Activation of AMPK/SIRT1/FOXO3a signaling by BMS-477118 (saxagliptin) mitigates chronic colitis in rats: uncovering new anti-inflammatory and antifibrotic roles.

Ulcerative colitis (UC) is a debilitating chronic disease marked by persistent inflammation and intestinal fibrosis. Despite the availability of various treatments, many patients fail to achieve long-term remission, underscoring a significant unmet therapeutic need. BMS-477118, a reversible inhibitor of dipeptidyl peptidase 4 (DPP4), has demonstrated anti-inflammatory properties in preclinical and clinical studies with minimal adverse effects compared to other antidiabetic agents. However, the potential benefits of BMS-477118 in chronic UC have not yet been explored. In this study, we aimed to investigate the effects of BMS-477118 in rats subjected to chronic dextran sodium sulfate (DSS) administration. Our findings indicate that BMS-477118 activates the interconnected positive feedback loop involving AMPK, SIRT1, and FOXO3a, improving histological appearance in injured rat colons. BMS-477118 also reduced fibrotic changes associated with the chronic nature of the animal model, alleviated macroscopic damage and disease severity, and improved the colon weight-to-length ratio. Additionally, BMS-477118 prevented DSS-induced weight loss and enhanced tight junction proteins. These effects, in conjunction with reduced oxidative stress and its potential anti-inflammatory, antiapoptotic, and autophagy-inducing properties, fostered prolonged survival in rats with chronic UC. To conclude, BMS-477118 has the potential to activate the AMPK/SIRT1/FOXO3a signaling pathway in inflamed colons. These results suggest that the AMPK/SIRT1/FOXO3a pathway could be a new therapeutic target for UC. Further research is mandatory to explore the therapeutic possibilities of this pathway. Additionally, continued studies on the therapeutic potential of BMS-477118 and other DPP4 inhibitors are promising for creating new treatments for various conditions, including UC in diabetic patients.

Pharmacokinetic/Pharmacodynamic modelling of Saxagliptin and its active metabolite, 5-hydroxy Saxagliptin in rats with Type 2 Diabetes Mellitus.

BACKGROUND AND PURPOSES: It is unclear whether the parent Saxagliptin (SAX) in vivo is the same as that in vitro, which is twice that of 5-hydroxy Saxagliptin (5-OH SAX). This study is to construct a Pharmacokinetic-Pharmacodynamic (PK-PD) link model to evaluate the genuine relationship between the concentration of parent SAX in vivo and the effect. METHODS: First, we established a reliable Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS/MS) method and DPP-4 inhibition ratio determination method. Then, the T2DM rats were randomly divided into four groups, intravenous injection of 5-OH SAX (0.5 mg/kg) and saline group, intragastric administration of SAX (10 mg/kg) and Sodium carboxymethyl cellulose (CMC-Na) group. Plasma samples were collected at different time points for subsequent testing. Finally, we used the measured concentrations and inhibition ratios to construct a PK-PD link model for 5-OH SAX and parent SAX. RESULTS: A two-compartment with additive model showed the pharmacokinetic process of SAX and 5-OH SAX, the concentration-effect relationship was represented by a sigmoidal Emax model and sigmoidal Emax with E0 model for SAX and 5-OH SAX, respectively. Fitting parameters showed SAX was rapidly absorbed after administration (Tmax=0.11 h, t1/2, ka=0.07 h), widely distributed in the body (V ≈ 20 L/kg), plasma exposure reached 3282.06 ng*h/mL, and the elimination half-life was 6.13 h. The maximum plasma dipeptidyl peptidase IV (DPP-4) inhibition ratio of parent SAX was 71.47%. According to the final fitting parameter EC50, EC50, 5-OH SAX=0.46EC50, SAX(parent), it was believed that the inhibitory effect of 5-OH SAX was about half of the parent SAX, which is consistent with the literature. CONCLUSIONS: The PK-PD link model of the parent SAX established in this study can predict its pharmacokinetic process in T2DM rats and the strength of the inhibitory effect of DPP-4 based on non-clinical data.

Neuroprotective effects of saxagliptin against radiation-induced cognitive impairment: Insights on Akt/CREB/SIRT1/BDNF signaling pathway.

Radiation-induced cognitive impairment has recently fueled scientific interest with an increasing prevalence of cancer patients requiring whole brain irradiation (WBI) in their treatment algorithm. Saxagliptin (SAXA), a dipeptidyl peptidase-IV (DPP-IV) inhibitor, has exhibited competent neuroprotective effects against varied neurodegenerative disorders. Hence, this study aimed at examining the efficacy of SAXA in alleviating WBI-induced cognitive deficits. Male Sprague Dawley rats were distributed into control group, WBI group exposed to 20 Gy ϒ-radiation, SAXA group treated for three weeks with SAXA (10 mg/kg. orally, once daily), and WBI/SAXA group exposed to 20 Gy ϒ-radiation then treated with SAXA (10 mg/kg. orally, once daily). SAXA effectively reversed memory deterioration and motor dysfunction induced by 20 Gy WBI during behavioural tests and preserved normal histological architecture of the hippocampal tissues of irradiated rats. Mechanistically, SAXA inhibited WBI-induced hippocampal oxidative stress via decreasing lipid peroxidation while restoring catalase antioxidant activity. Moreover, SAXA abrogated radiation-induced hippocampal neuronal apoptosis through downregulating proapoptotic Bcl-2 Associated X-protein (Bax) and upregulating antiapoptotic B-cell lymphoma 2 (Bcl-2) expressions and eventually diminishing expression of cleaved caspase 3. Furthermore, SAXA boosted hippocampal neurogenesis by upregulating brain-derived neurotrophic factor (BDNF) expression. These valuable neuroprotective capabilities of SAXA were linked to activating protein kinase B (Akt), and cAMP-response element-binding protein (CREB) along with elevating the expression of sirtuin 1 (SIRT-1). SAXA successfully mitigated cognitive dysfunction triggered by WBI, attenuated oxidative injury, and neuronal apoptosis, and enhanced neurogenesis through switching on Akt/CREB/BDNF/SIRT-1 signaling axes. Such fruitful neurorestorative effects of SAXA provide an innovative therapeutic strategy for improving the cognitive capacity of cancer patients exposed to radiotherapy.

Formulation of Saxagliptin Oral Films: Optimization, Physicochemical Characterization, In-Vivo Assessment, and In-Vitro Real-Time Release Monitoring via a Novel Polyaniline Nanoparticles-Based Solid-Contact Screen Printed Ion-Selective Electrode.

Oral dispersible films have received broad interest due to fast drug absorption and no first-path metabolism, leading to high bioavailability and better patient compliance. Saxagliptin (SXG) is an antidiabetic drug that undergoes first-path metabolism, resulting in a less active metabolite, so the development of SXG oral dispersible films (SXG-ODFs) improves SXG bioavailability. The formula optimisation included a response surface experimental design and the impact of three formulation factors, the type and concentration of polymer and plasticiser concentration on in-vitro disintegration time and folding endurance. Two optimised SXG-ODFs prepared using either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose were investigated. SXG-ODFs prepared with PVA demonstrated a superior rapid disintegration time, ranging from 17 to 890 s, with the fastest disintegration time recorded at 17 s. These short durations can be attributed to the hydrophilic nature of PVA, facilitating rapid hydration and disintegration upon contact with saliva. Additionally, PVA-based films displayed remarkable folding endurance, surpassing 200 folds without rupture, indicating flexibility and stability. The high tensile strength of PVA-based films further underscores their robust mechanical properties, with tensile strength values reaching up to 4.53 MPa. SXG exhibits a UV absorption wavelength of around 212 nm, posing challenges for traditional quantitative spectrophotometric analysis, so a polyaniline nanoparticles-based solid-contact screen-printed ion-selective electrode (SP-ISE) was employed for the determination of SXG release profile effectively in comparison to HPLC. SP-ISE showed a better real-time release profile of SXG-ODFs, and the optimised formula showed lower blood glucose levels than commercial tablets.

Differential inhibition of sildenafil and macitentan on saxagliptin metabolism.

The development of diabetes mellitus (DM) is generally accompanied by erectile dysfunction (ED) and pulmonary arterial hypertension (PAH), which increases the use of combination drug therapy and the risk of drug-drug interactions. Saxagliptin for the treatment of DM, sildenafil for the treatment of ED and PAH, and macitentan for the treatment of PAH are all substrates of CYP3A4, which indicates their potential involvement in drug-drug interactions. Therefore, we investigated potential pharmacokinetic interactions between saxagliptin and sildenafil/macitentan. We investigated this speculation both in vitro and in vivo, and explored the underlying mechanism using in vitro hepatic metabolic models and molecular docking assays. The results showed that sildenafil substantially inhibited the metabolism of saxagliptin by occupying the catalytic site of CYP3A4 in a competitive manner, leading to the alterations in the pharmacokinetic properties of saxagliptin in terms of increased maximum plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-t)), area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUC(0-∞)), decreased clearance rate (CLz/F), and prolonged terminal half-life (t1/2). In contrast, a slight inhibition was observed in saxagliptin metabolism when concomitantly used with macitentan, as no pharmacokinetic parameters were altered, except for CLz/F. Thus, dosage adjustment of saxagliptin may be required in combination with sildenafil to achieve safe therapeutic plasma concentrations and reduce the risk of potential toxicity, but it is not necessary for co-administration with macitentan.

Physiologically Based Pharmacokinetic (PBPK) Modeling to Predict CYP3A-Mediated Drug Interaction between Saxagliptin and Nicardipine: Bridging Rat-to-Human Extrapolation.

The aim of this study was to predict the cytochrome P450 3A (CYP3A)-mediated drug-drug interactions (DDIs) between saxagliptin and nicardipine using a physiologically based pharmacokinetic (PBPK) model. Initially, in silico and in vitro parameters were gathered from experiments or the literature to construct PBPK models for each drug in rats. These models were integrated to predict the DDIs between saxagliptin, metabolized via CYP3A2, and nicardipine, exhibiting CYP3A inhibitory activity. The rat DDI PBPK model was completed by optimizing parameters using experimental rat plasma concentrations after co-administration of both drugs. Following co-administration in Sprague-Dawley rats, saxagliptin plasma concentration significantly increased, resulting in a 2.60-fold rise in AUC, accurately predicted by the rat PBPK model. Subsequently, the workflow of the rat PBPK model was applied to humans, creating a model capable of predicting DDIs between the two drugs in humans. Simulation from the human PBPK model indicated that nicardipine co-administration in humans resulted in a nearly unchanged AUC of saxagliptin, with an approximate 1.05-fold change, indicating no clinically significant changes and revealing a lack of direct translation of animal interaction results to humans. The animal-to-human PBPK model extrapolation used in this study could enhance the reliability of predicting drug interactions in clinical settings where DDI studies are challenging.

Continuous Glucose Monitoring Profiles and Health Outcomes after Dapagliflozin Plus Saxagliptin vs Insulin Glargine.

CONTEXT: Glycemic variability and hypoglycemia during diabetes treatment may impact therapeutic effectiveness and safety, even when glycated hemoglobin (HbA1c) reduction is comparable between therapies. OBJECTIVE: We employed masked continuous glucose monitoring (CGM) during a randomized trial of dapagliflozin plus saxagliptin (DAPA+SAXA) vs insulin glargine (INS) to compare glucose variability and patient-reported outcomes (PROs). DESIGN: 24-week sub-study of a randomized, open-label, two-arm, parallel-group, phase 3b study. SETTING: Multicenter study (112 centers in 11 countries). PATIENTS: 283 adults with type 2 diabetes (T2D) inadequately controlled with metformin ± sulfonylurea. INTERVENTIONS: DAPA+SAXA vs INS. MAIN OUTCOME MEASURES: Changes in CGM profiles, HbA1c, and PROs. RESULTS: Changes from baseline in HbA1c with DAPA+SAXA were similar to those observed with INS, with mean difference [95% CI] between decreases of -0.12% [-0.37 to 0.12%], P = .33. CGM analytics were more favorable for DAPA+SAXA, including greater percent time in range (> 3.9 and ≤ 10 mmol/L; 34.3 ± 1.9 vs 28.5 ± 1.9%, P = .033), lower percent time with nocturnal hypoglycemia (area under the curve ≤ 3.9 mmol/L; 0.6 ± 0.5 vs 2.7 ± 0.5%, P = .007), and smaller mean amplitude of glycemic excursions (-0.7 ± 0.1 vs -0.3 ± 0.1 mmol/L, P = .017). Improvements in CGM were associated with greater satisfaction, better body weight image, less weight interference, and improved mental and emotional well-being. CONCLUSIONS: DAPA+SAXA and INS were equally effective in reducing HbA1c at 24 weeks, but people with T2D treated with DAPA+SAXA achieved greater time in range, greater reductions in glycemic excursions and variability, less time with hypoglycemia, and improved patient-reported health outcomes.

Evaluation of the Drug-Induced Liver Injury Potential of Saxagliptin through Reactive Metabolite Identification in Rats.

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.

Relationship between saxagliptin use and left ventricular diastolic function assessed by cardiac MRI.

AIMS: Type 2 diabetes mellitus (T2DM) increases the risk of major cardiovascular events. In SAVOR-TIMI53 trial, the excess heart failure (HF) hospitalization among patients with T2DM in the saxagliptin group remains poorly understood. Our aim was to evaluate left ventricular (LV) diastolic function after 6 months of saxagliptin treatment using cardiac magnetic resonance imaging (CMR) in patients with T2DM. METHODS: In this prospective study, 16 T2DM patients without HF were prescribed saxagliptin as part of routine guideline-directed management. CMR performed at baseline and 6 months after initiation of saxagliptin treatment were evaluated in a blinded fashion. We assessed LV diastolic function by measuring LV peak filling rate with correction for end-diastolic volume (PFR/LVEDV), time to peak filling rate with correction for cardiac cycle (TPF/RR), and early diastolic strain rate parameters [global longitudinal diastolic strain rate (GLSR-E), global circumferential diastolic strain rate (GCSR-E)] by feature tracking (FT-CMR). RESULTS: Among the 16 patients (mean age of 59.9, 69% males, mean hemoglobin A1c 8.3%, mean left ventricular ejection fraction 57%), mean PFR was 314 ± 108 ml/s at baseline and did not change over 6 months (- 2.7, 95% CI - 35.6, 30.2, p = 0.86). There were also no significant changes in other diastolic parameters including PFR/EDV, TPF, TPF/RR, and GLSR-E and GCSR-E (all p > 0.50). CONCLUSION: In T2DM patients without HF receiving saxagliptin over 6 months, there were no significant subclinical changes in LV diastolic function as assessed by CMR.

The Safety and Efficacy of Combining Saxagliptin and Pioglitazone Therapy in Streptozocin-Induced Diabetic Rats.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic progressive disease due to insulin resistance. Oxidative stress complicates the etiology of T2DM. Saxagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor, while Pioglitazone is a thiazolidinedione insulin sensitizer. This study aimed to assess the effect of Saxagliptin and Pioglitazone monotherapy and combination therapy on the biochemical and biological parameters in streptozotocin (STZ)-induced diabetic rats. METHODS: The study included thirty-five male albino rats. Diabetes mellitus was induced by intraperitoneal STZ injection (35 mg/kg). For a 1-month duration, rats were divided into five groups. Glucose homeostasis traits, lipid profiles, kidney functions, liver enzymes, and oxidative stress markers were measured. Gene expression of miRNA-29a, phosphoenolpyruvate carboxykinase (PEPCK), phosphoinositide-3-kinase (PI3K), and interleukin 1 beta (IL-1ß) was assessed using qRT-PCR. RESULTS: At a 1-month treatment duration, combination therapy improves oxidative stress markers more than either drug alone. The combination therapy had significantly higher levels of SOD, catalase, and GSH and lower levels of MDA compared to the monotherapy. Additionally, the diabetic group showed a significant increase in the expression levels of miRNA-29a, PEPCK, and IL-1ß and a significant decrease in PI3K compared to the normal control group. However, combination therapy of Saxagliptin and Pioglitazone was more effective than either Saxagliptin or Pioglitazone alone in reversing these results, especially for PEPCK and IL-1ß. CONCLUSIONS: Our findings revealed that combining Saxagliptin and Pioglitazone improves glycemic control and genetic and epigenetic expression profiles, which play an essential regulatory role in normal metabolism.

Effects of Incretin-Based Treatment on the Diastolic (Dys)Function in Patients with Uncontrolled Type 2 Diabetes Mellitus: A Prospective Study with 1-Year Follow-Up.

Left ventricular diastolic dysfunction (DD) is a subclinical cardiac abnormality in patients with type 2 diabetes mellitus (T2DM) that can progress to heart failure (HF) and increase cardiovascular risk. This prospective study evaluated the DD in T2DM patients without atherosclerotic cardiovascular disease after one year of incretin-based drugs added to standard treatment. Of the 138 enrolled patients (49.30% male, mean age 57.86 ± 8.82, mean T2DM history 5 years), 71 were started on dipeptidyl peptidase-4 inhibitor sitagliptin/saxagliptin, 21 on glucagon-like peptide-1 receptor agonist exenatide, and 46 formed the control group (metformin and sulphonylurea/acarbose). At baseline, 71 patients had grade 1 DD, another 12 had grade 2 and 3 DD, and 15 had indeterminate DD. After one year, DD was evidenced in 50 cases. Diastolic function improved in 9 cases, and 27 patients went from grade 1 to indeterminate DD. The active group benefited more, especially patients treated with exenatide; their metabolic and inflammation profiles also improved the most. An in-depth analysis of echocardiographic parameters and paraclinical results in the context of literature data justifies the conclusion that early assessment of diastolic function in T2DM patients is necessary and the benefits of affordable incretin-based treatment may extend to subclinical cardiovascular manifestations such as DD.

Influence of Gegenqinlian decoction on pharmacokinetics and pharmacodynamics of saxagliptin in type 2 diabetes mellitus rats.

Gegenqinlian decoction (GQD) is a classic prescription of traditional Chinese medicine (TCM), which originated from Shanghanlun. The combination of GQD and hypoglycemic drugs (saxagliptin, Sax, metformin) is often used to treat Type 2 diabetes mellitus (T2DM) in TCM clinics. However, the herb-drug interactions (HDIs) between GQD and hypoglycemic drugs are still unclear. In order to determine the safety of the combination, we assessed the influences of GQD on the pharmacokinetics and pharmacodynamics of Sax in T2DM rats. The plasma concentration of Sax (5 mg/kg) pretreated with GQD (freeze-dried powder, 1.35 g/kg) or not was determined by high-performance liquid chromatography (HPLC), and pharmacokinetics parameters were calculated. The influence of GQD on the pharmacodynamics of Sax was investigated by detecting the levels of weight, (see abbreviations list) OGTT, TC, TG, LDL-C, HDL-C, FBG, FINS, HOMA-IR, QUICKI, AST, ALT, and the liver coefficient. The Cmax , AUC0-t ,and AUC0-∞ of Sax increased significantly in the combination group whether in normal or T2DM rats. The results of pharmacodynamics showed that the weight of rats in each treatment group increased. FBG, TC, TG, LDL-C, and HOMA-IR decreased, HDL-C, FINS, and QUICKI increased significantly (p < 0.05) compared with the model control group. The result showed that the combination of GQD and Sax could not only improve the hypoglycemic effect but also increase the plasma exposure of Sax. The potential HDIs between GQD and Sax should be taken into consideration in clinics. Moreover, for the complexity of the human compared with experimental animals, as well as genetic differences, the in-depth study should be carried out to assess the uniformity of the pharmacokinetics and pharmacodynamics between rats and humans.

Saxagliptin promotes random skin flap survival.

BACKGROUND: Flap necrosis is a common issue encountered in clinical flap transplantation surgery. Here, we assessed the effects of saxagliptin, a dipeptidyl peptidase-4 inhibitor, on flap survival and explored the underlying mechanisms. METHODS: A dorsal McFarlane flap model was established in 36 rats, which were randomly divided into a high-dose saxagliptin (HS) group (saxagliptin, 30 mg/kg/day, n = 12), low-dose saxagliptin (LS) group (saxagliptin, 10 mg/kg/day, n = 12), and control group (n = 12). On day 7, flap survival was examined by eye in six rats from each group, along with determination of blood perfusion by laser Doppler flowmetry and angiogenesis by angiography. The remaining rats were sacrificed for harvesting of flap tissue. The status of the flap tissue was examined histopathologically by staining with hematoxylin and eosin (H&E). Oxidative stress was evaluated by determination of superoxide dismutase (SOD) activity and malonaldehyde (MDA) content. Gasdermin D (GSDMD), vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), NOD-like receptor pyrin domain containing 3 (NLRP3), interleukin (IL)-6, IL-18, Toll-like receptor 4 (TLR4), IL-1ß, caspase-1, and nuclear factor-κB (NF-κB) expression were detected by immunohistochemical analysis. RESULTS: The experimental group exhibited a larger area of flap survival, with more blood perfusion and neovascularization and better histopathological status than the control group. The degree of oxidative stress and the levels of NF-κB, TLR4, proinflammatory cytokines, and pyroptosis-associated protein were decreased in the experimental group, while the VEGF level was increased in a saxagliptin dose-dependent manner. CONCLUSION: Saxagliptin promotes random skin flap survival.

Physiologically Based Pharmacokinetic Modeling Characterizes the Drug-Drug Interaction Between Saxagliptin and Rifampicin in Patients With Renal Impairment.

The aim of the present study is to develop physiologically based pharmacokinetic (PBPK) models for saxagliptin and its active metabolite, 5-hydroxy saxagliptin, and to predict the effect of coadministration of rifampicin, a strong inducer of cytochrome P450 3A4 enzymes, on the pharmacokinetics of saxagliptin and 5-hydroxy saxagliptin in patients with renal impairment. The PBPK models of saxagliptin and 5-hydroxy saxagliptin were developed and validated in GastroPlus for healthy adults with or without rifampicin and adults with varying renal functions. Then, the effect of renal impairment combined with drug-drug interaction on saxagliptin and 5-hydroxy saxagliptin pharmacokinetics was investigated. The PBPK models successfully predicted the pharmacokinetics. For saxagliptin, the prediction suggests that rifampin greatly weakened the effect of renal impairment on reducing clearance, and the inductive effect of rifampin on parent drug metabolism seems to be increased with an increase in the degree of renal impairment severity. For patients with the same degree of renal impairment, rifampicin would have a slightly synergistic effect on the increase of 5-hydroxy saxagliptin exposure compared with dosed alone. There is an unsignificant decline for the saxagliptin total active moiety exposure values in patients with the same degree of renal impairment. It seems that patients with renal impairment are unlikely to require additional dose adjustments when coadministered with rifampicin, compared with saxagliptin alone. Our study provides a reasonable approach to explore unknown DDI potential in renal impairment.

Saxagliptin alleviates erectile dysfunction through increasing stromal cell-derived factor-1 in diabetes mellitus.

BACKGROUND: Diabetes mellitus-induced erectile dysfunction (DMED) is one of the complications of diabetes and has a poor response to phosphodiesterase type 5 inhibitor, the first-line treatment for ED. Saxagliptin (Sax), a dipeptidyl peptidase-4 inhibitor (DPP-4i), has been officially used in the treatment of type 2 diabetes. Stromal cell-derived factor-1 (SDF-1) is one of the important substrates of DPP-4, and has been proven to be beneficial for several DM complications. However, it is unknown whether Sax contributes to the management of DMED. OBJECTIVES: To explore the effect and possible underlying mechanisms of Sax in the treatment of DMED. METHODS: The model of DM was established by intraperitoneal injection of streptozotocin. All rats were divided into three groups (n = 8 per group): control group, DMED group and DMED+Sax group. In cellular experiments, the corpus cavernosum smooth muscle cells (CCSMCs) were exposed to high glucose (HG), and treated with Sax and AMD3100 (SDF-1 receptor inhibitor). The penile tissue and CCSMCs were harvested for detection. RESULTS: We found that erectile function was impaired in DMED rats compared with the control group, which was partially relieved by Sax. Decreased expression of DPP-4 and increased level of SDF-1 were also observed in DMED+Sax group, together with elevation of PI3K/AKT pathway and inhibition of endothelial dysfunction, oxidative stress and apoptosis in corpus cavernosum. Moreover, Sax could also regulate oxidative stress and apoptosis in CCSMCs under HG condition, which was blocked in part by AMD3100. CONCLUSION: Sax could alleviate DMED through increasing SDF-1 and PI3K/AKT pathway, in company with moderation of endothelial dysfunction, oxidative stress and apoptosis. Our findings indicated that DPP-4 is may be beneficial to the management of DMED.

Protective effect of Saxagliptin on diabetic rats with renal ischemia reperfusion injury by targeting oxidative stress and mitochondrial apoptosis pathway through activating Nrf-2/HO-1 signaling.

Oxidative stress and apoptosis play vital role in diabetic rats suffering from renal ischemia reperfusion injury (IRI). As a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, Saxagliptin(SAX)has been confirmed in the regulation of inflammation and apoptosis by targeting Nrf-2/HO-1signalling. The study was designed to explore the efficacy and potential mechanisms of SAX on inflammation and apoptosis for treating of IRI in diabetic rats. Through testing the expressions of Nrf-2, HO-1, Cleaved-Caspase9, Cleaved-Caspase3, Bax, BCL-2, Bak, Apaf-1, cytochrome C (Cytc), Cystatin C (CysC), ß2-microglobulin (ß2-MG), creatinine (Cr), urea nitrogen (BUN), TUNEL and pathological morphology, the effects of SAX on IRI diabetic rats have been investigatedg. The results has displayed SAX treatment significantly attenuate the cell apoptosis and pathological damage of kidney as well as lessening the expression of cleaved-caspase-9, cleaved-caspase3, Bax, cytoplasmic-Cytc, MDA, Bak, and Apaf-1 molecules, and the contents of ROS, Cr, CysC, ß2-MG, and BUN. Furthermore, SAX therapy also increased the expression of Nrf-2, BCL-2, HO-1 and mitochondrial cytochrome Cytc, and enhanced the activity of SOD, CAT and GPx. Therefore, our study has indicated that SAX treatment alleviated IRI in diabetic rats by suppressing oxidative stress and mitochondrial apoptotic pathways by activating the Nrf-2/HO-1 signaling.

Voglibose and saxagliptin ameliorate the post-surgical stress and cognitive dysfunction in chronic anaesthesia exposed diabetic MCAo induced ischemic rats.

Background: Chronic surgical anaesthesia and uncontrolled hyperglycemia are bidirectional risk factors for the development of psychiatric, cerebrovascular, and cardiovascular diseases. Objective: The current study was designed to elucidate the neuroprotective effects of anti-diabetic agents in pre and post-surgical anaesthesia exposure on diabetic ischemic rats. Methods: The diabetes type-2 was induced and rats having more than 250 gm/dl blood glucose levels were considered for study. Administration of anaesthetic agents (ketamine 100 mg/kg IP, xylazine 10 mg/kg IP) were done pre and post MCAo surgery for 7 days. The treatment with anti-diabetic agents (voglibose, saxagliptin, repaglinide, dapagliflozin) was carried out after 7 days of Post MCAo surgery for one week. After treatment, assessment of neurobehavioral function was carried out using Morris Water Maze. After that, brains were excised and bloods were collected from all groups subjected for assessment of neuromodulator levels, oxidative stress parameters, serum biochemical biomarkers. Results: The treatment with voglibose and saxagliptin not only improved neuromodulator levels statistically significant (p < 0.001) and cognitive profile but also significantly improved (p < 0.01) overall stroke serum biomarkers (Serum Glucose, GGT, CRP, CK-MB, LDH). Conclusion: The results of the present study, suggested that chronic exposure of anaesthesia worsens the cognition and increases risk of stroke biomarkers in diabetic conditions. We can conclude that voglibose, saxagliptin, and dapagliflozin can significantly improve the postoperative mortality, morbidity, and cognitive dysfunction caused by post-surgical stress and chronic anaesthesia-induced cognitive dysfunction.

Formulation, Characterization, and Evaluation of Eudragit-Coated Saxagliptin Nanoparticles Using 3 Factorial Design Modules.

Background and Introduction: Saxagliptin is a hypoglycemic drug that acts as a dipeptidyl peptidase-4 (DPP-4) inhibitor and is preferably used in the treatment of Type 2 Diabetes Mellitus (T2DM). It is safe and tolerable; however, the major disadvantage associated with it is its low bioavailability. Aim: The present research aimed to enhance the bioavailability of the drug by enteric coating with a polymer that controls the rate of drug delivery, and it was prepared as Solid Lipid Nanoparticles (SLNs). Methodology: In the current study, various SLN formulations were developed using a central composite design (CCD) module using Design Expert-11 software. A modified solvent injection technique was used to prepare Saxagliptin nanoparticles coated with Eudragit RS100. The CCD was used to determine the independent variables and their effect on dependent variables at varied levels. Evaluation studies such as particle size analysis, Zeta potential, polydispersity index (PDI), drug loading, entrapment efficiency, in-vitro drug release studies, and in vivo pharmacokinetic studies were performed for the optimized SLN formulation. The reversed-phase HPLC method was developed and validated for the estimation of the pharmacokinetic parameters of the pure drug and prepared SLNs. Results: The effect of independent variables (A1: amount of lipid, A2: amount of polymer, A3: surfactant concentration, and A4: homogenization speed) on dependent variables (R1: particle size, and R2: entrapment efficiency) was established in great detail. Observed responses of the prepared and optimized Saxagliptin SLN were close to the predicted values by the CCD. The prepared SLNs depicted particle sizes in the range of 212-442 nm. The particle size analysis results showed that an increase in the lipid concentration led to an increase in particle size. The developed bioanalytical method was noted to be very specific and robust. The method accuracy varied from 99.16% to 101.95% for intraday, and 96.08% to 103.12% for inter day operation at low (5 mcg/mL), moderate (10 mcg/mL), and higher (15 mcg/mL) drug concentrations. The observed Zeta potential values for the prepared SLNs were in the range of -41.09 ± 0.11 to 30.86 ± 0.63 mV suggesting quite good stability of the SLNs without any aggregation. Moreover, the polydispersity indices were in the range of 0.26 ± 0.051 to 0.45 ± 0.017, indicative of uniformity of sizes among the prepared SLNs. In vivo study outcomes proved that Saxagliptin oral bioavailability significantly enhanced in male Albino Wistar Rats via SLN formulation and Eudragit RS100 coating approach. Conclusions: The developed and optimized Saxagliptin SLNs revealed enhanced Saxagliptin bioavailability in comparison to the native drug. Thus, this formulation strategy can be of great importance and can be implied as a promising approach to enhance the Saxagliptin bioavailability for facilitated T2DM therapy.