 i) not only inhibit degradation of incretins to control blood glucose levels, but also improve EPC bioactivity and induce anti-inflammatory effects in tissues. In the present study, we investigated the effects of such an inhibitor, MK-06266, in an ischemia model of MS using diet-induced obese (DIO) mice. EPC bioactivity was examined in MK-0626-administered DIO mice and a non-treated control group, using an EPC colony-forming assay and bone marrow cKit+ Sca-1+ lineage-cells, and peripheral blood-mononuclear cells. Our results showed that, in vitro, the effect of MK-0626 treatment on EPC bioactivities and differentiation was superior compared to the control. Furthermore, microvascular density and pericyte-recruited arteriole number increased in MK-0626-administered mice, but not in the control group. Lineage profiling of isolated cells from ischemic tissues revealed that MK-0626 administration has an inhibitory effect on unproductive inflammation. This occurred via a decrease in the influx of total blood cells and pro-inflammatory cells such as neutrophils, total macrophages, M1, total T-cells, cytotoxic T-cells, and B-cells, with a concomitant increase in number of regeneration-associated cells, such as M2/M ratio and Treg/T-helper. Laser Doppler analysis revealed that at day 14 after ischemic injury, blood perfusion in hindlimb was greater in MK-0626-treated DIO mice, but not in control. In conclusion, the DPP-4 i had a positive effect on EPC differentiation in MS model of DIO mice. Following ischemic injury, DPP-4 i sharply reduced recruitment of pro-inflammatory cells into ischemic tissue and triggered regeneration and reparation, making it a promising therapeutic agent for MS treatment.
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Kim Y, Kang ES, Jang HC, Kim DJ, Oh T, Kim ES, Kim N, Choi KM, Kim S, You J, Kim S, Lee M. Teneligliptin versus sitagliptin in Korean patients with type 2 diabetes inadequately controlled with metformin and glimepiride: A randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2019; 21:631-639. [PMID: 30362280 PMCID: PMC6587707 DOI: 10.1111/dom.13566] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 10/11/2018] [Accepted: 10/23/2018] [Indexed: 01/02/2023]
Abstract
AIM To assess the efficacy and safety of add-on therapy with the dipeptidyl peptidase-4 inhibitor teneligliptin compared with sitagliptin in patients with type 2 diabetes (T2DM) inadequately controlled with metformin and glimepiride. MATERIALS AND METHODS This was a phase 3, randomized, double-blind, non-inferiority study of adult Korean subjects with T2DM (n = 201), with HbA1c ranging from 7.0% to 11.0%, on stable doses of metformin plus glimepiride. Subjects were randomized in a 1:1 fashion to receive either oral teneligliptin 20 mg or sitagliptin 100 mg for 24 weeks. The primary endpoint was change from baseline in HbA1c. RESULTS At baseline, mean age was 60.56 ± 9.41 years, body mass index was 25.23 ± 2.85 kg/m2 and HbA1c was 8.11% ± 0.79%. At 24 weeks, both groups achieved significant reductions from baseline in HbA1c (teneligliptin, -1.03% ± 0.10% [P < 0.0001]; sitagliptin, -1.02% ± 0.10% [P < 0.0001]). The inter-group difference was -0.01% (95% confidence interval [CI]: -0.28, 0.26; P = 0.9497); the upper limit of the 95% CI was within the preset limit for non-inferiority (0.4%). There were no significant differences between groups in the proportion of patients achieving HbA1c targets, or changes from baseline in fasting plasma glucose, body weight or lipid levels at 24 weeks. Rates of adverse events (teneligliptin, n = 63 [61.76%]; sitagliptin, n = 61 [62.24%]; P = 0.9442) and hypoglycaemia (teneligliptin, n = 32 [31.37%]; sitagliptin, n = 28 [28.57%]; P = 0.6656) were similar. CONCLUSION Teneligliptin was non-inferior to sitagliptin in the context of triple therapy for T2DM and is an important option in this setting.
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Affiliation(s)
- Yonghyun Kim
- Department of Internal Medicine, Daejin Medical CenterSeongnamKorea
| | - Eun Seok Kang
- Department of Internal MedicineYonsei University College of MedicineSeoulKorea
| | - Hak Chul Jang
- Department of Internal Medicine, Seoul National University Bundang HospitalSeongnamKorea
| | - Dong Jun Kim
- Department of Internal Medicine, Inje University Ilsanpaik HospitalGoyangKorea
| | - Taekeun Oh
- Department of Internal Medicine, Chungbuk National University HospitalCheongjuKorea
| | - Eun Sook Kim
- Department of Internal Medicine, Ulsan University HospitalUlsanKorea
| | - Nan‐Hee Kim
- Department of Internal Medicine, Korea University Ansan HospitalAnsanKorea
| | - Kyung Mook Choi
- Department of Internal Medicine, Korea University Guro HospitalSeoulKorea
| | - Sung‐Rae Kim
- Department of Internal Medicine, The Catholic University of Korea, Bucheon St. Mary's HospitalBucheonKorea
| | - JiYoung You
- Clinical Research ScienceHandok Inc.SeoulKorea
| | - Se‐Jin Kim
- Clinical Research OperationHandok Inc.SeoulKorea
| | - Moon‐Kyu Lee
- Division of Endocrinology and Metabolism, Department of Internal MedicineSamsung Medical Center, Sungkyunkwan UniversitySeoulKorea
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Erande S, Sarwardekar S, Desai B. QT/QTc safety and efficacy evaluation of teneligliptin in Indian type 2 diabetes mellitus patients: the "thorough QT/QTc" study (Q-SET study). Diabetes Metab Syndr Obes 2019; 12:961-967. [PMID: 31417296 PMCID: PMC6593689 DOI: 10.2147/dmso.s202458] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 03/20/2019] [Indexed: 11/23/2022] Open
Abstract
Background: Newer therapies, such as dipeptidyl peptidase-IV inhibitors, are increasingly being used in the treatment of type 2 diabetes mellitus (T2DM). Teneligliptin, a DPP4 inhibitor, currently commonly used as monotherapy or as add-on therapy, was generally well tolerated in patients with T2DM during clinical trials. No AEs related to QT prolongation were detected with 40 mg/day of teneligliptin, but were seen at a supratherapeutic dose of 160 mg/day. Aims and objective: To evaluate the safety of teneligliptin in type 2 diabetes patients with respect to QTc prolongation. Methodology: This was an open-label, prospective, multi-centric trial conducted in patients with T2DM aged ≥18 to ≤65 years with a hemoglobin A1c (HbA1c) ≥7.0% and gliptin naïve. Teneligliptin 20 mg once a day was added to the standard treatment. The dose of teneligliptin was increased to 40 mg once a day if required, on the basis of glycemic parameters. Twelve-lead ECG was recorded at baseline and follow-up visits. The QTc was calculated by using the Bazett's formula (QTc=QT/√RR). Results: The mean QT interval at screening (Visit 1, Day 0, baseline ECG) was 0.33±0.07 seconds, while at visit 2 (Day 1, post 2 hours of Teneligliptin dosing) it was 0.32±0.04 seconds, at visit 3 (Day 15) it was 0.32±0.04 seconds, and at visit 4 (Day 90) it was 0.32±0.03 seconds. The mean QTc interval at baseline was 0.37±0.04 seconds, while at visit 2 it was 0.37±0.04 seconds, at visit 3 it was 0.37±0.03 seconds, and at visit 4 it was 0.37±0.03 seconds. There was a significant reduction in fasting blood glucose (P=0.002), postprandial blood glucose (P<0.001), and HbA1c (P<0.001) at the end of the 3 months as compared to baseline. Conclusion: Teneligliptin at a therapeutic dose of 20 mg/day or 40 mg/day improved glycemic parameters significantly and did not cause QT/QTc interval prolongation.
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Affiliation(s)
- S Erande
- Department of Medicine, Akshay Hospital, Pune411004, India
- Correspondence: S ErandeAkshay Hospital, opp. SNDT College, Karve Road, Pune411004, IndiaTel +91 982 202 5149Email
| | - S Sarwardekar
- Department of Medicine, Sawardekar Clinic, Mumbai400055, India
| | - B Desai
- Department of Cardiology, Desai Heart Care Clinic, Mumbai400092, India
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Kadowaki T, Sarai N, Hirakawa T, Taki K, Iwasaki K, Urushihara H. Persistence of oral antidiabetic treatment for type 2 diabetes characterized by drug class, patient characteristics and severity of renal impairment: A Japanese database analysis. Diabetes Obes Metab 2018; 20:2830-2839. [PMID: 29974673 PMCID: PMC6282986 DOI: 10.1111/dom.13463] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 06/21/2018] [Accepted: 06/29/2018] [Indexed: 12/24/2022]
Abstract
AIM To evaluate the persistence with oral antidiabetic drug (OAD) treatment characterized by drug class, patient characteristics and severity of renal impairment (RI) in patients with type 2 diabetes (T2DM) in Japan. MATERIALS AND METHODS This retrospective, observational study extracted data from a large-scale hospital database (April 2008 to September 2016). Patients with T2DM aged ≥40 years on the day of their first prescription (index date) of any OAD (biguanides [BGs], thiazolidinediones [TZDs], sulphonylureas [SUs], glinides, dipeptidyl peptidase-4 [DPP-4] inhibitors, or α-glucosidase inhibitors [α-GIs]) available between January 1, 2014 and September 30, 2016 were identified. Sodium-glucose co-transporter-2 inhibitors were not available at study initiation. Treatment persistence was assessed by Kaplan-Meier survival curves. Patients were also categorized by RI status using estimated glomerular filtration rate: ≥90 mL/min/1.73 m2 (G1); 60 to <90 mL/min/1.73 m2 (G2); 30 to <60 mL/min/1.73 m2 (G3); and <30 mL/min/1.73 m2 (G4+). RESULTS We identified 206 406 index dates from 162 116 eligible patients. The largest number of index dates (91634) was observed for DPP-4 inhibitors, followed by BGs, SUs, α-GIs, glinides and TZDs. Treatment persistence was longest for DPP-4 inhibitors (median 17.0 months, 95% confidence interval [CI] 16.4-17.5) and BGs (median 17.3 months, 95% CI 16.6-18.2), and shortest for α-GIs (median 5.6 months, 95% CI 5.4-5.9) and SUs (median 4.3 months, 95% CI 4.2-4.6). Persistence was longest with DPP-4 inhibitors at all RI stages (G1-G4+), followed by BGs at stages G1/G2. CONCLUSIONS The longest OAD persistence was observed for BGs and DPP-4 inhibitors at RI stages G1/G2, and for DPP-4 inhibitors at RI stages G3/G4+.
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Affiliation(s)
- Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of MedicineUniversity of TokyoTokyoJapan
| | - Nobuaki Sarai
- Clinical Development and Medical AffairsNippon Boehringer Ingelheim Co., LtdTokyoJapan
| | - Takeshi Hirakawa
- Clinical Development and Medical AffairsNippon Boehringer Ingelheim Co., LtdTokyoJapan
| | - Kentaro Taki
- Medicine Development Unit JapanEli Lilly Japan K.K.KobeJapan
| | | | - Hisashi Urushihara
- Division of Drug Development and Regulatory Science, Faculty of PharmacyKeio UniversityTokyoJapan
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Plant dipeptidyl peptidase-IV inhibitors as antidiabetic agents: a brief review. Future Med Chem 2018; 10:1229-1239. [PMID: 29749760 DOI: 10.4155/fmc-2017-0235] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus is an increasing public health problem in the world. Type 2 diabetes is the most common type of diabetes whose complications contribute to its high death rate. It seriously impacts healthcare systems and patients' quality of life. Therefore, effective measures and new treatment strategies are needed to solve this increasingly serious global problem. In recent years, inhibition of dipeptidyl peptidase IV (DPP-IV) has emerged as a new treatment option for Type 2 diabetes. This article reviews various plant DPP-IV inhibitors that showed inhibition toward enzyme as a major target for the management of Type 2 diabetes. These studies can contribute to the future development of DPP-IV inhibitors as drugs.
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Li X, Huang X, Bai C, Qin D, Cao S, Mei Q, Ye Y, Wu J. Efficacy and Safety of Teneligliptin in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Pharmacol 2018; 9:449. [PMID: 29780322 PMCID: PMC5946087 DOI: 10.3389/fphar.2018.00449] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/17/2018] [Indexed: 01/11/2023] Open
Abstract
Background: Teneligliptin is a 3rd-generation dipeptidyl peptidase-4 (DPP-4) inhibitor. There is a limited evidence regarding the effect of teneligliptin. Therefore, this study is to assess the efficacy and safety of teneligliptin in type 2 diabetes mellitus (T2DM) patients with inadequately glycemic controlled. Methods: A search of PubMed, Medline, Embase, and The Cochrane Library during 2000.01-2018.03 was performed for randomized controlled trials of teneligliptin compared to placebo in patients with T2DM with monotherapy or add-on treatment. Results: Ten trials with 2119 patients were analyzed. Teneligliptin produced absolute reductions in glycated hemoglobin A1c (HbA1c) levels (weighted mean difference (WMD) 0.82%, 95% confidence interval (CI) [-0.91 to -0.72], p < 0.00001) compared with placebo. However, after 36-42 weeks of follow-up (open-label), HbA1c level rise higher than duration (double-blind) in teneligliptin group. Teneligliptin led to greater decrease of fasting plasma glucose (FPG) level (vs. placebo, WMD -18.32%, 95% CI [-21.05 to -15.60], p < 0.00001). Teneligliptin also significantly decreased the 2 h post-prandial plasma glucose (2 h PPG) (WMD -46.94%, 95% CI [-51.58 to -42.30], p < 0.00001) and area under the glucose plasma concentration-time curve from 0 to 2 h (AUC0-2h) for PPG (WMD -71.50%, 95% CI [-78.09 to -64.91], p < 0.00001) compared with placebo. Patients treated with teneligliptin achieved increased homeostasis model assessment of β cell function (HOMA-β) with 9.31 (WMD, 95% CI [7.78-10.85], p < 0.00001). However, there was no significant difference between teneligliptin and placebo in overall adverse effects (0.96 risk ratio (RR), 95% CI [0.87, 1.06], p = 0.06). The risks of hypoglycemia were not significantly different between teneligliptin and placebo (1.16 RR, 95% CI [0.59, 2.26], p = 0.66). Conclusions: Teneligliptin improved blood glucose levels and β-cells function with low risk of hypoglycemia in patients with T2DM. Common adverse effects of teneligliptin including hypoglycemia were identified and reviewed. Risks of cardiovascular events are less certain, and more data for long-term effects are needed.
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Affiliation(s)
- Xiaoxuan Li
- Laboratory of Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Xuefei Huang
- Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Chongfei Bai
- Laboratory of Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
- Department of Chinese Materia Medica, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Dalian Qin
- Laboratory of Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Shousong Cao
- Laboratory of Cancer Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Qibing Mei
- Laboratory of Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
| | - Yun Ye
- Department of Clinical Pharmacy, School of Pharmacy, Southwest Medical University, Luzhou, China
- Department of Pharmacy, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jianming Wu
- Laboratory of Chinese Materia Medica, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, China
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Deshpande PB, Butle SR. Determination of Dipeptidyl Peptidase-4 Inhibitors by Spectrophotometric and Chromatographic Methods. JOURNAL OF ANALYTICAL CHEMISTRY 2018. [DOI: 10.1134/s1061934818040032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Mechanistic study for the simultaneous determination of metformin and teneligliptin in human plasma using hydrophilic interaction liquid chromatography–MS/MS. Bioanalysis 2018; 10:475-488. [DOI: 10.4155/bio-2018-0007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Aim: A simple, selective and sensitive hydrophilic interaction liquid chromatography-MS/MS method is developed for the simultaneous determination of metformin (MET) and teneligliptin (TEN) in human plasma using deuterated internal standards. The mechanism of retention of analytes was studied by varying the proportion of organic diluent, buffer strength, pH of the mobile phase and temperature. Results: The results showed a mixed-mode mechanism comprising of hydrophilic (partition) and electrostatic interaction (ion exchange) for MET and essentially hydrophilic for TEN. The linear calibration curves were established in the concentration range of 1.0–1000 ng/ml for MET and 0.50–750 ng/ml for TEN. Conclusion: The method was applied to determine plasma concentration of MET and TEN in healthy subjects.
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Agarwal P, Jindal C, Sapakal V. Efficacy and Safety of Teneligliptin in Indian Patients with Inadequately Controlled Type 2 Diabetes Mellitus: A Randomized, Double-blind Study. Indian J Endocrinol Metab 2018; 22:41-46. [PMID: 29535935 PMCID: PMC5838908 DOI: 10.4103/ijem.ijem_97_16] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
AIMS This study evaluated the efficacy and safety of teneligliptin in patients with inadequately controlled type 2 diabetes mellitus (T2DM). SETTINGS AND DESIGN This was a randomized, doubleblind, placebocontrolled, parallelgroup, multicenter, Phase III study. SUBJECTS AND METHODS Patients with T2DM and inadequate glycemic control (glycosylated hemoglobin [HbA1c]: >7.0-≤8.5%) were enrolled. Patients were randomly assigned (ratio: 2:1) to receive teneligliptin 20 mg (Glenmark) or placebo. The primary efficacy variable was change from baseline in HbA1c at week 16. Additional analyses included the proportion of patients who achieved target of HbA1c ≤7.0%, changes in fasting plasma glucose (FPG), and postprandial glucose (PPG). STATISTICAL ANALYSIS Mean change in HbA1c was analyzed using an analysis of covariance model, least square (LS) means, 95% confidence intervals (CIs), and P values were calculated. RESULTS Overall, 237 patients were included. Patients of the teneligliptin group showed reduced HbA1c levels (LS mean difference = -0.304% for intent-to-treat [ITT]; -0.291% for per-protocol (PP) populations) after 16 weeks of treatment, and a statistically significant difference was observed between the ITT (LS mean difference = 0.555; 95% CI: 0.176-0.934; P = 0.0043) and PP populations (LS mean difference = 0.642; 95% CI: 0.233-1.052; P = 0.0023). Target HbA1c level was achieved by a greater proportion of teneligliptin group patients (ITT, 43.4%; PP, 43.6%) than placebo group patients (ITT, 27.3%; PP, 26.6%). Reduction in FPG levels was observed in ITT (LS mean difference: 8.829; 95% CI: -4.357-22.016; P = 0.1883) and PP populations (LS mean difference: 11.710 mg/dL; 95% CI: -2.893-26.312; P = 0.1154). Reduction in PPG levels was higher in teneligliptin group than placebo group in both ITT (LS mean difference = 25.849 mg/dL; 95% CI: 7.143-44.556; P = 0.0070) and PP populations (LS mean difference = 25.683 mg/dL; 95% CI: 5.830-45.536; P = 0.0115). Overall, 44 patients (18.6%) experienced at least one adverse event. Three or more hypoglycemic events were experienced by 2.5% patients of teneligliptin group and none in placebo group. CONCLUSION Treatment with once-daily teneligliptin led to statistically significant and clinically meaningful reductions in HbA1c and PPG, and was well tolerated in Indian patients with T2DM.
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Affiliation(s)
- Piyush Agarwal
- Department of Medical Services, Glenmark Pharmaceuticals Limited, Mumbai, Maharashtra, India
| | - Chhavi Jindal
- Department of Medical Services, Glenmark Pharmaceuticals Limited, Mumbai, Maharashtra, India
| | - Vinayak Sapakal
- Department of Medical Services, Glenmark Pharmaceuticals Limited, Mumbai, Maharashtra, India
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Kumar N, Devineni SR, Aggile K, Gajjala PR, Kumar P, Dubey SK. Facile new industrial process for synthesis of teneligliptin through new intermediates and its optimization with control of impurities. RESEARCH ON CHEMICAL INTERMEDIATES 2017. [DOI: 10.1007/s11164-017-3120-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure. Biochem Pharmacol 2017; 145:64-80. [PMID: 28859968 DOI: 10.1016/j.bcp.2017.08.021] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 08/25/2017] [Indexed: 12/20/2022]
Abstract
Saxagliptin treatment has been associated with increased rate of hospitalization for heart failure in type 2 diabetic patients, though the underlying mechanism(s) remain elusive. To address this, we assessed the effects of saxagliptin on human atrial trabeculae, guinea pig hearts and cardiomyocytes. We found that the primary target of saxagliptin, dipeptidyl peptidase-4, is absent in cardiomyocytes, yet saxagliptin internalized into cardiomyocytes and impaired cardiac contractility via inhibition of the Ca2+/calmodulin-dependent protein kinase II-phospholamban-sarcoplasmic reticulum Ca2+-ATPase 2a axis and Na+-Ca2+ exchanger function in Ca2+ extrusion. This resulted in reduced sarcoplasmic reticulum Ca2+ content, diastolic Ca2+ overload, systolic dysfunction and impaired contractile force. Furthermore, saxagliptin reduced protein kinase C-mediated delayed rectifier K+ current that prolonged action potential duration and consequently QTc interval. Importantly, saxagliptin aggravated pre-existing cardiac dysfunction induced by ischemia/reperfusion injury. In conclusion, our novel results provide mechanisms for the off-target deleterious effects of saxagliptin on cardiac function and support the outcome of SAVOR-TIMI 53 trial that linked saxagliptin with the risk of heart failure.
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Kadowaki T, Inagaki N, Kondo K, Nishimura K, Kaneko G, Maruyama N, Nakanishi N, Iijima H, Watanabe Y, Gouda M. Efficacy and safety of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: Results of a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2017; 19:874-882. [PMID: 28177187 PMCID: PMC5484989 DOI: 10.1111/dom.12898] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 01/23/2017] [Accepted: 01/25/2017] [Indexed: 12/24/2022]
Abstract
AIMS To investigate efficacy and safety of the sodium-glucose co-transporter 2 (SGLT2) inhibitor canagliflozin administered as add-on therapy to the dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS We conducted a multicentre, randomized, double-blind, placebo-controlled, phase 3 clinical trial in Japanese patients with T2DM who had inadequate glycaemic control with teneligliptin. Patients were randomized to receive teneligliptin 20 mg plus either canagliflozin 100 mg (T + C, n = 70) or placebo (T + P, n = 68) once daily. The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. Other endpoints included changes in fasting plasma glucose, body weight, proinsulin/C-peptide ratio, homeostatic model assessment 2-%B and adverse events. Patients also underwent mixed-meal tolerance tests. RESULTS The difference between the T + C and T + P groups for HbA1c change from baseline to week 24 was -0.88% (least-squares mean, P < .001). Fasting plasma glucose, body weight and the proinsulin/C-peptide ratio were significantly lower in the T + C group than in the T + P group. Homeostatic model assessment 2-%B improved with T + C compared with T + P. The T + C group exhibited a decrease in the 2-hour postprandial plasma glucose and plasma glucose area under the curve (AUC)0-2h in a mixed-meal tolerance test. No significant between-group differences were observed for C-peptide AUC0-2h or glucagon AUC0-2h after meals. Incidences of adverse events were 60.0% and 47.1% in the T + C and T + P groups, respectively. No hypoglycaemia was observed. CONCLUSIONS Canagliflozin administered as add-on therapy to teneligliptin was effective and well tolerated in Japanese T2DM patients.
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Affiliation(s)
- Takashi Kadowaki
- Department of Diabetes and Metabolic Diseases, Graduate School of MedicineThe University of TokyoTokyoJapan
| | - Nobuya Inagaki
- Department of Diabetes, Endocrinology and Nutrition, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kazuoki Kondo
- Mitsubishi Tanabe Pharma Corporation, Sohyaku. Innovative research DivisionTokyoJapan
| | - Kenichi Nishimura
- Mitsubishi Tanabe Pharma Corporation, Sohyaku. Innovative research DivisionTokyoJapan
| | - Genki Kaneko
- Mitsubishi Tanabe Pharma Corporation, Sohyaku. Innovative research DivisionTokyoJapan
| | - Nobuko Maruyama
- Mitsubishi Tanabe Pharma Corporation, Sohyaku. Innovative research DivisionTokyoJapan
| | - Nobuhiro Nakanishi
- Mitsubishi Tanabe Pharma Corporation, Sohyaku. Innovative research DivisionTokyoJapan
| | - Hiroaki Iijima
- Mitsubishi Tanabe Pharma Corporation, Ikuyaku. Integrated DivisionTokyoJapan
| | - Yumi Watanabe
- Mitsubishi Tanabe Pharma Corporation, Ikuyaku. Integrated DivisionTokyoJapan
| | - Maki Gouda
- Mitsubishi Tanabe Pharma Corporation, Ikuyaku. Integrated DivisionTokyoJapan
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Kutoh E, Wada A, Terayama S. Teneligliptin, a Chemotype Prolyl-Thiazolidine-Based Novel Dipeptidyl Peptidase-4 Inhibitor with Insulin Sensitizing Properties. Clin Drug Investig 2017; 36:809-18. [PMID: 27352309 DOI: 10.1007/s40261-016-0427-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND AND OBJECTIVES Teneligliptin, a chemotype prolyl-thiazolidine-based novel dipeptidyl peptidase (DPP)-4 inhibitor, was preliminarily shown to reduce insulin resistance in patients with type 2 diabetes mellitus (T2DM). The objective of this study is to further investigate the insulin sensitising properties of teneligliptin in comparison to those of sitagliptin. METHODS Treatment-naïve subjects with T2DM were administered 20 mg/day teneligliptin monotherapy (n = 45). As a comparator, 25-50 mg/day sitagliptin monotherapy was performed in a non-randomized manner (n = 71). No other drugs were administered. At 3 months, levels of diabetic parameters were compared with those at baseline. RESULTS At 3 months, while similar reductions of glycated hemoglobin (HbA1c) levels were observed with these two drugs, indexes for insulin sensitivity [homeostasis model assessment (HOMA)-R and 20/(C-peptide × fasting blood glucose (FBG)) levels] ameliorated only with teneligliptin. Then, the subjects were divided into two groups representing distinct degrees of insulin resistance; high HOMA-R (≥4) and low HOMA-R (<2) groups. With teneligliptin, similar decreases of HbA1c levels were observed in high (9.85-7.66 %, p < 0.0005) and low (10.12-8.51 %, p < 0.01) HOMA-R groups. HOMA-R (-32.6 %, p < 0.05) and non-high density lipoprotein cholesterol (non-HDL-C, -6 %, p < 0.05) levels significantly decreased and 20/(C-peptide × FBG) levels significantly increased (53 %, p < 0.001) in high HOMA-R group. HOMA-B levels increased in both groups with significant inter-group differences (+101.7 % in low HOMA-R group vs. +55.4 % in high HOMA-R group). Group 2. With sitagliptin, similar decreases of HbA1c levels were observed from those of teneligliptin in either high or low HOMA-R group, but no changes of HOMA-R, non-HDL-C or 20/(C-peptide × FBG) levels were noted. Increases of HOMA-B levels with sitagliptin were comparable to those with teneligliptin in either high or low HOMA-R group. CONCLUSIONS These results indicate that: (i) teneligliptin ameliorates insulin sensitivity and non-HDL-C levels in subjects with high degrees of insulin resistance. This is not the case with sitagliptin, though similar glycemic efficacies were observed. (ii) glycemic efficacy of teneligliptin may be determined by the balance of its capacity in modulating insulin resistance and beta-cell function depending on the degrees of baseline insulin resistance.
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Affiliation(s)
- Eiji Kutoh
- Department of Clinical Research, Biomedical Center, Tokyo, Japan.
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan.
| | - Asuka Wada
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan
| | - Sayaka Terayama
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan
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Affiliation(s)
- Awadhesh Kumar Singh
- Department of Endocrinology, GD Hospital and Diabetes Institute, Kolkata, West Bengal, India
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Kumar TNVG, Vidyadhara S, Narkhede NA, Silpa YS, Lakshmi MR. Method development, validation, and stability studies of teneligliptin by RP-HPLC and identification of degradation products by UPLC tandem mass spectroscopy. J Anal Sci Technol 2016. [DOI: 10.1186/s40543-016-0107-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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