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Diabetes mellitus (DM) is a rapidly prevailing disease throughout the world that poses boundless risk factors linked to several health problems. Vildagliptin is the standard dipeptidyl peptidase-4 (DPP-4) inhibitor type of medication that is used for the treatment of diabetes anti-hyperglycemic agent (anti-diabetic drug). The current study aimed to synthesize vildagliptin-loaded ZnO NPs for enhanced efficacy in terms of increased retention time minimizing side effects and increased hypoglycemic effects. Herein, Zinc Oxide (ZnO) nanoparticles (NPs) were constructed by precipitation method then the drug vildagliptin was loaded and drug loading efficiency was estimated by the HPLC method. X-ray diffraction analysis (XRD), UV-vis spectroscopy, FT-IR, scanning electron microscope (SEM), and EDX analysis were performed for the characterization of synthesized vildagliptin-loaded ZnO NPs. The UV-visible spectrum shows a distinct peak at 363 nm which confirms the creation of ZnO NPs and SEM showed mono-dispersed sphere-shaped NPs. EDX analysis shows the presence of desired elements along with the elemental composition. The physio-sorption studies, which used adsorption isotherms to assess adsorption capabilities, found that the Freundlich isotherm model explains the data very well and fits best. The maximum adsorption efficiency of 58.83% was obtained. Further, In vitro, anti-diabetic activity was evaluated by determining the α-amylase and DPP IV inhibition activity of the product formed. The formulation gave maximum inhibition of 82.06% and 94.73% of α-amylase and DPP IV respectively. While at 1000 µg/ml concentration with IC50 values of 24.11 µg/per ml and 42.94 µg/ml. The inhibition of α-amylase can be ascribed to the interactive effect of ZnO NPs and vildagliptin.
Subject(s)
Hypoglycemic Agents , Nanoparticles , Vildagliptin , Zinc Oxide , Vildagliptin/chemistry , Vildagliptin/pharmacology , Zinc Oxide/chemistry , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Nanoparticles/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , X-Ray Diffraction , Drug Carriers/chemistry , Spectroscopy, Fourier Transform Infrared , Nitriles/chemistry , HumansABSTRACT
Physiologically based pharmacokinetic (PBPK) modeling is of great importance in the field of medicine. This study aims to construct a PBPK model, which can provide reliable drug pharmacokinetic (PK) predictions in both healthy and chronic kidney disease (CKD) subjects. To do so, firstly a review of the literature was thoroughly conducted and the PK information of vildagliptin was collected. PBPK modeling software, PK-Sim®, was then used to build and assess the IV, oral, and drug-specific models. Next, the average fold error, visual predictive checks, and predicted/observed ratios were used for the assessment of the robustness of the model for all the essential PK parameters. This evaluation demonstrated that all PK parameters were within an acceptable limit of error, i.e., 2 fold. Also to display the influence of CKD on the total and unbound AUC (the area under the plasma concentration-time curve) and to make modifications in dose, the analysis results of the model on this aspect were further examined. This PBPK model has successfully depicted the variations of PK of vildagliptin in healthy subjects and patients with CKD, which can be useful for medical practitioners in dosage optimization in renal disease patients.
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India has a high prevalence of type 2 diabetes mellitus (T2DM) with unique clinical characteristics compared to other populations. Despite advancements in diabetes therapy, a significant number of patients in India still experience poor glycemic control and complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors continue to be an important component of T2DM treatment due to their favorable efficacy and tolerability profile. Given the current scenario, there is a need to revisit the role of DPP-4 inhibitors in T2DM management in Indian patients. This consensus paper aims to provide guidance on the utilization of DPP-4 inhibitors in T2DM management from an Indian perspective. A consensus group of 100 experts developed recommendations based on an extensive literature review and discussions. The expert group emphasized the importance of timely glycemic control, combination therapy, and targeting the underlying pathophysiology of T2DM. The combinations of DPP-4 inhibitors with metformin and/or sodium-glucose transport protein-2 inhibitors are rationalized in this paper, considering their complementary mechanisms of action. This paper provides valuable insights for clinicians in optimizing the management of T2DM in the Indian population with the use of DPP-4 inhibitors and proposes an algorithm for selecting DPP-4 inhibitor-based therapies.
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Objectives: This study aimed to evaluate the safety and efficacy of remogliflozin compared to vildagliptin as an add-on drug to metformin in type 2 diabetes mellitus (T2DM) treatment. Metformin is considered a first-line drug in T2DM. However, as the disease progresses with heightened insulin resistance and declining ß-cell function, the use of metformin alone is often inadequate to achieve optimum glucose levels. Methods: This prospective, randomised study was conducted at Maulana Azad Medical College and Associated Hospital in New Delhi, India, between February 2020 to January 2021. This study recruited 60 T2DM patients aged 35-70 years with glycated haemoglobin (HbA1c) >6.5% taking metformin at a daily dosage of 1,500-3,000 mg for ≥3 months. Patients were randomly assigned in a 1:1 ratio to receive either vildagliptin (50 mg) or remogliflozin (100 mg) twice daily for 90 days. The primary endpoint was a change in HbA1c levels from baseline to the end of 90 days whereas secondary endpoints were changes in lipid profile and weight. Results: The decrement in mean HbA1c levels was significantly higher in the remogliflozin group than in the vildagliptin group (-8.1% versus -2.4%; P <0.001). In addition, more significant weight loss was found in remogliflozin-treated patients (-5.2% versus -0.6%; P <0.01). Both treatments were well tolerated throughout the study. Conclusion: Compared to vildagliptin, remoglilflozin was significantly more effective in glycaemic control and weight loss in patients with T2DM and can therefore be considered as an add-on drug in T2DM not adequately controlled by metformin monotherapy.
Subject(s)
Diabetes Mellitus, Type 2 , Drug Therapy, Combination , Hypoglycemic Agents , Metformin , Vildagliptin , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/blood , Vildagliptin/pharmacology , Vildagliptin/therapeutic use , Metformin/therapeutic use , Metformin/pharmacology , Middle Aged , Male , Female , Hypoglycemic Agents/therapeutic use , Hypoglycemic Agents/pharmacology , Prospective Studies , Aged , Adult , Drug Therapy, Combination/methods , India , Glycated Hemoglobin/analysis , Glycated Hemoglobin/drug effects , Glucosides/therapeutic use , Glucosides/pharmacology , Treatment Outcome , Blood Glucose/analysis , Blood Glucose/drug effects , Sorbitol/analogs & derivatives , Sorbitol/therapeutic use , Sorbitol/pharmacology , Sorbitol/adverse effects , Sorbitol/administration & dosage , PyrazolesABSTRACT
OBJECTIVE: The present work represents a reverse-phase high-performance liquid chromatography method in addition to stability studies for sequential estimation of remogliflozin etabonate, vildagliptin, and metformin HCl in tablet formulation. METHOD: The mentioned method utilizes a Phenomenex Luna C18 column (250×4.6mm, 5µm). It consists of a column oven's temperature of 35°C. Mobile phase includes a mixture of 50% phosphate buffer (pH - 6.8) and 50% acetonitrile along with a flow rate of 0.8mL/min and 20minutes of run time. The injection volume was 20µL; 217nm is a detection wavelength, and a PDA detector is used for detection. RESULTS: The suggested technique was proven and validated per the ICH Q2 (R1) guideline. The combination was put under stress conditions that included acid, base, thermal, photolytic, and oxidative degradation. The combination was considerably degraded under oxidative, acidic, and basic circumstances for deterioration, and the degradation results were accurately identified from the observed peaks, demonstrating the method's effectiveness in detecting stability. CONCLUSION: The technique was quick, precise, sensitive, and accurate; as a result, it may be used in quality control laboratories and the pharmaceutical industry for routine quality monitoring of tablets containing all three medications.
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INTRODUCTION: Experimental hepatopulmonary syndrome (HPS) is best reproduced in the rat common bile duct ligation (CBDL) model. Vildagliptin (Vild) is an anti-hyperglycemic drug that exerts beneficial anti-inflammatory, anti-oxidant and anti-fibrotic effects. Therefore, the present search aimed to explore the possible effectiveness of Vild in CBDL-induced HPS model. METHODS: Four groups of male Wistar rats which weigh 220-270 g were used, including the normal control group, the sham control group, the CBDL group and CBDL+Vild group. The first three groups received i.p. saline, while the last group was treated with i.p. Vild (10 mg/kg/day) from the 15th to 28th day of the experiment. RESULTS: CBDL decreased the survivability and body weight of rats, increased diameter of the pulmonary vessels, and altered the arterial blood gases and the liver function parameters. Additionally, it increased the pulmonary expressions of endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) mRNA as well as endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) proteins. The CBDL rats also exhibited elevation of the pulmonary interleukin-6 (IL-6), dipeptidyl peptidase-4 (DPP-4) and nitric oxide (NO) levels along with reduction of the pulmonary total anti-oxidant capacity and glucagon-like peptide-1 (GLP-1) levels. Vild mitigated these alterations and improved the histopathological abnormalities caused by CBDL. CONCLUSION: Vild effectively attenuated CBDL-induced HPS through its anti-oxidant and anti-inflammatory effects along with its modulatory effects on ET-1/NOS/NO and TNF-α/IL-6/VEGF-A signaling implicated in the regulation of intrapulmonary vasodilatation and angiogenesis, respectively.
Subject(s)
Common Bile Duct , Hepatopulmonary Syndrome , Rats, Wistar , Vasodilation , Vildagliptin , Animals , Hepatopulmonary Syndrome/drug therapy , Vildagliptin/pharmacology , Male , Ligation , Common Bile Duct/surgery , Rats , Vasodilation/drug effects , Disease Models, Animal , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Vascular Endothelial Growth Factor A/metabolism , Lung/blood supply , Lung/drug effects , Neovascularization, Pathologic/drug therapy , Adamantane/analogs & derivatives , Adamantane/pharmacology , Adamantane/therapeutic use , AngiogenesisABSTRACT
BACKGROUND/AIM: Vildagliptin is one of the dipeptidyl peptidase-4 (DPP-4) inhibitors that have been shown to improve hyperglycemia in clinical trials among patients with type 2 diabetes. However, few studies have examined the efficacy of vildagliptin in patients with diabetic kidney disease (DKD). PATIENTS AND METHODS: Eight patients with DKD received oral vildagliptin 50-100 mg/day. The duration of diabetes was 6.7±5.9 years and observation period was 23.6±9.8 months. Changes in fasting blood glucose, and hemoglobin A1c (HbA1c), estimated glomerular filtration rate (eGFR), and urine protein-to-creatinine ratio (UPCR) were studied before and after the administration of vildagliptin. RESULTS: Vildagliptin treatment significantly decreased fasting blood glucose and HbA1c, compared to baseline (132±56 mg/dl, p=0.036, 6.0±0.3, p=0.041, respectively). UPCR tended to be decreased, albeit without statistical significance. However, eGFR was decreased after the administration of vildagliptin. No significant adverse effects were observed in all patients during the study. CONCLUSION: Although the sample size was limited and the observation period was brief, vildagliptin was found to be an effective and reasonably well-tolerated treatment for patients with DKD.
Subject(s)
Adamantane , Blood Glucose , Diabetes Mellitus, Type 2 , Diabetic Nephropathies , Dipeptidyl-Peptidase IV Inhibitors , Glomerular Filtration Rate , Glycated Hemoglobin , Nitriles , Pyrrolidines , Vildagliptin , Humans , Vildagliptin/therapeutic use , Vildagliptin/adverse effects , Vildagliptin/administration & dosage , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Male , Female , Diabetic Nephropathies/drug therapy , Middle Aged , Aged , Glomerular Filtration Rate/drug effects , Blood Glucose/drug effects , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Dipeptidyl-Peptidase IV Inhibitors/adverse effects , Glycated Hemoglobin/metabolism , Glycated Hemoglobin/analysis , Adamantane/analogs & derivatives , Adamantane/therapeutic use , Adamantane/adverse effects , Treatment Outcome , Pyrrolidines/therapeutic use , Pyrrolidines/adverse effects , Pyrrolidines/administration & dosage , Nitriles/therapeutic use , Nitriles/adverse effects , Nitriles/administration & dosage , Creatinine/bloodABSTRACT
Background Type 2 diabetes mellitus (T2DM) patients commonly undergo metformin monotherapy. This study aims to compare the efficacy, safety, and tolerability of combination therapy of dapagliflozin plus linagliptin versus dapagliflozin plus vildagliptin as add-on therapy in T2DM patients inadequately controlled on metformin. Methodology This was an 18-week, multicenter, randomized, double-blind, active-controlled, parallel-group, phase III clinical study. About 236 participants were randomly assigned to receive either a fixed-dose combination of dapagliflozin 10 mg plus linagliptin 5 mg tablets or a fixed-dose combination of dapagliflozin 10 mg plus vildagliptin SR 100 mg tablets added to metformin monotherapy. The primary outcome was the mean change in hemoglobin A1c (HbA1c) from baseline to the end of week 16. The key secondary endpoints were mean change in postprandial blood glucose (PPBG), fasting blood glucose (FBG), body weight, and the proportion of participants achieving HbA1c less than 7.0%. Results The dapagliflozin/linagliptin combination therapy showed a more significant change in HbA1c from baseline to the end of 16 weeks (mean reduction: -1.59% vs. -1.25%) compared to dapagliflozin/vildagliptin (p < 0.0001). Additionally, compared to the dapagliflozin/vildagliptin group, the dapagliflozin/linagliptin group demonstrated a significant reduction in both PPBG (mean reduction: -59.99 mg/dL vs. -55.34 mg/dL) and FPG (mean reduction: -32.91 mg/dL vs. -26.78 mg/dL). A total of 18 adverse events were reported in 17 (7.20%) participants, all of which were mild and resolved completely. There were no serious adverse events. Conclusions Compared to dapagliflozin and vildagliptin combination therapy, dapagliflozin and linagliptin fixed-dose combination provided clinically significant improvements in glycemic control. Because of its effectiveness, safety, and tolerability, the fixed-dose combination of dapagliflozin and linagliptin was a better option for treating T2DM patients who had previously only received metformin monotherapy.
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Growing evidence suggests that phosphoinositide 3-kinase (PI3K) and adenosine monophosphate-activated protein kinase (AMPK) signaling cascades are critical in ulcerative colitis (UC) pathophysiology by influencing gut mucosal inflammation. Recently, the coloprotective properties of dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged. Thus, this study assessed for the first time the potential mitigating impact of a DPP-IV inhibitor, vildagliptin (Vilda), on oxazolone (OXZ)-induced colitis in rats, targeting the role of PI3K/AKT/mTOR and AMPK/Nrf2 pathways. Thirty-two adult Albino rats were divided into four groups: control, Vilda (10 mg/kg/day orally), OXZ (300 µL of 5 % OXZ in 50 % aqueous ethanol solution introduced once into the colon via catheter), and Vilda+OXZ. Inflammatory cytokines (interleukin 13, tumor necrosis factor-α, interleukin 10), oxidative/endoplasmic reticulum stress markers (myeloperoxidase, reduced glutathione, catalase, CHOP), mitochondrial reactive oxygen species, adenosine triphosphate levels, and mitochondrial transmembrane potential were estimated. p-AMPK, p-AKT, beclin-1, and SQSTM1 levels were immunoassayed. Nrf2, PI3K, and mTOR expression levels were quantified using the real-time polymerase chain reaction. Furthermore, p-NF-ĸBp65 and LC3II immunoreactivity were evaluated. Vilda administration effectively ameliorated OXZ-induced colitis, as evidenced by the reduced Disease Activity Index, macroscopic colon damage score, colon weight/length ratio, ulcer index, and histopathological and electron microscopic changes in the colon tissues. Vilda treatment also counteracted OXZ-triggered inflammation, oxidative/endoplasmic reticulum stress, mitochondrial dysfunction, and enhanced autophagy in the colon. Vilda substantially suppressed PI3K/AKT/mTOR and activated the AMPK/Nrf2 pathway. Vilda has potent coloprotective and anti-ulcerogenic properties, primarily attributed to its antiinflammatory, antioxidant, and modulatory impact on mitochondrial dysfunction and autophagy activity. These effects were mostly mediated by suppressing PI3K/AKT/mTOR and activating AMPK/Nrf2 signaling cascades, suggesting a potential role of Vilda in UC therapy.
Subject(s)
Colitis, Ulcerative , Oxazolone , Signal Transduction , Vildagliptin , Animals , Male , Rats , AMP-Activated Protein Kinases/metabolism , Anti-Inflammatory Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/drug therapy , Colitis, Ulcerative/pathology , Colon/pathology , Colon/drug effects , Cytokines/metabolism , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/therapeutic use , Disease Models, Animal , NF-E2-Related Factor 2/metabolism , Oxidative Stress/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/metabolism , Vildagliptin/pharmacology , Vildagliptin/therapeutic useABSTRACT
Drug-induced bullous pemphigoid (DBP) may present identical to an idiopathic type of illness. Thus, DBP should be considered as a differential diagnosis when evaluating the cause of bullous pemphigoid (BP) in elderly individuals with diabetes. We present the case of a 65-year-old "young-elderly" female who developed bullous lesions after initiation of medication. This case report casts light on a commonly prescribed antidiabetic drug, a dipeptidyl peptidase-4 inhibitor, vildagliptin, and its unforeseen complication in the elderly. The long-term complication is BP. With long-term use, there is an increased likelihood of encountering such cases among the elderly. Thus, we recommend that DBP be considered an important early differential diagnosis among elderly diabetics presenting with initial signs and symptoms of BP.
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BACKGROUND: Vildagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i) is a widely used type 2 diabetes medication that is associated with an up-to 10-fold increased risk for the development of bullous pemphigoid (BP), an autoimmune skin disease. The mechanism by which vildagliptin promotes the development of BP remains unknown. OBJECTIVE: To elucidate effects of vildagliptin treatment on the mouse cutaneous proteome. METHODS: We analyzed the cutaneous proteome of nondiabetic mice treated for 12 weeks with vildagliptin using label-free shotgun mass spectrometry (MS), two-dimensional difference gel electrophoresis (2D-DIGE), immunohistochemistry, immunoblotting, and quantitative real-time polymerase chain reaction. RESULTS: Although vildagliptin treatment did not cause any clinical signs or histological changes in the skin, separate MS and 2D-DIGE analyses revealed altered cutaneous expression of several proteins, many of which were related to actin cytoskeleton remodeling. Altogether 18 proteins were increased and 40 were decreased in the vildagliptin-treated mouse skin. Both methods revealed increased levels of beta-actin and C->U-editing enzyme APOBEC2 in vildagliptin-treated mice. However, elevated levels of a specific moesin variant in vildagliptin-treated animals were only detected with 2D-DIGE. Immunohistochemical staining showed altered cutaneous expression of DPP-4, moesin, and galectin-1. The changed proteins detected by MS and 2D-DIGE were linked to actin cytoskeleton remodeling, transport, cell movement and organelle assembly. CONCLUSION: Vildagliptin treatment alters the cutaneous proteome of nondiabetic mice even without clinical signs in the skin. Cytoskeletal changes in the presence of other triggering factors may provoke a break of immune tolerance and further promote the development of BP.
Subject(s)
Diabetes Mellitus, Type 2 , Pemphigoid, Bullous , Mice , Animals , Vildagliptin/adverse effects , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Proteome , Proteomics , Pemphigoid, Bullous/chemically induced , Actin CytoskeletonABSTRACT
This research aims to identify regional differences in vildagliptin absorption across the intestinal membrane. Furthermore, it was to investigate the effect of verapamil or metformin on vildagliptin absorptive clearance. The study utilized an in situ rabbit intestinal perfusion technique to determine vildagliptin oral absorption from duodenum, jejunum, ileum, and ascending colon. This was conducted both with and without perfusion of metformin or verapamil. The findings revealed that the vildagliptin absorptive clearance per unit length varied by site and was in the order as follows: ileum < jejunum < duodenum < ascending colon, implying that P-gp is significant in the reduction of vildagliptin absorption. Also, the arrangement cannot reverse intestinal P-gp, but the observations suggest that P-gp is significant in reducing vildagliptin absorption. Verapamil co-perfusion significantly increased the vildagliptin absorptive clearance by 2.4 and 3.2 fold through the jejunum and ileum, respectively. Metformin co-administration showed a non-significant decrease in vildagliptin absorptive clearance through all tested segments. Vildagliptin absorption was site-dependent and may be related to the intestinal P-glycoprotein content. This may aid in understanding the important elements that influence vildagliptin absorption, besides drug-drug interactions that can occur in type 2 diabetic patients taking vildagliptin in conjunction with other drugs that can modify the P-glycoprotein level.
Subject(s)
Metformin , Animals , Humans , Rabbits , Vildagliptin/pharmacology , Metformin/pharmacology , Verapamil/pharmacology , Intestinal Absorption , Intestines , ATP Binding Cassette Transporter, Subfamily BABSTRACT
Vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor is effective in reducing HbA1c levels in patients with type 2 diabetes (T2DM) when administered as monotherapy, dual or triple combination therapy. In India, Vildagliptin is commonly prescribed in T2DM patients because it reduces mean amplitude of glycemic excursion (MAGE), has lower risk of hypoglycemia and is weight neutral. Early combination therapy with vildagliptin and metformin is effective and well-tolerated in patients with T2DM, regardless of age or ethnicity. In view of already existing data on vildagliptin and the latest emerging clinical evidence, a group of endocrinologists, diabetologists and cardiologists convened for an expert group meeting to discuss the role and various combinations of vildagliptin in T2DM management. This practical document aims to guide Physicians and Specialists regarding the different available strengths and formulations of vildagliptin for the initiation and intensification of T2DM therapy.
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Diabetes mellitus (DM) is the most prevalent cause of diabetic retinopathy (DRP). DRP has been recognized for a long time as a microvascular disease. Many drugs were used to treat DRP, including vildagliptin (VLD). In addition to its hypoglycemic effect, VLD minimizes ocular inflammation and improves retinal blood flow for individuals with type 2 diabetes mellitus. Nevertheless, VLD can cause upper respiratory tract infections, diarrhea, nausea, hypoglycemia, and poor tolerability when taken orally regularly due to its high water solubility and permeability. Effective ocular administration of VLD is achieved using solid lipid nanoparticles (SLNPs), which improve corneal absorption, prolonged retention, and extended drug release. Ocuserts (OCUs) are sterile, long-acting ocular dosage forms that diminish the need for frequent dosing while improving residence time and stability. Therefore, this study intends to develop VLD solid lipid nanoparticle OCUs (VLD-SLNPs-OCUs) to circumvent the issues commonly associated with VLD. SLNPs were prepared using the double-emulsion/melt dispersion technique. The optimal formula has been implemented in OCUs. Optimization and development of VLD-SLNPs-OCUs were performed using a Box-Behnken Design (BBD). VLD-SLNPs-OCUs loading efficiency was 95.28 ± 2.87%, and differential scanning calorimetry data (DSC) showed the full transformation of VLD to an amorphous state and the excellent distribution in the prepared OCUs matrices. The in vivo release of VLD from the optimized OCUs after 24 h was 35.12 ± 2.47%, consistent with in vitro drug release data of 36.89 ± 3.11. The optimized OCUs are safe to use in the eye, as shown by the ocular irritation test. VLD-SLNPs-OCUs provide extended VLD release, an advantageous alternative to conventional oral dose forms, resulting in fewer systemic adverse effects and less variation in plasma drug levels. VLD-SLNPs-OCUs might benefit retinal microvascular blood flow beyond blood glucose control and may be considered a promising approach to treating diabetic retinopathy.
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A liver injury was recently reported for saxagliptin, which is a dipeptidyl peptidase-4 (DPP-4) inhibitor. However, the underlying mechanisms of saxagliptin-induced liver injury remain unknown. This study aimed to evaluate whether saxagliptin, a potent and selective DPP-4 inhibitor that is globally used for treating type 2 diabetes mellitus, binds to the nucleophiles in vitro. Four DPP-4 inhibitors, including vildagliptin, were evaluated for comparison. Only saxagliptin and vildagliptin, which both contain a cyanopyrrolidine group, quickly reacted with L-cysteine to enzyme-independently produce thiazolinic acid metabolites. This saxagliptin-cysteine adduct was also found in saxagliptin-administered male Sprague-Dawley rats. In addition, this study newly identified cysteinyl glycine conjugates of saxagliptin and 5-hydroxysaxagliptin. The observed metabolic pathways were hydroxylation and conjugation with cysteine, glutathione, sulfate, and glucuronide. In summary, we determined four new thiazoline-containing thiol metabolites (cysteine and cysteinylglycine conjugates of saxagliptin and 5-hydroxysaxagliptin) in saxagliptin-administered male rats. Our results reveal that saxagliptin can covalently bind to the thiol groups of cysteine residues of endogenous proteins in vivo, indicating the potential for saxagliptin to cause drug-induced liver injury.
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DPP-4 inhibitors are frequently used as first-line agents for the treatment of type 2 diabetes in Japan. This study aimed to examine the effects of vildagliptin on glucose metabolism and arterial stiffness. Twenty treatment-naïve patients with type 2 diabetes (8 males and 12 females) received vildagliptin 50 mg twice daily for 6 months. Self-monitored blood glucose measurements and a 75 g OGTT were performed. Arterial stiffness was assessed using the CAVI. After the vildagliptin treatment, a significant decrease in the median HbA1c (from 8.3 to 6.4%) and fasting HOMA-ß (from 26.1 to 34.5%), and a marginally significant decrease in the CAVI (from 8.9 to 8.4, p = 0.087) were observed. The glycemic variability parameters also improved, whereas the insulin sensitivity and oxidative stress remained unchanged. Participants with a lower glycemic variability on the 75 g OGTT after vildagliptin treatment showed a significant decrease in their CAVI. The baseline BMI was significantly higher for the participants with a decreased CAVI than in those with no change in their CAVI (24.5 vs. 20.8 kg/m2). After vildagliptin treatment, a decrease in the CAVI was observed, especially in the individuals with improved glycemic variability on the 75 g OGTT. Vildagliptin may be suitable for vascular protection in individuals with high glycemic variability and/or an elevated BMI.
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Renal interstitial fibrosis in mice can be modeled using unilateral ureteral obstruction (UUO). Here, we investigated the anti-fibrotic effects of the dipeptidyl peptidase-4 inhibitor vildagliptin in this model. We found that vildagliptin given in the drinking water at 10.6 ± 1.5 mg/kg/d prevented fibrosis. Mechanistically, UUO was associated with extracellular signal-regulated kinase (ERK) phosphorylation and with the accumulation of the toxic lipid peroxidation product expression of 4-hydroxy-2-nonenal (4-HNE). Both were significantly inhibited by vildagliptin. Similarly, UUO caused reductions in heme oxygenase-1 (HO-1) mRNA in the kidney, whereas interleukin-6 (IL-6) and cyclooxygenase-1 (COX-1) mRNA were increased; these effects were also prevented by vildagliptin. Taking these data together, we propose that vildagliptin reduces renal interstitial fibrosis resulting from UUO by means of its effects on ERK phosphorylation and the amounts of 4-HNE, HO-1, IL-6 and COX-1 in the kidney.
Subject(s)
Kidney Diseases , Ureteral Obstruction , Mice , Animals , Ureteral Obstruction/complications , Ureteral Obstruction/drug therapy , Vildagliptin/pharmacology , Vildagliptin/therapeutic use , Vildagliptin/metabolism , Disease Models, Animal , Interleukin-6/metabolism , Kidney Diseases/drug therapy , Kidney Diseases/etiology , Kidney , Extracellular Signal-Regulated MAP Kinases/metabolism , Fibrosis , RNA, Messenger/metabolismABSTRACT
Dipeptidyl peptidase-4 (DPP-4), a ubiquitous proteolytic enzyme, inhibits insulin secretion from pancreatic beta cells by inactivating circulating incretin hormones GLP-1 and GIP. High circulating levels of DPP-4 is presumed to compromise insulin secretion in people with type 2 diabetes (T2D). Our group recently reported lipid induced DPP-4 expression in pancreatic beta cells, mediated by the TLR4-NFkB pathway. In the present study, we looked at the role of Vildagliptin on pancreatic DPP-4 inhibition, preservation of islet mass and restoration of insulin secretion. MIN6 mouse insulinoma cells incubated with palmitate and fetuin-A, a proinflammatory organokine associated with insulin resistance, showed activation of TLR4-NFkB pathway, which was rescued on Vildagliptin treatment. In addition, Vildagliptin, by suppressing palmitate-fetuin-A mediated DPP-4 expression in MIN6, prevented the secretion of IL-1beta and fetuin-A in the culture media. DPP-4 siRNA abrogated TLR4-NFkB pathway mediated islet cell inflammation. Vildagliptin also reduced palmitate-fetuin-A mediated intracellular lipid accumulation in MIN6 and isolated islets from high fat fed (HFD) mice as observed by Oil O Red staining with downregulation of CD36 and PPARgamma. Vildagliptin also preserved islet mass and rescued insulin secretory defect in HFD mice. Our results suggest that inhibition of DPP-4 by Vildagliptin protects pancreatic beta cells from the deleterious effects of lipid and fetuin-A, preserves insulin secretory functions and improves hyperglycemia.
Subject(s)
Diabetes Mellitus, Type 2 , Insulin-Secreting Cells , Humans , Mice , Animals , Vildagliptin/pharmacology , Vildagliptin/metabolism , Insulin-Secreting Cells/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , alpha-2-HS-Glycoprotein/metabolism , Toll-Like Receptor 4/metabolism , Insulin/metabolism , Palmitates/pharmacologyABSTRACT
Exploring the significant role of natural polymers in developing drug delivery systems has been a promising area of research interest. The current investigation uses a D-optimal quadratic mixture design to design and evaluate neem and tamarind gum-based vildagliptin extended-release matrix tablets. Studying the combination effect of gums is one of the major objectives. Initial screening studies were performed to select the factors and their levels. The variables selected at different levels in mg/tablet are neem gum, tamarind gum, polyvinylpyrrolidone, and lactose monohydrate. Based on the screening experiments with both gums, the polymer content of 165 mg was chosen as the highest level in the DOE. Nineteen runs were generated to screen the desired parameters as responses. The total weight of the formulation was kept constant at 275 mg. Time (hours) required for 50 %, 90 % and 100 % of drug release and tablet hardness were selected as the responses for each run. The wet granulation method was adopted, and the critical variables were optimised using the design of experiments following Design Expert software. Statistical analysis was conducted, and the optimised formulations were prepared and evaluated to compare with the predicted responses. Stability studies were performed for the optimised batches. Results indicated that the prepared batches met the compendial limits and confirmed the application of neem and tamarind gum in the development of extended-release tablets of vildagliptin for 24 h. An optimised formulation comprising of 16.52 mg of neem gum and 148.48 mg of tamarind gum with a hardness of 7.5-8.5 kp produced 50 %, 90 % and 100 % drug release in 12, 22 and 25 h.
Subject(s)
Tamarindus , Delayed-Action Preparations , Vildagliptin , Plant Gums , TabletsABSTRACT
Vildagliptin is one of the dipeptidyl peptidase-4 inhibitors. This study aimed to compare vildagliptin exposure between 50-mg immediate-release (IR) and 100-mg new sustained-release (SR) tablets, and evaluate the food effect on the pharmacokinetics (PKs) of vildagliptin. A randomized, open-label, 3-period, 3-treatment, 6-sequence crossover study was conducted on healthy subjects. During each period, subjects received the SR tablet either in the fasted (T1) or high-fat fed (T2) state once a day, or IR tablets administered twice a day in the fasted state (R). Blood samples for PK analysis were obtained serially up to 24 hours after dosing. Thirty-four subjects completed the study. The geometric mean ratios for the Cmax and AUC0-24h of T1 to R were 1.15 and 0.89, respectively. The corresponding values of T2 to T1 were 0.94 and 1.07, respectively. Vildagliptin exposure over 24 hours was similar between the SR and IR tablets. In addition, the PK profiles of the SR tablets were not altered by food. The SR tablets can be administered without a food effect and be an alternative option to IR tablets.