Efficacy and Safety of Vildagliptin and Remogliflozin as Add-on Therapy to Metformin in Patients of Type 2 Diabetes Mellitus: An open-label comparative study.

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.

Synthesis and Anti-Diabetic Activity of an 8-Purine Derivative as a Novel DPP-4 Inhibitor in Obese Diabetic Zücker Rats.

Type 2 diabetes mellitus (T2DM) is one of the world's principal metabolic diseases characterized by chronic hyperglycemia. The gut incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), which has been proposed as a new treatment for T2DM, are extensively metabolized by Dipeptidyl peptidase 4 (DPP-4). Inhibitors of DPP-4 block the degradation of GLP-1 and GIP and may increase their natural circulating levels, favoring glycemic control in T2DM. A novel and potent selective inhibitor of DPP-4 with an 8-purine derived structure (1) has been developed and tested in vitro and in vivo in Zücker obese diabetic fatty (ZDF) rats, an experimental model of the metabolic syndrome and T2DM to assess the inhibitory activity using vildagliptin as reference standard. ZDF rats were subdivided into three groups (n = 7/group), control (C-ZDF), and those treated with compound 1 (Compound1-ZDF) and with vildagliptin (V-ZDF), both at 10 mg/kg/d rat body weight, in their drinking water for 12 weeks, and a group of lean littermates (ZL) was used. ZDF rats developed DM (fasting hyperglycemia, 425 ± 14.8 mg/dL; chronic hyperglycemia, HbA1c 8.5 ± 0.4%), compared to ZL rats. Compound 1 and vildagliptin reduced sustained HbAl1c (14% and 10.6%, P < 0.05, respectively) and fasting hyperglycemia values (24% and 19%, P < 0.05, respectively) compared to C-ZDF group (P < 0.001). Compound 1 and vildagliptin have shown a potent activity with an IC50 value of 4.92 and 3.21 µM, respectively. These data demonstrate that oral compound 1 administration improves diabetes in ZDF rats by the inhibitory effect on DPP-4, and the potential to be a novel, efficient and tolerable approach for treating diabetes of obesity-related T2DM, in ZDF rats.

Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Acute quadruple extremity compartment syndrome due to angio-oedema after polypharmacy overdose including olmesartan medoxomil, telmisartan and vildagliptin.

This case report describes a rare manifestation of acute compartment syndrome (ACS) involving all four extremities, precipitated by angio-oedema in a middle-aged woman who consumed an overdose of multiple medications: nifedipine, azelnidipine, amlodipine besylate, olmesartan medoxomil, telmisartan, esaxerenone and vildagliptin. She presented with haemodynamic instability, necessitating intubation. Despite stabilising haemodynamic parameters within 24 hours, she manifested escalating extremity oedema. At 52 hours after ingestion, mottled skin was observed, along with necrotic alterations in the swollen hands and compartment pressures exceeding 30 mm Hg in all extremities. ACS was diagnosed, leading to fasciotomies. The aetiology is postulated to be drug-induced angio-oedema, possibly intensified by the concurrent overdose of olmesartan medoxomil, telmisartan and vildagliptin, each of which has a risk of angio-oedema even at standard dosages. This scenario is a very rare case caused by drug-induced angio-oedema, which underscores the importance of vigilant monitoring to detect ACS in patients with progressing limb oedema.

Potential mitigating impact of a dipeptidyl peptidase-IV inhibitor, vildagliptin, on oxazolone-induced ulcerative colitis: Targeting the role of PI3K/AKT/mTOR and AMPK/Nrf2 signaling pathways.

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.

Pharmacotherapeutic advances for chronic myelogenous leukemia: beyond tyrosine kinase inhibitors.

INTRODUCTION: Despite the notable success of tyrosine kinase inhibitors (TKIs) in treating chronic myeloid leukemia (CML), a subset of patients experiences resistance, or relapse after discontinuation. This challenge is attributed to the Ph+ leukemia stem cells (LSCs) pool not fully involved in the inhibition process due to the current therapeutic approach. AREAS COVERED: Current pharmacological advancements in CML therapy focus on targeting LSCs, intervening in self-renewal pathways, and exploiting biological vulnerabilities. Beyond BCR::ABL1 inhibition, innovative approaches include immunotherapy, epigenetic modulation, and interference with microenvironmental mechanisms. EXPERT OPINION: Diverse therapeutic strategies beyond TKIs are under investigation. Immunotherapy with interferon-α (IFN-α) shows some biological effects, although further research is needed for optimal application in enhancing discontinuation rates. Other compounds were able to mobilize Ph+ LSCs from the bone marrow niche (DPP-IV inhibitor vildagliptin or PAI-1 inhibitor TM5614) increasing the LSC clearance or target the CD26, a Ph+ specific surface receptor. It is noteworthy that the majority of these alternative strategies still incorporate TKIs. In conclusion, novel therapeutic perspectives are emerging for CML, holding the potential for substantial advancements in disease treatment.

In situ evaluation of the impact of metformin or verapamil coadministration with vildagliptin on its regional absorption from the rabbit's intestine.

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.

Proteomic changes related to actin cytoskeleton function in the skin of vildagliptin-treated mice.

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.

A novel mechanism of Vildagliptin in regulating bone metabolism and mitigating osteoporosis.

Osteoporosis has become a global social problem with the tendency toward the aging population. The challenge in managing osteoporosis is to develop new anti-osteoporosis drugs that target bone anabolism. The purpose of this study was to uncover the novel mechanism of Vildagliptin on bone metabolism. We revealed that Vildagliptin significantly promoted osteogenic differentiation of precursor osteoblasts and bone marrow mesenchymal stem cells (BMSCs). At the same time, it significantly enhanced the polarization of RAW264.7 macrophages to the M2 type and the secretion of osteogenic factors BMP2 and TGF-ß1. This was confirmed by the increased osteogenic differentiation observed in the osteoblast-RAW264.7 co-culture system. Moreover, Vildagliptin significantly enhanced the transformation of BMSCs into the osteogenic morphology in the osteoblast-BMSC co-culture system. Finally, Vildagliptin also inhibited osteoclastic differentiation of RAW 264.7 cells. The potential mechanism underlying these effects involved targeting the GAS6/AXL/ERK5 pathway. In the in vivo study, Vildagliptin significantly alleviated postmenopausal osteoporosis in ovariectomized mice. These findings represent the first comprehensive revelation of the regulatory effect of Vildagliptin on bone metabolism. Specifically, Vildagliptin demonstrates the ability to promote bone anabolism and inhibit bone resorption by simultaneously targeting osteoblasts, BMSCs, and osteoclasts. The bone-protective effects of Vildagliptin were further confirmed in a postmenopausal osteoporosis model. The clinical significance of this study lies in laying a theoretical foundation for bone protection therapy in type-2 diabetes patients with compromised bone conditions or postmenopausal osteoporosis.

A comparative study on vildagliptin brand and its generic equivalents using dissolution test as quality control measure tool.

Market drugs including brand or generic with poor quality, don't meet the acceptable standard guidelines. Vildagliptin is an important antidiabetic drugs used in monotherapy or in combinations protocols for treatment of diabetes mellites. The main goal of the current study is to assess the pharmaceutical equivalence of two marketed generics of vildagliptin 50 mg tablets compared to the branded product (Galvus 50 mg). The in vitro dissolution test was used as a quality control tool to obtain the dissolution profile of vildagliptin compared to the reference drug. The results revealed that all tested samples showed dissolution behavior like standard drug. Whole samples dissolution reached after 15 min in accordance with the standard. According to the similarity factors records, tested vildagliptin samples showed a comparable dissolution to the reference drug. The current work presents an in vitro protocol for quality evaluation of recently released generic drugs.

Vildagliptin Treatment Ameliorates Renal Interstitial Fibrosis in a Murine Model of Unilateral Ureteral Obstruction.

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.

Usage of vildagliptin among patients with type 2 diabetes mellitus attending a public primary healthcare clinics in Kuala Selangor District, Selangor.

INTRODUCTION: Studies showed that vildagliptin can lower HbA1c levels by 0.8%-1%. However, there is limited data looking at vildagliptin use among suburban populations. The efficacy of vildagliptin use may differ among different populations, especially those with low socio-economic status. Thus, this study aimed to assess the HbA1c reduction after vildagliptin initiation, treatment patterns and the reason for its initiation among patients with type 2 diabetes mellitus attending outpatient clinics in Kuala Selangor District, Selangor. MATERIALS AND METHODS: This is a cross-sectional, retrospective study design. All patients who received vildagliptin in the Pharmacy Integrated Health System (PHIS) registry database from 2016 to 2021 were included as study samples. The exclusion criteria were being less than 18 years old and having type 1 diabetes mellitus. Patients' medical records were retrieved after sampling, and data were collected. One medical record was missing, thus SPSS analysis were performed on 144 vildagliptin users. RESULTS: In total, 84 females (58.3%) and 60 males (41.7%) with a mean age of 62.1 (±10.1) years were analysed in this study. Mean HbA1c pre-therapy was 8.5 ± 2.1%; while posttherapy 6 months demonstrated a mean HbA1c of 7.9 ± 1.8%. Use of vildagliptin alone or as an adjunct was associated with a mean reduction of 0.6% in HbA1c (p = 0.01). Factors influencing this HbA1c reduction were advancing age, specifically individuals aged 62 years and older (p = 0.02), patients who are already receiving insulin therapy (p=0.00) and those who express a willingness to commence insulin treatment during the counselling session prior to initiating the treatment plan (p = 0.00). Reasons for vildagliptin initiation documented by prescribers were non-insulin acceptance (n = 59, 40.97%), frequent hypoglycaemia (n = 6, 4.1%) and non-compliance with medications (n = 23, 15.9%). There was no association between demographic, medical background and reason for starting vildagliptin variables and HbA1c reduction (p < 0.001). CONCLUSION: This study showed that initiating vildagliptin alone or as an adjunct therapy significantly reduced HbA1c and is beneficial for uncontrolled diabetes patients. While advancing age, concurrent administration of insulin and the patients' willingness to accept insulin treatment prior to the commencement of therapy were the factors that influenced HbA1c reduction among patients receiving vildagliptin therapy, we recommend primary care providers prioritise all of the significant variables discovered before initiating vildagliptin for their patients.

Vildagliptin inhibits high fat and fetuin-A mediated DPP-4 expression, intracellular lipid accumulation and improves insulin secretory defects in pancreatic beta cells.

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.

Exploring the potential of neem and tamarind gum as release retardants: Design and statistical optimisation of vildagliptin extended release matrix systems using D-optimal quadratic mixture design.

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.

Simultaneous Chromatographic Estimation of Vildagliptin and Dapagliflozin Using Hybrid Principles of White Analytical Chemistry and Analytical Quality by Design.

BACKGROUND: The fixed-dose combination of vildagliptin (VDG) and dapagliflozin (DGZ) is used in the treatment of type 2 diabetes mellitus. According to the literature survey, RP-HPLC and HPTLC methods have been reported for routine analysis of VDG and DGZ. These chromatographic methods have been developed using potentially neurotoxic and teratogenic solvents, which are unsafe for human and aquatic animal life and hazardous to the environment. These types of organic solvents shall be replaced or reduced during chromatographic analysis of drugs for the safety of human and aquatic animal life and the protection of the environment. The novel white analytical chemistry (WAC) approach has been introduced, which emphasizes robust, green, user-friendly, economical, and rapid analysis of drug samples. OBJECTIVE: Hence, the WAC-based RP-HPLC method has been developed for the estimation of VDG and DGZ using lower toxic and economical solvents. METHOD: The development of the RP-HPLC method includes the implementation of the analytical quality by design approach using principles of design of experiments to reduce organic waste generation and regulatory compliance of analytical method. The central composite design was applied for response surface modeling (RSM) and optimization of the RP-HPLC method. The method validation was carried out according to ICH Q2 (R1) guidelines. RESULTS: The fixed-dose combinations of VDG and DGZ were assayed, and results were found in compliance with their labeled claim. The published and proposed RP-HPLC methods were assessed for chromatographic analysis of VDG and DGZ using the Red-Green-Blue (RGB) model, AGREE calculator, Eco-Scale Assessment tool, GAPI software, and NEMI standards. CONCLUSIONS: The proposed method was found to be robust, green, economical, and user-friendly for chromatographic analysis of VDG and DGZ. The proposed method can be an economical and eco-friendly analytical tool in the pharmaceutical industry for quality control and routine analysis of fixed-dose combinations of VDG and DGZ. HIGHLIGHTS: Hybrid principles of WAC and analytical quality by design to RP-HPLC method for simultaneous estimation of VDG and DGZ in their fixed-dose combinations.

Pharmacokinetics and Food Effect Between a 100-mg Sustained-Release Tablet and a 50-mg Immediate-Release Tablet of Vildagliptin in Healthy Subjects.

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.

Efficacy of Bee Products (Anzer Honey, Pollen and Propolis) in Detection and Healing of Damage Induced by Antidiabetic Drug Vildagliptin/Metformin Hydrochloride in Healthy Human Pancreatic Cells: Cytotoxic, Genotoxic and Biochemical Studies.

BACKGROUND AND OBJECTIVE: Although drugs are powerful therapeutic agents, they have a range of side effects. These side effects are sometimes cellular and not clinically noticeable. Vildagliptin/metformin hydrochloride is one of the most widely used oral antidiabetic drugs with two active ingredients. In this study, we investigated its harmful effects on the metabolic activation system in healthy human pancreatic cells "hTERT-HPNE", and we aimed to improve these harmful effects by natural products. To benefit from the healing effect, we used the unique natural products produced by the bees of the Anzer Plateau in the Eastern Black Sea Region of Turkey. METHODS: Cytotoxic and genotoxic effects of the drug were investigated by different tests, such as MTT, flow cytometry-apoptosis and comet assays. Anzer honey, pollen and propolis were analyzed by gas chromatography/mass spectrometry (G/C-MS). A total of 19 compounds were detected, constituting 99.9% of the samples. RESULTS: The decrease in cell viability at all drug concentrations was statistically significant compared to the negative control (P<0.05). A statistically significant decrease was detected in the apoptosis caused by vildagliptin/metformin hydrochloride with the supplementation of Anzer honey, pollen and propolis in hTERT-HPNE cells (P<0.05). CONCLUSION: This study can contribute to other studies testing the healing properties of natural products against the side effects of oral antidiabetics in human cells. In particular, Anzer honey, pollen and propolis can be used as additional foods to maintain cell viability and improve heal damage and can be evaluated against side effects in other drug studies.

A systematic review on the clinical pharmacokinetics of vildagliptin in healthy and disease populations.

INTRODUCTION: Vildagliptin, a dipeptidyl peptidase-4 inhibitor, is indicated to cure type 2 diabetes mellitus (T2DM). This systematic literature search aims to assess the current knowledge about the clinical pharmacokinetics (PK) of vildagliptin to provide recommendations for clinical use to prevent the harmful effects of this drug. METHODS: The PubMed, Science Direct, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar databases were screened for articles related to the clinical PK of vildagliptin using systematic search strategies. RESULTS: The literature search identified 2118 records, among which 28 were subsumed in this systematic review that fulfilled the inclusion standards. CONCLUSIONS: This systematic review can help dose optimization among critically ill patients (e.g. renal impairment) without exposing them to the drug's toxic effects.

Monitoring for adverse drug events of high-risk medications with a computerized clinical decision support system: a prospective cohort study.

Monitoring is recommended to prevent severe adverse drug events, but such examinations are often missed. To increase the number of monitoring that should be ordered for high-risk medications, we introduced a clinical decision support system (CDSS) that alerts and orders the monitoring for high-risk medications in an outpatient setting. We conducted a 2-year prospective cohort study at a tertiary care teaching hospital before (phase 1) and after (phase 2) the activation of a CDSS. The CDSS automatically provided alerts for liver function tests for vildagliptin, thyroid function tests for immune checkpoint inhibitors (ICIs) and multikinase inhibitors (MKIs), and a slit-lamp examination of the eyes for oral amiodarone when outpatients were prescribed the medications but not examined for a fixed period. The order of laboratory tests automatically appeared if alert was accepted. The alerts were hidden and did not appear on the display before activation of the CDSS. The outcomes were the number of prescriptions with alerts and examinations. During the study period, 330 patients in phase 1 and 307 patients in phase 2 were prescribed vildagliptin, 20 patients in phase 1 and 19 patients in phase 2 were prescribed ICIs or MKIs, and 72 patients in phase 1 and 66 patients in phase 2 were prescribed oral amiodarone. The baseline characteristics were similar between the phases. In patients prescribed vildagliptin, the proportion of alerts decreased significantly (38% vs 27%, P < 0.0001), and the proportion of examinations increased significantly (0.9% vs 4.0%, P < 0.0001) after activation of the CDSS. In patients prescribed ICIs or MKIs, the proportion of alerts decreased significantly (43% vs 11%, P < 0.0001), and the proportion of examinations increased numerically, but not significantly (2.6% vs 7.0%, P = 0.13). In patients prescribed oral amiodarone, the proportion of alerts decreased (86% vs 81%, P = 0.055), and the proportion of examinations increased (2.2% and 3.0%, P = 0.47); neither was significant. The CDSS has potential to increase the monitoring for high-risk medications. Our study also highlighted the limited acceptance rate of monitoring by CDSS. Further studies are needed to explore the generalizability to other medications and the cause of the limited acceptance rates among physicians.

DPP-4i versus SGLT2i as modulators of PHD3/HIF-2α pathway in the diabetic kidney.

RATIONALE: Renal hypoxia is one of the currently highlighted pathophysiologic mechanisms of diabetic nephropathy (DN). Both hypoxia-inducible factor-1α (HIF-1α) and HIF-2α are major regulators of renal adaptive responses to hypoxia. OBJECTIVES: This study aims to compare the effects of vildagliptin (a dipeptidyl peptidase-IV inhibitor, DPP-4i) and empagliflozin (a sodium-glucose cotransporter 2 inhibitor, SGLT2i) on the differential expression of renal HIF-1α/2α. Tissue expression of prolylhydroxylase 3 (PHD3), a key regulator of HIF-2α stability, was also highlighted in a diabetic nephropathy rat model. Type 1 diabetes mellitus was induced and diabetic rats were treated with either Vildagliptin or Empagliflozin (10 mg/kg/d each) for 12 weeks. Improvements in the kidney functional and histopathological parameters were addressed and correlated to changes in the renal expression of HIF-1α/2α, and PHD3. Urinary KIM-1 concentration was tested as a correlate to HIF pathway changes. FINDINGS: Both vildagliptin- and empagliflozin-treated groups exhibited significant improvement in the functional, pathological, and ultra-structural renal changes induced by chronic diabetes. Compared to the untreated group, renal gene expression of HIF-1α was decreased while that of HIF-2α was increased in both treated groups, with significantly greater effects observed with SGLT2i. Renal PHD3 immune-reactivity was also decreased by both drugs, again with better efficacy for the SGLT2i. Importantly, improvements in the diabetic kidney biochemical and structural biomarkers were significantly correlated to PHD3 reductions and HIF-2α increments. CONCLUSIONS: Both DPP-4i and SGLT2i could delay the progression of DN through their differential modulating effects on the PHD3/ HIF-2α pathway with significantly better efficacy for SGLT2i.