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Advances in Medical Sciences Sep 2023Dipeptidyl peptidase 4 (DPP) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP) by DPP directly...
PURPOSE
Dipeptidyl peptidase 4 (DPP) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP) by DPP directly influences glucose homeostasis. This study aimed to describe the mode of interaction between sitagliptin (an antidiabetic drug) and human DPP using in silico approaches.
MATERIALS AND METHODS
Docking studies were conducted using AutoDock Vina, 2D and 3D schematic drawings were obtained using PoseView and PLIP servers, and the DPP-sitagliptin complex was visualized with Pymol software.
RESULTS
The best affinity energy to form the DPP-sitagliptin complex was E-value = - 8.1 kcal mol, as indicated by docking simulations. This result suggests a strong interaction. According to our observations, hydrophobic interactions involving the amino acids residues Tyr and Val, hydrogen bonds (Glu, Glu, Tyr, and Tyr), π-Stacking interactions (Phe and Tyr), and halogenic bonds (Arg, Glu, and Arg) were prevalent in the DPP-sitagliptin complex. Root Mean Square Deviation prediction also demonstrated that the global structure of the human DPP did not have a significant change in its topology, even after the formation of the DPP-sitagliptin complex.
CONCLUSION
The stable interaction between the sitagliptin ligand and the DPP enzyme was demonstrated through molecular docking simulations. The findings presented in this work enhance the understanding of the physicochemical properties of the sitagliptin interaction site, supporting the design of more efficient gliptin-like iDPP inhibitors.
Topics: Humans; Sitagliptin Phosphate; Molecular Docking Simulation; Dipeptidyl-Peptidase IV Inhibitors; Hypoglycemic Agents; Peptides; Diabetes Mellitus, Type 2
PubMed: 37837799
DOI: 10.1016/j.advms.2023.10.002 -
Molecular and Cellular Endocrinology Oct 2022Fibroblast growth factor 21 (FGF21), a hormone with pleiotropic metabolic effects, is inactivated by fibroblast activation protein (FAP), a member of the dipeptidyl... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Fibroblast growth factor 21 (FGF21), a hormone with pleiotropic metabolic effects, is inactivated by fibroblast activation protein (FAP), a member of the dipeptidyl peptidase-IV (DPP-IV) family. We investigate if sitagliptin (DPP-IV inhibitor) inhibits FAP-activity and increases intact FGF21.
METHODS
Patients with impaired glucose metabolism were randomized to 100 mg sitagliptin (n = 34) or placebo (n = 37) treatment for 12 weeks. Plasma samples obtained at study entry and at 12-weeks were analysed for FAP-activity, FAP, total FGF21 and intact FGF21.
RESULTS
Sitagliptin significantly inhibited FAP-activity (497 ± 553 vs. 48 ± 712 RFU/min, p < 0.01) and correspondingly increased intact FGF21 (253 ± 182 vs 141 ± 80 ng/L, p < 0.01) compared to placebo in plasma. Sitagliptin dose-dependently inhibited the FAP-activity in vitro. Intact FGF21 was higher in patients obtaining a normal glucose tolerance regardless of treatment (p = 0.03).
CONCLUSION
A sitagliptin-induced increase of intact FGF21 may contribute to an improved metabolic effect in patients with impaired glucose metabolism.
Topics: Dipeptidyl-Peptidase IV Inhibitors; Fibroblast Growth Factors; Glucose; Humans; Sitagliptin Phosphate
PubMed: 35926756
DOI: 10.1016/j.mce.2022.111738 -
Journal of Endocrinological... Jan 2024There are evidences showing that sitagliptin and spironolactone can potentially improve the clinical outcomes of COVID-19 cases. In this observational study on acutely... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
BACKGROUND
There are evidences showing that sitagliptin and spironolactone can potentially improve the clinical outcomes of COVID-19 cases. In this observational study on acutely symptomatic outpatient COVID-19 cases, we investigated the effects of spironolactone and sitagliptin on the outcomes of the disease.
METHODS
This is a prospective, naturally randomized cohort study. We followed mild to moderate symptomatic COVID-19 patients, who were treated with either combination (spironolactone 100 mg daily and sitagliptin 100 mg daily) or standard (steroid, antiviral and/or supportive care) therapy up to 30 days. The primary outcome was hospitalization rate. The secondary outcomes included ER visit, duration of disease, and complications, such as hypoglycemia, low blood pressure or altered mental status.
RESULTS
Of the 206 patients referred to clinics randomly, 103 received standard therapy and 103 treated with combination therapy. There were no significant differences in baseline characteristics, except for slightly higher clinical score in control group (6.92 ± 4.01 control, 4.87 ± 2.92 combination; P < 0.0001). Treatment with combination therapy was associated with lower admission rate (5.8% combination, 22.3% control; P = 0.0011), ER visits (7.8% combination, 23.3% control; P = 0.0021) and average duration of symptoms (6.67 ± 2.30 days combination, 18.71 ± 6.49 days control; P ≤ 0.0001).
CONCLUSIONS
The combination of sitagliptin and spironolactone reduced duration of COVID infection and hospital visits better than standard therapeutic approaches in outpatients with COVID-19. The effects of combination of sitagliptin and spironolactone in COVID-19 patients should be further verified in a double-blind, randomized, placebo-controlled trial.
Topics: Humans; Sitagliptin Phosphate; COVID-19; Spironolactone; Outpatients; Prospective Studies; Cohort Studies; Treatment Outcome; Double-Blind Method
PubMed: 37354247
DOI: 10.1007/s40618-023-02141-0 -
Acta Pharmaceutica (Zagreb, Croatia) Jun 2021Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4...
Recently, an outbreak of a fatal coronavirus, SARS-CoV-2, has emerged from China and is rapidly spreading worldwide. Possible interaction of SARS-CoV-2 with DPP4 peptidase may partly contribute to the viral pathogenesis. An integrative bioinformatics approach starting with mining the biomedical literature for high confidence DPP4-protein/gene associations followed by functional analysis using network analysis and pathway enrichment was adopted. The results indicate that the identified DPP4 networks are highly enriched in viral processes required for viral entry and infection, and as a result, we propose DPP4 as an important putative target for the treatment of COVID-19. Additionally, our protein-chemical interaction networks identified important interactions between DPP4 and sitagliptin. We conclude that sitagliptin may be beneficial for the treatment of COVID-19 disease, either as monotherapy or in combination with other therapies, especially for diabetic patients and patients with pre-existing cardiovascular conditions who are already at higher risk of COVID-19 mortality.
Topics: COVID-19; Cardiovascular Diseases; Computational Biology; Coronavirus Infections; Crystallography, X-Ray; Data Mining; Diabetes Complications; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Delivery Systems; Drug Repositioning; Gene Regulatory Networks; Humans; Molecular Structure; Pandemics; Pneumonia, Viral; Sitagliptin Phosphate
PubMed: 33151168
DOI: 10.2478/acph-2021-0013 -
AAPS PharmSciTech Dec 2019The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels...
The development of oral solid dosage forms, such as tablets that contain a high dose of drug(s), requires polymers and other additives to be incorporated at low levels as possible, to keep the final tablet weight low, and, correspondingly, the dosage form size small enough to be acceptable from a patient perspective. Additionally, a multi-step batch-based manufacturing process is usually required for production of solid dosage forms. This study presents the development and production, by twin-screw melt granulation technology, of a high-dose immediate-release fixed-dose combination (FDC) product of metformin hydrochloride (MET) and sitagliptin phosphate (SIT), with drug loads of 80% w/w and 6% w/w, respectively. For an 850/63 mg dose of MET/SIT, the final weight of the caplets was approximately 1063 mg compared with 1143 mg for the equivalent dose in Janumet®, the marketed product. Mixtures of the two drugs and polymers were melt-granulated at temperatures below the individual melting temperatures of MET and SIT (231.65 and 213.89°C, respectively) but above the glass transition temperature or melting temperature of the binder(s) used. By careful selection of binders, and processing conditions, direct compressed immediate-release caplets with desired product profiles were successfully produced. The melt granule formulations before compression showed good flow properties, were larger in particle size than individual starting API materials and were easily compressible. Melt granulation is a suitable platform for developing direct compressible high-dose immediate-release solid dosage forms of FDC products.
Topics: Chemistry, Pharmaceutical; Drug Combinations; Humans; Metformin; Sitagliptin Phosphate; Transition Temperature
PubMed: 31832799
DOI: 10.1208/s12249-019-1553-2 -
Frontiers in Endocrinology 2022The dipeptidyl peptidase-4 inhibitor (DPP-4i) drugs, such as evogliptin, as the second-line drugs for type 2 diabetes mellitus (T2DM) treatment have been reported to... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
The dipeptidyl peptidase-4 inhibitor (DPP-4i) drugs, such as evogliptin, as the second-line drugs for type 2 diabetes mellitus (T2DM) treatment have been reported to facilitate insulin secretion by reducing glucagon and inhibiting glucagon like peptides. With a vague consensus, the advantageous and non-inferior effects of evogliptin relative to other DPP-4i drugs were recently demonstrated on hemoglobin A1c (HbA1c) levels and overall adverse events in T2DM patients. Thus, the aim was to evaluate the overall influence of evogliptin on HbA1c levels and the adverse events in T2DM patients compared to sitagliptin and linagliptin.
METHODS
Complying with PRISMA guidelines, we conducted a systematic literature search in databases and a meta-analysis. Data about HbA1c levels and the adverse events of T2DM patients were collected and analyzed.
RESULTS
From 1,397 studies, we found five matched studies involving 845 subjects (mean age: 54.7 ± 3 years). The meta-analysis revealed that evogliptin was non-inferior to sitagliptin/linagliptin with a mean difference of 0.062 (95% CI: -0.092 to 0.215. I: 0%. = 0.431) regarding the HbA1c level reduction, and the risk ratio was -0.006 (95% CI: -0.272 to 0.260. I: 1.7%. = 0.966) regarding the adverse effects, indicating no significant difference between evogliptin and linagliptin or sitagliptin in affecting the HbA1c level and adverse effects.
CONCLUSION
The study provides preliminary evidence regarding the similarity in the efficacy of evogliptin compared to other DPP-4i drugs, including sitagliptin and linagliptin, for managing HbA1c levels and adverse events.
Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Linagliptin; Middle Aged; Piperazines; Sitagliptin Phosphate
PubMed: 36060938
DOI: 10.3389/fendo.2022.962385 -
Journal of Biochemical and Molecular... Feb 2021This study was carried out to investigate the potential effects of vitamin B12 and sitagliptin, and their possible synergistic effect with doxorubicin (DOX) on the...
This study was carried out to investigate the potential effects of vitamin B12 and sitagliptin, and their possible synergistic effect with doxorubicin (DOX) on the Ehrlich solid tumor model. B12, sitagliptin, and their combination with DOX were administered to tumor-bearing mice for 21 days. Treatment with B12, sitagliptin, as well as their combinations with DOX caused a significant inhibition of tumor growth and increased the survival time. Malondialdehyde levels and the relative expression of tumor necrosis factor-α and nuclear factor kappa B were significantly decreased, whereas the total antioxidant capacity was significantly increased in all treated groups, except the DOX-treated one, when compared with the positive control group. Moreover, increased apoptosis was also observed by increased cleaved caspase-3 immunostaining and histopathological examination. In conclusion, the antitumor activity of B12 and sitagliptin could be attributed to their ability to induce apoptosis and suppress oxidative stress and inflammation.
Topics: Animals; Carcinoma, Ehrlich Tumor; Female; Inflammation; Mice; NF-kappa B; Oxidative Stress; Sitagliptin Phosphate; Tumor Necrosis Factor-alpha; Vitamin B 12
PubMed: 33016524
DOI: 10.1002/jbt.22645 -
Turkish Journal of Medical Sciences Apr 2021Dipeptidyl peptidase-4 (DPP4) inhibitors, a class of oral antidiabetic drugs, have been shown to be protective on the vascular system because of their antiinflammatory,...
BACKGROUND/AIM
Dipeptidyl peptidase-4 (DPP4) inhibitors, a class of oral antidiabetic drugs, have been shown to be protective on the vascular system because of their antiinflammatory, antiatherosclerotic, and vasodilatory effects. ß2-adrenoceptors (ß2-ARs) mediate the vasorelaxation in the aorta. However, ß3-adrenoceptor-mediated relaxation has not been studied in diabetic aorta yet. Thus, we aimed to study the effect of sitagliptin treatment on ß2- and ß3-adrenoceptor-mediated relaxations in the diabetic rat aorta.
MATERIALS AND METHODS
Eight-week old Sprague Dawley rats were divided into three groups: control, diabetic, sitagliptin treated diabetic. Diabetes was induced by injection of streptozotocin (35 or 40 mg/kg, intraperitoneally). After 10 weeks of diabetes, some of the diabetic rats were treated with sitagliptin (orally, 10mg/kg/day). ß2- and ß3-AR-mediated relaxation responses were evaluated by using isoprenaline and CL 316,243, respectively. ß3-AR-mediated relaxation experiments were repeated in presence of L-NAME. Western blotting and immunohistochemistry were performed to determine the abundance of ß3-adrenoceptor and endothelial nitric oxide synthase (eNOS).
RESULTS
The isoprenaline-mediated relaxation response was impaired in the diabetic group and sitagliptin treatment did not improve it. There was no significant change in CL316,243 mediated-relaxation or protein expression of ß3-ARs among the groups. However, the ratio of phosphorylated eNOS/NOS protein was increased markedly in the sitagliptin treated group, which points the stimulating effect of this drug towards the eNOS pathway.
CONCLUSION
Our results indicate that sitagliptin treatment does not alter ß-AR-mediated relaxation in streptozotocin-diabetic rat aorta; however, it significantly stimulates the eNOS pathway. Future studies are needed to clarify the relationship between the eNOS pathway and DPP-4 inhibition.
Topics: Animals; Aorta; Diabetes Mellitus, Experimental; Endothelium, Vascular; Isoproterenol; Nitric Oxide; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Receptors, Adrenergic, beta-2; Sitagliptin Phosphate; Streptozocin
PubMed: 33185366
DOI: 10.3906/sag-2007-234 -
European Review For Medical and... Nov 2021Diabetes mellitus is a chronic metabolic disease which has an adverse impact on the quality of patient's life, so patients often need to receive treatment for a long... (Clinical Trial)
Clinical Trial Comparative Study
OBJECTIVE
Diabetes mellitus is a chronic metabolic disease which has an adverse impact on the quality of patient's life, so patients often need to receive treatment for a long time. Selection of medications with high therapeutics effects and low cost is very important for patients to take medicine for a longer period of time. Sitagliptin is a drug which is widely used in clinics and can effectively control blood glucose level. This article explores the pharmacoeconomic value of Sitagliptin in the treatment of diabetes mellitus.
PATIENTS AND METHODS
A total of 100 patients with diabetes mellitus treated were recruited in this study. The patients were randomly divided into 4 groups with 25 cases in each group. Patients in group A were treated with pioglitazone, group B with Sitagliptin, group C with metformin and group D with glimepiride. The cost of the drugs, the treatment results and adverse effects were compared.
RESULTS
Compared with group A, C and D, the cost-effectiveness ratio of group B was low (p<0.05), and the therapeutic effect was high (p<0.05). In addition, the incidence of adverse reactions in group B was lower than that in group A, C and D (p<0.05). There was no significant difference in the levels of FPG, 2hPG and HbAlc in patients among the four groups before treatment (p>0.05). After treatment, the levels of FPG, 2hPG and HbAlc in group B were significantly lower than those in groups A, C and D (p<0.05). Finally, there was no significant difference in waist circumference and BMI among the four groups before treatment (p>0.05). After treatment, the waist circumference and BMI in group B were lower than those in groups A, C and D (p<0.05).
CONCLUSIONS
The application of Sitagliptin in the treatment of diabetic patients can effectively enhance the therapeutic effect. The cost effectiveness is satisfactory, and the blood glucose level can be maintained at a stable state.
Topics: Adult; Aged; Aged, 80 and over; Cost-Benefit Analysis; Diabetes Mellitus; Economics, Pharmaceutical; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Pioglitazone; Sitagliptin Phosphate; Sulfonylurea Compounds
PubMed: 34859870
DOI: 10.26355/eurrev_202111_27258 -
International Journal of Cardiology Jan 2023
Topics: Humans; Glucagon-Like Peptides; Sitagliptin Phosphate; Diabetes Mellitus, Type 2; Hypoglycemic Agents
PubMed: 36243180
DOI: 10.1016/j.ijcard.2022.10.017