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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 substudy of a randomized, open-label, 2-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% confidence interval] 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., Conclusion: 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Influenza A virus infection, commonly known as the flu, has persisted in the community for centuries. Although we have yearly vaccinations to prevent seasonal flu, there remains a dire need for antiviral drugs to treat active infections. The constantly evolving genome of the influenza A virus limits the number of effective antiviral therapeutic options. Over time, antiviral drugs become inefficient due to the development of resistance, as seen with adamantanes, which are now largely ineffective against most circulating strains of the virus. Neuraminidase inhibitors have long been the drug of choice, but due to selection pressure, strains are becoming resistant to this class of drugs. Baloxavir marboxil, a drug with a novel mode of action, can be used against strains resistant to other classes of drugs but is still not available in many countries. Deep research into nanoparticles has shown they are effective as antiviral drugs, opening a new avenue of research to use them as antiviral agents with novel modes of action. As this deadly virus, which has killed millions of people in the past, continues to develop resistance, there is an urgent need for new therapeutic agents with novel modes of action to halt active infections in patients. This review article covers the available therapeutic antiviral drug options with different modes of action, their effectiveness, and resistance to various strains of influenza A virus., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Soluble epoxide hydrolase (sEH) has previously been demonstrated to play an important part in kidney diseases by hydrolyzing renoprotective epoxyeicosatrienoic acids to their less active diols. However, little is known about the role of sEH in primary glomerular diseases. Here, we investigated the effects of sEH inhibition on proteinuria in primary glomerular diseases and the underlying mechanism. The expression of sEH in the renal tubules of patients with minimal change disease, IgA nephropathy, and membranous nephropathy was significantly increased. Renal sEH expression level was positively correlated with the 24 h urine protein excretion and negatively correlated with serum albumin. In the animal model of Adriamycin (ADR)-induced nephropathy, renal sEH mRNA and protein expression increased significantly. Pharmacological inhibition of sEH with AUDA effectively reduced urine protein excretion and attenuated renal pathological damage. Furthermore, sEH inhibition markedly abrogated the abnormal expressions of nephrin and desmin in glomerular podocytes induced by ADR. More importantly, AUDA treatment inhibited renal NF-κB activation and reduced TNF-α levels in rats with ADR-induced nephropathy. Overall, our findings suggest that sEH inhibition ameliorates renal inflammation and podocyte injury, thus reducing proteinuria and exerting renoprotective effects. Targeting sEH might be a potential strategy for the treatment of proteinuria in primary glomerular diseases.

Background: Although Hashimoto's thyroiditis (HT) is one of most common autoimmune thyroid diseases, its treatment remains focused on symptom relief. The soluble epoxide hydrolase (sEH) shows potential functions as a drug target in alleviating some autoimmune diseases; however, we seldom know its role in HT., Methods: The protein expression of sEH and related downstream molecules were evaluated by immunohistochemistry, Western blotting, ELISA, or immunofluorescence staining. RNA sequencing of tissue samples was performed to analyze differential genes and dysregulated pathways in HT and controls. The thyroid follicular epithelial cells (TFECs) and rat HT model were used to verify the biological function of sEH and the inhibition role of adamantyl-ureido-dodecanoic acid (AUDA) in HT., Results: The sEH was significantly upregulated in HT patients compared with healthy individuals. Transcriptome sequencing showed cytokine-related pathways and chemokine expression; especially chemokine CXCL10 and its receptor CXCR3 were aberrant in HT patients. In TFECs and a rat HT model, blocking sEH by AUDA inhibitor could effectively inhibit the autoantibody, proinflammatory nuclear kappa factor B (NF-κB) signaling, chemokine CXCL10/CXCR3 expression, and type-1 helper CD4+ T cells., Conclusion: Our findings suggest that sEH/NF-κB p65/CXCL10-CXCR3 might be promising therapeutic targets for HT., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

Aim: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D)., Materials and Methods: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104., Results: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT., Conclusions: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Hepatopulmonary syndrome (HPS) is a liver disease-induced pulmonary complication manifested with arterial hypoxemia. Hepatic cholestasis, encountered in several clinical situations, leads to biliary cirrhosis and HPS, both of which are best reproduced by rat common bile duct ligation (CBDL). Experience from liver transplantation suggests hepatoprotective-based therapy would be most effective in HPS treatment Dipeptidyl peptidase-4 (DPP-4) enzyme is involved in different pathogenic mechanisms of liver diseases. Vildagliptin (Vild) is a DPP-4 inhibitor which possesses favorable anti-inflammatory, anti-oxidant and anti-fibrotic effects. The present work explored hepatoprotective mechanisms of Vild and their participation in its prophylactic effectiveness in HPS induced by CBDL in rats. Male Wistar rats weighing 220-280 g were allocated into 4 groups: normal control, sham, CBDL and CBDL + Vild groups. i.p. saline was administered to the first 3 groups and i.p. Vild (10 mg/kg/day) was given to the fourth group for 6 weeks starting 2 week before CBDL. CBDL produced liver fibrosis, arterial hypoxemia and decreased survivability of rats. It altered liver functions and induced oxidative stress, pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6)], vasodilatory molecules [endothelin-1 (ET-1), and inducible and endothelial nitric oxide synthases] and angiogenesis-associated protein [vascular endothelial growth factor-A (VEGF-A)] in liver and lung. Vild ameliorated liver fibrosis, and improved hypoxemia and survivability of CBDL rats and reversed these biochemical alterations. Prophylactic Vild administration attenuated CBDL-induced HPS in rats via direct hepatoprotective effects in the form of anti-oxidant, anti-inflammatory, anti-angiogenic and anti-fibrotic effects beside inhibition of pathological intrahepatic vasodilatation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aim: Many patients with type 1 diabetes mellitus (T1DM) met the histological criteria for non-alcoholic steatohepatitis (NASH), which leads to cardiovascular disease morbidity and mortality. Matrix metalloproteinase-14 (MMP-14) is involved in cardiovascular disease and atherosclerosis., Objectives: To assess the impact of oral dipeptidyl peptidase-4 inhibitor, vildagliptin, as adjunctive therapy on NASH in adolescents with T1DM and its effect on glycaemic control, MMP-14 levels and carotid intima media thickness (CIMT)., Methods: Sixty adolescents with T1DM and NASH were randomly assigned to receive oral vildagliptin (50 mg once daily) for 6 months or not. Glycated haemoglobin, lipid profile, hepatic steatosis index, triglyceride glucose (TyG) index and MMP-14 levels were assessed. Transient elastography with controlled attenuation parameter (CAP) was performed together with measuring CIMT., Results: By transient elastography, 12 (20%) patients with T1DM with NASH had elevated liver stiffness ≥7 kPa (F2 stage or higher). Baseline MMP-14 was positively correlated to insulin dose (p = 0.016), triglycerides and TyG index, CIMT, liver stiffness and CAP levels among the studied patients (p < 0.001 for all). After 6 months, patients with T1DM on vildagliptin therapy had significantly lower glycated haemoglobin, lipid profile, hepatic steatosis index and TyG index, as well as MMP-14 (p < 0.001). CIMT, liver stiffness and CAP were significantly decreased post-therapy compared with baseline levels and compared with the control group (p < 0.001). Vildagliptin was safe and well-tolerated., Conclusions: Administration of vildagliptin for adolescents with T1DM and NASH improved glycaemic control, dyslipidaemia and MMP-14 levels and decreased liver stiffness and CIMT; hence, reducing subclinical atherosclerosis and disease progression., (© 2024 John Wiley & Sons Ltd.)

Objectives: This post hoc analysis of the RAJ2 study assessed long-term safety and effectiveness of peficitinib 100 mg/day for treatment of rheumatoid arthritis., Methods: Eligible patients previously completed two Phase 3 (RAJ3 and RAJ4) studies of peficitinib in Asia. All patients received peficitinib 100 mg/day at RAJ2 Week (W)0; dose change to 50 mg/day or 150 mg/day was permitted. Safety endpoints included treatment-emergent adverse events and laboratory test results. Effectiveness endpoints included peficitinib exposure pattern, achievement of Clinical Disease Activity Index (CDAI) remission by peficitinib exposure pattern at W0 and W48, and association of demographics/characteristics with CDAI remission at W0 and W48., Results: Overall, no new safety findings were reported at W48, and renal function was unaffected. Of patients included in effectiveness analyses at W48, 70.9% (451/636) had maintained peficitinib 100 mg/day since W0. Of patients who achieved CDAI remission at W0 and maintained peficitinib 100 mg/day to W48, 50.3% (79/157) maintained CDAI remission to W48. Low disease activity and a lower number of prior disease-modifying antirheumatic drugs were significantly associated with CDAI remission at W48., Conclusions: Long-term peficitinib treatment at a dose of 100 mg/day was generally well tolerated and, following induction therapy, maintained effectiveness through to W48., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Objectives: The current study assesses the utility of matrix metalloprotease-3 (MMP-3) as a biomarker for joint damage in patients with rheumatoid arthritis receiving peficitinib., Methods: Rheumatoid arthritis patients with inadequate response to methotrexate were randomised to peficitinib 100 mg, peficitinib 150 mg, or placebo, combined with methotrexate, for 52 weeks; patients receiving placebo switched to peficitinib 100/150 mg at Week (W)12/28. This post hoc analysis investigated association between MMP-3 above/below upper limit of normal (ULN) at W12/28 and radiographic progression [modified total Sharp score (mTSS), joint space narrowing score, or erosion score >0.5] at W52 or swollen joint count 66 at W28, stratified by baseline glucocorticoid use and renal function., Results: MMP-3 levels decreased in both peficitinib-treated groups but more slowly in patients with baseline glucocorticoids and those with radiographic progression at W52. There was no clear correlation between MMP-3 change from baseline (CFB) at W12, CFB in mTSS, joint space narrowing score, or erosion score at W52, or CFB in swollen joint count 66 at W28. More patients with MMP-3 ≤ULN versus >ULN at W12 had radiographic non-progression at W52. MMP-3 normalisation at W12 was significantly associated with mTSS non-progression at W52., Conclusions: Normalisation of MMP-3 at W12 may be a predictor for subsequent non-progression of joint damage at W52., (© Japan College of Rheumatology 2023. Published by Oxford University Press.)

Inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic strategy for treating neuropathic pain. These inhibitors effectively reduce diabetic neuropathic pain and inflammation induced by Freund's adjuvant which makes them a suitable alternative to traditional opioids. This study showcased the notable analgesic effects of compound AMHDU (1,1'-(hexane-1,6-diyl)bis(3-((adamantan-1-yl)methyl)urea)) in both inflammatory and diabetic neuropathy models. While lacking anti-inflammatory properties in a paw edema model, AMHDU is comparable to celecoxib as an analgesic in 30 mg/kg dose administrated by intraperitoneal injection. In a diabetic tactile allodynia model, AMHDU showed a prominent analgesic activity in 10 mg/kg intraperitoneal dose ( p < 0.05). The effect is comparable to that of gabapentin, but without the risk of dependence due to a different mechanism of action. Low acute oral toxicity (>2000 mg/kg) and a high therapeutic index makes AMHDU a promising candidate for further structure optimization and preclinical evaluation.

Introduction: Experimental hepatopulmonary syndrome (HPS) is best reproduced in the rat common bile duct ligation (CBDL) model. Vildagliptin (Vild) is an anti-hyperglycemic drug that exerts beneficial anti-inflammatory, anti-oxidant and anti-fibrotic effects. Therefore, the present search aimed to explore the possible effectiveness of Vild in CBDL-induced HPS model., Methods: Four groups of male Wistar rats which weigh 220-270 g were used, including the normal control group, the sham control group, the CBDL group and CBDL+Vild group. The first three groups received i.p. saline, while the last group was treated with i.p. Vild (10 mg/kg/day) from the 15th to 28th day of the experiment., Results: CBDL decreased the survivability and body weight of rats, increased diameter of the pulmonary vessels, and altered the arterial blood gases and the liver function parameters. Additionally, it increased the pulmonary expressions of endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) mRNA as well as endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) proteins. The CBDL rats also exhibited elevation of the pulmonary interleukin-6 (IL-6), dipeptidyl peptidase-4 (DPP-4) and nitric oxide (NO) levels along with reduction of the pulmonary total anti-oxidant capacity and glucagon-like peptide-1 (GLP-1) levels. Vild mitigated these alterations and improved the histopathological abnormalities caused by CBDL., Conclusion: Vild effectively attenuated CBDL-induced HPS through its anti-oxidant and anti-inflammatory effects along with its modulatory effects on ET-1/NOS/NO and TNF-α/IL-6/VEGF-A signaling implicated in the regulation of intrapulmonary vasodilatation and angiogenesis, respectively., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors were not involved in the editorial review or the decision to publish this article., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The development of in situ tumor vaccines offers promising prospects for cancer treatment. Nonetheless, the generation of plenary autologous antigens in vivo and their codelivery to DC cells along with adjuvants remains a significant challenge. Herein, we developed an in situ tumor vaccine using a supramolecular nanoparticle/hydrogel composite (ANP MTO /ALCD) and a deformable nanoadjuvant (PPE R848 ). The ANP MTO /ALCD composite consisted of β-cyclodextrin-decorated alginate (Alg- g -CD) and MTO-encapsulated adamantane-decorated nanoparticles (ANP MTO ) through supramolecular interaction, facilitating the long-term and sustained production of plenary autologous antigens, particularly under a 660 nm laser. Simultaneously, the produced autologous antigens were effectively captured by nanoadjuvant PPE R848 and subsequently transported to lymph nodes and DC cells, benefiting from its optimized size and deformability. This in situ tumor vaccine can trigger a robust antitumor immune response and demonstrate significant therapeutic efficacy in inhibiting tumor growth, suppressing tumor metastasis, and preventing postoperative recurrence, offering a straightforward approach to programming in situ tumor vaccines.

Objective: To explore the complementary effects of a combination of dipeptidyl peptidase 4 and sodium-glucose cotransporter 2 inhibitors added to metformin on hormonal and metabolic responses to meal ingestion., Research Design and Methods: Forty-five patients (age 58 ± 8 years; HbA1c 58 ± 6 mmol/mol; BMI 30.7 ± 3.2 kg/m2) with type 2 diabetes uncontrolled with metformin were evaluated at baseline and 3 and 28 days after 5 mg saxagliptin (SAXA), 10 mg dapagliflozin (DAPA), or 5 mg saxagliptin plus 10 mg dapagliflozin (SAXA+DAPA) using a mixed-meal tolerance test (MMTT) spiked with dual-tracer glucose to assess glucose metabolism, insulin secretion, and sensitivity., Results: At day 3, fasting and mean MMTT glucose levels were lower with SAXA+DAPA (-31.1 ± 1.6 and -91.5 ± 12.4 mg/dL) than with SAXA (-7.1 ± 2.1 and -53 ± 10.5 mg/dL) or DAPA (-17.0 ± 1.1 and -42.6 ± 10.0 mg/dL, respectively; P < 0.001). Insulin secretion rate (SAXA+DAPA +75%; SAXA +11%; DAPA +3%) and insulin sensitivity (+2.2 ± 1.7, +0.4 ± 0.7, and +0.4 ± 0.4 mg ⋅ kg-1⋅ min-1, respectively) improved with SAXA+DAPA (P < 0.007). Mean glucagon-like peptide 1 (GLP-1) was higher with SAXA+DAPA than with SAXA or DAPA. Fasting glucagon increased with DAPA and SAXA+DAPA but not with SAXA. Fasting endogenous glucose production (EGP) increased with SAXA+DAPA and DAPA. During MMTT, EGP suppression was greater (48%) with SAXA+DAPA (vs. SAXA 44%; P = 0.02 or DAPA 34%; P = 0.2). Metabolic clearance rate of glucose (MCRglu) increased more with SAXA+DAPA. At week 4, insulin secretion rate, β-cell glucose sensitivity, and insulin sensitivity had further increased in the SAXA+DAPA group (P = 0.02), with no additional changes in GLP-1, glucagon, fasting or MMTT EGP, or MCRglu., Conclusions: SAXA+DAPA provided superior glycemic control compared with DAPA or SAXA, with improved β-cell function, insulin sensitivity, GLP-1 availability, and glucose clearance., (© 2024 by the American Diabetes Association.)

Background/aim: Vildagliptin is one of the dipeptidyl peptidase-4 (DPP-4) inhibitors that have been shown to improve hyperglycemia in clinical trials among patients with type 2 diabetes. However, few studies have examined the efficacy of vildagliptin in patients with diabetic kidney disease (DKD)., Patients and Methods: Eight patients with DKD received oral vildagliptin 50-100 mg/day. The duration of diabetes was 6.7±5.9 years and observation period was 23.6±9.8 months. Changes in fasting blood glucose, and hemoglobin A1c (HbA1c), estimated glomerular filtration rate (eGFR), and urine protein-to-creatinine ratio (UPCR) were studied before and after the administration of vildagliptin., Results: Vildagliptin treatment significantly decreased fasting blood glucose and HbA1c, compared to baseline (132±56 mg/dl, p=0.036, 6.0±0.3, p=0.041, respectively). UPCR tended to be decreased, albeit without statistical significance. However, eGFR was decreased after the administration of vildagliptin. No significant adverse effects were observed in all patients during the study., Conclusion: Although the sample size was limited and the observation period was brief, vildagliptin was found to be an effective and reasonably well-tolerated treatment for patients with DKD., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: There has been increasing evidence that the gut microbiota is closely related to type 2 diabetes (T2D). Metformin (Met) is often used in combination with saxagliptin (Sax) and repaglinide (Rep) for the treatment of T2D. However, little is known about the effects of these combination agents on gut microbiota in T2D., Research Design and Methods: A T2D mouse model induced by a high-fat diet (HFD) and streptozotocin (STZ) was employed. The T2D mice were randomly divided into six groups, including sham, Met, Sax, Rep, Met+Sax and Met+Rep, for 4 weeks. Fasting blood glucose level, serum biochemical index, H&E staining of liver, Oil red O staining of liver and microbiota analysis by 16s sequencing were used to access the microbiota in the fecal samples., Results: These antidiabetics effectively prevented the development of HFD/STZ-induced high blood glucose, and the combination treatment had a better effect in inhibiting lipid accumulation. All these dosing regimens restored the decreasing ratio of the phylum Bacteroidetes: Firmicutes, and increasing abundance of phylum Desulfobacterota, expect for Met. At the genus level, the antidiabetics restored the decreasing abundance of Muribaculaceae in T2D mice, but when Met was combined with Rep or Sax, the abundance of Muribaculaceae was decreased. The combined treatment could restore the reduced abundance of Prevotellaceae&#95;UCG-001, while Met monotherapy had no such effect. In addition, the reduced Lachnospiraceae&#95;NK4A136&#95;group was well restored in the combination treatment groups, and the effect was much greater than that in the corresponding monotherapy group. Therefore, these dosing regimens exerted different effects on the composition of gut microbiota, which might be associated with the effect on T2D., Conclusions: Supplementation with specific probiotics may further improve the hypoglycemic effects of antidiabetics and be helpful for the development of new therapeutic drugs for T2D., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The marine polyarsenical metabolite arsenicin A is the landmark of a series of natural and synthetic molecules characterized by an adamantane-like tetraarsenic cage. Arsenicin A and related polyarsenicals have been evaluated for their antitumor effects in vitro and have been proven more potent than the FDA-approved arsenic trioxide. In this context, we have expanded the chemical space of polyarsenicals related to arsenicin A by synthesizing dialkyl and dimethyl thio-analogs, the latter characterized with the support of simulated NMR spectra. In addition, the new natural arsenicin D, the scarcity of which in the Echinochalina bargibanti extract had previously limited its full structural characterization, has been identified by synthesis. The dialkyl analogs, which present the adamantane-like arsenicin A cage substituted with either two methyl, ethyl, or propyl chains, were efficiently and selectively produced and evaluated for their activity on glioblastoma stem cells (GSCs), a promising therapeutic target in glioblastoma treatment. These compounds inhibited the growth of nine GSC lines more potently than arsenic trioxide, with GI 50 values in the submicromolar range, both under normoxic and hypoxic conditions, and presented high selectivity toward non-tumor cell lines. The diethyl and dipropyl analogs, which present favorable physical-chemical and ADME parameters, had the most promising results.

Current pharmacological treatments of atherosclerosis often target either cholesterol control or inflammation management, to inhibit atherosclerotic progression, but cannot lead to direct plaque lysis and atherosclerotic regression, partly due to the poor accumulation of medicine in the atherosclerotic plaques. Due to enhanced macrophage recruitment during atheromatous plaque progression, a macrophage-liposome conjugate was facilely constructed for targeted anti-atherosclerosis therapy via synergistic plaque lysis and inflammation alleviation. Endogenous macrophage is utilized as drug-transporting cell, upon membrane-modification with a β-cyclodextrin (β-CD) derivative to form β-CD decorated macrophage (CD-MP). Adamantane (ADA) modified quercetin (QT)-loaded liposome (QT-NP), can be conjugated to CD-MP via host-guest interactions between β-CD and ADA to form macrophage-liposome conjugate (MP-QT-NP). Thus, macrophage carries liposome "hand-in-hand" to significantly increase the accumulation of anchored QT-NP in the aorta plaque in response to the plaque inflammation. In addition to anti-inflammation effects of QT, MP-QT-NP efficiently regresses atherosclerotic plaques from both murine aorta and human carotid arteries via CD-MP mediated cholesterol efflux, due to the binding of cholesterol by excess membrane β-CD. Transcriptome analysis of atherosclerotic murine aorta and human carotid tissues reveal that MP-QT-NP may activate NRF2 pathway to inhibit plaque inflammation, and simultaneously upregulate liver X receptor to promote cholesterol efflux., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Directly Observed Treatment Short-course (DOTs), is an effective and widely recommended treatment for tuberculosis (TB). The antibiotics used in DOTs, are immunotoxic and impair effector T cells, increasing the risk of re-infections and reactivation. Multiple reports suggest that addition of immune-modulators along with antibiotics improves the effectiveness of TB treatment. Therefore, drugs with both antimicrobial and immunomodulatory properties are desirable. N 1 -(Adamantan-2-yl)-N 2 -[(2E)-3,7-dimethylocta-2,6-dien-1-yl]ethane-1,2-diamine (SQ109) is an asymmetric diamine derivative of adamantane, that targets Mycobacterial membrane protein Large 3 (MmpL3). SQ109 dissipates the transmembrane electrochemical proton-gradient necessary for cell-wall biosynthesis and bacterial activity. Here, we examined the effects of SQ109 on host-immune responses using a murine TB model. Our results suggest the pro-inflammatory nature of SQ109, which instigates M1-macrophage polarization and induces protective pro-inflammatory cytokines through the p38-MAPK pathway. SQ109 also promotes Th1 and Th17-immune responses that inhibit the bacillary burden in a murine model of TB. These findings put forth SQ109 as a potential-adjunct to TB antibiotic therapy., (© 2022. The Author(s).)

Objectives: To evaluate peficitinib efficacy and safety in Asian patients with rheumatoid arthritis (RA), stratified by age (≥20-<50, ≥50-<65, and ≥65 years)., Methods: Efficacy data from two Phase 3 studies were analysed. Safety data from one Phase 2, two Phase 3, and one open-label extension study were pooled. Incidence rates per 100 patient-years of adverse events of special interest were calculated, and Cox proportional hazard analysis was conducted., Results: 1052 patients received peficitinib for 2 years (median). Peficitinib demonstrated efficacy improvements versus placebo across all age categories. Incidence rates (95% confidence interval) per 100 patient-years for ≥20-<50, ≥50-<65, and ≥65 years were 0.8 (0.4, 1.9), 2.6 (1.8, 3.7), and 4.7 (3.1, 7.0) for serious infections and 3.7 (2.5, 5.4), 6.4 (5.0, 8.2), and 11.2 (8.5, 14.7) for herpes zoster-related disease, respectively. Twenty patients reported malignancies in pooled Phase 2/3 studies. Incidences of serious infections and herpes zoster-related disease increased significantly with age, but there was no association with baseline estimated glomerular filtration rate., Conclusions: Peficitinib was efficacious in adult Asian RA patients of all ages. Age, but not estimated glomerular filtration rate, was associated with serious infections and herpes zoster-related disease, demonstrating the importance of an appropriate RA treatment strategy in older patients., (© Japan College of Rheumatology 2021. Published by Oxford University Press.)

Saxagliptin is an effective and selective dipeptidyl peptidase-4 (DPP-4) inhibitor. This study was designed to determine possible protective effects of saxagliptin against damage caused by renal ischaemia/reperfusion (I/R) in rats. In this study, 40 rats were divided into 4 groups ( n  = 10 for each). Group 1 (Control), Group 2 (I/R) in both kidneys ischaemia of 45 min was performed, and then reperfusion was applied for 24 h. Saxagliptin (Group 3: 2 mg/kg and Group 4: 10 mg/kg) was administered by oral gavage to the animals in treatment groups, before the I/R. Saxagliptin decreased the markers (BUN, Cre, NGAL, KIM-1 and IL-18) of acute renal damage in blood and kidney tissue. Saxagliptin provided increase in antioxidant enzyme levels and decrease in MDA and apoptosis. Histological results showed that the administration of saxagliptin exhibited a protective effect against renal damage caused by I/R. These results indicates that saxagliptin provide protection against kidney injury caused by I/R.

Diabetes is a chronic disease leading to memory difficulties and deterioration of learning abilities. The previous studies showed that modulation of inflammatory pathways in the diabetic brain may reduce dysfunction or cell death in brain areas which are important for control of cognitive function. In the present study, we investigated the neuroprotective actions of newly synthesized adamantane derivatives on diabetes-induced cognitive impairment in mice. Our study relied on the fact that both vildagliptin and saxagliptin belong to DPP4 inhibitors and, contain adamantanyl group. Efficacy of tested compounds at reversing diabetes-induced different types of memory impairment was evaluated with the use of selected behavioural tests. The following neuroinflammatory indicators were also analyzed: neuroinflammatory indicators and the expression of genes involved in the inflammatory response of brain (Cav1, Bdnf). Our study demonstrated that new adamantane derivatives, similarly to DPP4 inhibitors, can restrict diabetes-induced cognitive deficits. We demonstrated that the overexpression of GLP-1-glucagon-like peptide as well as Bdnf, Cav1 genes translate into central blockade of pro-inflammatory synthesis of cytokines and significantly improvement on memory performance in diabetes mice. Newly synthesized adamantane derivatives might have important roles in prevention and treatment of cognitive impairment by inflammatory events in patients with diabetes or related diseases., (© 2022. The Author(s).)

The current study was conducted to investigate the nephroprotective effects of vildagliptin-metformin combination in an experimental model of fructose/salt-induced metabolic syndrome (MetS). A major aim was to evaluate the potential capacity of vitamin D3 to potentiate the pleiotropic nephroprotective effects of vildagliptin-metformin combination. MetS was induced in adult male Wistar rats by adding fructose (10%) to everyday drinking water and salt (3%) to the diet for 6 weeks. Along with the same concentrations of fructose/salt feeding, MetS rats were then treated orally with either vildagliptin (10 mg/kg/day)-metformin (200 mg/kg/day) combination, vitamin D3 (10 μg/kg/day), or the triple therapy for a further 6 weeks. The incidence of MetS was confirmed 6 weeks after fructose/salt consumption, when the rats exhibited significant weight gain, dyslipidemia, hyperuricemia, insulin resistance, hyperinsulinemia, and impaired glucose tolerance. At the end of the 12-week experimental period, MetS rats displayed significantly deteriorated renal function, enhanced intrarenal oxidative stress and inflammation together with exaggerated renal histopathological damages and interstitial fibrosis. The study has corroborated antioxidant, anti-inflammatory, and antifibrotic effects of vildagliptin-metformin combination, vitamin D3, and the triple collaborative therapy, conferring renoprotection in the setting of MetS. Due attention has been paid to the crucial role of dipeptidyl peptidase-4 inhibition and sirtuin-1/5' adenosine monophosphate-activated protein kinase activation as novel therapeutic targets to optimize renoprotection. The apparent potentiating effect, evoked upon coadministration of vitamin D3 with vildagliptin-metformin combination, may provide a cornerstone for further clinical investigations., (© 2021 Société Française de Pharmacologie et de Thérapeutique.)

P2X receptors are potential therapeutic targets for the treatment of various neurodegenerative disorders, pain, inflammation, hypertension, and cancer. Adamantane ring has been reported to exhibit significant inhibitory potential towards P2X receptors, especially for P2X7R. We have utilized uniqueness of adamantane moiety in our synthesized compounds and introduced various substitutions that enhanced the potency as well as selectivity for P2XR subtypes. Among synthesized derivatives, 4n and 5b were found to be most potent and selective inhibitors for h-P2X4R and h-P2X7R, respectively. 4n was found to be highly selective for h-P2X4R with IC 50 ± SEM = 0.04 ± 0.01 μM, that is 22 times more potent than BX-430, a standard selective inhibitor of h-P2X4R. 5b has IC 50 ± SEM of 0.073 ± 0.04 μM, which is comparable with the known antagonists of h-P2X7R. 4n and 5b were studied for mode of inhibition of P2XRs and both were found to be negative allosteric modulators. In silico studies were also conducted to find the type of interactions as well as mode of inhibition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background and Aims: This study aimed to assess the effects of vildagliptin on the prevention of cardiovascular diseases in Thai patients with type 2 diabetes mellitus using the Thai Cardiovascular Risk Score., Methods: All patients with type 2 diabetes mellitus who used vildagliptin at a secondary hospital in Thailand were screened and recruited. The relevant variables were obtained from patient medication charts at the first visit on which the patients were prescribed vildagliptin and from the 6-month, 12-month, and 18-month post-treatment visits. The Thai Cardiovascular Risk Score was calculated and monitored as a primary outcome, whereas changes in separate cardiometabolic parameters were assessed as secondary outcomes., Results: Of the 321 patients screened, only 95 were recruited for the analysis. The average 10-year cardiovascular risks of patients increased from 19.65% at baseline to 20.74%, 20.69%, and 23.78% at 6, 12, and 18 months post treatment, respectively. However, a better trend of reduction in cardiovascular risk was observed in patients with a high baseline cardiovascular risk. The glucose-lowering effects of vildagliptin were significantly observed 12 months of treatment onwards, but non-significant changes were found in lipid and blood pressure levels as well as body mass index., Conclusion: Vildagliptin provided a promising glucose-lowering effect in Thai patients with type 2 diabetes mellitus. However, the mean 10-year cardiovascular risk did not significantly decrease. However, a negative correlation between cardiovascular risk reduction and baseline cardiovascular risk was observed in this study. Low sample size was a major limitation of this study., Competing Interests: Declaration of competing interest The author declares no conflicts of interest in this work., (Copyright © 2022 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Aim: To determine what the variation was in the initial use of vildagliptin in patients with type 2 diabetes following approval of open access funding in October 2018, including by ethnicity, gender, age, funding model and patient HbA1c levels., Methods: Data were collected from 31 general practices for all adult patients with type 2 diabetes. National Health Index-matched medication data were obtained from the national Pharmaceutical Collection. Patients were included for analysis if they had received at least one diabetes medication in the 12 months prior to funding approval for vildagliptin. The proportion of patients who initiated vildagliptin therapy following open access funding approval was then evaluated, as was the time taken until the first dispensing (days since funding approval)., Results: A total of 724 of 3,971 (18.2%) of patients initiated vildagliptin therapy; mean time to first dispensing was 192.1±112.4 days. In logistic regression, Asian patients were more likely and Māori less likely to receive vildagliptin than Europeans. Younger patients and those with an HbA1c of >64mmol/mol were also more likely to initiate therapy. Vildagliptin use by general practice ranged from 0.0-82.4%., Conclusions: Despite open access funding, there was inequity in the initial use of vildagliptin. Substantial variation by general practice indicates that practitioner education may be needed to ensure appropriate and early adoption of new diabetes medications., Competing Interests: Nil.

Peficitinib, a pan-JAK inhibitor, is known to suppress the activation of fibroblast-like synoviocytes (FLSs) and thereby reduces joint inflammation associated with rheumatoid arthritis (RA). However, the effect on osteoporosis in RA remains to be elucidated. In this study, the effect of peficitinib or etanercept on joint inflammation, and consequently decreased bone mineral density (BMD) was evaluated in mice with collagen-induced arthritis (CIA). Additionally, the effect on RANKL production from osteoblasts differentiated from the mesenchymal stem cells of RA patients was evaluated. Administration of peficitinib for established CIA ameliorated arthritis and improved BMD in the femoral metaphysis, but not in the femoral diaphysis. Conversely, etanercept suppressed an increase in synovial inflammatory markers but did not improve arthritic conditions or the reduction of BMD in either region. All elevated bone formation and bone resorption markers were decreased with peficitinib but only partially decreased with etanercept. Furthermore, production of RANKL by human osteoblasts was suppressed by peficitinib but enhanced by etanercept. Unlike etanercept, peficitinib is thought to increase BMD by ameliorating the high bone turnover associated with RA states, resulting in improvement of bone fragility. Our data provide evidence that peficitinib would be expected to show efficacy for osteoporosis associated with RA., (Copyright © 2021 The Authors. Production and hosting by Elsevier B.V. All rights reserved.)

Depression is a widespread, withering illness, resulting in a massive personal suffering and economic loss. The chronic exposure to stress may be involved in the etiology of human psychiatric disorders; such as depression. In the current study, the animals were subjected to chronic unpredictable mild stress (CUMS) for 14 days. Saxagliptin (SAXA) is a member of dipeptidyl peptidase-4 (DPP-4) inhibitors class. The current study was the first one to examine the anti-depressive effect of SAXA in an experimental model of CUMS-induced depression in rats and the possible underlying mechanisms. Animals were orally treated with SAXA (0.5, 1 and 2 mg/kg) for 14 days. SAXA treatment reversed the CUMS-induced alterations in the behavioral, biochemical as well as histopathological parameters. Moreover, it hindered the CUMS-induced increase in the oxidative stress, inflammatory, and apoptotic markers. On the other hand, it increased the monoamines levels and the neurogenic brain derived neurotrophic factor (BDNF). In addition, SAXA treatment increased the incretin hormones, glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), which are linked to the activation of protein kinase B (AKT)/phosphatidylinositol3-kinase (PI3K) pathway. In conclusion, the current study revealed that the modulation of the interplay between the key events involved in depression, including oxidative stress, inflammation, and GLP-1/PI3K/AKT signaling pathway, can explain the anti-depressant activity of SAXA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Polycyclodextrin (denoted PCD) composed of cyclodextrin monomer units and 1,3-diethoxypropan-2-ol containing many hydroxyl groups with lone pairs of electrons, easily coordinated with transition metals with empty orbitals. The CD unit can also provide host-guest binding sites for functional molecules. This article utilizes this feature of PCD for the first time as a "linker" to combine transition metal nanomaterials with synergistic functional molecules. We synthesized PCD with 50% CD monomer by epichlorohydrin cross-linking method. Utilizing the coordination effect of the hydroxyl group in PCD and the iron ion in photothermal nanoparticles (PB-Yb), the PCD is coated on its surface; simultaneously, CD in PCD can form a host-guest complex with adamantane-modified zinc phthalocyanine (Pc) photosensitizer. Using PCD as a "linker", PB-Yb and Pc (denoted PYPP) were combined to improve the solubility of PB-Yb, reduce the aggregation degree of Pc to increase their activity, and achieve photothermal and photodynamic synergistic tumor therapy., (Copyright © 2021. Published by Elsevier Ltd.)

For a significant proportion of patients with inflammatory bowel disease (IBD), primary non-response and secondary loss of response to treatment remain significant issues. Anti-tumor necrosis factor therapies have been licensed for use in IBD. Other disease-related pathways have been targeted as well, including the interleukin 12/23 axis and lymphocyte tracking. However, the need for parenteral administration and the associated costs of dispensing and monitoring all biologics remain a burden on healthcare systems and patients. Janus kinase inhibitors are small-molecule drugs that can be administered orally and are relatively inexpensive, thus offering an additional option for treating IBD. They have been shown to be effective in patients with ulcerative colitis (UC), but they are less effective in those with Crohn's disease (CD). Nonetheless, given the immune-system-based mechanism of these drugs, their safety profile remains a cause for concern. This article provides an overview of Janus kinase (JAK) inhibitors and new trends in the treatment of IBD.

Background and Aims: Studies of dipeptidyl peptidase inhibitors (DPP4is) report heterogeneous effects on cardiovascular targets in type 2 diabetes. This study aimed to investigate, in patients with impaired glucose tolerance (IGT), whether saxagliptin, a DPP4i, had beneficial cardiovascular effects at fasting and during the post-prandial state., Methods and Results: In this randomized, placebo-controlled, double-blind, single-center pilot exploratory study, we included obese individuals with IGT. Twenty-four individuals (BMI 36.8 ± 4.8 kg/m 2 ) were randomized to receive for 12 weeks either saxagliptin 5 mg a day or placebo. They were explored before and after a standardized breakfast for biological markers; microcirculatory blood flow at baseline and after transcutaneous administration of acetylcholine (Periflux System 5000® PERIMED); post-occlusive digital reactive hyperhemia (Endopat2000®); pulse wave velocity, augmentation index, central pulse pressure and subendocardial viability ratio (Sphygmocor®); cardiac hemodynamic parameters and cardiovascular autonomic nervous system activity (Task force monitor®). The results of all the investigations were similar after breakfast in the two groups at Visit 1 (acute post-prandial effects, after the first tablet) and Visit 2 (long-term post-prandial effects), and at fasting at Visit 1 and 2 (long-term effects, after 12 weeks of treatment). Only at Visit 2 the decrease in cardiac vagal activity occurring after breakfast was more sustained in the saxagliptin group than in the placebo group (interaction between treatment and time effect: p = 0.016)., Conclusion: In obese patients with IGT, the effects of saxagliptin on the large set of cardiovascular parameters measured are neutral, except for a more marked post-prandial depression of vagal activity., Clinical Trial Registration Number: NCT01521312., Competing Interests: Declaration of competing interest Amel Rezki, Marinos Fysekidis and Sabrina Chiheb declare they do not have any conflict of interest in relation with this manuscript. Eric Vicaut declares counseling activities for Abbott, Boston, Genomichealth, Celgen, CEMKA, Bristol-Myers-Squibb, CreativPharmaceuticals, Genomic health, and having received research grants from Astra-Zeneca, Bristol-Myers-Squibb and Pfizer. Emmanuel Cosson declares counseling activities for Abbott, AlphaDiab, Ascencia, Lilly, Medtronic, Merck-Sharp-Dohme, Novartis, Novo-Nordisk, Roche Diagnostics, Sanofi-Aventis, YpsoMed; having given lectures for Abbott, Astra-Zeneca, Bezins, Bristol-Myers-Squibb, LifeScan, Lilly, Merck-Sereno, Novartis, Novo-Nordisk, Roche Diagnostics, Sanofi-Aventis; and received research grants from Abbott, Air Liquide, Astra-Zeneca, Lilly, Novo-Nordisk, Roche diagnostics, Sanofi-Aventis, Ypsomed. Paul Valensi declares having given lectures for Abbott, AstraZeneca, Bayer, Eli-Lilly, Hikma, Merck-Sharp-Dohme, Novo-Nordisk, Novartis, Pfizer, Sanofi, Servier; received research grants from Abbott, Bristol-Myers-Squibb-AstraZeneca, Novo-Nordisk; and participated to Expert Committees for Astra Zeneca, Boehringer Ingelheim, Merck-Serono, Novo-Nordisk, Daiichi-Sankyo, Sanofi, Servier., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aims: Meta-analyses of randomized trials on Dipeptidyl Peptidase-4 inhibitors (DPP4i) reported discordant results on major cardiovascular events (MACE), mortality, and heart failure. Aim of this meta-analysis of randomized trials is the assessment of the cardiovascular safety of DPP4i., Data Synthesis: A Medline, Embase, Cochrane database search for sitagliptin, vildagliptin, omarigliptin, saxagliptin, alogliptin, trelagliptin, anagliptin, linagliptin, gemigliptin, evogliptin, and teneligliptin was performed up to up January 1st, 2020. All trials with a duration ≥24 weeks and comparing the effects of DPP4i with placebo or active drugs were collected. Mantel-Haenszel odds ratio (MH-OR) with 95% Confidence Interval (95% CI) was calculated for all outcomes defined above. A total of 182 eligible trials were identified. DPP-4i were not associated with an increased risk of MACE (MH-OR 0.99 [0.93, 1.04]), all-cause mortality (MH-OR 0.99 [0.93, 1.06]), and heart failure (MH-OR 1.05 [0.96, 1.15]) with no significant differences across individual molecules, except for saxagliptin, which was associated with an increased risk of heart failure., Conclusions: As a class, DPP4i are not associated with any increase or reduction of MACE, all-cause mortality, and heart failure. Saxagliptin seems to be associated with an increased risk of hospitalization for heart failure., Competing Interests: Declaration of competing interest BN is presently an employee of Novo Nordisk; CM, MG, and AG have no conflicts of interest to declare; MM has received speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis and research grants from Bristol Myers Squibb; EM has received consultancy fees from Merck and Novartis, speaking fees from Astra Zeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Eli-Lilly, Merck, Novo Nordisk, Sanofi, and Novartis, and research grants from Merck, Novartis, and Takeda. All the authors approved the final version of this manuscript. Dr. Matteo Monami is the person who takes full responsibility for the work as a whole, including the study design, access to data, and the decision to submit and publish the manuscript., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Several adamantanes have established actions against coronaviruses. Amantadine, rimantadine, bananins and the structurally related memantine are effective against human respiratory coronavirus HCoV-OC43, bovine coronavirus and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and a spiroadamantane amine is effective against the coronavirus strain 229E. Molecular docking studies suggest that amantadine may block the viral E protein channel, leading to impaired viral propagation. Additionally, amantadine analogues may inhibit entry of the virus into the host cell by increasing the pH of the endosomes and thus inhibiting the action of host cell proteases such as Cathepsin L. High-throughput drug screen gene expression analysis identified compounds able to down-regulate Cathepsin L expression where the fifth most potent agent of 466 candidates was amantadine. Amantadine inhibits severe acute respiratory syndrome coronavirus 2 replication in vitro but does not inhibit the binding of the spike protein to ACE2. Adamantanes also may act against coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via antagonism of glutamate (NMDA) and the α-7 subtype of the nicotinic acetylcholine receptor located on bronchial and alveolar epithelial cells. As an NMDA receptor antagonist, memantine has the potential to inhibit entry of SARS-CoV-2 into these cell populations. Amantadine and memantine are widely employed for the treatment of neurodegenerative diseases and a pathophysiologic link between the antiviral and anti-Parkinson actions of amantadine has been entertained. Case reports involving 23 patients with reverse transcription polymerase chain reaction-confirmed coronavirus disease 2019 (COVID-19) and a range of co-morbidities including type 2 diabetes mellitus, Parkinson's disease, multiple sclerosis and severe cognitive impairment reveal significant potential benefits of amantadine and memantine for the prevention and/or treatment of coronavirus disease 2019 and its neurological complications., (© 2021. The Author(s).)

Aims: Saxagliptin, a selective/potent dipeptidyl peptidase-4 inhibitor, has revealed remarkable anti-inflammatory features in murine models of nephrotoxicity, hepatic injury, and neuroinflammation. However, its potential effect on ethanol-induced gastric mucosal injury has not been examined. Hence, the present work investigated the prospect of saxagliptin to attenuate ethanol-evoked gastric injury, with emphasis on the AMPK/mTOR-driven autophagy and NLRP3/ASC/caspase-1 pathway., Materials and Methods: In ethanol-induced gastropathy, the gastric tissues were examined by immunohistochemistry, immunoblotting, histopathology, and ELISA., Key Findings: The results demonstrated that saxagliptin (10 mg/kg; by gavage) suppressed the gastric pathological signs (area of gastric ulcer and ulcer index scores), histopathologic aberrations/damage scores, without provoking hypoglycemia in rats. These protective features were attributed to the enhancement of gastric mucosal autophagy flux, as proven with increased expression of LC3-II and Beclin 1, decreased accumulation of p62 SQSTM1, and activation of the autophagy-linked AMPK/mTOR pathway by increasing the expression of p-AMPK/AMPK and decreasing the expression of the autophagy suppressor p-mTOR/mTOR signal. In tandem, saxagliptin counteracted the ethanol-induced pro-apoptotic events by downregulating Bax, upregulating Bcl2 protein, and lowering the Bax/Bcl2 ratio. Equally important, saxagliptin suppressed the NLRP3 inflammasome in the gastric tissue by lowering the expression of NLRP3, ASC, and nuclear NF-κBp65, decreasing the activity of caspase-1, and diminishing the IL-1β levels. In the same regard, saxagliptin suppressed the mucosal oxidative stress by lowering lipid peroxide levels, increasing GSH and GPx antioxidants, and activating Nrf2/HO-1 pathway., Significance: Saxagliptin may be a promising intervention against ethanol-evoked gastropathy by activating AMPK/mTOR-driven autophagy and inhibiting NLRP3 inflammasome., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: Hepatocellular carcinoma (HCC) is a highly invasive form of hepatic cancer. It is a highly intricate disease with multiple pathophysiological mechanisms underlying its pathogenesis., Materials and Methods: The results of the current investigation shed light on the ability of saxagliptin (SAXA) (12.5 mg/kg) to defer HCC progression in an experimental model of thioacetamide (TAA)-induced hepatocarcinogenesis., Results: SAXA administration improved liver function biomarkers, with a concomitant histopathological recovery. Mechanistically, the observed hepatoprotective impact was associated with significant suppression of the hepatic content of Wnt3a, β-catenin, Notch1, Smo, and Gli2 and enhanced expression of GSK 3β. Nevertheless, the hepatic expression of PCNA, P53, and cyclin D1 was significantly enhanced, with a parallel increase in the tumor expression of caspase-3. Thus, it appears that SAXA significantly enhanced tumor apoptosis, with concomitant suppression of HCC proliferation., Conclusion: SAXA deferred experimentally-induced HCC via suppressing Wnt/Hedgehog/Notch1 Signaling, with enhanced tumor apoptosis and suppressed proliferation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

As a complicated metabolic disorder, type 2 diabetes mellitus (T2DM) is becoming a major health concern worldwide. Drugs including acarbose, saxagliptin and vildagliptin are applied, but their efficacy is still required to be compared. Therefore, the study aimed to evaluate the efficacy and safety of acarbose, saxagliptin and vildagliptin in the treatment of T2DM. Ninety patients diagnosed with T2DM were treated with acarbose, saxagliptin and vildagliptin, respectively (30 patients for each drug). All patients were examined at 0, 4 and 12 weeks after treatment with vital signs recorded. Fasting blood glucose and blood biochemical indices were analyzed. In addition, fecal samples were taken for microbial macrogenome sequencing and safety evaluation within 12 weeks after treatment. Blood glucose level decreased at 4 and 12 weeks after treatment, and the total cholesterol (TC) and high-density lipoprotein (HDL) levels at 12 weeks were different. Genus abundance of intestinal flora was altered at different time points. Acarbose increased Butyricimonas level first and then decreased it during drug treatment. Saxagliptin increased Megamonas and decreased Turicibacter genus level gradually. Pseudomonas, Klebsiella, Blautia, Faecalibacterium and Roseburia levels fluctuated after Vildagliptin treatment, which increased fasting C-peptide level greater than the other two drugs. Saxagliptin showed higher adverse reactions than acarbose and vildagliptin. Collectively, acarbose, vildagliptin, and saxagliptin can effectively reduce the HbA1c level and affect the intestinal flora distribution in T2DM patients, and the adverse reactions of acarbose and vildagliptin are less than saxagliptin, providing alternative strategies for the treatment of T2DM., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.

Objective: To evaluate the safety of peficitinib for the treatment of rheumatoid arthritis (RA) in Asian patients., Methods: Safety data from one Phase 2b, two Phase 3, and one open-label long-term extension study [data cut-off 31 May 2018] were pooled into Phase 3 studies (peficitinib 100 and 150 mg/day, and placebo) and Phase 2/3 studies (all peficitinib-treated patients). Incidence rates per 100 patient-years (PY) of adverse events (AEs) of special interest were calculated., Results: Overall, 1052 patients received peficitinib for 2336.3 PY of exposure (median 2.1 years); four deaths occurred, including one death after the studies. AE incidence was similar across peficitinib 100 and 150 mg/day groups (Phase 3 studies). Respective peficitinib and placebo incidence rates (95% confidence interval) per 100 PY were 2.9 (1.9, 4.6) and 0.0 for serious infections, 5.7 (4.2, 7.9) and 2.3 (0.6, 9.4) for herpes zoster-related disease, and 0.6 (0.2, 1.6) and 1.2 (0.2, 8.3) for malignancies (excluding non-melanoma skin cancer) (Phase 3 studies), and 0.1 (0.0, 0.3) for venous thromboembolism in all peficitinib-treated patients (Phase 2/3 studies)., Conclusion: Peficitinib was well tolerated in Asian patients with RA over a median of 2 years, with no observed dose or temporal dependency for AEs with prolonged administration.

Background: Despite introduction of modern antiepileptic drugs, 30% of epileptic patients are still drug resistant. Remarkable three-dimensional spatial structure of 1-Adamantane carboxylic acid (AdCA), yet the simplicity of the molecule, makes AdCA a promising lead compound., Methods: Sedative/motor impairment and 24-h mortality rate of AdCA were determined in mice. Impact of AdCA on (1) threshold and occurrence of clonic seizures induced by pentylenetetrazole (PTZ) in mice, (2) incidence of tonic seizures induced by maximal electroshock (MES) in mice, and (3) incidence of generalized seizures and duration of evoked afterdischarges in amygdala-kindled rats, were determined. The role of benzodiazepine receptors in the AdCA effect on clonic seizure threshold was also assessed., Results: AdCA showed sedative effect (median toxic dose [TD50] = 224.5 [190.2-289.9] mg/kg). Median lethal dose (LD50) = 805.5 (715.2–988.1) mg/kg was obtained for AdCA. The compound increased PTZ seizure threshold from 180 mg/kg (p < 0.05) and also inhibited the incidence of clonic seizures (ED50 = 256.3 [107.4-417.3] mg/kg). AdCA also decreased afterdischarge duration (p < 0.01) and the incidence of generalized seizures (ED50 < 50 mg/kg) in the kindled rats. However, AdCA did not protect mice against tonic seizures induced by MES. The benzodiazepine receptor antagonist flumazenil prevented the increase of seizure threshold by AdCA., Conclusion: AdCA possesses anticonvulsant activity in kindling and PTZ models through the activation of benzodiazepine/GABAA receptors with acceptable therapeutic index.

Purpose: A recent large cardiovascular outcome trial in patients with type 2 diabetes (T2DM) demonstrated excess heart failure hospitalization with saxagliptin. We sought to evaluate the impact of saxagliptin on cardiac structure and function using cardiac magnetic resonance imaging (CMR) in patients with T2DM without pre-existing heart failure., Methods: In this prospective study, patients with T2DM without heart failure were prescribed saxagliptin as part of routine guideline-directed management. Clinical assessment, CMR imaging and biomarkers were assessed in a blinded fashion and compared following 6 months of continued treatment. The primary outcome was the change in left ventricular (LV) ejection fraction (LVEF) after 6 months of therapy. Key secondary outcomes included changes in LV and right ventricular (RV) end-diastolic volume, ventricular mass, LV global strain and cardiac biomarkers [N terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP)] over 6 months., Results: The cohort (n = 16) had a mean age of 59.9 years with 69% being male. The mean hemoglobin A1c (HbA1c) was 8.3%. Mean baseline LVEF was 57% ± 3.4, with no significant change over 6 months (- 0.2%, 95% CI - 2.5, 2.1, p = 0.86). Detailed CMR analyses that included LV/RV volumes, LV mass, and feature tracking-derived strain showed no significant change (all p > 0.50). NT-proBNP and hsCRP levels did not significantly change (p > 0.20)., Conclusions: In this cohort of stable ambulatory patients with T2DM without heart failure, saxagliptin treatment was not associated with adverse ventricular remodeling over 6 months as assessed using CMR and biomarkers.

Background and Aims: Dipeptidyl-peptidase inhibitors might be useful in type 2 diabetes prevention. ACCES (ACute and Chronic Effects of Saxagliptin) was a randomized, placebo-controlled, double-blind, controlled phase 2, pilot study aiming to examine in obese patients with impaired glucose tolerance (IGT) the acute effects and the effects after 12 weeks of treatment by saxagliptin on glucose levels at fasting and postprandially after a standard breakfast, and on glucose tolerance., Methods and Results: We included 24 obese patients with IGT. Patients were randomized to receive saxagliptin 5 mg or placebo in the morning. The treatment was taken on Visit 1 before breakfast, then continued for 12 weeks. Biochemical measurements were performed before, one, two and three hours after a standard breakfast including 75 g of carbohydrates, during Visit 1 and Visit 2 (12 weeks). Glucose variability (GV) was evaluated at Visit 1 from 24-h continuous glucose monitoring including the breakfast. A second OGTT was performed at Visit 3 (3-5 days after Visit 2). Compared with placebo-treated patients, saxagliptin-treated patients had lower 1 h and 2 h post-meal plasma glucose levels at Visit 1 and similar changes at Visit 2 (p < 0.01 to p < 0.004), with lower GV indexes after breakfast at Visit 1. At Visit 3, all patients but one in saxagliptin group and only 4 patients in placebo group turned to normal glucose tolerance. Lower glucose response to breakfast at Visit 1 was predictive of recovery of glucose tolerance., Conclusion: Saxagliptin has metabolically beneficial effects in glucose-intolerant obese patients by significantly lowering postprandial blood glucose levels., Clinical Trial Registration Number: NCT01521312: https://clinicaltrials.gov/ct2/show/NCT01521312., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

The aim of our study was to assess and compare the effects of dipeptidyl peptidase 4 (DPP4) inhibitors, saxagliptin and sitagliptin, on metabolic control of disease and cardiac function in rats with diabetes mellitus type 2 (T2DM). This research would provide novel understanding into the potentially protective effects of DPP4 inhibitors in helping salvage of the heart exposed to ischaemia-reperfusion (I-R) injury. Forty-eight Wistar albino rats were randomly divided into four groups: CTRL, Control healthy group; T2DM, rats with T2DM; T2DM + Sit, rats with T2DM treated with 0.6 mg/kg of sitagliptin; T2DM + Sax, rats with T2DM treated with 0.45 mg/kg of saxagliptin for 3 weeks. At the end of the protocol, in vivo cardiac function was assessed by echocardiography, while in the blood samples glucose and insulin were determined. Additionally, ex vivo heart function was estimated on a model of I-R injury using Langendorff apparatus. Immunohistochemical analysis was used to determine the degree of myocardial apoptosis and necrosis, while DPP4 staining was performed to assess the cardiac DPP4 expression. Data were analyzed using a one-way analysis of variance (ANOVA) and the post hoc Bonferroni test for multiple comparisons. Improved glycoregulation was noticed in rats that received DPP4 inhibitors compared to untreated diabetic rats (P < .05). Moreover, better in vivo systolic function was observed in rats treated with both DPP4 inhibitors as evidenced by an increase in fractional shortening when compared to T2DM (P < .05). Most parameters of cardiac function in treated rats remained unaltered during reperfusion, thus suggesting that both drugs protected myocardium during flow restoration. Better effects on coronary circulation were achieved after sitagliptin application. Additionally, both DPP4 inhibitors showed similar potential to attenuate cardiac necrosis and apoptosis. Saxagliptin and sitagliptin might be efficient in preserving myocardial function and morphology in ex vivo induced I-R cardiac injury in rats with T2DM., (© 2020 John Wiley & Sons Australia, Ltd.)

The marketed tablet formulation of peficitinib differs from the tablet used during the clinical trials. The bioequivalence of the marketed formulation and developmental tablet, and the food effect on the marketed formulation, were analyzed in 2 Japanese open-label, randomized, 2-way crossover studies in healthy male volunteers. Volunteers received a single oral dose of the marketed 150-mg peficitinib tablet under fasted conditions (bioequivalence), and under fed or fasted conditions (food effect). Bioequivalence was compared with the developmental 150-mg tablet. Samples for pharmacokinetic analysis were collected before dose and ≤72 hours after dose. Safety assessments included adverse events, vital signs, and laboratory variables. In total, 40 and 18 subjects were randomized to the bioequivalence and food effect studies, respectively. The 2 peficitinib formulations were bioequivalent (90% confidence intervals of the geometric mean ratios for C max and AUC t of peficitinib were within predefined limits of 0.8 to 1.25). The AUC last and the C max of the marketed tablet were 36.8% and 56.4% higher, respectively, under fed versus fasted conditions. Peficitinib was well tolerated. The marketed 150-mg tablet formulation of peficitinib was bioequivalent to the developmental 150-mg formulation, with no discernible safety differences. Bioavailability increased under fed conditions with the marketed tablet formulation., (© 2020 Astellas Pharma Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Calcium-sensing receptor (CaSR) is widely involved in the cell proliferation, differentiation, migration, adhesion and apoptosis, which can affect the vascular remodeling in the humanbody. The main ligand of CaSR is extracellular Ca 2+ . CaSR has the physiological significance in Ca 2+ homeostasis. Pulmonary vascular remodeling is one of the main histopathological changes of pulmonary hypertension (PH). The abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) results in the pulmonary vascular remodeling. CaSR is an important regulator of [Ca 2+ ] i . [Ca 2+ ] i is the main cause of the excessive pulmonary vascular remodeling in patients with PH. In this review, it was conclued that the structure of CaSR was prone to explore the devolopment or the treatment of PH. It was found that the regulation of CaSR with some miRNA could inhibit the proliferation of PASMCs, and that CaSR could affect the occurrence of autophagy in PH. Therefore, CaSR would become a new therapeutic target to PH.

Objective: To assess the long-term cost effectiveness of dapagliflozin (DAPA) and saxagliptin (SAXA) separately or together in patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin (MET)., Methods: Five head-to-head randomised controlled trials of the efficacy of DAPA and SAXA in type 2 diabetes mellitus (T2DM) patients were found by searching PubMed, Embase and Cochrane from inception to October 2019. The lifetime disease progression and long-term effectiveness of therapy in patients were projected by the United Kingdom Prospective Diabetes Study Outcome Model 2 (UKPDS OM2) in three T2DM therapeutic groups: DAPA + SAXA, DAPA and SAXA. Each group used DAPA and/or SAXA as an add-on therapy to MET. The study took the perspective of Chinese healthcare service providers. Univariate, scenario and probabilistic sensitivity analyses were performed., Results: The quality-adjusted life-years (QALYs) value of the DAPA + SAXA, SAXA and DAPA groups were 11.28, 11.26 and 11.45 years, respectively. The total costs were US$27,954.84, US$23,254.46 and US$25,608.49, respectively. DAPA was dominant over DAPA + SAXA. The DAPA + SAXA group presented an estimated QALY gain of 0.02 and a total cost increase of US$4700.39 over the SAXA group, with an incremental cost of US$217,530.10 per QALY. Compared with the SAXA group, the DAPA group had a QALY gain of 0.19 years and a total cost increase of US$2354.04, for an incremental cost of US$12,191.97 per QALY. The pharmacoeconomic results were robust to univariate, scenario and probabilistic sensitivity analyses., Conclusions: Compared with DAPA + SAXA or SAXA, DAPA appears to be a cost-effective therapy as add-on to MET for Chinese patients whose T2DM is insufficiently controlled by MET.

Objectives: Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety., Methods: Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration., Results: The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale., Conclusion: The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management., Competing Interests: Competing interests: DA has received grants from AbbVie, Novartis and Roche, consulting and lecture fees from Abbvie, Amgen, Celgene, Lilly, Medac, Merck Sharpe & Dohme, Novartis, Pfizer, Roche, Sandoz and Sanofi/Genzyme. W-HB has received a research grant from Pfizer and honoraria for advice from Abbvie, Alimirall, BMS, Celgene, Janssen, Leo, Lilly, Novartis and UCB. TD received study support and/or consulting fees by AbbVie, Celgene, Eli-Lilly, EMD/Merck, Janssen, Novartis, Pfizer, Roche, Sanofi, UCB Pharma. MD: grants from Pfizer, Abbvie, UCB, Janssen, Novartis and honoraria from Pfizer, Abbvie, UCB, Janssen, MSD, Novartis, BMS, Celgene, Biogen, Sandoz. PE: grants from AbbVie, Novartis, Samsung, Lilly and honoraria from AbbVie, Novartis, BMS, Gilead, Samsung, Lilly. XB, KG received consultancy and lecture fees from Novartis, Pfizer and Roche and investigational grants from Roche. EBL reports grants from Green pharma, Seoul, grants from Handoc, Seoul, and personal fees from Pfizer. PTN has received research grants and funding for clinical trials and honoraria for advice and lectures on behalf of Abbvie, BMS, Boehringer Ingelheim, Celgene, Eli-Lilly, Gilead, Janssen, Merck, Novartis, Pfizer, Roche, Sanofi, UCB Pharma. JEP has consulted for Amgen, AbbVie, BMS, Celltrion, Gilead, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, Samsung, Sandoz, Sanofi, Teva, UCB. RMF has received research grants and funding for clinical trials and honoraria for adbice from Abbvie, Amgen, Astra-Zeneca, BMS, Celltrion, Lilly, Gilead, GSK, Janssen, Novartis, Pfizer, Regeneron, Roche, Sandoz, Sanofi, Tahio and UCB. DvdH received consulting fees AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma and is Director of Imaging Rheumatology bv. JDI has received research funding or honoraria from Abbvie, Bristol-Myers Squibb, Eli Lilly, Gilead, Janssen, Merck, Pfizer, Roche. AK has received lecture fees from Bristol-Myers Squibb, Celgene, Merck Sharp and Dohme and Pfizer. JK received grant support for clinical research from Abbvie, BMS, Lilly, Novartis, Pfizer and consulted with Abbvie, BMS, Lilly, Novartis, Pfizer and Regeneron/Sanofi. IBM has received research funding or honoraria from Abbvie, Astra Zeneca, Celgene, GSK, Lilly, Boehringer, Pfizer, Janssen, Novartis, UCB, BMS, Sanofi. WPM has served as a consultant, and/or received honoraria and/or has received research/educational grants from AbbVie, Boehringer Ingelheim, Celgene, Eli Lilly and Company, Galapagos, Janssen, Novartis, Pfizer and UCB Pharma, and is Chief Medical Officer of CARE Arthritis Limited. MV: no conflict of interest. JSS has received research Grants for his institution from AbbVie, BMS, Lilly, MSD, Pfizer, Roche and honoraria for consultancies and/or speaking engagements: Abbvie, Amgen, Astra-Zeneca, Astro-Celltrion, BMS, Celgene, ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB. MS-M has no conflicts of interest. LST received grant support from Janssen, GSK and Pfizer and honoraria for consultations and/or speaking engagements from Janssen, Pfizer, Sanofi, Abbvie and Lilly. TT received grants from Astellas, AbbVie GK, Eisai; speaking fee from: AbbVie GK, Eli Lilly Japan, Astellas, Eisai, Gilead, Pfizer Japan; and consultancy fees from: Astellas, AbbVie GK, Gilead. YT has received speaking fees and/or honoraria from Daiichi-Sankyo, Eli Lilly, Novartis, YL Biologics, Bristol-Myers, Eisai, Chugai, Abbvie, Astellas, Pfizer, Sanofi, Asahi-kasei, GSK, Mitsubishi-Tanabe, Gilead, Janssen and has received research grants from Mitsubishi-Tanabe, Chugai, Abbvie, Takeda, UCB, Daiichi-Sankyo, Eisai. MT: Speaker for BMS, Falk Foundation, Gilead and MSD; advisory boards for Albireo, BiomX, Boehringer Ingelheim, Falk Pharma GmbH, Genfit, Gilead, Intercept, MSD, Novartis, Phenex and Regulus. He further received unrestricted research grants from Albireo, Cymabay, Falk, Gilead, Intercept, MSD and Takeda. He is also co-inventor of patents on the medical use of norUDCA (filed by the medical University of Graz as previous employer). FvdB received consultancy and/or speaker fees from Abbvie, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer and UCB. MdW has received honoraria for consultancies and speaking through Stichting Tools from AbbVie, BMS, Celgene, Janssen, Lilly, Novartis, Pfizer, Roche. RW: honoraria for speaking engagements and advice from Galapagos, Gilead and Celltrion. KLW received grant support from BMS and Pfizer and honoraria for consultations and /or speaking engagements from Pfizer, BMS, Abbvie, Gilead, Galapagos, Lilly, GSK, UCB. RX received consultancy and/or speaker fees from Abbvie, Lilly, Pfizer, UCB, Janssen., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Exogenous treatment of a neurotensin receptor 1 (NTR1) agonist exerted the neuroprotection in an obese and Alzheimer's model. However, the effects of NTR1 modulation on peripheral/hippocampal impairment and cognitive deficit following sustained HFD consumption are poorly understood. Forty rats received a normal diet (ND) or HFD for 16 weeks. At week 13, the ND group received a vehicle (n = 8). Thirty-two HFD-fed group were randomized into four subgroups (n = 8/subgroup) with a vehicle, 1 mg/kg of NTR1 agonist, 1 mg/kg of NTR antagonist, and combined treatment (NTR1 agonist-NTR antagonist) for 2 weeks, s.c. injection. Then, the cognitive tests and peripheral/hippocampal parameters were determined. Our findings demonstrated that NTR1 activator reversed obesity and attenuated metabolic impairment in pre-diabetic rats. It also alleviated hippocampal pathologies and synaptic dysplasticity, leading to deceleration or prevention of cognitive impairment progression. Therefore, NTR1 activation would be a possible novel therapy to decelerate or prevent progression of neuropathology and cognitive impairment in the pre-diabetes.

Introduction: Saxagliptin, a member of the dipeptidyl peptidase-4 inhibitor (DPP-4i) class of drugs, was approved by the FDA for the treatment of type 2 diabetes (T2D) in 2009, and has been in clinical use for more than a decade. Since the drug was first launched, much real-world evidence has also been accumulated. The efficacy and safety of saxagliptin, especially its cardiovascular safety, are of particular interest., Areas Covered: This review provides an overview of the safety and efficacy of saxagliptin based on observational studies, pharmacovigilance, and meta-analyses. In addition, with the findings of recent cardiovascular outcome trials (CVOTs), the authors discuss, herein, the efficacious use of saxagliptin., Expert Opinion: Saxagliptin exhibits a moderate glucose-lowering effect and is well tolerated by patients with T2D. SAVOR-TIMI 53, a CVOT of saxagliptin, reported neutral effects of saxagliptin in respect of the cardiovascular outcomes, but did raise a concern about the risk of heart failure. Conversely, recent CVOTs on sodium-glucose co-transporter-2 inhibitors (SGLT2i) have shown a favorably reduced risk of heart failure with these drugs. Also, DPP-4is decrease the serum glucagon level, whereas the SGLT2is increase it. Given the characteristics of the two classes of drugs, combined therapy with the two might be a promising option.

Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human Plasmodium vivax VISs where subjects were treated with chloroquine ( n = 24) or artefenomel ( n = 8) and compared them with studies in Thailand ( n = 41) and Malaysia ( n = 76). In the VISs, alanine transaminase (ALT) increased to ≥ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5-8 days post-treatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ≥ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26-14.59; P = 0.02) for every log 10 increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ≥ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91-27.47; P = 0.06), this risk disappeared when corrected for PCB. Peak ALT also correlated with peak C-reactive protein ( R = 0.44; P = 0.012). Elevations in ALT (≥ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental P. vivax infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory.