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Kalkan AT, Yorulmaz G, Akalin A, Dinleyici EC. Intestinal Microbiota Composition in Patients with Type 2 Diabetes and Effects of Oral Antidiabetics. J Clin Med 2025; 14:2786. [PMID: 40283615 PMCID: PMC12027695 DOI: 10.3390/jcm14082786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2025] [Revised: 04/14/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
Introduction: The cause-effect relationships between microbiota composition changes and type 2 diabetes (T2D) are complex, likely involving two-way interactions, and require further elucidation. Few studies have examined the interactions of antidiabetic drugs with the gut microbiota. This study's goal was to evaluate the gut microbiota of patients with type 2 diabetes at first diagnosis and again after 12 weeks of taking oral antidiabetic drugs. Methods: We performed a fecal microbiota analysis of adult patients who recently received a T2D diagnosis and healthy adults. We compared the microbiota compositions between the T2D patients and healthy controls; we also evaluated changes from baseline to 12 weeks of treatment in the total group receiving oral antidiabetics, as well as in the subgroups receiving metformin and linagliptin. Results: The alpha diversity and beta diversity indices were different at baseline between patients with type 2 diabetes and healthy controls. The LEfSe analysis showed that, at the genus level, the Lactobacillus, Rothia, Collinsella, and Eubacterium genera increased in relative abundance in the T2D group while, at the species level, the Rothia mucilaginosa, Collinsella aerofaciens, and Eubacterium bioforme strains were found to be dominant in the T2D group. Faecalibacterium at the genus level and Faecalibacterium prausnitzii at the strain level increased in relative abundance in the T2D group after 12 weeks. After 12 weeks of intervention, the alpha diversity indices were significantly lower in the T2D group compared to the control group. At the end of the 12th week, the Gemmiger and Collinsella genera were dominant in the T2D group, with Gemmiger formicilis and Collinsella aerofaciens being dominant at the species level; in the control group, Bacteroides and Alistipes were dominant at the genus level, and Prevotella stercorea and Alistipes finegoldii were dominant. There was no difference in the LEfSe analysis results between baseline and 12 weeks of linagliptin treatment. At the strain level, Gemmiger formicilis, Ruminococcus bromii, Rothia mucilaginosa, and Lactobacillus ruminis were predominant at the start of metformin treatment; however, after 12 weeks, Collinsella aerofaciens became predominant. Conclusions: We report that there is a substantial change in the composition of the gut microbiota in patients with T2D. Oral antidiabetic treatments, especially metformin, have some beneficial effects on microbiota composition. Few studies have explored the interaction of antidiabetic drugs with the gut microbiota; further research will elucidate the clinical impact of these changes in gut microbiota composition in diabetes.
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Affiliation(s)
- Ahmet Toygar Kalkan
- Faculty of Medicine, Department of Endocrinology, Eskisehir Osmangazi University, Eskisehir 26040, Türkiye
| | - Goknur Yorulmaz
- Faculty of Medicine, Department of Endocrinology, Eskisehir Osmangazi University, Eskisehir 26040, Türkiye
| | - Aysen Akalin
- Faculty of Medicine, Department of Endocrinology, Eskisehir Osmangazi University, Eskisehir 26040, Türkiye
| | - Ener Cagri Dinleyici
- Faculty of Medicine, Department of Pediatrics, Eskisehir Osmangazi University, Eskisehir 26040, Türkiye;
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Mahmoud MO, Al-Hamid HA, Hassan NF, El-Ansary MR, Gomaa SB. Linagliptin Mitigates DMH-Induced Colorectal Cancer in Rats: Crosstalk Between NFAT and IL-6/JAK2/STAT3/NF-κB Signaling Hubs. J Biochem Mol Toxicol 2025; 39:e70206. [PMID: 40070168 DOI: 10.1002/jbt.70206] [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: 09/07/2024] [Revised: 01/30/2025] [Accepted: 03/02/2025] [Indexed: 05/13/2025]
Abstract
Colorectal cancer (CRC) is a multicomponent disease and the second most frequent root of cancer-related deaths globally. Linagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. It has been repurposed in recent experimental studies due to its marked anti-inflammatory activities. This study aimed to evaluate the ameliorative role of linagliptin in 1,2-dimethylhydrazine (DMH)-induced CRC via modulation of NFAT-mediated IL-6 and JAK2/STAT3/NF-κB signaling pathways. CRC model has been successfully established via a dose equal 40 mg/kg two times a week of DMH for 8-week duration. Twenty-four Wistar rats were segregated into three groups of eight rats each; normal control, DMH-induced CRC and DMH + linagliptin (10 mg/kg; p.o). Linagliptin attenuated DMH-induced oxidative stress by restoring the declined levels of some antioxidant enzymes. Linagliptin suppressed the elevated nuclear factor kappa B (NF-κB) induced by DMH which is highlighted using immunohistochemistry analysis. The anti-inflammatory role of linagliptin has been fortified by the decline in nuclear factor of activated T-cells (NFAT) mRNA expression level along with the reduction in vascular endothelial growth factor (VEGF), interlukin-6 (IL-6) and cyclooxygenase-2 (COX-2) levels. Linagliptin mitigate the protein expression of DMH-activated oncogenic janus-activated kinase/signal transducers and activators of transcription (JAK2/STAT3). Linagliptin exerted a proapoptotic effect to tumor cells manifested by a remarkable decline in B-cell lymphoma 2 (Bcl-2) and a significant elevation in Bcl-2-associated X protein (Bax) expression levels. The histopathological analysis revealed that linagliptin has inhibitory potential against the DMH induced dysplastic aberrant crypt foci (ACF) and adenocarcinoma. Linagliptin ameliorated CRC by modulating NFAT-mediated IL-6 with JAK2/STAT3/NF-κB signaling cascades.
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Affiliation(s)
- Mohamed O Mahmoud
- Biochemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Hager Abd Al-Hamid
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Noha F Hassan
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Mona R El-Ansary
- Biochemistry Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
| | - Safaa B Gomaa
- Biochemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
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Liana A, Hałuszczuk A, Gawor A, Bulska E. Identification and Structural Characterization of Degradation Products of Linagliptin by Mass Spectrometry Techniques. Int J Mol Sci 2024; 25:2591. [PMID: 38473837 DOI: 10.3390/ijms25052591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 02/17/2024] [Accepted: 02/21/2024] [Indexed: 03/14/2024] Open
Abstract
As part of the development and production of pharmaceuticals, the purity of Active Pharmaceutical Ingredients stands as a fundamental parameter that significantly influences the quality, safety, and efficacy of the final drug product. Impurities in Active Pharmaceutical Ingredients are various unwanted substances that can appear during the whole manufacturing process, from raw materials to the final product. These impurities can stem from multiple sources, including starting materials, intermediates, reagents, solvents, and even degradation products resulting from exposure to environmental factors such as heat, light, or moisture. Their presence can potentially compromise the therapeutic effect of the drug, introduce unexpected side effects, or even pose safety risks to patients. This study aims to conduct the forced degradation of linagliptin and subsequently attempt to identify the resulting degradants. The degradation procedures were carried out in accordance with the guidelines of the International Committee for Harmonization. The degradation profile of linagliptin was investigated under various conditions, including acid hydrolysis, alkaline hydrolysis, oxidation, heat, and light exposure, utilizing ultra-performance liquid chromatography connected to a photo array detector. Identification and characterization of the degradation products were achieved using an ultra-performance liquid chromatography coupled with a single quadrupole detector mass spectrometer and also a liquid chromatography coupled with a high-resolution mass spectrometry. The identified degradation products demonstrate that linagliptin is particularly susceptible to degradation when exposed to acid and peroxide. Whereas, no significant degradation effects were observed under alkali, thermolytic, and photolytic conditions.
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Affiliation(s)
- Aleksandra Liana
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland
- Pharmaceutical Plant Polpharma S.A., Pelpińska 19, 83-200 Starograd Gdański, Poland
| | - Adam Hałuszczuk
- Faculty of Chemistry, Gdańsk University of Technology, Gabriela Narutowicza 11/12, 80-233 Gdańsk, Poland
| | - Andrzej Gawor
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland
| | - Ewa Bulska
- Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland
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Nour IM, Mohamed AR, Badrawy M. Innovative UV Protocols Based on Straightforward Mathematical Filtration for Concurrent Estimation of Two Antidiabetic Drugs in Their Brand-New Combination: A Comparative Study. J AOAC Int 2024; 107:40-45. [PMID: 37824214 DOI: 10.1093/jaoacint/qsad123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Revised: 08/30/2023] [Accepted: 10/06/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND In 2019, the U.S. Food and Drug Administration approved a brand-new combination of linagliptin and empagliflozin in a formulation called Glyxambi® tablets for managing type 2 diabetes mellitus. Nowadays, spectrophotometric techniques occupy the first place among their peers in terms of ease of application, friendliness to the environment, and low costs. OBJECTIVE This research discusses the development of two very simple spectrophotometric protocols based on zero-order spectra for the determination of linagliptin and empagliflozin. METHODS The developed protocols were the induced dual-wavelength and absorption correction protocols. Linagliptin could be determined directly at 305 nm, at which the empagliflozin spectrum was zero-crossing. Empagliflozin was determined using the two developed protocols. The induced dual-wavelength technique was developed by calculating the equality factor of linagliptin to cancel its interference. The absorption correction technique was developed by measuring the correction absorption factor. RESULTS The concentration ranges of linagliptin and empagliflozin were 1-10 µg/mL and 3-30 µg/mL, respectively. Excellent recovery results were found in bulk, dosage form, and synthetic mixtures. Low LOD and LOQ values were obtained, indicating the high sensitivity of the protocols. The statistical Student's t-test was performed to compare the results of the applied and reported protocols, indicating no difference between them. CONCLUSION The proposed protocols have the advantages of being straightforward, affordable, and requiring no sophisticated manipulations, just simple mathematical calculations. The proposed protocols are acceptable for routine usage in QC laboratories and in future research applications. HIGHLIGHTS Two novel univariate methods were developed for quantitative analysis of linagliptin and empagliflozin in their pharmaceutical and laboratory mixtures, and produced satisfactory results.
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Affiliation(s)
- Israa M Nour
- Egyptian Russian University, Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr 11829, Egypt
| | - Ahmed R Mohamed
- Egyptian Russian University, Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr 11829, Egypt
| | - Mohamed Badrawy
- Egyptian Russian University, Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr 11829, Egypt
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Pauly I, Kumar Singh A, Kumar A, Singh Y, Thareja S, Kamal MA, Verma A, Kumar P. Current Insights and Molecular Docking Studies of the Drugs under Clinical Trial as RdRp Inhibitors in COVID-19 Treatment. Curr Pharm Des 2023; 28:3677-3705. [PMID: 36345244 DOI: 10.2174/1381612829666221107123841] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/08/2022] [Accepted: 09/19/2022] [Indexed: 11/10/2022]
Abstract
Study Background & Objective: After the influenza pandemic (1918), COVID-19 was declared a Vth pandemic by the WHO in 2020. SARS-CoV-2 is an RNA-enveloped single-stranded virus. Based on the structure and life cycle, Protease (3CLpro), RdRp, ACE2, IL-6, and TMPRSS2 are the major targets for drug development against COVID-19. Pre-existing several drugs (FDA-approved) are used to inhibit the above targets in different diseases. In coronavirus treatment, these drugs are also in different clinical trial stages. Remdesivir (RdRp inhibitor) is the only FDA-approved medicine for coronavirus treatment. In the present study, by using the drug repurposing strategy, 70 preexisting clinical or under clinical trial molecules were used in scrutiny for RdRp inhibitor potent molecules in coronavirus treatment being surveyed via docking studies. Molecular simulation studies further confirmed the binding mechanism and stability of the most potent compounds. MATERIAL AND METHODS Docking studies were performed using the Maestro 12.9 module of Schrodinger software over 70 molecules with RdRp as the target and remdesivir as the standard drug and further confirmed by simulation studies. RESULTS The docking studies showed that many HIV protease inhibitors demonstrated remarkable binding interactions with the target RdRp. Protease inhibitors such as lopinavir and ritonavir are effective. Along with these, AT-527, ledipasvir, bicalutamide, and cobicistat showed improved docking scores. RMSD and RMSF were further analyzed for potent ledipasvir and ritonavir by simulation studies and were identified as potential candidates for corona disease. CONCLUSION The drug repurposing approach provides a new avenue in COVID-19 treatment.
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Affiliation(s)
- Irine Pauly
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Ankit Kumar Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Adarsh Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Yogesh Singh
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Suresh Thareja
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
| | - Mohammad A Kamal
- King Fahd Medical Research Center, King Abdulaziz University, Jaddah, Saudi Arabia.,Enzymoics, 7 Peterlee Place, Hebersham, NSW 2770, Australia.,Novel Global Community Educational Foundation, Australia Institutes for Systems Genetics, Frontiers Science Center for Disease-related Molecular Network, Australia
| | - Amita Verma
- Bioorganic and Medicinal Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj, 211007, India
| | - Pradeep Kumar
- Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, 151401, India
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DSC, FT-IR and NIR with Chemometric Assessment Using PCA and HCA for Estimation of the Chemical Stability of Oral Antidiabetic Drug Linagliptin in the Presence of Pharmaceutical Excipients. Molecules 2022; 27:molecules27134283. [PMID: 35807528 PMCID: PMC9268681 DOI: 10.3390/molecules27134283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/30/2022] [Accepted: 07/01/2022] [Indexed: 02/01/2023] Open
Abstract
Pharmaceutical excipients should not interact with active substances, however, in practice, they sometimes do it, affecting the efficacy, stability and safety of drugs. Thus, interactions between active substances and excipients are not desirable. For this reason, two component mixtures of oral antidiabetic drug linagliptin (LINA) with four excipients of different reactivity, i.e., lactose (LAC), mannitol (MAN), magnesium stearate (MGS) and polyvinylpyrrolidone (PVP), were prepared in a solid state. A high temperature and a high humidity of 60 °C and 70% RH, respectively, were applied as stressors in order to accelerate the potential interactions between LINA and excipients. Differential scanning calorimetry (DSC) as well as Fourier transform infrared (FT-IR) and near infrared (NIR) spectroscopy were used to estimate the changes due to potential interactions. In addition, chemometric computation of the data with principal component analysis (PCA) and hierarchical cluster analysis (HCA) was applied to adequately interpret the findings. Of the excipients used in the present experiment, all of them were not inert in relation to LINA. Some of the interactions were shown without any stressing, whereas others were observed under high-temperature/high-humidity conditions. Thus, it could be concluded that selection of appropriate excipients for LINA is very important question to minimize its degradation, especially when new types of formulations with LINA are being developed and manufactured.
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Mehmandoust M, Erk N, Karaman C, Karaman O. An electrochemical molecularly imprinted sensor based on CuBi 2O 4/rGO@MoS 2 nanocomposite and its utilization for highly selective and sensitive for linagliptin assay. CHEMOSPHERE 2022; 291:132807. [PMID: 34762887 DOI: 10.1016/j.chemosphere.2021.132807] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/26/2021] [Accepted: 11/04/2021] [Indexed: 06/13/2023]
Abstract
The molecularly imprinted polymers (MIP) is an outstanding electrochemical tool that demonstrates good chemical sensitivity and stability. These main advantages, coupled with the material's vast microfabrication flexibility, make molecularly imprinted sensors an attractive sensing device. Herein, it was aimed to develop a state-of-art molecularly imprinted sensor based on CuBi2O4/rGO@MoS2 nanocomposite to be utilized for the detection of linagliptin (LNG), a novel hypoglycemic drug. The electrochemical characterizations of linagliptin on the surface of the modified electrode was examined via cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). Several characterization methods including transmission electron microscope (TEM), X-ray diffraction (XRD), scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FT-IR), and Energy-dispersive X-ray spectroscopy(EDX), were utilized for electrode characterization. The LNG imprinted voltammetric sensor was developed in 80.0 mM phenol containing 20.0 mM LNG. CuBi2O4/rGO@MoS2 nanocomposite on LNG imprinted screen-printed carbon electrode (SPCE) (MIP/CuBi2O4/rGO@MoS2 nanocomposite/SCPE) exhibited a linear relationship between peak current and LNG concentration in the range 0.07-0.5 nM with a detection limit of 0.057 nM. In the existence of interfering substances, an LNG imprinted electrode was utilized to analyze urine, human plasma, and tablet samples with adequate selectivity. The developed sensor was also illustrated for stability, repeatability, reproducibility, and reusability.
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Affiliation(s)
- Mohammad Mehmandoust
- Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06560, Ankara, Turkey; Sakarya University, Biomaterials, Energy, Photocatalysis, Enzyme Technology, Nano & Advanced Materials, Additive Manufacturing, Environmental Applications, and Sustainability Research & Development Group (BIOENAMS R&D Group), 54187, Sakarya, Turkey
| | - Nevin Erk
- Ankara University, Faculty of Pharmacy, Department of Analytical Chemistry, 06560, Ankara, Turkey; Sakarya University, Biomaterials, Energy, Photocatalysis, Enzyme Technology, Nano & Advanced Materials, Additive Manufacturing, Environmental Applications, and Sustainability Research & Development Group (BIOENAMS R&D Group), 54187, Sakarya, Turkey.
| | - Ceren Karaman
- Akdeniz University, Vocational School of Technical Sciences, Department of Electricity and Energy, Antalya, 07070, Turkey
| | - Onur Karaman
- Akdeniz University, Vocational School of Health Services, Department of Medical Services and Techniques, Antalya, 07070, Turkey.
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Iacobellis G, Baroni MG. Cardiovascular risk reduction throughout GLP-1 receptor agonist and SGLT2 inhibitor modulation of epicardial fat. J Endocrinol Invest 2022; 45:489-495. [PMID: 34643917 DOI: 10.1007/s40618-021-01687-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/01/2021] [Indexed: 12/17/2022]
Abstract
Epicardial adipose tissue is a novel cardiovascular risk factor. It plays a role in the progression of coronary artery disease, heart failure and atrial fibrillation. Given its rapid metabolism, clinical measurability, and modifiability, epicardial fat works well as therapeutic target of drugs modulating the adipose tissue. Epicardial fat responds to glucagon-like peptide 1 receptor agonists (GLP1A) and sodium glucose co-transporter 2 inhibitors (SGLT2i). GLP-1A and SGLT2i provide weight loss and cardiovascular protective effects beyond diabetes control, as recently demonstrated. The potential of modulating the epicardial fat morphology and genetic profile with targeted pharmacological agents can open new avenues in the pharmacotherapy of diabetes and obesity, with particular focus on cardiovascular risk reduction.
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Affiliation(s)
- G Iacobellis
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, 1400 NW 10th Ave, Dominion Tower suite 805-807, Miami, FL, 33136, USA.
| | - M G Baroni
- Endocrinology and Diabetes, Department of Clinical Medicine, Public Health, Life and Environmental Sciences (MeSVA), University of L'Aquila, L'Aquila, Italy
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Iacobellis G, Basilico S, Malavazos AE. Targeting Epicardial Fat in Obesity and Diabetes Pharmacotherapy. Handb Exp Pharmacol 2022; 274:93-108. [PMID: 35156138 DOI: 10.1007/164_2021_577] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Epicardial adipose tissue surrounds and infiltrates the heart. Epicardial fat displays unique anatomic, genetic, and biomolecular properties. People with obesity and in particular, those with abdominal obesity and associated type 2 diabetes mellitus, have an increased amount of epicardial adipose tissue (EAT). Epicardial fat works well as therapeutic target due to its fast-responding metabolism, organ fat specificity, and easy measurability. Epicardial fat responds to thiazolidinediones (TZD), glucagon-like peptide 1-receptor agonists (GLP1A), sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), and statins. Modulating epicardial fat morphology and genetic profile with targeted pharmacological agents suggests novel strategies in the pharmacotherapy of diabetes and obesity.
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Affiliation(s)
- Gianluca Iacobellis
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA.
| | - Sara Basilico
- Endocrinology Unit, Clinical Nutrition and Cardiovascular Prevention Service, IRCCS Policlinico San Donato, Milan, Italy
| | - Alexis Elias Malavazos
- Endocrinology Unit, Clinical Nutrition and Cardiovascular Prevention Service, IRCCS Policlinico San Donato, Milan, Italy
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Elmasry MS, Hassan WS, Merey HA, Nour IM. Simple mathematical data processing method for the determination of sever overlapped spectra of linagliptin and empagliflozin in their pure forms and pharmaceutical formulation: Fourier self deconvulated method. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 254:119609. [PMID: 33684852 DOI: 10.1016/j.saa.2021.119609] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/19/2021] [Accepted: 02/06/2021] [Indexed: 06/12/2023]
Abstract
A new and simple spectrophotometric method was developed for the simultaneous determination of a new antidiabetic mixture of linagliptin and empagliflozin namely fourier self deconvulated method. The developed method based on minimal mathematical data processing on the zero order spectrum for solving sever overlapping spectra of the mentioned drugs in their pure forms and pharmaceutical dosage form. The zero order spectra of linagliptin and empagliflozin were deconvulated using Fourier transforms function. The peak amplitudes at 232 nm were selected for linagliptin and at 239 nm for empagliflozin. The constructed calibration graphs were linear over the range (5-30 µg/mL) and (2-12 µg/mL) for empagliflozin and linagliptin, respectively. The adopted method was simple, accurate, precise and validated according to the ICH guidelines.
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Affiliation(s)
- Manal S Elmasry
- Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
| | - Wafaa S Hassan
- Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Hanan A Merey
- Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr-El-Aini, Cairo 11562, Egypt; Analytical Chemistry Department, Faculty of Pharmacy, October 6 University, 6 October City, Giza 12585, Egypt
| | - Israa M Nour
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, Egypt
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Elmasry MS, Hasan MA, Hassan WS, Merey HA, Nour IM. Flourimetric study on antidiabetic combined drugs; empagliflozin and linagliptin in their pharmaceutical formulation and human plasma. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2021; 248:119258. [PMID: 33310272 DOI: 10.1016/j.saa.2020.119258] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/20/2020] [Accepted: 11/25/2020] [Indexed: 06/12/2023]
Abstract
Empagliflozin and linagliptin are newly approved FDA combination that used for the treatment of type 2 diabetes mellitus (T2DM) under trade name Glxambi. Two spectroflourimetric methods were developed for simple quantitative determination of empagliflozin and linagliptin in their pharmaceutical formulation and human plasma without need any tedious processing operations. Empagliflozin has a native fluorescence nature, therefore can be directly determined by measuring emission peak at 305 nm after excitation at 234 nm. There is no any interference from linagliptin at this emission wavelength. On the other hand, linagliptin is a very weak florescent compound that needs to react with fluorogenic reagent to be quantitatively determined without any reaction of empagliflozin. So, quantitative analysis of linagliptin was achieved by coupling with NBD-Cl which is an electro active halide reagent (targeting only Linagliptin with no effect on empagliflozin). Dark yellow fluorophore with high fluorescence is a result of this reaction and can be measured at emission wavelength 538 nm after excition at wavelength 469 nm. Experimental conditions of the suggested methods were well checked and optimized. The regression plots were found to be linear over the range of 40-1200 ng/mL and 3-700 ng/mL for empagliflozin and linagliptin, respectively. The obtained results by the suggested methods were statistically compared with those obtained by the reported methods, showing no significant difference with respect to accuracy and precision at p = 0.05.
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Affiliation(s)
- Manal S Elmasry
- Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt.
| | - Mohamed A Hasan
- Pharmaceutical Analytical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo 11751, Egypt
| | - Wafaa S Hassan
- Analytical Chemistry Department, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
| | - Hanan A Merey
- Analytical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr-El-Aini, Cairo 11562, Egypt; Analytical Chemistry Department, Faculty of Pharmacy, October 6 University, 6 October City, Giza 12585, Egypt
| | - Israa M Nour
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, Egypt
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Gahlan AA, Haredy AM, Derayea SM, Omar MA, Saleh GA. A Glassy Carbon Electrode for the Determination of Linagliptin, an Antidiabetic Drug in Pure Form, Tablets and Some Biological Fluids by Adsorptive Stripping Voltammetry. Curr Pharm Des 2020; 27:2415-2424. [PMID: 32981495 DOI: 10.2174/1381612826666200925123245] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/18/2020] [Indexed: 11/22/2022]
Abstract
AIM The present work provides a fast, simple, accurate, and inexpensive analytical method for the determination of Linagliptin (anti-diabetic drug). METHODS The analysis was performed using a square wave adsorptive anodic stripping voltammetric technique (SWAASV) and glassy carbon electrode (GCE) as a working electrode. The experimental and instrumental parameters were studied and discussed to ensure the validity of the method. RESULTS The method has a very good linearity (R2 = 0.9984), wide concentration range (0.189 - 2.268 μg mL-1), low detection limit of 0.052 μg mL-1 and low quantitation limit of 0.172 μg mL-1. CONCLUSION Linagliptin was identified successfully using the proposed method in pharmaceutical formulations, spiked human urine and plasma with 99.67, 91.96, and 92.78% recovery, respectively, and the results obtained were compared with other reported methods.
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Affiliation(s)
- Ahmed A Gahlan
- Chemistry Department, Faculty of Science, Al-Azhar University, Assiut Branch, Assiut, Egypt
| | - Ahmed M Haredy
- Analytical Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Sayed M Derayea
- Analytical Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Mahmoud A Omar
- Analytical Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Gamal A Saleh
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Assiut University, Assiut, Egypt
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13
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El-Deeb OS, Soliman GM, Elesawy RO. Linagliptin, the dipeptidyl peptidase-4 enzyme inhibitor, lessens CHOP and GRP78 biomarkers levels in cisplatin-induced neurobehavioral deficits: A possible restorative gateway. J Biochem Mol Toxicol 2020; 34:e22541. [PMID: 32567747 DOI: 10.1002/jbt.22541] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 05/15/2020] [Accepted: 05/29/2020] [Indexed: 12/13/2022]
Abstract
Cisplatin (CP) is a cornerstone chemotherapeutic agent, however, its neurotoxicity is a chief cause of its limited usage. Linagliptin, which is a dipeptidyl peptidase-4 enzyme inhibitor, has exhibited considerable neuroprotective potential. We aimed to evaluate the linagliptin modulatory effects on endoplasmic reticulum (ER) stress, redox status, and apoptosis in CP-induced neurotoxicity. Thirty mice were allocated equally into the control group, Group II: CP group, and Group III: linagliptin treated CP group. All groups were subjected to the measurement of hippocampal messenger RNA gene expression of glucose-regulated protein-78 and C/EBP homologous protein (CHOP). Peroxisome proliferator-activated receptor γ coactivator 1α and cleaved caspase-3 levels were assessed by the enzyme-linked immunosorbent assay technique while malondialdehyde, reduced glutathione levels and superoxide dismutase activity were detected spectrophotometrically. Linagliptin ameliorated ER stress and enhanced antioxidant status with cognitive function improvement. Linagliptin may be considered a promising neuroprotective agent owing to its ability to reduce ER/oxidative stress.
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Affiliation(s)
- Omnia S El-Deeb
- Medical Biochemistry Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Gehan M Soliman
- Histology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Rasha O Elesawy
- Pharmacology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
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14
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Iacobellis G, Gra-Menendez S. Effects of Dapagliflozin on Epicardial Fat Thickness in Patients with Type 2 Diabetes and Obesity. Obesity (Silver Spring) 2020; 28:1068-1074. [PMID: 32352644 DOI: 10.1002/oby.22798] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/04/2020] [Accepted: 03/06/2020] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Epicardial adipose tissue (EAT) thickness is a marker of visceral fat and an emerging therapeutic target. Dapagliflozin, a selective sodium-glucose cotransporter 2 inhibitor, improves glucose control and induces moderate weight loss in patients with type 2 diabetes mellitus. Dapagliflozin has recently been shown to reduce cardiovascular risk. Nevertheless, whether dapagliflozin could reduce EAT thickness is unknown. METHODS This hypothesis was tested in a 24-week, randomized, double-blind, placebo-controlled clinical trial in 100 patients with type 2 diabetes mellitus with BMI ≥ 27 kg/m2 and a hemoglobin A1c level ≤ 8% on metformin monotherapy. Individuals were randomly assigned to 2 groups to receive additional dapagliflozin up to 10 mg once daily or to remain on metformin up to 1,000 mg twice daily. Ultrasound-measured EAT thickness was measured at baseline, 12 weeks, and 24 weeks. RESULTS In the dapagliflozin group, EAT decreased by 20% from baseline to 24 weeks, by 15% after 12 weeks, and by 7% between 12 and 24 weeks, respectively (P < 0.01 for all), whereas in the metformin group, there was a significant but smaller EAT reduction. There was no statistically significant correlation between EAT and body weight changes. CONCLUSIONS Dapagliflozin causes a rapid and significant EAT reduction that could be independent of weight loss.
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Affiliation(s)
- Gianluca Iacobellis
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA
| | - Silvia Gra-Menendez
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Miller School of Medicine, University of Miami, Miami, Florida, USA
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15
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Jadhav SB, Reddy PS, Narayanan KL, Bhosale PN. Development of RP-HPLC, Stability Indicating Method for Degradation Products of Linagliptin in Presence of Metformin HCl by Applying 2 Level Factorial Design; and Identification of Impurity-VII, VIII and IX and Synthesis of Impurity-VII. Sci Pharm 2017; 85:E25. [PMID: 28653975 PMCID: PMC5620513 DOI: 10.3390/scipharm85030025] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2017] [Revised: 06/06/2017] [Accepted: 06/07/2017] [Indexed: 01/19/2023] Open
Abstract
The novel reverse phase-high performance liquid chromatography (RP-HPLC), stability indicating method was developed for determination of linagliptin (LGP) and its related substances in linagliptin and metformin HCl (MET HCl) tablets by implementing design of experiment to understand the critical method parameters and their relation with critical method attributes; to ensure robustness of the method. The separation of nine specified impurities was achieved with a Zorbax SB-Aq 250 × 4.6 mm, 5 µm column, using gradient elution and a detector wavelength of 225 nm, and validated in accordance with International Conference on Harmonization (ICH) guidelines and found to be accurate, precise, reproducible, robust, and specific. The drug was found to be degrading extensively in heat, humidity, basic, and oxidation conditions and was forming degradation products during stability studies. After slight modification in the buffer and the column, the same method was used for liquid chromatography-mass spectrometry (LC-MS) and ultra-performance liquid chromatography -time-of-flight/mass spectrometry UPLC-TOF/MS analysis, to identify m/z and fragmentation of maximum unspecified degradation products i.e., Impurity-VII (7), Impurity-VIII (8), and Impurity-IX (9) formed during stability studies. Based on the results, a degradation pathway for the drug has been proposed and synthesis of Impurity-VII (7) is also discussed to ensure an in-depth understanding of LGP and its related degradation products and optimum performance during the lifetime of the product.
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Affiliation(s)
- Sushant B Jadhav
- Research and Development, Integrated Product Development, Dr. Reddy's Laboratories Ltd, Bachupally, Hyderabad 500 090, Telangana, India.
- Department of Chemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India.
| | - P Sunil Reddy
- Research and Development, Integrated Product Development, Dr. Reddy's Laboratories Ltd, Bachupally, Hyderabad 500 090, Telangana, India.
| | - Kalyanaraman L Narayanan
- Research and Development, Integrated Product Development, Dr. Reddy's Laboratories Ltd, Bachupally, Hyderabad 500 090, Telangana, India.
| | - Popatrao N Bhosale
- Department of Chemistry, Shivaji University, Kolhapur 416 004, Maharashtra, India.
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Michurina SV, Ishenko IJ, Klimontov VV, Archipov SA, Myakina NE, Cherepanova MA, Zavjalov EL, Koncevaya GV, Konenkov VI. Linagliptin alleviates fatty liver disease in diabetic db/ db mice. World J Diabetes 2016; 7:534-546. [PMID: 27895822 PMCID: PMC5107713 DOI: 10.4239/wjd.v7.i19.534] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2016] [Revised: 08/18/2016] [Accepted: 09/08/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To study the effects of linagliptin on the structural signs of non-alcoholic fatty liver disease (NAFLD) in db/db mice.
METHODS Male diabetic db/db mice (BKS.Cg-Dock7m+/+Leprdb/J) aged 10 wk received the dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin (10 mg/kg) or saline as a placebo once per day by gavage for 8 wk. Intact db/db mice served as controls. Structural changes in the liver were analyzed from light and electron microscopic images of sections from intact, placebo-treated and linagliptin-treated animals. We estimated the changes in hepatocytes, sinusoidal cells, liver microvasculature and lymphatic roots. Hepatic staining for lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) was assessed by immunohistochemistry.
RESULTS In 18-wk-old diabetic mice, liver steatosis (predominantly microvesicular and mediovesicular steatosis) was accompanied by dilation of the roots of the lymphatic system, interlobular blood vessels and bile canaliculi. Compared to saline-treated mice, linagliptin-treated mice exhibited a reduction in the mean numeral densities of hepatocytes with lipid droplets (92.4% ± 1.7% vs 64.9% ± 5.8% per field of view, P = 0.0002) and a lower proportion of hepatocytes with a high density of lipid droplets (20.7% ± 3.6% vs 50.4% ± 3.1%, P = 0.0007). We observed heterogeneous hepatocytes and relatively preserved cell structures in the linagliptin group. Dilation of blood and lymphatic vessels, as well as ultrastructural changes in the hepatocyte endoplasmic reticulum and mitochondria, were alleviated by linagliptin treatment. In intact and placebo-treated mice, immunohistochemical staining for LYVE-1 was observed in the endothelial cells of interlobular lymphatic vessels and on the membranes of some endothelial sinusoidal cells. We observed an enlarged LYVE-1 reaction area in linagliptin-treated mice compared to intact and placebo-treated mice. The improvement in the structural parameters of the liver in linagliptin-treated mice was independent to changes in the plasma glucose levels.
CONCLUSION The DPP4 inhibitor linagliptin alleviates liver steatosis and structural changes in the hepatic microvasculature and lymphatic roots in a model of NAFLD in diabetic db/db mice.
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Chen XW, He ZX, Zhou ZW, Yang T, Zhang X, Yang YX, Duan W, Zhou SF. Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus. Clin Exp Pharmacol Physiol 2016; 42:999-1024. [PMID: 26173919 DOI: 10.1111/1440-1681.12455] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 06/11/2015] [Accepted: 07/06/2015] [Indexed: 12/16/2022]
Abstract
Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose-lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.
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Affiliation(s)
- Xiao-Wu Chen
- Department of General Surgery, The First People's Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, China
| | - Zhi-Xu He
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China
| | - Zhi-Wei Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Tianxin Yang
- Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Centre, Salt Lake City, UT, USA
| | - Xueji Zhang
- Research Centre for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, China
| | - Yin-Xue Yang
- Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Vic., Australia
| | - Shu-Feng Zhou
- Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China.,Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
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18
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Zhao BT, Le DD, Nguyen PH, Ali MY, Choi JS, Min BS, Shin HM, Rhee HI, Woo MH. PTP1B, α-glucosidase, and DPP-IV inhibitory effects for chromene derivatives from the leaves of Smilax china L. Chem Biol Interact 2016; 253:27-37. [PMID: 27060210 DOI: 10.1016/j.cbi.2016.04.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Revised: 03/16/2016] [Accepted: 04/05/2016] [Indexed: 12/29/2022]
Abstract
Two new flavonoids, bismilachinone (11) and smilachinin (14), were isolated from the leaves of Smilax china L. together with 14 known compounds. Their structures were elucidated using spectroscopic methods. The PTP1B, α-glucosidase, and DPP-IV inhibitory activities of compounds 1-16 were evaluated at the molecular level. Among them, compounds 4, 7, and 10 showed moderate DPP-IV inhibitory activities with IC50 values of 20.81, 33.12, and 32.93 μM, respectively. Compounds 3, 4, 6, 11, 12, and 16 showed strong PTP1B inhibitory activities, with respective IC50 values of 7.62, 10.80, 0.92, 2.68, 9.77, and 24.17 μM compared with the IC50 value for the positive control (ursolic acid: IC50 = 1.21 μM). Compounds 2-7, 11, 12, 15, and 16 showed potent α-glucosidase inhibitory activities, with respective IC50 values of 8.70, 81.66, 35.11, 35.92, 7.99, 26.28, 11.28, 62.68, 44.32, and 70.12 μM. The positive control, acarbose, displayed an IC50 value of 175.84 μM. In the kinetic study for the PTP1B enzyme, compounds 6, 11, and 12 displayed competitive inhibition with Ki values of 3.20, 8.56, and 5.86 μM, respectively. Compounds 3, 4, and 16 showed noncompetitive inhibition with Ki values of 18.75, 5.95, and 22.86 μM, respectively. Molecular docking study for the competitive inhibitors (6, 11, and 12) radically corroborates the binding affinities and inhibition of PTP1B enzymes. These results indicated that the leaves of Smilax china L. may contain compounds with anti-diabetic activity.
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Affiliation(s)
- Bing Tian Zhao
- College of Pharmacy, Catholic University of Daegu, Gyeongsan 38430, Republic of Korea
| | - Duc Dat Le
- College of Pharmacy, Catholic University of Daegu, Gyeongsan 38430, Republic of Korea
| | - Phi Hung Nguyen
- College of Pharmacy, Catholic University of Daegu, Gyeongsan 38430, Republic of Korea; Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, 18-Hoang Quoc Viet, Hanoi, Vietnam
| | - Md Yousof Ali
- Department of Food Science & Nutrition, Pukyong National University, Busan 48513, Republic of Korea
| | - Jae-Sue Choi
- Department of Food Science & Nutrition, Pukyong National University, Busan 48513, Republic of Korea
| | - Byung Sun Min
- College of Pharmacy, Catholic University of Daegu, Gyeongsan 38430, Republic of Korea
| | - Heung Mook Shin
- Department of Physiology, College of Oriental Medicine, Dongguk University, Seoul 04620, Republic of Korea
| | - Hae Ik Rhee
- Department of Biotechnology, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Mi Hee Woo
- College of Pharmacy, Catholic University of Daegu, Gyeongsan 38430, Republic of Korea.
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19
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Yasir A, Hardigan T, Ergul A. Diabetes-mediated middle cerebral artery remodeling is restored by linagliptin: Interaction with the vascular smooth muscle cell endothelin system. Life Sci 2016; 159:76-82. [PMID: 26944436 DOI: 10.1016/j.lfs.2016.02.096] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 02/25/2016] [Accepted: 02/29/2016] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Endothelin-1 (ET-1) mediates cerebrovascular remodeling in vascular smooth muscle layer of the middle cerebral arteries (MCA) in type-2 diabetic Goto-Kakizaki (GK) rats. While metformin, oral glucose lowering agent, prevent/restores vascular remodeling and reduce systemic and local ET-1 levels whether this effect was specific to metformin remained unknown. Our working hypotheses were 1) linagliptin, a DPP-IV inhibitor, can reverse diabetes-mediated cerebrovascular remodeling and this is associated with decreased ET-1, and 2) linagliptin prevents the high glucose induced increase in ET-1 and ET receptors in brain vascular smooth muscle cells (bVSMCs). METHODS Diabetic and non-diabetic GK rats were treated with linagliptin (4weeks). MCAs were fixed in buffered 4% paraformaldehyde and used for morphometry. Human bVSMCs incubated in normal glucose (5.5mM)/high glucose (25mM) conditions were treated with the linagliptin (100nM; 24h). ET-1 secretion and ET receptors were measured in media and cell lysate respectively. Immunostaining was performed for ET-A and ET-B receptor. ET receptors were also measured in cells treated with ET-1 (100nM) and linagliptin. RESULTS Linagliptin treatment regressed vascular remodeling of MCAs in diabetic animals but had no effect on blood glucose. bVSMCs in normal/high glucose condition did not show any significant difference in ET-1 secretion or ET-A and ET-B receptor expression. ET-1 treatment in high glucose condition significantly increased the ET-A receptors and this effect was inhibited by linagliptin. CONCLUSIONS Linagliptin is effective in reversing established pathological cerebrovascular remodeling associated with diabetes. Attenuation of the ET system could be a pleiotropic effect of linagliptin that provides vascular protection.
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Affiliation(s)
- Abdul Yasir
- Charlie Norwood Veterans Administration Medical Center, Augusta University, Augusta, Georgia, United States; Department of Physiology, Augusta University, Augusta, Georgia, United States
| | - Trevor Hardigan
- Department of Physiology, Augusta University, Augusta, Georgia, United States
| | - Adviye Ergul
- Charlie Norwood Veterans Administration Medical Center, Augusta University, Augusta, Georgia, United States; Department of Physiology, Augusta University, Augusta, Georgia, United States.
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Fisman EZ, Tenenbaum A. Antidiabetic treatment with gliptins: focus on cardiovascular effects and outcomes. Cardiovasc Diabetol 2015; 14:129. [PMID: 26415691 PMCID: PMC4587723 DOI: 10.1186/s12933-015-0294-0] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Accepted: 09/21/2015] [Indexed: 12/11/2022] Open
Abstract
The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50 % of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25 %. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins—also called dipeptidyl peptidase 4 (DPP4) inhibitors—are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials—notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years—did not show an increased risk for ischemic events. Anyway, it should be emphasized that the encouraging results from basic science were not yet translated into clinical evidence, probably due the multiple and pleiotropic enzymatic effects of DPP4 inhibition. Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased. Gliptins as a group constitute a widely accepted therapy for the management of T2DM, usually as a second-line medication. Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.
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Affiliation(s)
- Enrique Z Fisman
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel. .,Cardiovascular Diabetology Research Foundation, 58484, Holon, Israel.
| | - Alexander Tenenbaum
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Tel Aviv, Israel. .,Cardiovascular Diabetology Research Foundation, 58484, Holon, Israel. .,Cardiac Rehabilitation Institute, Sheba Medical Center, 52621, Tel Hashomer, Israel.
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Mishriky BM, Cummings DM, Tanenberg RJ. The efficacy and safety of DPP4 inhibitors compared to sulfonylureas as add-on therapy to metformin in patients with Type 2 diabetes: A systematic review and meta-analysis. Diabetes Res Clin Pract 2015; 109:378-88. [PMID: 26059071 DOI: 10.1016/j.diabres.2015.05.025] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Revised: 01/29/2015] [Accepted: 05/02/2015] [Indexed: 12/15/2022]
Abstract
There is no consensus on the selection of specific drug therapies when metformin fails in Type 2 diabetes (T2D). This meta-analysis was performed to determine the efficacy and safety of Dipeptidyl peptidase-4 inhibitors (DPP4-I) compared to sulfonylurea (SU) as add-on therapy to metformin in inadequately controlled T2D patients. We searched MEDLINE, CENTRAL, EMBASE, and CINAHL for randomized trials comparing DPP4-I to SU as add-on therapy to metformin and reported a change in hemoglobin A1c (HbA1c). Sixteen articles were included. There was a significantly greater reduction in HbA1c from baseline to 12 weeks with SU versus DPP4-I (MD[95% CI]=0.21%(2 mmol/mol) [0.06, 0.35]) but no significant difference at 52 and 104 weeks (MD[95% CI]=0.06%(-1 mmol/mol) [-0.03, 0.15] and 0.02%(-1 mmol/mol) [-0.13,0.18] respectively). SU was associated with weight gain and DPP4-I with weight loss at all time-points. The incidence of hypoglycemia at 12, 52, and 104 weeks was significantly greater with SU (20%, 24%, and 27% respectively) compared to DPP4-I (6%, 3%, and 4% respectively). The proportion of patients with HbA1c<7%(53 mmol/mol) without hypoglycemia was significantly higher at 52 and 104 weeks among patients on DPP4-I (RR[95% CI]=1.20 [1.05, 1.37] and 1.53 [1.16, 2.02] respectively). There was no significant difference between the two groups in the incidence of other side effects. While both SU and DPP4-I can be considered as options for add-on therapy to metformin in inadequately controlled T2D, SU results in a significantly increased risk of hypoglycemia and weight gain. By contrast, DPP4-I produce 0.4-0.6% (4-7 mmol/mol) reduction in HbA1c, lower risk of hypoglycemia, and weight loss.
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Affiliation(s)
- Basem M Mishriky
- Department of Internal Medicine, East Carolina University, Greenville, NC, United States
| | - Doyle M Cummings
- Department of Family Medicine, East Carolina University, Greenville, NC, United States.
| | - Robert J Tanenberg
- Division of Endocrinology, East Carolina University, Greenville, NC, United States
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Deshmukh V, Sathyanarayana S, Menon S, Patil S, Jones R, Uppal S, Siddiqui K. Safety and efficacy of initial combination of linagliptin and metformin in patients with type 2 diabetes: A subgroup analysis of Indian patients from a randomized, double-blind, placebo-controlled study. Indian J Endocrinol Metab 2015; 19:256-261. [PMID: 25729688 PMCID: PMC4319266 DOI: 10.4103/2230-8210.149319] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
CONTEXT AND OBJECTIVES The number of people with diabetes is increasing exponentially in India. Owing to a unique "Asian Indian Phenotype," Indians develop diabetes a decade earlier and have an earlier onset of complications than Western populations. Therefore, it is essential to evaluate more effective treatment strategies at an earlier stage of disease progression, such as initial combination therapy, in Indian patients. In this study, we evaluated the efficacy and safety of initial combination therapy with linagliptin plus metformin in comparison to linagliptin or metformin monotherapy in Indian patients with type 2 diabetes mellitus. METHODS This is a subgroup analysis of Indian patients who participated in a Phase III, 24-week, double-blind, placebo-controlled, trial. Overall, 249 Indian patients were randomized to one of six treatment arms (Two free combination therapy arms: Linagliptin 2.5 mg twice daily [bid] + either low [500 mg, n = 36] or high [1000 mg, n = 44] dose metformin bid and four monotherapy arms: Linagliptin 5 mg once daily [qd, n = 40], metformin 500 mg [n = 49] or 1000 mg bid [n = 45], or placebo [n = 23]). RESULTS The placebo-corrected mean change in glycated hemoglobin from baseline (8.9%) to week 24 was -1.83% for linagliptin + metformin 1000 mg bid; -1.46% for linagliptin + metformin 500 mg bid; -1.30% for metformin 1000 mg bid; -1.00% for metformin 500 mg bid; and -0.77% for linagliptin 5 mg qd. None of the patients in the combination therapy arms had hypoglycemia, whereas there was one event in the metformin 1000 mg bid arm. Rates of adverse event were similar across various treatments. CONCLUSIONS In this subgroup analysis of Indian patients, initial combination therapy with linagliptin + metformin was more efficacious in improving glycemic control than the monotherapy arms, with a comparable tolerability profile. The results were comparable to the overall population.
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Affiliation(s)
| | | | - Shalini Menon
- Department of Medical Affairs, Boehringer Ingelheim India Pvt. Ltd., Mumbai, Maharashtra, India
| | - Shiva Patil
- Department of Medical Affairs, Boehringer Ingelheim India Pvt. Ltd., Mumbai, Maharashtra, India
| | - Russel Jones
- Department of Statistics, Boehringer Ingelheim, Bracknell, West Berkshire, UK
| | - Shweta Uppal
- Department of Medical Affairs, Eli Lilly, Gurgaon, Haryana, India
| | - Kamran Siddiqui
- Department of Medical Affairs, Boehringer Ingelheim, Singapore
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Tang YZ, Wang G, Jiang ZH, Yan TT, Chen YJ, Yang M, Meng LL, Zhu YJ, Li CG, Li Z, Yu P, Ni CL. Efficacy and safety of vildagliptin, sitagliptin, and linagliptin as add-on therapy in Chinese patients with T2DM inadequately controlled with dual combination of insulin and traditional oral hypoglycemic agent. Diabetol Metab Syndr 2015; 7:91. [PMID: 26500706 PMCID: PMC4616160 DOI: 10.1186/s13098-015-0087-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 10/08/2015] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE We aimed to evaluate the efficacy and safety of the three dipeptidyl peptidase 4 (DPP-4) inhibitors (vildagliptin, sitagliptin, and linagliptin) as add-on therapy in Chinese patients with type 2 diabetes mellitus (T2DM)inadequately controlled on dual combination of insulin and metformin or acarbose. METHODS A total of 535 T2DM patients who failed to achieve glycemic control with insulin and a traditional oral hypoglycemic agent were randomized to receive vildagliptin, sitagliptin, or linagliptin. Body mass index, glycosylated hemoglobin (HbA1c), fasting and postprandial plasma glucose (FPG and PPG), insulin dose, and adverse events were evaluated during the study. RESULTS The baseline HbA1c was 9.59 ± 1.84 % (vildagliptin group), 9.22 ± 1.60 % (sitagliptin group), and 9.58 ± 1.80 % (linagliptin group). At week 12 it was 8.16 ± 1.29 % (vildagliptin), 8.56 ± 1.96 % (linagliptin), and 8.26 ± 1.10 % (sitagliptin). The changes in HbA1c from baseline were -1.33 ± 0.11 % (vildagliptin), -0.84 ± 0.08 % (sitagliptin) and -0.81 ± 0.08 % (linagliptin), the vildagliptin group had the greatest reduction in HbA1c (P < 0.05). The proportions of patients that reached target HbA1c were 66.27 % (vildagliptin), 52.73 % (sitagliptin), and 55.49 % (linagliptin), the vildagliptin group had the highest one (P < 0.05). The baseline FPG and PPG values in the three groups were at the same level. At week 12, mean FPG levels in the vildagliptin (7.31 ± 1.50 mmol/L) and linagliptin (6.90 ± 1.55 mmol/L) groups were significantly lower than in the sitagliptin group (8.02 ± 4.48 mmol/L; P < 0.05); the linagliptin group had the lowest mean PPG followed by the vildagliptin group which was also significant lower (P = 0.000) than the sitagliptin group. Additionally, the required insulin dosage in the vildagliptin group was the lowest among the groups at weeks 6 and 12. Only mild AEs were reported during the study. CONCLUSION The three DPP-4 inhibitors appear to be effective and safe as add-on therapy for T2DM patients on dual combination of insulin and a traditional OHA. Vildagliptin was more effective in decreasing insulin requirement and achieving glycemic control when compared to the other two.
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Affiliation(s)
- Yun-Zhao Tang
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Gang Wang
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Zhen-Huan Jiang
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Tian-Tian Yan
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Yi-Jun Chen
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Min Yang
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Ling-Ling Meng
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Yan-Juan Zhu
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Chen-Guang Li
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Zhu Li
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Ping Yu
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
| | - Chang-Lin Ni
- Key Laboratory of Hormones and Development (Ministry of Health), Metabolic Diseases Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tongan Road 66, Heping District, Tianjin, 300070 China
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The DPP-IV inhibitor linagliptin and GLP-1 induce synergistic effects on body weight loss and appetite suppression in the diet-induced obese rat. Eur J Pharmacol 2014; 741:254-63. [DOI: 10.1016/j.ejphar.2014.08.010] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 08/14/2014] [Accepted: 08/18/2014] [Indexed: 01/13/2023]
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Franconi F, Campesi I. Sex and gender influences on pharmacological response: an overview. Expert Rev Clin Pharmacol 2014; 7:469-85. [DOI: 10.1586/17512433.2014.922866] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Hepatotoxicidad inducida por linagliptina y sitagliptina: ¿es un efecto de clase? Rev Clin Esp 2014; 214:54-5. [DOI: 10.1016/j.rce.2013.10.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 10/17/2013] [Accepted: 10/20/2013] [Indexed: 11/20/2022]
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