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The solid form landscape of sitagliptin phosphate was systematically evaluated by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy and X-ray powder diffraction (XRPD), supported by a plethora of auxiliary analytical techniques. The preformulation experiments resulted in the transition of sitagliptin phosphate monohydrate into a new anhydrous form (designated as form IV), obtained after recrystallization from absolute ethanol. The anhydrous form IV remained stable under stressed conditions (1 month at 25 °C/60 %RH and 40 °C/75 %RH). On the other hand, thermal heating (dehydration) of sitagliptin phosphate monohydrate resulted in conversion into another anhydrous form II. Form II was found to be metastable, because after melting, under exposure at 40 °C/75 %RH for 1 month, or when dissolved in absolute ethanol converted to the stable anhydrous form IV of sitagliptin phosphate. A monotropic relationship was found between both studied anhydrous forms. Intrinsic dissolution tests revealed differences in the dissolution rates between the monohydrate and the anhydrous forms of sitagliptin phosphate. This research corrects the record with an accurate chemical composition of the anhydrous form IV of sitagliptin phosphate that was previously regarded as a hemiethanolate. In addition, the crystal structure of anhydrous form II of sitagliptin phosphate has been solved and reported for the first time. The preformulation experiments revealed dehydration of sitagliptin phosphate monohydrate after dissolving in absolute ethanol. The resulting product after evaporation of the solvent was designated as a new anhydrous form IV. The anhydrous form IV remained stable even after exposure at stressed conditions. On the other hand, after classical thermal/heating (dehydration), sitagliptin phosphate monohydrate first underwent into anhydrous form II. Interestingly, this anhydrous form II, by melting or either after recrystallization from absolute ethanol or exposed at 40 °C/75 %RH for one month, converted into anhydrous form IV of sitagliptin phosphate. A monotropic relationship was found between both anhydrous form II and form IV. The research sheds new light on the properties and structural features of the form IV of sitagliptin phosphate that was previously regarded as a hemiethanolate. In addition, the crystal structure of anhydrous form II as well as the unit cell parameters for the anhydrous form IV of sitagliptin phosphate have been reported for the first time. [Display omitted] • Previously reported sitagliptin phosphate hemiethanolate was found to be a novel anhydrous form (designated as form IV) • Sitagliptin phosphate monohydrate dehydrated into metastable sitagliptin phosphate anhydrous form II • Crystal structure of sitagliptin phosphate anhydrous form II was solved and unit cell parameters for anhydrous form IV were reported • Sitagliptin phosphate anhydrous form II transformed into form IV either upon melting, stressed, or in absolute ethanol • Sitagliptin phosphate monohydrate converted into the anhydrous form IV when dissolved in absolute ethanol. [ABSTRACT FROM AUTHOR]

[Display omitted] • Systematical SO 4 •− oxidation of solid-phase pharmaceuticals was first explored. • SO 4 •− effectively oxidized different pharmaceuticals in solid and liquid phases. • Mechanistic differences between solid and liquid pharmaceuticals were proposed. • The degradation products of pharmaceuticals remained some environmental risks. As a class of organic micropollutants of global concern, pharmaceuticals have prevalent distributions in the aqueous environment (e.g., groundwater and surface water) and solid matrices (e.g., soil, sediments, and dried sludge). Their contamination levels have been further aggravated by the annually increased production of expired drugs as emerging harmful wastes worldwide. Sulfate radicals (SO 4 •−)-based oxidation has attracted increasing attention for abating pharmaceuticals in the environment, whereas the transformation mechanisms of solid-phase pharmaceuticals remain unknown thus far. This investigation presented for the first time that SO 4 •−, individually produced by mechanical force-activated and heat-activated persulfate treatments, could effectively oxidize three model pharmaceuticals (i.e., methotrexate, sitagliptin, and salbutamol) in both solid and liquid phases. The high-resolution mass spectrometric analysis suggested their distinct transformation products formed by different phases of SO 4 •− oxidation. Accordingly, the SO 4 •−-mediated mechanistic differences between the solid-phase and liquid-phase pharmaceuticals were proposed. It is noteworthy that the products from both systems were predicted with the remaining persistence, bioaccumulation, and multi-endpoint toxicity. Therefore, some post-treatment strategies need to be considered during practical applications of SO 4 •−-based technologies in remediating different phases of micropollutants. This work has environmental implications for understanding the comparative transformation mechanisms of pharmaceuticals by SO 4 •− oxidation in remediating the contaminated solid and aqueous matrices. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase 4 (DPP 4) inactivates a range of bioactive peptides. The cleavage of insulinotropic peptides and glucagon-like peptide 1 (GLP 1) by DPP 4 directly influences glucose homeostasis. This study aimed to describe the mode of interaction between sitagliptin (an antidiabetic drug) and human DPP 4 using in silico approaches. Docking studies were conducted using AutoDock Vina, 2D and 3D schematic drawings were obtained using PoseView and PLIP servers, and the DPP 4 -sitagliptin complex was visualized with Pymol software. The best affinity energy to form the DPP 4 -sitagliptin complex was E -value ​= ​- 8.1 ​kcal ​mol−1, as indicated by docking simulations. This result suggests a strong interaction. According to our observations, hydrophobic interactions involving the amino acids residues Tyr663 and Val712, hydrogen bonds (Glu203, Glu204, Tyr663, and Tyr667), π-Stacking interactions (Phe355 and Tyr667), and halogenic bonds (Arg123, Glu204, and Arg356) were prevalent in the DPP 4 -sitagliptin complex. Root Mean Square Deviation prediction also demonstrated that the global structure of the human DPP 4 did not have a significant change in its topology, even after the formation of the DPP 4 -sitagliptin complex. The stable interaction between the sitagliptin ligand and the DPP 4 enzyme was demonstrated through molecular docking simulations. The findings presented in this work enhance the understanding of the physicochemical properties of the sitagliptin interaction site, supporting the design of more efficient gliptin-like iDPP 4 inhibitors. [ABSTRACT FROM AUTHOR]

Development of efficient drug carriers has become an integral part of advanced drug delivery systems. This work aims at developing composites by adopting an economically viable method for sustained release of anti-diabetic drug sitagliptin — a potent and selective dipeptidyl peptidase-IV inhibitor. To combat the harsh environment of gastrointestinal tract, the composite (F13) was prepared using biodegradable polymers namely chitosan, guar gum and poly(vinyl alcohol) with montmorillonite clay as nano-filler and tetraethyl orthosilicate as the cross linker. The composites were characterized using FT-IR, XRD, DSC and SEM techniques. Physical properties such as thickness, swelling capacity, folding endurance and water solubility were studied. In vitro analysis of composites (F17, F19 and F20) in simulated gastric medium showed <14 % cumulative release in 2 h while a sustained release was observed in simulated intestinal medium. Drug release kinetics was investigated using five mathematical models namely zero order, first order, Higuchi, Hixon-Crowell and Korsemeyer-Peppas wherein the latter was the best fit model (R2, 0.969). Antimicrobial studies of drug free composite (F13) revealed good activity against bacteria as well as fungi. The results implied that the composites were pH sensitive and could serve as a potential choice for sustained release of drugs. • Chitosan/guar gum/poly(vinyl alcohol) composite reinforced with montmorillonite nanoclay • Use of green cross-linker TEOS with significantly lower toxicity profile • Sustained release profile of sitagliptin from the composite in SGF (<14 % in 2 h) and SIF [ABSTRACT FROM AUTHOR]

We aimed to evaluate patient preferences towards three oral antihyperglycaemic therapies using conjoint analysis to determine which attributes may influence use. We used an online survey, completed by 553 US respondents with type 2 diabetes mellitus (T2DM; mean age 64 ± 9 years; 55% had cardiovascular [CV] risk; 27% had CV disease), to present hypothetical, blinded, pairwise, drug profile comparison choices, between different benefit/risk attributes and effect ranges. Attributes were derived from phase 3 trials for empagliflozin 25 mg (SGLT2 inhibitor), oral semaglutide 14 mg (GLP-1 receptor agonist) and sitagliptin 100 mg (DPP-4 inhibitor). Predicted therapy preference outcomes and relative importance of each attribute were calculated (presented as a percentage). Preference score was highest for the profile matching empagliflozin (56%), versus sitagliptin (38%; z-test, P < 0.001) and oral semaglutide (6%, z-test, P < 0.001). Results were overall consistent in subgroup analyses. Genital infection risk was the most important attribute (relative score: 19% [z-test, P = 0.077 ]). Other important attributes were fasting requirements (15%), weight reduction (15%), risk of vomiting (14%), CV benefit (12%), and risk of nausea (11%). HbA1c reduction (8%) and ability to take medication with other drugs (6%) were considered less important. While blinded to drug name/dose, respondents chose a drug profile similar to empagliflozin (41%) versus sitagliptin (31%), oral semaglutide (11%), or 'none of the options' (17%). While the drug profile comparable to empagliflozin was preferred, CV benefit was not the top patient priority. A shared physician-patient decision model and increased patient education are needed to ensure optimal use of guideline-directed T2DM therapies. • Novel research measuring patient preferences for new oral anti-diabetic treatment options (80/85 characters) • Patients seem to prefer a drug comparable to empagliflozin over sitagliptin or oral semaglutide (83/85 characters) • Increasing patient awareness of cardiovascular benefits of newer oral therapies is needed (79/85 characters) [ABSTRACT FROM AUTHOR]

• Inhibition of DPP4 as a medication for women with type 2 diabetes and specific cancer could have various consequences. • In the case of breast cancer (BC), DPP4 inhibition induces EMT, invasion, metastasis, and chemotherapy resistance. • In ovarian cancer (OV), DPP4 inhibition induces EMT, invasion, and metastasis, while there is no supporting evidence for chemo-resistance. • For endometrial cancer (EC), inhibition of DPP4 decreased invasion and migration but no synergistic effects were found for chemo-resistance. • Concerning cervical cancer (CC), DPP4 inhibition by sitagliptin increases invasion and migration. The inhibition of dipeptidyl- peptidase 4 (DPP-4) is an essential therapy for controlling hyperglycemia in patients with type 2 diabetes (T2DM). However, the role of DPP-4 in cancer is not yet clear, with some studies suggesting that it may either promote or suppress tumors. This makes it crucial to have personalized treatment for diabetic women with cancer to effectively manage their diabetes whilst and preventing cancer mortality. To address this issue, we conducted an integrative in-silico analysis and systematic review of the literature to comprehensively examine the relationship between DPP-4 expression and the effects of its inhibitors on prevalent female malignancies. We specifically chose studies that examined the effects of DPP-4 expression and DPP-4 inhibition (DPP-4i) on prevalent cancers in women, such as breast cancer (BC), ovarian cancer (OV), cervical cancer (CC), and endometrial cancer (EC). These studies comprised those conducted both in vivo and in vitro. The review of the literature indicated that DPP-4i may worsen aggressive traits such as metastasis, Epithelial-to-mesenchymal transition (EMT), and chemotherapy resistance in BC cells. However, cohort studies on diabetic and BC patients did not confirm these findings. In vitro studies indicate that on OV, DPP-4 upregulation has been shown to prevent metastasis, while CCappears to be influenced by DPP-4 expression in terms of cell migration. sitagliptin, a pharmaceutical inhibitor of DPP-4, had a significant impact on reducing adhesion in CC cells in vitro. Overexpression of DPP-4 increased cell migration and proliferation in CC and EC cells, and hence the application of sitagliptin is expected to prevent this effect. On the other hand, the result of in-silico data confirmed that a significant correlation exists between DPP-4 expression and immune cell infiltration in breast, ovarian, cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) as well as downregulated in these cancers compared to their normal tissue samples. Furthermore, a significant (p < 0.05) effect on OS of BC and CESC patients has been reported due to the elevation of DPP-4 methylation on a specific CPG Island. These findings could aid in creating specialized treatments for diabetic women with specific malignancies, but caution should be exercised when considering the patient's medical history and cancer type. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is widely prescribed to treat different malignancies as well as autoimmune diseases. However, it causes a range of side effects in different organs such as testis. This study aims to clarify the role of dipeptidyl peptidase 4 (DPP4) in MTX-induced testicular damage via pathways involved in oxidative stress and evaluates the protective effects of sitagliptin as a DPP4 inhibitor. Twenty-four animals randomly allocated into four groups including: (I) control, (II) MTX (20 mg/kg, i.p.), (III) sitagliptin (20 mg/kg, i.p., for four consecutive days), and MTX + sitagliptin in which received chemicals resembling group II and III. Histopathological examinations conducted to assess the structural changes in testes of different experimental groups. Also, ELISA method employed to investigate the levels of DPP4, AKT, p-AKT, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase-1 (HO-1). In addition, the total malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) were assessed. The results indicated that MTX administration was accompanied with testicular damage, which reversed by sitagliptin treatment. The biochemical observations demonstrated that MTX markedly increased the levels of DPP4, decreased p-AKT/AKT ratio followed by a marked decrement in Nrf2 and HO-1 levels. Also, it was observed that MTX decreased the activity of SOD and increased total MDA content in testicular specimen. However, sitagliptin treatment diminished mentioned alterations effectively. Altogether, our findings supported the possible role of DPP4 in MTX-induced testicular toxicity along with the potential protective features of sitagliptin via suppressing of the histopathological and biochemical alterations induced by MTX. [Display omitted] • MTX administration alters the structure of testicular tissue. • MTX administration increases DPP4 levels in testicular tissues. • MTX administration suppresses pAKT/AKT ratio and suppresses Nrf2, HO-1 and SOD activities. • DPP4 inhibition by sitagliptin treatment diminishes these alterations induced by MTX in testicular tissues. [ABSTRACT FROM AUTHOR]

[Display omitted] • Successfully modification of AgNPs by 4-mercaptophenylbronic acid. • Introducing MPBA-AgNPs as a colorimetric sensor to detect Moxi and Sit drugs. • High sensitivity and selectivity response of MPBA-AgNPs sensor for Moxi and Sit drugs. • A detection limit of 0.27 and 16.63 µM for Moxi and Sit drugs with MPBA-AgNPs sensor can be achieved. Nowadays, considering the vital role of drugs, identifying and diagnosing them with simple and cost-effective methods and materials is very important. This study explores a colorimetric approach using silver nanoparticles (AgNPs) modified with 4-mercaptophenylboronic acid (MPBA) as a rapid and economical sensor for detecting Sitagliptin (Sit) and Moxifloxacin (Moxi) drugs. The MPBA-AgNPs sensor was synthesized via chemical synthesis of AgNPs followed by surface modification by MPBA. The effect of different parameters on the responsiveness of the MPBA-AgNPs sensor was investigated. The surface morphology, chemical structure, and size of the MPBA-AgNPs sensor in different conditions were examined by FE-SEM, FT-IR, DLS, and TEM analysis. Finally, the results of various investigations showed that the surface of AgNPs successfully modified by MPBA and MPBA-AgNPs as a colorimetric sensor for the detection of Sit and Moxi drugs has excellent detection limits of 16.63 and 0.27 µM. The recovery of the experiment in real samples was obtained in the range of 92.37–105.44 %. [ABSTRACT FROM AUTHOR]

Intrahepatic cholestasis is a common clinical form of hepatobiliary injury characterized by the intrahepatic accumulation of toxic bile acids. Besides its antidiabetic activity, the dipeptidyl peptidase IV inhibitor sitagliptin (SG) has been recently assigned diverse pharmacological activities and therapeutic potential against different disorders owing to its emerging antioxidant and anti-inflammatory properties. The current study explored the potential hepatoprotective effect of SG on α-naphthyl isothiocyanate (ANIT)-induced cholestatic liver injury (CLI) in mice and investigate its possible targeted signaling pathways. Mice received SG (10 and 20 mg/kg) for four consecutive days, two days before and after a single oral administration of ANIT (75 mg/kg). Our results revealed that SG administration remarkably prevented ANIT-induced histopathological lesions in the liver and maintained hepatic functions and oxidative/antioxidant balance. Ultimately, SG counteracted the inflammatory response in the liver, as indicated by the marked suppression of hepatic expression of NF-κB, TNF-α, and IL-6. Moreover, it inhibited the endoplasmic reticulum (ER) stress response in the liver. These beneficial effects of SG were accompanied by upregulation of SIRT1, p-AMPK, and Nrf2 expressions while downregulating keap1 expression in the liver. In conclusion, this study is the first to demonstrate the ability of SG to protect against ANIT-induced CLI through modulating multiple signaling cascades, including SIRT1/AMPK, Nrf2/keap1, and NF-кB, which resulted in enhanced antioxidant capacity and repressed inflammatory and ER stress responses in the liver. [Display omitted] • SIRT1/AMPK signaling regulates oxidative stress-mediated ER stress and inflammation • Sitagliptin activates SIRT1/AMPK regulatory axis during cholestatic liver injury • Sitagliptin enhances Nrf2 antioxidant response during cholestatic liver injury • Sitagliptin inhibits NF-κB inflammatory response during cholestatic liver injury • Sitagliptin inhibits ER stress response during cholestatic liver injury [ABSTRACT FROM AUTHOR]

High fat diet (HFD) consumption can cause dysregulation of glucose and lipid metabolism, coupled with increased ectopic lipid deposition in renal tissue leading to steatosis and dysfunction. Sitagliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor clinically used for type II diabetes therapy; however its effect on renal steatosis in obese state is still uncertain. Herein, obesity was induced by feeding male Wistar rats HFD for 18 weeks, thereafter received either drug vehicle, or sitagliptin (10 mg/kg, PO) along with HFD for further 6 weeks and compared with age-matched rats receiving normal chow diet (NCD). After 24 weeks, serum and kidneys were collected for histological and biochemical assessments. Compared to NCD-fed group, HFD-fed rats displayed marked weight gain, increased fat mass, insulin resistance, dyslipidemia, impaired kidney functions and renal histological alterations. Sitagliptin effectively ameliorated obesity and related metabolic perturbations and improved kidney architecture and function. There were increased levels of triglycerides and cluster of differentiation 36 (CD36) in kidneys of obese rats, that were lowered by sitagliptin therapy. Sitagliptin significantly repressed the expression of lipogenesis genes, while up-regulated genes involved in mitochondrial biogenesis and fatty acid oxidation in kidneys of HFD-fed rats. Sitagliptin was found to induce down-regulation of endoplasmic reticulum (ER) stress and apoptotic markers in kidneys of obese rats. These findings together may emphasize a novel concept that sitagliptin can be an effective therapeutic approach for halting obesity-related renal steatosis and CKD. • Sitagliptin alleviates obesity & related metabolic disorders in HFD-induced obese rats. • Sitagliptin improves renal histological architecture and kidney function of obese rats. • Sitagliptin attenuates ectopic lipid deposition and lipotoxicity in kidneys of obese rats. • Sitagliptin promotes mitochondrial biogenesis and β-oxidation in kidneys of obese rats. • Sitagliptin silences endoplasmic reticulum stress and apoptosis in kidneys of obese rats. [ABSTRACT FROM AUTHOR]

The potential immunoregulatory capacity of sitagliptin on interleukin-29 (IL-29) and genes involved in its intracellular pathway were explored in type 2 diabetes mellitus (T2D). T2D patients treated with six months of sitagliptin (Sita+), patients not treated with sitagliptin (Sita−), and healthy controls (HCs) were included. IL-29 levels in the supernatant of stimulated mononuclear immune cells was determined with ELISA. The mRNA expression levels of IL-29 , FOS , JUN , NF-AT2 , NF-KB1 , STAT1-2 , IRF1 , IRF3 , IRF7 , and IRF9 was assessed with real-time qPCR. Increased protein and gene levels of IL-29 were observed in Sita− group compared to HCs (p < 0.001 and p = 0.026), while those levels were diminished in Sita+ group in comparison with Sita− group (p < 0.001 and p = 0.008). Expression of FOS , NF-AT2 and NF-KB1 in Sita− patients was higher than HCs (p = 0.018, p = 0.021, and p = 0.001). A significant decrease in expression of FOS , NF-AT2, and NF-KB1 was found in Sita+ group versus Sita− parients (p = 0.027, p = 0.003, and p = 0.002). In Sita− patients, IL-29 levels were correlated to glucose metabolism parameters including FPG and HbA1c (p < 0.05 for all). Sitagliptin administration has a regulatory effect on the aggressive expression of IL-29 and its signaling molecules including FOS , NF-AT2 and NF-KB1 in T2D. [ABSTRACT FROM AUTHOR]

Polycystic Ovary Syndrome (PCOS) is a multifactorial reproductive, endocrine and metabolic disturbance which is very commonly observed in females of reproductive age group. The disease is still incurable however the use of synthetic drugs in combination with lifestyle is recommended. Accordingly, the present study was conducted to investigate the possible beneficial effects of sitagliptin on PCOS induced rats on control diet (CD)/high fat- high fructose diet (HFFD). PCOS was induced by giving testosterone propionate (TP) for 28 days to both the CD/HFFD rats and treated with STG i.p. for last 15 days. At the end of the experiment lipid profile, inflammatory markers, expression of NF-κB-p65, miR-24 and miR-29a, fibrotic and apoptotic proteins from ovary tissue were examined. Moreover, lipid accumulation and fibrosis of ovary tissue was further confirmed using Sudan III and Masson's trichrome stain. STG treated rats exerted a significant decrease in levels of cholesterol, TG, LDL-C, VLDL-C, IL-6 and TNF-α and increased HDL-C level, miR-24 and miR-29a expression. STG treated groups expressed significantly decreased expression of NF-κB-p65, TGF-β1, p-Smad 2 and p-Smad 3 followed by no significant changes in the expression of BAX, caspase-9, caspase-3 and Bcl-2 in all the PCOS induced groups. Among all the CD/ HFFD fed groups, rats on HFFD showed more devastating effect which suggests that diet plays a major role in genesis of PCOS. In conclusion, current results reflect the potential impact of STG against dyslipidaemia, inflammation and fibrosis in PCOS rats via regulating dyslipidaemia and fibrosis via DPP 4 mediated miR-29a expression. • Lipid abnormality, oxidative stress and inflammatory cytokines analysis found in TP rats on either diet was reduced by STG. • STG regulated the expression of miR-24 and miR-29a and lowered the development of ovary tissue fibrosis in PCOS rats fed on either diet. • Findings of this study revealed the therapeutic potential of STG in PCOS rats against dyslipidaemia, inflammation and fibrosis via regulating lipid imbalance and DPP 4 mediated miR-29a expression, consequences of which resulted in melioration of inflammatory response, fibrosis, miR-24 and miR-29a expression. [ABSTRACT FROM AUTHOR]

Sitagliptin is an antihyperglycemic drug used in adults for the treatment of diabetes Type 2. Literature data and in-house experiments were applied in this monograph to assess whether methods based on the Biopharmaceutics Classification System (BCS) could be used to assess the bioequivalence of solid immediate-release (IR) oral dosage forms containing sitagliptin phosphate monohydrate, as an alternative to a pharmacokinetic study in human volunteers. The solubility and permeability characteristics of sitagliptin were reviewed according to the BCS, along with dissolution, therapeutic index, therapeutic applications, pharmacokinetics, pharmacodynamic characteristics, reports of bioequivalence (BE) / bioavailability problems, data on interactions between the drug and excipients and other data germane to the subject. All data reviewed in this monograph unambiguously support classification of sitagliptin as a BCS Class 1 drug. In light of its broad therapeutic index and lack of severe adverse effects, the clinical risks associated with moderately supraoptimal doses were deemed inconsequential, as were the risks associated with moderately suboptimal doses. Taking all evidence into consideration, it was concluded that the BCS-based biowaiver can be implemented for solid IR oral drug products containing sitagliptin phosphate monohydrate, provided (a) the test product is formulated solely with excipients commonly present in solid IR oral drug products approved in ICH or associated countries and used in amounts commonly applied in this type of product, (b) data in support of the BCS-based biowaiver are obtained using the methods recommended by the WHO, FDA, EMA or ICH and (c) the test product and the comparator product (which is the innovator product in this case) meet all in vitro dissolution specifications provided in the WHO, FDA, EMA or ICH guidance. [ABSTRACT FROM AUTHOR]

To assess the cost-effectiveness and cost utility of sitagliptin/metformin for the treatment of type 2 diabetes mellitus compared to those of glibenclamide/metformin in a semiprivate hospital and to compare the cost-effectiveness and cost utility of sitagliptin/metformin in a semiprivate hospital to those in the public health system (PHS) of Ecuador in 2019. A cost-effectiveness study considering the probability of cardiovascular death as the outcome and quality-adjusted life-year as a measure of utility, estimating direct medical costs in US dollars by a model case from the perspective of the third payer. The results will be presented as an incremental cost-effectiveness ratio. One-way and 2-way sensitivity analyses with tornado diagrams were performed. Direct medical costs were lower at the hospital than from the PHS in Ecuador. Considering the drugs metformin/sitagliptin, the total cost was $35.69 less in the hospital ($880.38) than from the comparator ($916.07). The highest percentage of direct medical costs corresponded to drugs (between 63.94% and 84.65%). An ICER of –$19 131.61 was obtained at the Hospital Un Canto a la Vida and –$1621.85 at PHS. In addition, the cost per quality-adjusted life-year earned was $611.11. Sensitivity analysis showed that the probability of drug use and the relative risk of cardiovascular death associated with such prescription were parameters that most affected the model. The combination therapy metformin/sitagliptin compared to metformin/glibenclamide was shown not to be cost-effective in the Hospital Un Canto a la Vida, and highly cost-effective in the PHS. • Some controversy persists regarding the drug of choice to be administered in conjunction with metformin when control goals are not achieved in patients with diabetes. Evidence of good quality did not show significant differences among 9 families of antidiabetic drugs; thus, it is recommended to rely on the specific characteristics of the patients to prescribe a second antidiabetic. Cost-effectiveness and cost-utility studies of dipeptidyl peptidase 4 inhibitors versus sulfonylureas showed that the former had better results. • The therapeutic combination of metformin/sitagliptin compared to metformin/glibenclamide was shown to be not cost-effective, because it exceeded the World Health Organization suggested ceiling of 3 times a country's gross domestic product per capita, in a second-level semiprivate hospital. Instead, in PHS the metformin/sitagliptin alternative was highly cost-effective. In the 2-way sensitivity analysis, the variable that modified the incremental cost-effectiveness ratio in both scenarios was the probability of using the metformin/glibenclamide combination. • The frequency of prescription of the different combinations of antidiabetics is a parameter to be considered so that new therapeutic options for diabetes mellitus can be cost-effective in clinical practice, especially considering that the drug cost is the most important parameter in direct medical costs. [ABSTRACT FROM AUTHOR]

• Insulin therapy in cystic fibrosis-related diabetes can be challenging and burdensome. • Chronic incretin-based therapy may be a reasonable option in the early stage of CFRD. • Three CFRD patients treated with sitagliptin for over 5 years responded to therapy. • Benefits of dipeptidyl peptidase-4 inhibitor persisted for one decade in 2 patients. • Long-term incretin-based therapy may remain effective if basal insulin needs are low. Cystic fibrosis-related diabetes (CFRD) affects 40–50% of adult patients with cystic fibrosis. Insulin therapy is recommended but there are therapeutic challenges, particularly risk of hypoglycemia and aversion of some patients to injectables. An oral incretin-based therapy using a DPP-4i (dipeptidyl peptidase-4 inhibitor), may be a reasonable option, especially in the early stage of the disease. The effect of chronic incretin-based therapy on CFRD is unknown. Here is a report of 3 cases of CFRD patients treated with sitagliptin and the response to therapy over a period of 5–10 years. An effective glycemic control was demonstrated in all the patients, at least during the first 5 years of sitagliptin treatment, and the benefit persisted for a decade in two of them. The secondary failure of the DPP-4i occurred in a CFRD patient with a phenotype resembling type 2 diabetes. A DPP-4i may have an important role in the management of CFRD. [ABSTRACT FROM AUTHOR]

[Display omitted] Chiglitazar (Carfloglitazar) is a novel peroxisome proliferator-activated receptor (PPAR) pan-agonist that has shown promising effects on glycemic control and lipid regulation in patients with type 2 diabetes. In this randomized phase 3 trial, we compared the efficacy and safety of chiglitazar with sitagliptin in patients with type 2 diabetes who had insufficient glycemic control despite a strict diet and exercise regimen. Eligible patients were randomized (1:1:1) to receive chiglitazar 32 mg (n = 245), chiglitazar 48 mg (n = 246), or sitagliptin 100 mg (n = 248) once daily for 24 weeks. The primary endpoint was the change in glycosylated hemoglobin A 1C (HbA 1c) from baseline at week 24 with the non-inferiority of chiglitazar over sitagliptin. Both chiglitazar and sitagliptin significantly reduced HbA 1c at week 24 with values of −1.40%, −1.47%, and −1.39% for chiglitazar 32 mg, chiglitazar 48 mg, and sitagliptin 100 mg, respectively. Chiglitazar 32 and 48 mg were both non-inferior to sitagliptin 100 mg, with mean differences of −0.04% (95% confidential interval (CI) −0.22 to 0.15) and −0.08% (95% CI −0.27 to 0.10), respectively. Compared with sitagliptin, greater reduction in fasting and 2-h postprandial plasma glucose and fasting insulin was observed with chiglitazar. Overall adverse event rates were similar between the groups. A small increase in mild edema in the chiglitazar 48 mg group and slight weight gain in both chiglitazar groups were reported. The overall results demonstrated that chiglitazar possesses good efficacy and safety profile in patients with type 2 diabetes inadequately controlled with lifestyle interventions, thereby providing adequate supporting evidence for using this PPAR pan-agonist as a treatment option for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Non-alcoholic fat liver disease (NAFLD) is the most common chronic liver disease in the world. NAFLD is a spectrum of diseases ranging from simple steatosis to hepatic carcinoma. The complexity of pathomechanisms makes treatment difficult. The oral antidiabetic agents, dipeptidyl peptidase four inhibitors (DPP-4i) have been proposed as possible therapeutic agents. This study was performed using a well-established NAFLD model in rats to elucidate whether sitagliptin could prevent steatohepatitis. Rats were fed a methionine/choline-deficient (MCD) diet with or without sitagliptin treatment for six weeks. Liver tissue was examined to estimate sitagliptin's effect on the development of NASH. The MCD diet decreased the SAM/SAH ratio, and increased plasma levels of homocysteine, free fatty acids, and long-chain acylcarnitines in the MCD rats. MMP2 and Col1A2 expression also increased under the MCD diet. Sitagliptin treatment did not reverse these effects and increased steatosis and long-chain acylcarnitines. In conclusion, sitagliptin was ineffective to prevent from NAFLD in the MCD rat model. This result challenges previous data reporting beneficial effects and is consistent with the clinical trials' negative results. • Sagliptin worsens steatosis in the MCD-NASH rat model. • Sitagliptin increased NASH markers in the MCD-NASH model. • Our results are consistent with sitagliptin negative effects in clinical trials. • Our results challenge previous data reporting sitagliptin beneficial effects. [ABSTRACT FROM AUTHOR]

Synthesis of novel and potent hit molecules have endless demand. The triazolo[4,3-a]pyrazine scaffold is used as an essential building block/scaffold in organic synthesis, which works as a key template for the development of various therapeutic agents. It displays a wide spectrum of potential biological activities that have been progressively studied in recent years on account of their versatile structure and the diverse derivatives that can be synthesized from it to ensure functional motifs. This review article gives an inclusive account of the synthetic utility of triazolo[4,3-a] pyrazine derivatives employed in the design and synthesis of different types of compounds containing various active heterocyclic rings with greater emphasis in recent literature. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase-IV (DPP-IV) inhibitor is one of the drug targets for the treatment of diabetes. Some classes of those drugs have dangerous side effects so is critical to develop safer drugs. By using rotation forest methods and in silico, it will be more efficient than conventional methods that require a lot more costs and are more time-consuming. One of in silico methods used in drug design is ligand-based virtual screening (LBVS). The interlocking structure capabilities are identified by the LBVS Process. The fingerprint is one of the structural interpretations. Molecular fingerprints are used as a criterion for LBVS in computational drug discovery. A circular fingerprint is found to improve LBVS performance. In this paper, we used the representation of ECFP and FCFP as a method to extract features, after which we used a Rotation Forest classifier to predict active and inactive compounds. The experiment result shows Rotation Forest has good prediction based on the different circular fingerprint and can successfully better classify with results of MCC being 85% and accuracy 92%. [ABSTRACT FROM AUTHOR]

Several of the DPP-4 inhibitors in the treatment of type 2 diabetes (T2DM) still have unsafe side effects in long-term use. It is necessary to develop a new DPP-4 inhibitor to minimize these unsafe side effects of the drug. QSAR is a model that can be used for the development of DPP-4 inhibitor drugs. The selection of a subset of DPP-4 inhibitor molecules by applying the clustering method can be made to improve the accuracy of the QSAR model. This study aims to select the corresponding DPP-4 inhibitor molecules by using the MiniBatchKMeans algorithm with Levenshtein distance and based on the log P criteria of 'Lipinski's Rule of 5' for QSAR modeling. The research began with the collection of DPP-4 inhibitor molecule data from the ChEMBL database site (https://www.ebi.ac.uk/chembl/) in CSV format. A representation of the molecular structure of the data is obtained from their SMILES features. Before running the clustering process, data in the form of SMILES is extracted into molecular fingerprints using several fingerprint generators, namely MACCS, ECFP, and FCFP. Clustering was carried out on five fingerprint datasets, including ECFP (with 4 and 6 diameters), FCFP (with 4 and 6 diameters), and MACCS (167 structural keys). The clustering process begins by determining the optimal number of clusters evaluated by applying the Davies-Bouldin index, the Silhouette coefficient, and the Calinski Harabasz score. Based on the clustering process, 1540 clusters were obtained from the minimum DBI cluster evaluation values of 0.545311, maximum SCO of 0.302842, and maximum CHS of 331.3942 from the MACCS fingerprint dataset. Based on log P criteria from 'Lipinski's Rule of 5', 1532 molecules were obtained for the molecular selection process that have log P values between -0.205 to 4.95. [ABSTRACT FROM AUTHOR]

Patients with type 2 diabetes mellitus require strict blood glucose control, and combination therapy with a thiazolidinedione and dipeptidyl peptidase-4 inhibitors, such as lobeglitazone and sitagliptin, is one of the recommended treatments. The objective of this study was to investigate a possible pharmacokinetic interaction between lobeglitazone and sitagliptin after multiple oral administrations in healthy Korean men. Two randomized, open-label, multiple-dose, 2-way crossover studies were conducted simultaneously in healthy men. In study 1, men were randomly assigned to 1 of 2 sequences, and 1 of the following treatments was administered in each period: 1 tablet of lobeglitazone sulfate (0.5 mg) once daily for 5 days and or 1 tablet each of lobeglitazone sulfate (0.5 mg) and sitagliptin (100 mg) once daily for 5 days. In study 2, men were also randomly assigned to 1 of 2 sequences and the treatments were as follows: 1 tablet of sitagliptin (100 mg) once daily for 5 days or 1 tablet each of sitagliptin (100 mg) and lobeglitazone sulfate (0.5 mg) once daily for 5 days. Serial blood samples were collected up to 48 h after dosing on the fifth day. Plasma drug concentrations were measured by LC-MS/MS. Pharmacokinetic parameters, including C max,ss and AUC 0–τ , were determined by noncompartmental analysis. The geometric least-square mean (GLSM) ratios and associated 90% CIs of log-transformed C max,ss and AUC 0–τ for separate or coadministration were calculated to evaluate pharmacokinetic interactions. Nineteen men from study 1 and 17 from study 2 completed the pharmacokinetic sampling and were included in the analyses. The GLSM ratios of C max,ss and AUC 0–τ were 0.9494 (95% CI, 0.8798–1.0243) and 1.0106 (95% CI, 0.9119–1.1198) for lobeglitazone (from study 1) and 1.1694 (95% CI, 1.0740–1.2732) and 1.0037 (95% CI, 0.9715–1.0369) for sitagliptin (from study 2), respectively. Except for the slight 17% increase in the sitagliptin C max,ss value, the pharmacokinetic parameters of lobeglitazone and sitagliptin met the pharmacokinetic equivalent criteria when administered separately or in combination. The increase in C max of sitagliptin when coadministered with lobeglitazone would not be clinically significant in practice. ClinicalTrials.gov Identifier: NCT02824874 and NCT02827890. • Sitagliptin C max,ss increased after multiple administrations with lobeglitazone. • Not a clinically significant increase in sitagliptin C max,ss. • Lobeglitazone and sitagliptin may be used in combination without dose adjustment. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a well-recognized independent risk factor for ASCVD, the aim of this study was to investigate the effects of a dipeptidyl peptidase-4 inhibitor, sitagliptin, on prevention of progression of coronary atherosclerosis assessed by three-dimensional quantitative coronary angiography (3D-QCA) in T2DM patients with coronary artery disease (CAD). This was a prospective, randomized, double-center, open-label, blinded end point, controlled 18-month study in patients with CAD and T2DM. A total of 149 patients, who had at least 1 atherosclerotic plaque with 20%–80% luminal narrowing in a coronary artery, and had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention, were randomized to sitagliptin group (n = 74) or control group (n = 75). Atherosclerosis progression was measured by repeat 3D-QCA examination in 88 patients at study completion. The primary outcome was changes in percent atheroma volume (PAV) from baseline to study completion measured by 3D-QCA. Secondary outcomes included change in 3D-QCA-derived total atheroma volume (TAV) and late lumen loss (LLL). The primary outcome of PAV increased of 1.69% (95%CL, −0.8%–4.2%) with sitagliptin and 5.12% (95%CL, 3.49%–6.74%) with the conventional treatment (p = 0.023). The secondary outcome of change in TAV in patients treated with sitagliptin increased of 6.45 mm3 (95%CL,-2.46 to 6.36 mm3) and 9.45 mm3 (95%CL,-4.52 to 10.14 mm3) with conventional treatment (p = 0.023), however, no significant difference between groups was observed (p = 0.175). Patients treated with sitagliptin had similar LLL as compared with conventional antidiabetics (−0.06, 95%CL, −0.22 to 0.03 vs. −0.08, −0.23 to −0.03 mm, p = 0.689). In patients with type 2 diabetes and coronary artery disease, treatment with sitagliptin resulted in a significantly lower rate of progression of coronary atherosclerosis compared with conventional treatment. Image 1 • Sitagliptin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, have anti-atherogenic effects both in an animal model and clinical setting. • At 18 months, sitagliptin attenuated the progression of coronary atherosclerosis in patients with coronary disease and type 2 diabetes independent of the effect on glycaemic control evaluated with three-dimension quantitative coronary angiography (3D-QCA) analysis. • This study may have important implications for defining the optimal strategy for management of patients with type 2 diabetes and coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

Chronic consumption of unhealthy diet and sedentary lifestyle induces fatty liver and metabolic complications. Adipocytes get overloaded with lipid succeeding low-grade inflammation and disrupting adipokine release. This research aims to investigate the effect of sitagliptin on white adipose tissue inflammation, adipokine level, metabolic syndrome, and fatty liver through 5' adenosine monophosphate-activated protein kinase (AMPK) pathway. In sixteen weeks of the experimental protocol, Swiss albino mice were kept in a standard environment and were fed 60% high-fat diet and 20% fructose water (HFFW) where they developed metabolic syndrome features, adipose tissue inflammation, and altered adipokine profile. Sitagliptin was administered for the last eight weeks. They were allocated to following six groups, control diet with regular water (1), HFFW only (2), HFFW and metformin 100 mg/kg (3), HFFW and sitagliptin 10 mg/kg (4), HFFW and sitagliptin 20 mg/kg (5), and HFFW and sitagliptin 30 mg/kg (6). Fasting serum insulin (FSI), glucagon-like peptide-1 (GLP-1), adipokines (adiponectin and leptin), serum lipid profile, hepatic lipid content, and white adipose tissue inflammation were assessed. Protein expression of P-AMPK, P-Acetyl co-a carboxylase (ACC), and mRNA expression of fatty acid metabolism genes were also evaluated in the liver. Sitagliptin significantly and effectively reversed metabolic syndrome complexity. FSI and GLP-1 levels were improved. A significant reduction in hepatic lipid content and oxidative stress was also observed. Also, sitagliptin significantly ameliorated adipose tissue inflammation and adiponectin levels at 20 mg/kg and 30 mg/kg. P-AMPK and P-ACC expression increased significantly. Moreover, expression of fatty acid synthesis genes was down-regulated, and fatty acid oxidation genes were up-regulated. Sitagliptin significantly ameliorated obesity-induced adipose tissue inflammation, metabolic syndrome, and fatty liver via regulation of adiponectin and AMPK levels in obese mice. Also, increased GLP-1 levels would have induced insulin-independent effects on adipose tissue and liver. Image 1 • 60% High-fat diet and 20% fructose water for sixteen weeks induces metabolic dysfunction and fatty liver in mice. • Fatty diet generates adipocyte stress predisposing them towards pro-inflammatory state and impairing adipokines release. • Sitagliptin ameliorates adipose tissue inflammation and adiponectin expression. • Sitagliptin induces hepatic AMPK phosphorylation improving fatty acid metabolism. • GLP-1 levels might have exerted insulin independent effects in liver and adipose tissue. [ABSTRACT FROM AUTHOR]

A case study on Sitagliptin drug products and Sitagliptin/Metformin drug products concerning contamination with N -nitrosamines was performed using two newly developed analytical methods for determination of N -nitroso-triazolopyrazine (NTTP; 7-nitroso-3-(trifluoromethyl)–5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a ]pyrazine) and its precursor triazolopyrazine (3-(trifluoromethyl)–5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3- a ]pyrazine). The method for determination of triazolopyrazine was previously unpublished, the method for determination of NTTP was published only for analysis of active pharmaceutical ingredient Sitagliptin and not the drug forms. Solving the N -nitrosamine contamination is requested by regulatory authorities all over the world and thus is vital for all pharmaceutical companies. The solution always requires a sensitive analytical method. Both newly developed methods use liquid chromatography coupled with mass spectrometry (single quadrupole analyzer in case of triazolopyrazine and triple quadrupole analyzer in case of NTTP). Separation of triazolopyrazine was achieved on a column Acquity CSH C18 using a mobile phase consisting of aqueous ammonium formate buffered at pH 4.2 and acetonitrile. Detection was performed using positive electrospray and selected ion monitoring at m/z 193. Separation of NTTP was achieved on a column Acquity HSS T3 using a mobile phase consisting of 0.1 % formic acid in water and methanol. Detection was performed using positive electrospray and multiple reaction monitoring at transitions m / z 222.15→42.05 (collision energy 17 eV) and m / z 222.15→192.15 (collision energy 11 eV). Two issues specific to NTTP and triazolopyrazine previously not described in scientific literature were successfully troubleshooted. Spontaneous degradation of Sitagliptin to triazolopyrazine and methyl (R)–3-amino-4-(2,4,5-trifluorophenyl)butanoate was solved by using N,N -dimethylformamide as sample solvent during development of the method for quantitation of triazolopyrazine. A bad peak shape of NTTP due to the presence of rotamers of NTTP was successfully troubleshooted by increasing column temperature. Both methods were used during an optimization study of manufacturing of Sitagliptin and Sitagliptin/Metformin drug products. The goal of the study was to decrease NTTP content in the final drug product under the strict legislative limit set by Federal Drug Agency. The efficacy of several solutions was proven, but could not be fully disclosed due to Intellectual Property Protection policy of Zentiva. Instead, a brief review of recently published strategies to cope with N -nitrosamine contamination is presented. [Display omitted] • N -Nitroso-triazolopyrazine (NTTP) – a new genotoxic impurity present in Sitagliptin. • LC-MS/MS method for quantification of NTTP was developed and validated. • Presence of rotamers and degradation were observed and successfully troubleshooted. • Screening of N -nitroso-triazolopyrazine and its precursor was performed. [ABSTRACT FROM AUTHOR]

The application of (R)-ω-transaminases as biocatalysts for chiral amine synthesis has been hampered by inadequate stereoselectivity and narrow substrate spectrum. Herein, an effective evolution strategy for (R)-ω-transaminase designing for the asymmetric synthesis of sitagliptin intermediate is presented. Since natural transaminases lack activity toward bulky prositagliptin ketone, transaminase scaffolds with catalytic machinery and activity toward the truncated prositagliptin ketone were firstly screened based on substrate walking principle. A transaminase chimera was established synchronously conferring catalytic activity and (R)-selectivity toward prositagliptin ketone through motif swapping, followed by stepwise evolution. The process resulted in a "best" engineered variant Mw TA M8 , which exhibited 79.2-fold higher activity than the chimeric scaffold Mw TA Mc. Structural analysis revealed that the heightened activity is mainly due to the enlarged and adaptive substrate pocket and tunnel. The novel (R)-transaminase exhibited unsatisfied industrial operation stability, which is expected to further modify the protein to enhance its tolerance to temperature, pH, and organic solvents to meet sustainable industrial demands. This study underscores a useful evolution strategy of engineering biocatalysts to confer new properties and functions on enzymes for synthesizing high-value drug intermediates. • Effective screening (R)-selective transaminase based on substrate walking strategy. • Simultaneously conferred (R)-selectivity and activity via motif swapping. • Semi-rational design for reshaping pocket achieve activity from scratch to strong. [ABSTRACT FROM AUTHOR]

Sitagliptin is an oral hypoglycemic drug that acts by selective inhibition of dipeptidyl peptidase-4 (DDP-4) enzyme. This study scrutinized the hepatoprotective impact of sitagliptin) against thioacetamide (TAA)-induced liver damage in mice. Male mice were injected with TAA (500 mg/kg) then treated with sitagliptin (20 mg/kg) orally for 5 days. Histopathological results of TAA group revealed severe degree of centrolobular hepatic necrosis. Additionally, biochemical findings showed marked elevation in the serum transaminases and gamma glutamyl transpeptidase (GGT) levels in TAA group. Injection of TAA significantly disrupted oxidant/antioxidants hemostasis of the hepatic tissues. Also, TAA markedly increased the expression of nuclear factor kappa-B (NF-KB); and enhanced Toll like receptor 4 (TLR4) as well as NLPR3 inflammosome production. Moreover, there was an elevation in the hepatic levels of tumor necrosis factor-alpha (TNF-α) and interleukin -1 beta (IL-1β) besides increased immunoexpression of Bcl-2-associated X protein (Bax) as well as caspase 3. In contrast, treatment with sitagliptin significantly attenuated TAA-induced histopathological, biochemical and immunohistochemical alterations. Our results suggest that the hepatoprophylactic impact of sitagliptin might be arbitrated via modulating TLR4 and NK-KB signaling cascade followed by depression of inflammation besides apoptosis. Unlabelled Image • Sitagliptin alleviated oxidative stress associating TAA-induced liver injury. • Sitagliptin exerted anti-inflammatory effect. • Sitagliptin inhibited TAA-induced apoptosis. [ABSTRACT FROM AUTHOR]

• Type I diabetes has a deleterious effect on bone microarchitecture. • Type I diabetes has a deleterious effect on implant osseointegration. • Sitagliptin had no direct action on bone osseointegration or on bone remodeling. Objective: To investigate the effects of sitagliptin, a dipeptidyl peptidase 4 inhibitor used to treat type II diabetes, on bone tissue and on implant osseointegration in diabetic rats. Design: Thirty-two male rats were divided into four groups: 1) Diabetic animals (GD); 2) Diabetic animals that received sitagliptin (GDS); 3) Normoglycemic animals (GN); and 4) Normoglycemic animals that received sitagliptin (GNS). All animals received titanium implants in the right tibia. Sitagliptin or water were administered for 4 weeks. Glycemia, HOMA-IR, insulinemia, microtomographic parameters of the left tibia and implant bone area fraction occupancy (BAFO) of the right tibia were evaluated. Results: The model used to induce diabetes led to hyperglycemia. However, HOMA-IR results showed no insulin resistance, and insulinemia was lower in diabetic animals, demonstrating the development of type I diabetes. Sitagliptin administration did not influence glycemic control. The diabetic animals showed a lower BAFO and bone volume fraction, as well as a lower trabecular number and thickness, revealing the deleterious effect of diabetes on bone metabolism and osseointegration. Conclusion: In this model, sitagliptin administration did not reverse the negative effects of type I diabetes on bone, suggesting that sitagliptin has no direct action on bone tissue and has no protective bone action in decompensated diabetic animals. [ABSTRACT FROM AUTHOR]

Abstract Inflammation and oxidative stress are the two processes crucial in atherogenesis. Platelet-activating factor acetylhydrolase (PAF-AH), a plasma lipoprotein-associated enzyme, degrades pro-inflammatory lipids generated within oxidatively modified lipoproteins. Extensive evidence shows that incretin-based drugs, a new class of anti-diabetic agents, can provide cardiovascular protection that cannot be attributed to their glucose-lowering effects. The present study was undertaken to determine whether the antiatherogenic effects of the GLP-1(glucagon-like peptide-1) receptor agonist (exenatide) and DPP-4(dipeptidyl peptidase-4) inhibitors (sitagliptin) may occur via the regulation of platelet-activating factor acetylhydrolase (PAF-AH) activity/mass and inhibition of low-density lipoprotein (LDL) oxidation in the fructose-fed rats. Normal and fructose-fed rats (8 wk) were treated (4 wk) with sitagliptin (5 and 10 mg/kg p.o.) or with exenatide (5 and 10 µg/kg, s.c.). Plasma PAF-AH activity and phosphatidylcholine (PC) concentration were measured colorimetrically. Plasma PAF-AH concentration, oxidized LDL (oxLDL), hexanoyl-Lys adduct (HEL), lyso-PC, apolipoprotein A-I (apoA-I), apoB, platelet-activating factor (PAF), monocyte chemoattractant protein-1 (MCP-1) and endothelin-1 (ET-1) were measured by ELISA. The four-week exenatide (5 µg/kg, sc.) treatment of fructose fed-rats significantly increased plasma PAF-AH activity (+33%, P < 0.001) and decreased the level of circulating oxLDL (-42%, P < 0.05) and MCP-1 (-23%, P < 0.01). These changes were accompanied by the decrease in plasma PC/lyso-PC (-47%, P < 0.001) and apoB/apoA-I ratio (-75%, P < 0.001). The effect of exenatide on enzyme activity was associated with only a minor effect on metabolic parameters and was independent of weight reduction. Exenatide but not sitagliptin inhibits oxidative modification of LDL probably due to favorable effect on plasma PAF-AH activity. [ABSTRACT FROM AUTHOR]

Abstract A simple and highly sensitive spectrofluorimetric method was developed and validated for the determination of sitagliptin phosphate (STP) and saxagliptin (SAX). The proposed method is based on Hantzsch reaction of both drugs through their reaction with acetyl acetone-formaldehyde reagent (AAF) followed by investigation of the fluorescence spectral behavior of the formed fluorescent products in presence of Sodium Dodecyl Sulfate (SDS) micellar system as additive to enhance the obtained flourescence at 483 nm after excitation at 419 nm for both drugs. The fluorescence intensity in the presence of SDS increased by 1.7 and 1.6 folds for STP and SAX, respectively than that of the surfactant free aqueous. The linearity of calibration curve was found at range of 50–700 ng mL−1 and 150–900 ng mL−1 with detection limits of 16.43 and 38.60 ng mL−1 for STP and SAX, respectively. The percent recovery ± standard deviation was found to be 99.87 ± 0.77 and 99.00 ± 0.52 for STP and SAX, respectively. The values of relative standard deviations were below 2% indicating good precision of the developed method. The analysis of the studied drugs in bulk, spiked human plasma, dosage form and content uniformity test was successfully applied with high accuracy. Highlights • A valid spectrofluorimetric method for STP and SAX analysis was developed. • The proposed method is based on Hantzsch reaction. • A SDS micellar system was used as additive to enhance the obtained fluorescence. • The method was successfully applied to spiked human plasma, dosage form and content uniformity test. [ABSTRACT FROM AUTHOR]

Highlights • Sitagliptin is a dipeptidyl peptidase 4 inhibitor used as an anti-diabetic drug. • We investigate the protective effect of sitagliptin on the cognition in AD. • Sitagliptin treatment effectively protected the cognition function of the AD mice. Abstract Background Sitagliptin is an anti-diabetic drug and its effects on Alzheimer's disease (AD) remain controversial. This study aimed to investigate the protective effect of sitagliptin on the cognition in AD and its underlying molecular mechanism. Methods The APP/PS1 (a model of AD) mice received daily gastric gavage administration of sitagliptin (20 mg/kg) for 8 weeks. Then animals were subjected to behavioral experiment or sacrificed to histological staining and protein level analysis. Results The MWM test showed that sitagliptin treatment significantly reduced the escape latency times in APP/PS1 mice in the learning phase (day 3–5) and elongated the time spent in the target quadrant in the probe test. Sitagliptin significantly reduced amyloid plaque deposition and elevated the spine density and the protein levels of synaptoneurosome GluA1- and GluA2-containing AMPA receptor (GluA1R and GluA2R) in the brain of the APP/PS1 mice. Sitagliptin treatment significantly up-regulated the brain BNDF protein and phosphorylation of tyrosine receptor kinase B (TrkB). Furthermore, exendin-(9–39) (a glucagon-like peptide-1 [GLP-1] receptor antagonist) and K252a (a Trk tyrosine kinase inhibitor) treatment significantly abolished the cognitive protective effect of sitagliptin in the MWM test. Conclusion Sitagliptin treatment effectively protected the cognition function of the AD mice by regulating synaptic plasticity, at least partially, through activating GLP-1 and BDNF-TrkB signalings. [ABSTRACT FROM AUTHOR]

Abstract This study tested whether sitagliptin and shock wave (SW)-assisted circulatory-derived autologous endothelial progenitor cell (EPC) therapy would effectively preserve residual renal function in chronic kidney disease (CKD) induced by 5/6 left-nephrectomy/remove right kidney plus daily feeding high-protein diet (HPD) in rat. Adult-male SD rats (n = 40) were categorized into group 1 (sham-operated control with HPD), group 2 (HPD-CKD), group 3 [HPD-CKD + EPC (1.2 × 106 cell)/intra-vessel administration by day 14 after CKD-induction], group 4 [HPD-CKD + SW (0.12 mJ/mm2/180 shorts) at days 14/21/28 after CKD-induction by ultrasound-guided application] and group 5 [HPD-CKD + SW + EPC + sitagliptin (Sita; 600 mg/kg/day since day 14 after CKD induction)]. All animals were euthanized by day 60. By day 60, renal blood flow (RBF) was highest in group 1 and progressively increased from groups 2 to 5, whereas the levels of creatinine/BUN/proteinuria exhibited an opposite pattern of RBF among the five groups (all p < 0.001). The circulating levels of GLP-1/SDF-1α and protein levels of angiogenesis (VEGF/SDF-1α/CXCR4) and GLP-1R in kidney were progressively increased from groups 1 to 5, whereas circulating DPP4 activity exhibited an opposite pattern of SDF-1α among the groups (all p < 0.0001). The protein expressions of oxidative-stress (NOX-1/NOX-2/oxidized protein), apoptosis (Bax/caspase-3/PARP), fibrosis (Smad3/TGF-ß) and inflammation (TNF-α/NF-κB/MMP-2) and kidney injury score displayed an opposite pattern, whereas the protein expressions of TMP2, endothelial-cell markers (CD31/eNOS) and podocyte integrity biomarkers (podocin/ZO-1/synaptopodin) exhibited an identical pattern of RBF among the groups (all p < 0.001). In conclusion Sita associated SW-assisted EPC effectively protected residual renal function in CKD. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Comprehensive evaluation of chemical stability of sitagliptin was performed. • Kinetics of degradation was examined for the first time. • Stability of the drug in the presence of excipients was checked for the first time. • Interactions between the parent drug and excipients were shown. • Impurities of sitagliptin were identified in a broad range of stress conditions. Abstract Sitagliptin was stored at high temperature/high humidity, dry hot air, UV/VIS light and different pH. Then, a selective LC-UV method was developed for determination of sitagliptin in the presence of degradation products and for estimation of degradation kinetics. Because parent drugs can react with excipients in final pharmaceutical formulations, stability of sitagliptin was also examined in the presence of excipients of different reactivity, using FT-IR and LC-UV methods. Finally, LC–MS method was used for identification of degradation products of sitagliptin. High degradation of sitagliptin, following the first order kinetics, was observed in strongly acidic, alkaline and oxidative media. The quickest degradation was found in 2 M HCl and 2 M NaOH. In addition, all excipients used in the present study, i.e. fumaric acid, lactose, mannitol and magnesium stearate showed potent interactions with sitagliptin. Some of these interactions were shown without any stress while others were accelerated by high temperature/high humidity and dry hot air, and less by UV/VIS light. Some mechanisms for the observed changes were proposed, i.e. the Michael addition in the presence of fumaric acid and the Maillard reaction in the presence of lactose. In addition, degradation of sitagliptin together with the occurrence of its impurities was stated in a broad range of stress conditions. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Adenine treatment increased blood pressure and induced chronic kidney disease. • Sitagliptin attenuated all adenine-induced biochemical and physiological changes. • Sitagliptin action is probably through anti-inflammatory and antioxidant effects. Abstract We assessed the effect of treatment with the dipeptidyl peptidase-4 inhibitor, sitagliptin, on adenine-induced chronic kidney disease (CKD). Six equal groups of rats were given either normal food or food mixed with adenine (0.25% w/w for five weeks) to induce CKD. Some of these groups were also simultaneously treated with sitagliptin (2.5 and 10 mg/kg/day, by gavage). Rats given adenine showed elevation of blood pressure, decreased body weight and increased relative kidney weight. Adenine also significantly increased plasma urea, creatinine, cystatin C, liver-type fatty acid–binding protein concentrations and neutrophil gelatinase-associated lipocalin activity by 404%, 354%, 667%, 91% and 281% respectively and reduced plasma α-Klotho by 50%. In addition, adenine significantly increased albumin/creatinine ratio and N -acetyl-β- d -glucosaminidase activity by 3553% and 400% respectively and reduced creatinine clearance by 91%. Adenine feeding also significantly elevated the plasma concentration of inflammatory cytokines (plasma tumor necrosis factor-alpha, interleukin-1beta and transforming growth factor beta-1) and significantly reduced antioxidant indices (catalase, glutathione reductase and superoxide dismutase). Histopathologically, adenine caused renal fibrosis, inflammation and atrophy. When given concomitantly with adenine, sitagliptin ameliorated all the measured adenine-induced physiological and biochemical changes but not the histopathological changes. Sitagliptin (10 mg/kg/day) reduced plasma urea and creatinine by 32% and 25% respectively and increased creatinine clearance by 248%. These findings suggest a renoprotective action of sitagliptin on adenine-induced CKD. [ABSTRACT FROM AUTHOR]

Aims: The aims of this study were to assess glycemic control, weight loss, and durability of glycemic control in patients initiated on canagliflozin (CANA) versus sitagliptin (SITA).Methods: Adults with type II diabetes mellitus initiated on CANA or SITA (index date) were identified from IQVIA™ Real-World Data Electronic Medical Records - US database (03/29/2012-04/30/2016). Inverse probability of treatment weighting accounted for baseline differences between cohorts. Outcomes were compared using weighted Cox regression and Kaplan-Meier curves and included time to reaching HbA1c thresholds (<7%[53 mmol/mol], <8%[64 mmol/mol], <9%[75 mmol/mol]), weight loss ≥5%, failure to maintain HbA1c below threshold, new antihyperglycemic (AHA) prescription, and failure to maintain HbA1c/new AHA prescription.Results: Weighted cohorts were well balanced (NCANA = 14,542; NSITA = 15,151). CANA patients were 12-15% more likely to reach the HbA1c thresholds, 47% more likely to lose ≥5% of body weight, 31% less likely to have a new AHA prescription, 10-15% less likely to fail to maintain HbA1c, and 13-26% less likely to fail to maintain HbA1c or have a new AHA, versus SITA patients.Conclusions: CANA patients were more likely to reach HbA1c and weight loss thresholds and maintain HbA1c below threshold versus SITA patients, while being less likely to have a prescription for a new AHA, suggesting more durable glycemic control with CANA. [ABSTRACT FROM AUTHOR]

Highlights • A potent ω-TA was identified using bioinformatic tools from 16 potential enzymes. • 3-ATfBA was produced with good conversion (81.9%) and 99% ee. • ω -TAIC was successfully used for the synthesis of various β-amino acids. • Lowering the reaction pH to 7.0 can circumvent the inhibition of ω -TAIC by 3-ATfBA. Abstract Enantiopure β-amino acids are essential precursors of various pharmaceuticals, agrochemicals and other industrially important chemicals. In this study, we selected sixteen potential ω-Transaminases (ω-TAs) by BLAST and phylogenetic tree analysis. These ω-TAs were cloned, purified and tested for their reactivity for the synthesis of model β-amino acid (R)-3-amino-4-(2,4,5-triflurophenyl) butanoic acid [3-ATfBA], a key precursor for sitagliptin. In an enzymatic cascade, lipase converted β-ketoester substrate to β-keto acid, which was subsequently aminated by the selected ω-TA to its corresponding β-amino acid. A potent enzyme from Ilumatobacter coccineus (ω-TAIC) was identified for the production of 3-ATfBA. The pH dependency of the product inhibition suggested that lowering the reaction pH to 7.0 can circumvent the inhibition of ω-TAIC by 3-ATfBA and about 92.3% conversion of 100 mM β-keto ester substrate could be achieved. The applicability of this enzymatic system was further evaluated at the scale of 140 mM, wherein 3-ATfBA was generated with excellent conversion (81.9%) and enantioselectivity (99% ee). Furthermore, ω-TAIC was successfully used for the synthesis of various β-amino acids from their corresponding β-keto ester substrates. [ABSTRACT FROM AUTHOR]

Abstract Insulin dysregulation (ID) is a common metabolic disorder in horses. Recently, incretin hormone release has been suggested to be involved in ID in horses. In human medicine, metformin and sitagliptin are commonly used in combination for metabolic syndrome. This combination could be useful in treating ID in horses. However, no pharmacokinetics data have been reported in this species. The objective of the present study was to establish the plasma concentration–time profile and to derive pharmacokinetics data for a combination of metformin and sitagliptin in horses after enteral administration. Six healthy adult Purebred Spanish horses were used. A metformin (15 mg/kg) plus sitagliptin (1.5 mg/kg) preparation was administered by intragastric route (IG) as an enteral solution. Blood samples were collected from 0 to 48 hours after IG drug administration. Plasma concentrations of metformin and sitagliptin were measured using high performance liquid chromatography methods. The t ½λz for metformin was 2.9 hours and for sitagliptin 21 hours. The C max was 442 ± 84 mg/L within 0.9 hours for metformin and 94 ± 14 mg/L within 1.3 hours for sitagliptin. No adverse effects were observed, and the combination of metformin and sitagliptin was well tolerated. Therefore, these results suggest that metformin plus sitagliptin might be a combination to consider in horses with ID. Additional studies are needed to establish the effectiveness and tolerance in equids affected by endocrine disorders. Highlights • Insulin dysregulation is a common metabolic disorder in horses. • Metformin plus sitagliptin combination has been widely used for this disorder in humans and has potential for treatment of this disorder in horses. • Metformin plus sitagliptin showed good tolerance and favorable pharmacokinetics profile in these horses. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • All of the target compounds demonstrated excellent DPP-4 inhibitory properties and hypoglycemic activity. • T1 - T4 exhibited NO releasing abilities, anti-platelet aggregation and ameliorating oxidative stress. • Research indicated that compounds T1 - T4 possessed amelioration of endothelial dysfunction. Abstract Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1 - T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC 50 value of 0.060 μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1 - T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) often leads to long-term neurocognitive dysfunctions. Adult neurogenesis in the hippocampal dentate gyrus (DG) serves critical functions in cognition but can be disrupted by brain injury and insult in serval forms. In the present study, we explore the cellular and molecular targets of DPP-4 inhibitors (or gliptins) as related to hippocampal function and TBI cognitive sequelae. Two structurally different gliptins, sitagliptin and vildagliptin, were examined using a controlled cortical impact (CCI) model of moderate TBI in mice. Sensorimotor CCI, although distal from the hippocampus, impaired hippocampal-dependent cognition without obvious hippocampal tissue destruction. Neurogenic cell proliferation in the DG was increased accompanied by large numbers of reactive astrocyte. Increased numbers of immature granule cells with abnormal dendritic outgrowth were ectopically localized in the outer granule cell layer (GCL) and hilus. Long-term potentiation of dentate immature granule cells was also impaired. Both sitagliptin and vildagliptin attenuated the CCI-induced ectopic migration of doublecortin-positive immature neurons into the outer GCL and hilus, restored the normal dendritic branching pattern of the immature neurons and prevented astrocyte reactivation. Both gliptins prevented loss of normal synaptic integration in the DG after sensorimotor CCI and improved cognitive behavior. Sensorimotor cortical injury thus results in an abnormal neurogenesis pattern and astrocyte reactivation in the distal hippocampus which appears to contribute to the development of cognitive dysfunction after TBI. DPP-4 inhibitors prevent astrocyte reactivation, normalize the posttraumatic hippocampal neurogenesis and help to maintain normal electrophysiology in the DG with positive behavioral effect in a mouse model. • Sensorimotor cortical injury distally impairs hippocampal-dependent cognition. • TBI-increased neurogenesis adversely affects long-term cognition. • TBI induces abnormal localization and complex dendritic pattern of immature neurons. • TBI induces hypertrophic astrocyte processes which facilitate aberrant neurogenesis. • Gliptins normalize post-TBI hippocampal neurogenesis, restore hippocampal function. [ABSTRACT FROM AUTHOR]

Afatinib, as the first-line treatment for non-small cell lung cancer (NSCLC), causes severe gastrointestinal adverse reactions that greatly affect patients' quality of life and even potentially result in treatment discontinuation. Multiple dose adjustments and concomitant use of anti-diarrheal medications are commonly employed to manage diarrhea, also allowing for a recovery period between each adjustment. However, these approaches are based on empirical guidance and still have limitations. This study aims to explore reliable approaches to alleviate diarrhea by focusing on two strategies: adjusting the dosing regimen of afatinib itself and implementing combination therapy. In this study, we firstly revealed a dose-dependent relationship between afatinib-induced diarrhea and gastrointestinal epithelial damage, resulting in atrophy, reduced expression of tight junction proteins, and increased permeability. We further found that even after discontinuation of the medication, although the severity of diarrhea had improved to baseline, the tight junction proteins and permeability of the intestinal epithelium did not fully recover, and the pharmacokinetics studies showed that drug absorption significantly increased than normal. This indicated the recovery period was longer than expected and may accelerate the occurrence of subsequent episodes of diarrhea. Hence, it would be prudent to consider adjustments to the starting dose or the recovery interval. Furthermore, we initially investigated the relationship between DPP enzyme and afatinib-induced diarrhea and found a significant decrease in plasma DPP enzyme activity following afatinib-induced diarrhea. Subsequently, we conducted continuous treatment with sitagliptin and observed significant improvement in afatinib-induced diarrhea. We observed that sitagliptin can promote the production of anti-inflammatory factors, increase the expression of intestinal epithelial tight junction proteins, and improve intestinal microbiota, further validating the mechanism through the use of GLP-23-33 as GLP-2 receptor inhibitor. In conclusion, sitagliptin exhibits promising potential as a therapeutic option for managing afatinib-induced diarrhea. Taken together, our study provides valuable insights into alleviating afatinib-induced diarrhea through both afatinib medication adjustment and sitagliptin combination therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

• Sitagliptin, dapagliflozin and lobeglitazone displayed good glucose-lowering efficacy and comparable safety profiles. • Dapagliflozin therapy demonstrated significant advantages in terms of body composition, blood pressure, and urinary protein excretion. • Dapagliflozin may be a suitable therapy to improve body composition and cardiometabolic profiles. Compare the efficacy and safety of sitagliptin, dapagliflozin, and lobeglitazone in patients with uncontrolled type 2 diabetes, despite metformin and sulfonylurea therapy. The study randomized patients into three groups, receiving sitagliptin 100 mg, dapagliflozin 10 mg, or lobeglitazone 0.5 mg daily (n = 26 each) and monitored changes in biochemical parameters and body composition for 24 months. The primary efficacy endpoint was changes in HbA1c at 24 months. The mean change in HbA1c in the sitagliptin, dapagliflozin, and lobeglitazone groups was –0.81 ± 0.21%, –1.05 ± 0.70%, and –1.08 ± 0.98%, after 24 months. Dapagliflozin treatment significantly lowered systolic blood pressure by 5.5 mmHg and alanine aminotransferase levels. Dapagliflozin and lobeglitazone treatment significantly reduced proteinuria and insulin resistance. Dapagliflozin decreased whole body fat percentage by 1.2%, whereas sitagliptin and lobeglitazone increased it by 1.1% and 1.8%, respectively. Whole body muscle percentage increased in the dapagliflozin group and decreased in the lobeglitazone group. The safety profiles of the three treatments were comparable. All three drugs displayed good glucose-lowering efficacy and comparable safety profiles. However, dapagliflozin therapy produced favorable changes in body composition. Dapagliflozin may be a suitable adjunct therapy for patients with type 2 diabetes seeking to improve their body composition. [ABSTRACT FROM AUTHOR]

Metformin has long been used in the treatment of polycystic ovarian syndrome (PCOS). Recently, sitagliptin has been reported to improve ovarian cycles and ovulation in PCOS. We suggest that a combination of sitagliptin and metformin can be more effective than either treatment alone in improving different aspects of PCOS. [ABSTRACT FROM AUTHOR]

Abstract Background Whether a dipeptidyl peptidase-4 (DPP-4) inhibitor can attenuate atherosclerosis is still controversial. Some clinical trials reported that DPP-4 inhibitors in diabetes patients without a previous history of cardiovascular (CV) events could reduce carotid intima-media thickness (IMT). However, in the PROLOGUE study, which enrolled diabetes patients both with and without previous CV events, sitagliptin failed to slow the progression of carotid IMT relative to conventional therapy. Aim and methods We hypothesized that the effect of DPP-4 inhibitors on carotid atherosclerosis might be different between the primary and secondary prevention groups. We performed a post hoc analysis of the PROLOGUE study and compared the effects of sitagliptin and conventional therapy on changes in carotid IMT in subgroups with or without previous CV events. Results No significant difference in the IMT changes between the treatment groups was found in the secondary prevention subgroup (sitagliptin, N = 102; conventional, 111). However, in the primary prevention subgroup (sitagliptin, 120; conventional, 109), we found significant inhibitory effects of sitagliptin on mean and max internal carotid artery IMT [estimated group difference: −0.096 mm (95% CI −0.175 to −0.018, p = 0.017) and −0.162 mm (95% CI −0.272 to −0.052, p = 0.004), respectively], although there was no significant difference in the common carotid artery IMT. Conclusions Our data suggest that there is a favorable effect of DPP-4 inhibitor treatment on carotid atherosclerosis in diabetes patients without previous CV events. Highlights • Sitagliptin failed to delay IMT progression in T2DM patients with previous CVD. • Sitagliptin slowed ICA-IMT progression in T2DM patients without previous CVD. • Sitagliptin therapy prior to CV event may be favorable for carotid atherosclerosis. • The therapy in patients with previous CVD may be insufficient to attenuate it. [ABSTRACT FROM AUTHOR]

Abstract The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 β (GSK-3β) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3β and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3β and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3β and p38MAPK. [ABSTRACT FROM AUTHOR]

Abstract Atherosclerosis is a major underlying cause of ischemic heart diseases, ischemic stroke, and peripheral artery disease. Atherosclerotic plaque progression is characterized by chronic progressive inflammation of the arterial wall, endothelial cell dysfunction, and subendothelial lipoprotein retention. Incretin drugs, glucagon-like peptide-1 receptor (GLP-1R) agonists, and dipeptidyl peptidase-IV (DPP-IV) inhibitors, are promising anti-hyperglycemic agents used for the treatment of type 2 diabetes mellitus (T2DM). In addition to glucose-lowering effects, emerging data suggest that incretin drugs have anti-atherogenic effects with the potential to stabilize atherosclerotic plaques and treat arterial inflammation. Clinical and preclinical studies have reported a plethora of therapeutic benefits of incretin drugs, including modulation of inflammatory response, reduction of intima-media thickening, improvement in lipid profiles, endothelial and smooth muscle cell modulation. Despite extensive research and widespread clinical use of incretin-based therapies, the research on the incretin hormones continues to expand. This review outlines clinical studies, molecular aspects, and potential therapeutic implications of incretin drugs in attenuation of atherosclerosis. Highlights • Clinical trials show favorable effects of incretin therapy on cardiovascular outcomes. • Incretin hormones modulate leukocyte extravasation, endothelial and smooth muscle cell function. • The incretin athero-protective role includes blood pressure and lipid profile control. • Incretin drugs prevent intima-media dysfunction via anti-inflammatory actions. • Incretin treatments for atherosclerosis include GLP-1R agonists and DPP-IV inhibitors. [ABSTRACT FROM AUTHOR]

Abstract Aims This study investigated the effect of sitagliptin prophylactic treatment on intestinal I/R rat model and explored the possible underlying mechanism. Main methods Forty-five male Sprague-Dawley rats were randomly assigned to 3 groups: Sham group (operation without clamping), I/R group (operation with clamping) and sitagliptin pretreated group (300 mg/kg/day; p.o.) for 2 weeks before I/R insult. Intestinal I/R was performed by clamping the superior mesenteric artery for 30 min, followed by 60 min reperfusion after removal of clamping. At the end of the experimental period, all rats were sacrificed for histopathological, biochemical, PCR and western blot assessment. Key findings Pretreatment with sitagliptin remarkably alleviated the pathological changes induced by I/R in the jejunum, suppressed upregulated NF-κB, TNF-α, IL-1βand MPO caused by I/R. Moreover, sitagliptin decreased the Bax/Bcl-2 ratio and accordingly suppressed apoptotic tissue damage as reflected by a caspase-3 level reduction in rat intestine subjected to I/R injury. Interestingly, sitagliptin could obviously increase the active GLP-1 level and GLP-1 receptor mRNA expression in the jejunum of I/R rats. This was associated with the augmentation of the cAMP level and enhancement of PKA activity. Simultaneously, sitagliptin treatment was able to increase the protein expression levels of phosphorylated PI3K and Akt. Significance Sitagliptin has shown protective effects against intestinal I/R injury in rats through reduction of intestinal inflammation and apoptosis. The molecular mechanisms may be partially correlated with activation of cAMP/PKA and PI3K/Akt signaling pathway by the GLP-1/GLP-1 receptor. Graphical abstract Unlabelled Image Highlights • Sitagliptin alleviates intestinal I/R injury in rats. • Sitagliptin exerts anti-inflammatory action via ↓ NF-κB pathway. • Sitagliptin exerts anti-apoptotic action via ↓ Bax/Bcl2 ratio and caspase-3 level. • The GLP-1R/cAMP-PKA; PI3K-Akt axis participate in sitagliptin protective mechanism. [ABSTRACT FROM AUTHOR]

The two dipeptidyl peptidase (DPP)-4 inhibitors, linagliptin and sitagliptin, were shown to exert different binding kinetics in vitro. Twenty-four hours after oral dosing particularly in vivo inhibition of renal-specific DPP-4 activity was more sustained in Sprague Dawley rats after exposure to linagliptin than it was after sitagliptin. [ABSTRACT FROM AUTHOR]