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Aims Materials and Methods Results Conclusions To evaluate the efficacy and safety of add‐on dapagliflozin in patients with type 2 diabetes mellitus (T2D) who had inadequate glycaemic control with metformin and linagliptin.A total of 235 patients with inadequate response to metformin (≥1000 mg/day) plus linagliptin (5 mg/day) were randomized to receive either dapagliflozin/linagliptin fixed‐dose combination (FDC [AJU‐A51]) 10/5 mg/day (n = 117) or linagliptin 5 mg plus placebo (n = 118) for 24 weeks. After the main treatment period, patients who received linagliptin plus placebo were treated with AJU‐A51 for an additional 28 weeks. Change in glycated haemoglobin (HbA1c) from baseline to Week 24 was the primary endpoint.AJU‐A51 significantly reduced HbA1c levels (from 7.93% ± 0.82% to 7.11% ± 0.61%) compared with linagliptin plus placebo (from 7.80% ± 0.71% to 7.87% ± 0.94%), with a least squares mean difference of −0.88% (95% confidence interval −1.07 to −0.68; p < 0.0001) at 24 weeks. The AJU‐A51 group had a significantly higher proportion of patients who achieved HbA1c <7.0% at Week 24 than the control group (44.8% vs. 18.6%; p < 0.001). The AJU‐A51 group maintained glycaemic efficacy up to 52 weeks, whereas the control group showed a substantial reduction in HbA1c after switching to AJU‐A51 in the extension study period. Both groups had similar incidence of treatment‐emergent and serious adverse events, and no cases of symptomatic hypoglycaemia were reported.Dapagliflozin and linagliptin FDC (AJU‐A51) showed potent glucose‐lowering effects, with good tolerability, in patients with T2D who had poor glycaemic control on metformin and linagliptin (ClinicalTrials.gov [NCT06329674]). [ABSTRACT FROM AUTHOR]

Objectives: Uncertainties remain regarding the effect of elevated glucose levels on lymphatic metastasis of cancer cells. Our study elucidated the mechanisms linking high glucose to lymphangiogenesis and lymphatic barrier‐related factors and investigated the protective role of linagliptin against lymphatic barrier dysfunction. Materials and Methods: A CAL‐27‐LEC co‐culture system was established. Sodium fluorescein permeability assay observed lymphatic endothelial cell permeability. Western blotting and RT‐qPCR detected protein and mRNA expression under different conditions, respectively. CCK‐8, scratch wound healing, and transwell assays revealed cell migration and proliferation. Tube formation experiment tested capacity for endothelial tube formation. Immunohistochemical staining analyzed tissue sections from 43 oral cancer individuals with/without diabetes. Results: In high‐glucose co‐culture system, we observed increased lymphatic barrier permeability and decreased expression of ZO‐1 and occludin, two tight‐junction proteins; conversely, the expression of PAR2, a high permeability‐related protein, was increased. Following linagliptin treatment, the expression levels of VEGF‐C, VEGFR‐3, and PAR2 decreased, while those of ZO‐1 and occludin increased. Considerably higher levels of LYVE‐1 expression in individuals with diabetes than in those without diabetes. Conclusions: By ameliorating the high glucose‐induced disruption of the lymphatic endothelial barrier, linagliptin may reduce lymphangiogenesis and exhibit an inhibitory effect on lymphatic metastasis in oral cancer patients with diabetes. [ABSTRACT FROM AUTHOR]

This research paper presents an electroanalytical investigation utilizing voltammetry to quantify the antidiabetic drug linagliptin with an unmodified boron-doped diamond electrode. Using cyclic voltammetry, linagliptin exhibited a single, distinct, irreversible oxidation peak at around + 1.03 V (vs. Ag/AgCl) in a 0.1 mol dm−3 phosphate buffer solution at pH 7.4. The square-wave voltammetry technique achieved acceptable linearity at approximately + 0.94 V in PBS (pH 7.4). The methodology demonstrated linearity within the concentration range of 1.0 and 50.0 μg cm−3 (equivalent to 2.1 × 10–6–1.1 × 10–4 mol dm−3) and yielded a limit of detection of 0.28 μg cm−3 (equivalent to 5.9 × 10–7 mol dm−3). The investigation of the proposed method's applicability was ultimately conducted through the sensing of linagliptin in drug formulations. The established methodologies can serve as viable alternatives to other analytical techniques due to their cost-effectiveness, user-friendliness, efficiency, and ability to yield reliable and repeatable results. [ABSTRACT FROM AUTHOR]

Dipeptidyl-peptidase 4 (DPP-4) inhibitors are one of the most commonly used anti-diabetic drugs because of their established safety and efficacy. Bullous pemphigoid which is an autoimmune blister skin disorder associated with DPP-4 inhibitors is a recognized adverse drug reaction (ADR) reported in some Southeast Asian Nations but has not been reported earlier from India. It is an uncommon, serious treatment with emergent adverse effects. Here, we report a series of five cases of DPP-4 inhibitor Linagliptin-induced bullous pemphigoid reaction in Type 2 diabetes mellitus patients. We are reporting five cases that showed various clinical manifestations in terms of gender (males 4), duration of diabetes (average 7.2 years), glycemic control (average HbA1C 6.7%), and latency period (average 3.6 weeks) for development of the ADR. Quality of life and treatment satisfaction were severely impacted by this ADR. Withdrawal of Linagliptin, use of topical and oral steroids and immunosuppressant like azathioprine were prescribed and effective for improving the lesions of all the cases. As per the World Health Organization-Uppsala Monitoring Center scale, causality was established as "probable" for all the cases. This case series serves to bring to the notice of prescribers regarding this important cutaneous ADR with the use of Linagliptin. This case intends to improve awareness among clinicians regarding the possibility of this cutaneous ADR among diabetic patients to facilitate early diagnosis and intervention. [ABSTRACT FROM AUTHOR]

Aim: We evaluated the efficacy and safety of cofrogliptin, a novel dipeptidyl peptidase‐4 inhibitor taken once every 2 weeks (Q2W), compared with linagliptin (taken daily) in patients with type 2 diabetes inadequately controlled on metformin in China. Materials and Methods: In this phase 3 randomized, double‐blind, active‐controlled, multicentre study, patients were randomly assigned 1:1:1 to receive cofrogliptin 10 mg Q2W, cofrogliptin 25 mg Q2W, or linagliptin 5 mg daily, all as an add‐on treatment to metformin, for 24 weeks. Eligible patients could enter an open‐label extension period and receive cofrogliptin 25 mg Q2W for an additional 28 weeks. The primary endpoint was change in glycated haemoglobin from baseline to 24 weeks, with a non‐inferiority margin of 0.4% for cofrogliptin versus linagliptin treatment. Results: Overall, 465 patients entered the 24‐week treatment period (median age: 57.0 years). The least‐squares mean (standard error) change in glycated haemoglobin from baseline to week 24 was −0.96 (0.063), −0.99 (0.064) and −1.07 (0.065) for the cofrogliptin 10 mg, cofrogliptin 25 mg and linagliptin 5 mg groups, respectively. The between‐group difference met the predefined margin for non‐inferiority of cofrogliptin (10 and 25 mg) versus linagliptin treatment. The incidence of common adverse events (≥5% patients) during the 24‐week treatment period was similar between treatment groups. There were no serious hypoglycaemic events. Conclusion: In Chinese patients with type 2 diabetes inadequately controlled on metformin, the glucose‐lowering effect of cofrogliptin (Q2W) was non‐inferior to linagliptin (daily), with a similar safety profile maintained over 52 weeks of treatment. [ABSTRACT FROM AUTHOR]

Objective: The current study aimed to compare the renal effects of Empagliflozin with Linagliptin combined with Metformin in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease. Materials and Methods: We conducted a randomized clinical trial on diabetic patients aged over 18 years with chronic renal failure and an EGFR between 20 to 60 ml/minutes/1.73 m2 corrected with the MDRD equation. Between January and December 2023, a total of 150 cases in Imam Hossein Hospital were randomized into two study arms of 75 cases receiving Empagliflozin (10 mg/day) and metformin or Linagliptin (5mg/day) and metformin for 6 months. The primary outcome was a change in chronic kidney disease (CKD) stage, while serum creatinine, fasting blood sugar (FBS), proteinuria, and blood pressure were evaluated at baseline, 3 and 6 months later. Results: The mean age of participants was 62.20 (± 4.45) years and 50% of them were females. Study indices including serum creatinine (P: 0.001), estimated glomerular filtration rate (eGFR) (P: 0.001), FBS (P: 0.001), HgA1c (P: 0.001), proteinuria (P: 0.001), and blood pressure (P: 0.001) reduced significantly over time in both groups. After adjustment for potential confounders, Empagliflozin reduced the level of serum creatinine independent of other factors. Conclusion: Empagliflozin significantly reduces the level of serum creatinine compared to Linagliptin in patients with T2DM and chronic renal failure.

Background: Linagliptin is an oral dipeptidyl peptidase DPP‐4 inhibitor, which is indicated for the treatment of Type 2 diabetes mellitus (T2DM) as monotherapy or add-on to therapy with other hypoglycemic drugs. Objectives: We aimed to summarize the evidence from randomized controlled trials (RCTs) to assess the safety of linagliptin focusing on cardiovascular risks among subjects with type 2 diabetes mellitus. Methods: We conducted a systematic search across the following databases: Medline, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to November 2021. Randomized controlled trials (RCTs) of linagliptin compared to placebo in patients with Type 2 diabetes were included. The primary safety points were cardiovascular (CV) adverse events including non-fatal stroke, non-fatal myocardial infarction (MI), CV death, MI, stroke, and hospitalization for unstable angina. While, secondary safety points included 17 reported adverse events such as infections, hypoglycemia and abdominal pain. Three reviewers independently screened and reviewed each study to extract relevant information. Any discrepancies were resolved by consensus. We conducted a meta-analysis using the random effects model. Pooled risk ratios (RRs) of targeted adverse events with linagliptin compared to placebo were estimated using the Mantel–Haenszel test. Results: A total of 24 studies with 19,981 adult patients were included. There was no difference in the incidence of all CV adverse events or individual CV adverse events between linagliptin and the placebo arms. The pooled estimate of the risk of upper respiratory tract infection was reported in twelve trials with a 38% risk reduction among patients treated with the linagliptin group compared to the placebo group (RR = 0.62, 95% CI: 0.45–0.85, and I2 = 0%), while no difference was found in other infections. For gastrointestinal disorders, the risk of abdominal pain showed a 65% risk reduction among patients treated with the linagliptin group compared to the placebo group (RR = 0.35, 95% CI: 0.16–0.77, and I2 = 0%). Conclusion: Our study showed an overall acceptable safety profile of linagliptin in patients with T2DM. Moreover, our study showed a risk reduction of upper respiratory tract infection and abdominal pain when using linagliptin compared to placebo. [ABSTRACT FROM AUTHOR]

Objective: The current study aimed to compare the renal effects of Empagliflozin with Linagliptin combined with Metformin in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease. Materials and Methods: We conducted a randomized clinical trial on diabetic patients aged over 18 years with chronic renal failure and an EGFR between 20 to 60 ml/minutes/1.73 m2 corrected with the MDRD equation. Between January and December 2023, a total of 150 cases in Imam Hossein Hospital were randomized into two study arms of 75 cases receiving Empagliflozin (10 mg/day) and metformin or Linagliptin (5mg/day) and metformin for 6 months. The primary outcome was a change in chronic kidney disease (CKD) stage, while serum creatinine, fasting blood sugar (FBS), proteinuria, and blood pressure were evaluated at baseline, 3 and 6 months later. Results: The mean age of participants was 62.20 (± 4.45) years and 50% of them were females. Study indices including serum creatinine (P: 0.001), estimated glomerular filtration rate (eGFR) (P: 0.001), FBS (P: 0.001), HgA1c (P: 0.001), proteinuria (P: 0.001), and blood pressure (P: 0.001) reduced significantly over time in both groups. After adjustment for potential confounders, Empagliflozin reduced the level of serum creatinine independent of other factors. Conclusion: Empagliflozin significantly reduces the level of serum creatinine compared to Linagliptin in patients with T2DM and chronic renal failure. [ABSTRACT FROM AUTHOR]

The increasing occurrence of childhood overweight and obesity has been followed by a substantial increase in youth-onset type 2 diabetes (T2D). Pharmacological treatment options for youth-onset T2D remain limited, with a clear unmet need for additional oral agents. This summary of research reports on the efficacy and safety of empagliflozin and linagliptin on glycaemic control in children and adolescents aged 10–17 years with T2D in the randomised, double-blind, parallel group, phase 3 DINAMO trial. Empagliflozin provided a clinically relevant, statistically significant, and durable improvement in glycaemic control; however, linagliptin did not. The safety profile of both empagliflozin and linagliptin was comparable to those observed in studies in adults. These results suggest that empagliflozin could be a new oral therapy option for youth-onset T2D. [ABSTRACT FROM AUTHOR]

The article describes two case scenarios in which liraglutide demonstrated glucose lowering similar to agents categorized as having very high efficacy. A 63-year-old Black man was referred to an outpatient clinic's in-house pharmacist-run diabetes education and management service while a 63-year-old White man was referred to the same clinical pharmacy service. The cases show the potential for robust A1C lowering with the use of liraglutide in patients with type 2 diabetes who overeat.

Lung cancer has the highest global fatality rate of all cancers, and most existing therapies have a wide range of toxic effects. This necessitates searching for new medications with potential anticancer properties and a better safety profile against normal cells. Dipeptidyl peptidase-4 (DPP4) inhibitors have recently shown anticancer efficacy in various malignancies such as colorectal, prostate, and renal cancer. Therefore, this study investigated the anticancer activity of sitagliptin (SITA) and linagliptin (LINA) against the lung cancer cell line A549 alone and in combination with cisplatin (CP). A549 cells were divided into six groups: control (untreated cells), CP-treated cells, SITA-treated cells, LINA-treated cells, CP plus SITA-treated cells (ratio 1:1), and CP plus LINA-treated cells (ratio 1:1). After 72 hours of incubation, a 3-(4,5-dimethylthiazol2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) test was used to determine cell viability and the concentration of 50% inhibition for cell viability (IC50) for each group. A549 cells were later seeded in six flasks and treated with the resulting IC50; cell pellets were collected and lysed to determine the malondialdehyde (MDA) level using ELISA kits. SITA and LINA therapy dramatically reduced A549 cell viability compared to the control (P < 0.0001), with results comparable to CP. When SITA and LINA were combined with CP, they demonstrated significantly higher anticancer efficacy than when used alone. Notably, both medicines lowered MDA levels when taken alone or in combination with CP. SITA and LINA showed promising anticancer and antioxidant activity against A549 cells. This may indicate a potential synergistic anticancer effect with CP. [ABSTRACT FROM AUTHOR]

Objective: Lung cancer (LC) has the highest mortality rate globally. Most chemotherapeutic medicines now in use are cytotoxic, prompting the search for novel compounds with anticancer properties and improved safety profiles for normal cells. Dipeptidyl peptidase-4 inhibitors have demonstrated anticancer effects and apoptotic properties by specifically inhibiting dipeptidyl peptidase-4, a glycoprotein found in various organs that support the spread of cancer and tumor formation. Based on that, this study aimed to evaluate the cytotoxicity and apoptotic activity of sitagliptin (SITA) and linagliptin (LINA) against the lung cancer cell line (A549) alone and in combination with cisplatin (CP). Methods: A549 cells were categorized into six groups: control (untreated cells), CP-treated cells, SITA-treated cells, LINA-treated cells, CP plus SITA treated cells (1:1 ratio), and CP plus LINA treated cells (1:1 ratio). After 72 hours of incubation, cell viability (or cytotoxicity) and concentration required to inhibit 50% of cell viability (IC50) for each group were determined using an MTT assay. This method is safe and easy to use, has more reproducibility, and is commonly used for cell viability and cytotoxicity tests. Later, A549 cells were cultured in six flasks and exposed to the IC50 for 36 hours. Afterward, the cells were harvested and centrifuged, and the supernatant was removed. The remaining cell pellets were collected and lysed using a lysis buffer to measure B-cell lymphoma type 2 (BCL-2) levels with ELISA test kits. The data was collected and subjected to statistical analysis techniques. Results: MTT assay results determined that SITA and LINA significantly increased A549 cell cytotoxicity compared to the control group (P<0.0001). Moreover, combining SITA or LINA with CP showed markedly increased antitumor efficacy and more significant cytotoxicity directed toward A549 cells. Additionally, these combinations highly reduced IC50 in comparison to monotherapy. Considerably, both drugs showed remarkable apoptotic activity on A549 cells when used alone or combined with CP by decreasing BCL2 levels. Consequently, it potentiates apoptotic effects and cytotoxicity of CP against cancer cells. Interestingly, Lina was more potent than Sita regarding cytotoxicity and apoptotic activity on A549 cells. Conclusion: SITA and Lina exhibited significant cytotoxic and apoptotic effects against A549 cells through the induction of apoptosis. Notably, the results suggest a potential synergistic anticancer impact on CP. [ABSTRACT FROM AUTHOR]

Separation and quantification of highly polar metformin (MTF) alone or in combination with dipeptidyl peptidase-4 inhibitors, such as evogliptin (EVG), sitagliptin, saxagliptin, vildagliptin, linagliptin and teneligliptin, specifically from human plasma and pharmaceutical products is still difficult in mostly preferred ODS based RP-HPLC techniques. Since, owing to weak retention of MTF in ODS, it elutes together with the biological fluid components and drug excipients. Therefore, in this study, alternative to ODS based RP-HPLC, comparatively less known analytical techniques like strong cation exchange chromatography (SCX-3), hydrophilic interaction liquid chromatography (HILIC) and mix-mode chromatography (MMC) were comprehensively evaluated for their potentials and limitations in simultaneous quantification of newly approved EVG and MTF combination (Valera-M). In results, prolonged application of SCX-3, exhibits irreproducible and irreversible retention of MTF and EVG. While in HILIC with Cyano column, excessive acetonitrile as eluent developed the precipitation of MTF and column back pressure. Comparatively, the Acclaimed® mix-mode HILIC-1, demonstrated much promising and reproducible results for MTF and EVG separation and importantly, it can be used either reverse phase or HILIC mode. Considering the overall benefits of Acclaimed® mix-mode HILIC-1, it was used in estimation of MTF and EVG from human plasma and pharmaceutical formulations.

The frequent drugs prescribed for type 2 diabetes patients are linagliptin (LNG) and empagliflozin (EMG) in different drug formulations. The objective of this research is to create and validate selective and simple methods to evaluate both medications in their dosage forms. Method A for the assay of LNG is based on the drug oxidation using an iodate/iodide mixture, while Method B involves the determination of EMG using permanganate oxidation. The regression graphs had good linearity in the ranges of 0.25–20 and 0.20–1.5 µg·ml−1 for the two drugs, respectively. The limits of detection were 0.082 and 0.065 µg·ml−1 for LNG and EMG, respectively. The two methods were validated and applied for the assay of the drugs in dosage forms successfully.

The article focuses on the use of semaglutide in patients receiving hemodialysis, highlighting unexpected benefits for managing hyperphosphatemia and hyperkalemia, despite limited treatment options for type 2 diabetes due to renal impairment and complex physiology. It reports illustrate significant improvements in phosphate levels in patients who initiated semaglutide alongside their hemodialysis treatment.

Type 1 diabetes mellitus (T1DM) is one of the main causes of ovarian atresia, but its molecular effect on the ovaries is not fully understood. Accumulating evidence suggests that T1DM causes excessive endoplasmic reticulum (ER) stress and insufficient adaptive unfolded protein response that triggers proapoptotic signaling pathways in ovarian tissue. In addition, problems such as amenorrhea and infertility, which are frequently seen in women with T1DM, continue despite the intensification of insulin therapy and improvement of metabolic control. Therefore new, and adjunctive treatments for women with T1DM need to be explored. We aimed to examine how the use of linagliptin, which has blood sugar‐lowering effects and high antioxidant activity, together with insulin affects the expression levels of proteins and genes that play a role in ER stress in type 1 diabetic mouse ovaries. Eighty‐four Balb/C 6‐week‐old female mice were randomly divided into seven groups: control, vehicle, diabetes + insulin, diabetes + linagliptin, diabetes + linagliptin + insulin, diabetes + TUDCA, and diabetes + TUDCA + insulin. TUDCA (an inhibitor of ER stress) groups are positive control groups created to compare linagliptin groups in terms of ER stress. Linagliptin and TUDCA were given by oral gavage and 1U insulin was administered subcutaneously for 2 weeks. A significant decrease was observed in the MDA and NOX1 levels and the number of atretic follicles in the ovaries of the diabetes + linagliptin + insulin group compared to the diabetes + insulin group. The use of linagliptin and insulin increased the expression of pro‐survival XBP1s transmembrane protein and decreased the expression of proapoptotic ATF4, pJNK1/2, cleaved caspase 12, and cleaved caspase 3 in mouse ovaries. Our study provides new therapeutic evidence that linagliptin administered in addition to insulin induces ER stress mechanism‐dependent survival in ovaries with type 1 diabetes. Significance Statement: In our study, we aimed to answer the question whether the use of linagliptin, a DPP4 inhibitor with high antioxidant activity, and insulin triggers the survival pathway or the apoptotic pathway of unfolded protein response (UPR) signaling activated by endoplasmic reticulum (ER) stress in type 1 diabetes mellitus (T1DM) mouse ovaries to reach new therapeutic targets. Our results showed that the addition of linagliptin to insulin induced pro‐survival UPR by decreasing ATF4 and increasing XBP1s proteins, while suppressing proapoptotic UPR by decreasing p‐JNK1 + JNK2, cleaved caspase 12, and cleaved caspase 3 proteins. This study will contribute to the literature in terms of the discovery of new methods to be used in the treatment of ovarian pathologies associated with diabetes‐induced ER stress. [ABSTRACT FROM AUTHOR]

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters—dopamine, serotonin and noradrenaline—and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

To investigate the mechanism of linagliptin on stromal cell-derived factor 1 and vascular endothelial growth factor protein after molar pulp revascularization in rats. 45 specific-pathogen free male Sprague-Dawley rats were divided into 5 groups based on the average body weight, with 9 rats in each group. The control group did not establish the rat model of molar pulp revascularization, and model group, low-linagliptin group, mediumlinagliptin group, and high-linagliptin group all established the rat model of molar pulp revascularization. On d 1 after modeling, rats in low-linagliptin group, medium-linagliptin group, and high-linagliptin group were gavaged with 1, 2, and 3 mg/ml linagliptin, respectively. Rats in control group and model group were gavaged with 0.9 % normal saline at equal volume, once a day for 28 d. After the last gavage, the rats were detected for the body weight and fasting blood glucose, and superoxide dismutase and serum oxidative stress indicators malondialdehyde were detected by kit; hematoxylin and eosin staining was employed to detect the pathological morphology of dental pulp tissue, immunohistochemistry and immunoblot were applied to detect the positive expression of vascular endothelial growth factor and stromal cell-derived factor 1 and the protein content. No significant differences were found in fasting blood glucose and body weight between the groups (p>0.05). In control group, loose connective tissue was found in the root canal of rats, and a large number of long spindle forming fibrocytes were distributed; in model group, a large number of inflammatory cells are found under the dental pulp, with the majority of neutrophils; in comparison with model group, inflammatory cells in pulp tissue of low-linagliptin group, medium-linagliptin group and high-linagliptin group gradually decreased, and scattered restorative dentin could be found in the pulp, and there was no inflammatory expression in the middle and lower tissues of the pulp. Dipeptidyl peptidase 4 inhibitor linagliptin has no effect on rats' body weight and blood glucose after revascularization, but it can improve the level of oxidative stress and accelerate revascularization and perhaps its mechanism links to the up-regulation of vascular endothelial growth factor and stromal cell-derived factor 1 expression. [ABSTRACT FROM AUTHOR]

The worldwide incidence of type 2 diabetes mellitus (T2DM), a chronic metabolic disorder, is increasing rapidly. A newer category of oral hypoglycemic medications called dipeptidyl peptidases-4 (DPP-4) inhibitors has come into existence for the management of T2DM. DPP-4 inhibitors, i.e., linagliptin, saxagliptin, and sitagliptin, belong to BCS class III, while alogliptin belongs to BCS class I. These drugs have high aqueous solubility and, therefore, short elimination half-life which necessitates the need for multiple daily dosing. Furthermore, the unrestrained drug release from conventional tablets can cause elevation in systemic drug concentrations which might instigate gastrointestinal side effects. The poor membrane permeability of BCS class III drugs also results in their poor oral bioavailability. Therefore, clinical compliance and therapeutic efficacy of DPP-4 inhibitors can be enhanced by nanotechnology-based techniques. This research paper has described various risk factors and pathophysiology of T2DM and also explained about the mode of action of DPP-4 inhibitors. The main objectives and rationale of this review include the exploration of preclinical pharmacological investigations and the summarization of developed nanoformulations of DPP-4 inhibitors researched in previous decades. The nanoformulations which has been synthesized for DPP-4 inhibitors in the past few decades for the management of T2DM include polymeric nanoparticle, solid lipid nanoparticle, transferosomes, niosomes, mucoadhesive nanoparticle, and self-microemulsifying drug delivery systems. [ABSTRACT FROM AUTHOR]

A well-made chitosan-PVP block copolymer platform was equipped with highly ordered and uniform nano-channels. This highly adhesive block copolymer platform was designed to ensure the efficient co-delivery of two synergistic-acting hypoglycemic drugs. Linagliptin oral bioavailability is 30% due to poor permeability and intestinal degradation. Its pharmacokinetics shows a non-linear profile. Empagliflozin exhibited decreased permeability and decreased solubility in aqueous media between pH 1 and 7.5. Cubosomes were functionalized as a good microdomain to guest and improve the physicochemical characteristics of drug molecules with decreased permeability and solubility. Cubosomes loaded with linagliptin (linagliptin cubosomes (LCs)) and empagliflozin (empagliflozin cubosomes ECs) were separately prepared using the top-down method and optimized by applying 23 factorial design. Optimized cubosomal systems LCs (F3) and ECs (F4) were incorporated into a chitosan-PVP gel to obtain dual cubosome-loaded platforms (LECF) optimized through 22 factorial design. The permeation study from the optimized LECF (C1) ensured enhanced empagliflozin permeation alongside continued efflux for linagliptin, resolving potential risks due to its non-linear plasma profile. The in-vivo study revealed that AUC(0–∞) of linagliptin and empagliflozin was enhanced by 2- and threefold, respectively. Therefore, the chitosan-PVP block copolymer platform buccal application for the co-delivery of linagliptin and empagliflozin could contribute to enhanced clinical effectiveness in treating diabetes. Graphical abstract showing dual cubosome-loaded platform tested in-vivo using a rabbit model [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that dysregulation of FOXO3a plays a significant role in the progression of various malignancies, including hepatocellular carcinoma (HCC). FOXO3a inactivation, driven by oncogenic stimuli, can lead to abnormal cell growth, suppression of apoptosis, and resistance to anticancer drugs. Therefore, FOXO3a emerges as a potential molecular target for the development of innovative treatments in the era of oncology. Linagliptin (LNGTN), a DPP‐4 inhibitor known for its safe profile, has exhibited noteworthy anti‐inflammatory and anti‐oxidative properties in previous in vivo studies. Several potential molecular mechanisms have been proposed to explain these effects. However, the capacity of LNGTN to activate FOXO3a through AMPK activation has not been investigated. In our investigation, we examined the potential repurposing of LNGTN as a hepatoprotective agent against diethylnitrosamine (DENA) intoxication. Additionally, we assessed LNGTN's impact on apoptosis and autophagy. Following a 10‐week administration of DENA, the liver underwent damage marked by inflammation and early neoplastic alterations. Our study presents the first experimental evidence demonstrating that LNGTN can reinstate the aberrantly regulated FOXO3a activity by elevating the nuclear fraction of FOXO3a in comparison to the cytosolic fraction, subsequent to AMPK activation. Moreover, noteworthy inactivation of NFκB induced by LNGTN was observed. These effects culminated in the initiation of apoptosis, the activation of autophagy, and the manifestation of anti‐inflammatory, antiproliferative, and antiangiogenic outcomes. These effects were concomitant with improved liver function and microstructure. In conclusion, our findings open new avenues for the development of novel therapeutic strategies targeting the AMPK/FOXO3a signaling pathway in the management of chronic liver damage. [ABSTRACT FROM AUTHOR]

Gastric hyperacidity and ulceration are chronic diseases characterized by repeated healing followed by re-exacerbation. The study aims to protect against gastric hyperacidity without interfering with gastric acid secretion. Pylorus ligation–induced hyperacidity is commonly utilized in the induction of gastric ulcers. Forty-two rats were distributed into seven groups (n = 6). Group I comprised sham-operated group. Group II served as pylorus-ligation group. Groups III–VII were given oral Linagliptin (LN; 3 and 6 mg/kg), L-arginine (LA; 150 and 300 mg/kg) and their combination (LN 3 + LA 150 mg/kg), respectively for 7 days. On the 8th day, groups II–VII were subjected to pylorus-ligation. Treatment of pylorus-ligated rats with LN, LA and their combination improved the gastric hyperacidity as exhibited by a marked reduction in the gastric juice volume, total and free acidities and pepsin contents with a noticeable increase in pH. Pre-treatment with LN, LA and their combination showed a marked alleviation in the gastric inflammatory indicators evidenced by reduction in the gastric levels of MCP-1and Il-1β as well as elevation of eNOS levels versus the sham-operated group. A marked up-regulation in the gastric gene expression of PGE, EP4 and VEGF accompanied by an improvement of the histopathologic pictures/scores, and TNF-α and caspase-3 immuno-staining were also recorded. By estimating the combination-index, it can be concluded that combining LN with LA exhibited prophylactic synergistic effects in ameliorating pylorus ligated-induced hyperacidity, mainly via up-regulation of EP4 receptor and improvement of vascular endothelial damage through VEGF expression in gastric mucosa. [ABSTRACT FROM AUTHOR]

Objective: To explore the efficacy and safety of dapagliflozin and linagliptin in the treatment of type 2 diabetes patients (T2DM) with normal body mass index (BMI) who have poor single drug efficacy of metformin. Method: 102 T2DM patients with normal BMI who visited our hospital from December 2021 to March 2023 were randomly divided into an observation group (51 cases) and a control group (51 cases) using a random number table method. The control group patients were treated with linagliptin in addition to metformin treatment, while the observation group was treated with dapagliflozin in addition to metformin treatment. The general indicators, blood glucose metabolism, biochemical indicators, and adverse reactions of the two groups of patients were compared. Result: After treatment, the body weight and BMI of both the observation group and the control group slightly decreased, while the systolic blood pressure of the observation group decreased. The changes in systolic blood pressure of the control group were not significant, and the differences were not statistically significant ([Formula: see text]); after treatment, the fasting blood glucose (FBG) and glycated hemoglobin (HbA1c) of both groups of patients decreased, and the FPG and HbA1c of the control group were not significantly lower than those of the observation group ([Formula: see text]). After treatment, the values of blood creatinine, blood uric acid, urinary microalbumin (UAlb), and urinary microalbumin/creatinine (UACR) in both groups of patients decreased, and the decrease in various biochemical indicators in the control group was not as significant as that in the observation group. The comparison of blood uric acid, UAlb, and UACR between the two groups showed statistical significance ([Formula: see text]). The incidence of adverse reactions in the observation group and control group patients was 8.70% and 13.04%, respectively, and there was no statistically significant difference ([Formula: see text]) after comparison. Conclusion: Both dapagliflozin and linagliptin have shown good efficacy in the treatment of T2DM patients with normal BMI and poor efficacy in monotherapy with metformin. Compared to linagliptin, dapagliflozin can cause slight weight loss in patients, but its control effect on blood glucose and blood pressure is better than that of linagliptin. The risk of hypoglycemia is lower, and it has a protective effect on the kidneys. The disadvantage is that it slightly increases the risk of urogenital tract infections, Overall, it has high security and can be promoted for use.

In the current study, we established a comprehensive quantitative systems pharmacology (QSP) model using linagliptin as the model drug, where drug disposition, drug intervention on dipeptidyl peptidase-4 (DPP-4), glucose-dependent insulinotropic peptide (GIP), Glucagon-like peptide-1 (GLP-1), glucagon, glucose, and insulin are integrated together with the cross talk and feedback loops incorporated among the whole glycemic control system. In the final linagliptin QSP model, the complicated disposition of linagliptin was characterized by a 2-compartment pharmacokinetic (PK) model with an enterohepatic cycling (EHC) component as well as target-mediated drug disposition (TMDD) processes occurring in both tissues and plasma, and the inhibitory effect of linagliptin on DPP-4 was determined by the linagliptin-DPP-4 complex in the central compartment based on target occupancy principle. The integrated GIP-GLP1-glucagon-glucose-insulin system contains five indirect response models as the "skeleton" structure with 12 feedback loops incorporated within the glucose control system. Our model adequately characterized the substantial nonlinear PK of linagliptin, time course of DPP-4 inhibition, as well as the kinetics of GIP, GLP-1, glucagon, and glucose simultaneously in humans. Our model provided valuable insights on linagliptin pharmacokinetics/pharmacodynamics and complicated glucose homeostasis. Since the glucose regulation modeling framework within the QSP model is "drug-independent", our model can be easily adopted by others to evaluate the effect of other DPP-4 inhibitors on the glucose control system. In addition, our QSP model, which contains more components than other reported glucose regulation models, can potentially be used to evaluate the effect of combination antidiabetic therapy targeting different components of glucose control system. [ABSTRACT FROM AUTHOR]

Dapagliflozin inhibits selective sodium--glucose co-transporter-2 and Linagliptin competitively and reversibly inhibits dipeptidyl peptidase-4 in fixed dose Combination (1:1) is used in the treatment of Type 2 Diabetes Mellitus. For estimation Dapagliflozin and Linagliptin in bulk and Tablet formulation, an accurate and precise method using RP-HPLC was developed and validated. In the method being discussed here was optimized using Hypersil C18 (250 x 4.6 mm, 5 µm) column as Stationary Phase, Mobile Phase being used is Acetonitrile: Water (90:10) adjusting pH 3 using Ammonium Acetate. The Flow Rate was adjusted to 1mL/min. Both Dapagliflozin and Linagliptin (1:1) sample was detected at analytical wavelength of 244nm using Photo diode array detector. The Linearity Range was between Concentration of 0.1µg/mL to 20µg/mL with correlation Coefficient of 0.995 and 0.999 for Dapagliflozin and Linagliptin Respectively. [ABSTRACT FROM AUTHOR]