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

Objectives: This study aimed to evaluate the safety and efficacy of remogliflozin compared to vildagliptin as an add-on drug to metformin in type 2 diabetes mellitus (T2DM) treatment. Metformin is considered a first-line drug in T2DM. However, as the disease progresses with heightened insulin resistance and declining ß-cell function, the use of metformin alone is often inadequate to achieve optimum glucose levels. Methods: This prospective, randomised study was conducted at Maulana Azad Medical College and Associated Hospital in New Delhi, India, between February 2020 to January 2021. This study recruited 60 T2DM patients aged 35-70 years with glycated haemoglobin (HbA1c) >6.5% taking metformin at a daily dosage of 1,500-3,000 mg for ≥3 months. Patients were randomly assigned in a 1:1 ratio to receive either vildagliptin (50 mg) or remogliflozin (100 mg) twice daily for 90 days. The primary endpoint was a change in HbA1c levels from baseline to the end of 90 days whereas secondary endpoints were changes in lipid profile and weight. Results: The decrement in mean HbA1c levels was significantly higher in the remogliflozin group than in the vildagliptin group (-8.1% versus -2.4%; P <0.001). In addition, more significant weight loss was found in remogliflozin-treated patients (-5.2% versus -0.6%; P <0.01). Both treatments were well tolerated throughout the study. Conclusion: Compared to vildagliptin, remoglilflozin was significantly more effective in glycaemic control and weight loss in patients with T2DM and can therefore be considered as an add-on drug in T2DM not adequately controlled by metformin monotherapy.

Sugar substitutes on caries prevention in permanent teeth among children and adolescents: a systematic review and meta-analysis.

OBJECTIVES: This study aimed to systematically review the effect of sugar substitute consumption on caries prevention in permanent teeth among children and adolescents. DATA: Randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing the clinical effect of sugar substitutes (both high- and low-intensity sweeteners) in preventing caries in permanent teeth among children and adolescents aged 6-19 were included. SOURCES: A systematic search was conducted in three databases (PubMed, Web of Science and Embase) without any restrictions on publication year. STUDY SELECTION: The initial search found 1,859 items, and finally, 15 studies (11 RCTs and 4 CCTs) with a total of 6325 participants (age: 6-18 years) were included. The Cochrane risk-of-bias assessment tools were used for quality assessment. Most (80%, 12/15) were graded as having a 'moderate' or 'high' risk of bias. All trials investigated sugar alcohol, which is a low-intensity sweetener. Xylitol was the most commonly investigated (73.3%, 11/15), followed by sorbitol (46.7%, 7/15), and erythritol (13.3%, 2/15). Results of the meta-analysis showed that both xylitol (standardized mean difference [SMD]: -0.50, 95% confidence interval [CI] -0.85 to -0.16, P = 0.005) and sorbitol (SMD: -0.10, 95% CI: -0.19 to -0.01, P = 0.03) had a significant effect in preventing dental caries compared to no treatment/placebo. No clinical trials on high-intensity sweeteners such as aspartame and saccharin were found. CONCLUSION: The consumption of xylitol or sorbitol is potentially effective in preventing caries in permanent teeth among children and adolescents. No clinical evidence is available regarding the role of high-intensity sweeteners in caries prevention. CLINICAL SIGNIFICANCE: The use of xylitol or sorbitol as sugar substitutes has a beneficial effect in preventing dental caries among children and adolescents.

Dipeptidyl peptidase-4 inhibitor and sodium-glucose cotransporter 2 inhibitor additively ameliorate hepatic steatosis through different mechanisms of action in high-fat diet-fed mice.

AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP-4 function. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin-independent manner by inhibiting renal reabsorption of glucose. DPP-4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high-fat diet-fed mice. METHOD: C57BL/6J male mice were fed a 60% high-fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP-4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4-week intervention were evaluated. RESULTS: There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation- and chemokine-related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups. CONCLUSION: The combination therapy with the DPP-4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti-inflammatory effects during the early phase of diet-induced liver steatosis.

Widely distributable and retainable in-situ gelling material for treating myocardial infarction.

Intramyocardial hydrogel injection is a promising therapy to prevent negative remodeling following myocardial infarction (MI). In this study, we report a mechanism for in-situ gel formation without external stimulation, resulting in an injectable and tissue-retainable hydrogel for MI treatment, and investigate its therapeutic outcomes. A liquid-like polymeric solution comprising poly(3-acrylamidophenylboronic acid-co-acrylamide) (BAAm), polyvinyl alcohol (PVA), and sorbitol (S) increases the viscous modulus by reducing the pre-added sorbitol concentration is developed. This solution achieves a sol-gel transition in-vitro in heart tissue by spontaneously diffusing the sorbitol. After intramyocardial injection, the BAAm/PVA/S with lower initial viscous modulus widely spreads in the myocardium and gelate compared to a viscoelastic alginate (ALG) hydrogel and is retained longer than the BAAm/S solution. Serial echocardiogram analyses prove that injecting the BAAm/PVA/S into the hearts of subacute MI rats significantly increases the fraction shortening and ejection shortening and attenuates the expansion of systolic LV diameter for up to 21 d after injection compared to the saline injection as a control, but the ALG injection does not. In addition, histological evaluation shows that only the BAAm/PVA/S decreases the infarct size and increases the wall thickness 21 d after injection. The BAAm/PVA/S intramyocardial injection is better at restraining systolic ventricular dilatation and cardiac failure in the rat MI model than in the control groups. Our findings highlight an effective injectable hydrogel therapy for MI by optimizing injectability-dependent distribution and retention of injected material. STATEMENT OF SIGNIFICANCE: In-situ gelling material is a promising strategy for intramyocardial hydrogel injection therapy for myocardial infarction (MI). Since the sol-gel transition of reported materials is driven by external stimulation such as temperature, pH, or ultraviolet, their application in vivo remains challenging. In this study, we first reported a synthetic in-situ gelling material (BAAm/PVA/S) whose gelation is stimulated by spontaneously reducing pre-added sorbitol after contacting the heart tissue. The BAAm/PVA/S solution spreads evenly, and is retained for at least 21 d in the heart tissue. Our study demonstrated that intramyocardial injection of the BAAm/PVA/S with more extensive distribution and longer retention had better effects on preventing LV dilation and improving cardiac function after MI than that of viscoelastic ALG and saline solution. We expect that these findings provide fundamental information for the optimum design of injectable biomaterials for treating MI.

Combined PMM2-CDG and hereditary fructose intolerance in a patient with mild clinical presentation.

We report a patient with an extremely rare, combined diagnosis of PMM2-CDG and hereditary fructose intolerance (HFI). By comparing with other patients, under-galactosylation was identified as a feature of HFI. Fructose/sorbitol/sucrose restriction was initiated right afterwards. The patient is at the mild end of the PMM2-CDG spectrum, raising the question of sorbitol's role in the pathogenesis of PMM2-CDG and whether fructose/sorbitol/sucrose restriction could benefit other PMM2-CDG patients. Additionally, epalrestat, an emerging potential PMM2-CDG therapy, may benefit HFI patients.

Host Sorbitol and Bacterial Sorbitol Utilization Promote Clostridioides difficile Infection in Inflammatory Bowel Disease.

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is a widespread gastrointestinal inflammatory disorder with globally increasing incidence. Clostridioides difficile infection (CDI) often occurs in patients with intestinal dysbiosis, such as after antibiotic therapy. Patients with IBD have increased incidence of CDI and the clinical outcome of IBD is reportedly worsened by CDI. However, the underlying reasons remain poorly understood. METHODS: We performed a retrospective single-center and a prospective multicenter analysis of CDI in patients with IBD, including genetic typing of C difficile isolates. Furthermore, we performed a CDI mouse model to analyze the role of the sorbitol metabolization locus that we found distinguished the main IBD- and non-IBD-associated sequence types (STs). Moreover, we analyzed sorbitol concentration in the feces of patients with IBD and healthy individuals. RESULTS: We detected a significant association of specific lineages with IBD, particularly increased abundance of ST54. We found that in contrast to the otherwise clinically predominant ST81, ST54 harbors a sorbitol metabolization locus and was able to metabolize sorbitol in vitro and in vivo. Notably, in the mouse model, ST54 pathogenesis was dependent on intestinal inflammation-induced conditions and the presence of sorbitol. Furthermore, we detected significantly increased sorbitol concentrations in the feces of patients with active IBD vs patients in remission or healthy controls. CONCLUSIONS: Sorbitol and sorbitol utilization in the infecting C difficile strain play major roles for the pathogenesis and epidemiology of CDI in patients with IBD. CDI in patients with IBD may thus be avoided or improved by elimination of dietary sorbitol or suppression of host-derived sorbitol production.

Effects of sugar-free polyol chewing gums on gingival inflammation: a systematic review.

OBJECTIVES: A systematic review of published data was conducted with the aim of assessing the effects of sugar-free polyol chewing gums on gingival inflammation. MATERIALS AND METHODS: Electronic and hand searches were performed to find clinical studies concerning the effects of sugar-free chewing gums on gingival scores. Prospective randomized controlled clinical trials published between 1971 and 2021 were included in the review. RESULTS: The initial search identified 46 erythritol, 102 xylitol, 23 sorbitol, and nine maltitol chewing gum articles. After applying inclusion and exclusion criteria, seven xylitol chewing gum studies, one sorbitol, and one maltitol chewing gum study with either high or fair quality were reviewed. In five out of the seven xylitol studies, xylitol gum decreased gingival scores. In two studies, xylitol decreased gingival scores compared to a polyol gum, and in three studies compared to no gum/gum base. As for sorbitol and maltitol, only sorbitol gum chewing showed a small decrease in gingival scores compared to the controls. CONCLUSIONS: Habitual xylitol gum chewing may reduce gingival inflammation. The low number of studies and their heterogeneity provide clear indications that the effects of sugar-free polyol chewing gums on gingival inflammation need further, well-controlled studies. CLINICAL RELEVANCE: Sugar-free chewing gums, especially xylitol gum, may function as adjuncts to toothbrushing for reducing gingival inflammation, but the evidence so far is inconclusive.

Licogliflozin for nonalcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a study.

Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that may advance to fibrosis and lead to mortality; however, no pharmacotherapy is currently available. We tested the hypothesis that inhibition of both the sodium-glucose cotransporters 1 and 2 with licogliflozin would lead to improvement in NASH. A total of 107 patients with phenotypic or histologic NASH were randomized (1:2:2) to receive oral administration of either placebo (n = 21), licogliflozin 30 mg (n = 43) or 150 mg (n = 43) once daily for 12 weeks. Licogliflozin 150 mg showed a significant 32% (80% confidence interval (CI): 21-43%; P = 0.002) placebo-adjusted reduction in serum alanine aminotransferase after 12 weeks of treatment, the primary endpoint of the study. However, the 30 mg dose of licogliflozin did not meet the primary endpoint (placebo-adjusted reduction 21% (80% CI: 7-32%; P = 0.061)). Diarrhea occurred in 77% (33 of 43), 49% (21 of 43) and 43% (9 of 21) of patients treated with licogliflozin 150 mg, 30 mg and placebo, respectively, which was mostly mild in severity. No other major safety concerns were identified. Treatment with 150 mg licogliflozin led to reductions in serum alanine aminotransferase in patients with NASH. Studies of longer duration and in combination with drugs that have different mechanisms of action are needed to validate these findings and to define a role of licogliflozin as a therapeutic option for NASH. ClinicalTrials.gov identifier: NCT03205150.

Stimulation of Alpha-1-Adrenergic Receptor Ameliorates Obesity-Induced Cataracts by Activating Glycolysis and Inhibiting Cataract-Inducing Factors.

BACKGROUND: Obesity, the prevalence of which is increasing due to the lack of exercise and increased consumption of Westernized diets, induces various complications, including ophthalmic diseases. For example, obesity is involved in the onset of cataracts. METHODS: To clarify the effects and mechanisms of midodrine, an α1-adrenergic receptor agonist, in cataracts induced by obesity, we conducted various analytic experiments in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of obesity. RESULTS: Midodrine prevented cataract occurrence and improved lens clearance in OLETF rats. In the lenses of OLETF rats treated with midodrine, we observed lower levels of aldose reductase, tumor necrosis factor-α, and sorbitol, but higher levels of hexokinase, 5'-adenosine monophosphate-activated protein kinase-alpha, adenosine 5´-triphosphate, peroxisome proliferator-activated receptordelta, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, superoxide dismutase, and catalase. CONCLUSION: The ameliorating effects of midodrine on cataracts in the OLETF obesity rat model are exerted via the following three mechanisms: direct inhibition of the biosynthesis of sorbitol, which causes cataracts; reduction of reactive oxygen species and inflammation; and (3) stimulation of normal aerobic glycolysis.

Patient-reported outcomes of intra-articular hyaluronic acid for osteoarthritis of the knee: a prospective and multicentric case series.

BACKGROUND: In the present study, patients with symptomatic knee osteoarthritis (OA) were treated with single intra-articular injection of a high molecular weight, non-cross-linked hyaluronic acid (HA), highly concentrated (2%) and associated with sorbitol (4%). The aims of this study were to (1) evaluate clinical outcome after 6 months, (2) evaluate clinical outcomes after 12 months and (3) evaluate clinical outcomes according to OA grade. Hypothesis of the study was that a single intra-articular injection of this HA associated with sorbitol leads to a significant clinical improvement within 6 months in patients with early or moderate knee OA. MATERIALS AND METHODS: A total of 77 patients were enrolled in this prospective multicentric study. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score was recorded at baseline and at months 1, 3, 6 and 12 following the intra-articular injection. Moreover, a stratified analysis of all WOMAC items following the OA grade was performed for both groups of patients, one with low (grade I-II according to Kellgren-Lawrence classification) and another with moderate OA grade (grade III according to Kellgren-Lawrence) and the differences between groups were evaluated. RESULTS: Seventy-three patients completed the 12 months follow-up. Pain, stiffness, functional limitation and total scores were significantly reduced at 1, 3 and 6 months (p < 0.05), but not at 12 months. Stratified analysis of all subscores according to OA grade showed that pain, functional limitation and total score decreased at 1, 3, 6 and 12 months (p < 0.05) in both groups. Stiffness was the only item that decreased significantly at 1, 3 and 6 months but not at 12 months in both groups. All subscore values were significantly lower in the group of patients with low OA grade compared to the one with moderate OA grade. No adverse events were reported. CONCLUSION: At 6 months after a single intra-articular injection of a high molecular weight, non-cross-linked HA associated with sorbitol, WOMAC scores decreased significantly. Clinical benefits were observed both in patients with low and in those with moderate OA grade, with better results in the first group.

Factors Influencing Change in Serum Uric Acid After Administration of the Sodium-Glucose Cotransporter 2 Inhibitor Luseogliflozin in Patients With Type 2 Diabetes Mellitus.

Although sodium-glucose cotransporter 2 (SGLT2) inhibitors lower serum uric acid, their long-term effect on uric acid metabolism is not well understood. We analyzed pooled data from studies wherein patients with type 2 diabetes mellitus received luseogliflozin, an SGLT2 inhibitor. Upon stratifying patients by baseline glycated hemoglobin (HbA1c ) or serum uric acid, lower HbA1c or higher serum uric acid level was associated with a greater reduction in serum uric acid after treatment. At week 12 of treatment, significant increases in urinary glucose/creatinine (Cr) ratio and urinary uric acid clearance/Cr clearance ratio (CUA /CCr ratio) and a significant reduction in serum uric acid were observed. Comparison of the subgroups of patients with a reduction or an increase in serum uric acid showed that the increase subgroup had a higher estimated glomerular filtration rate (eGFR) at baseline, and the eGFR was significantly reduced, associated with a significant reduction in the CUA /CCr ratio. Multiple regression analysis showed that the reduction in serum uric acid in the luseogliflozin group was strongly associated with baseline high serum uric acid, low HbA1c levels, and an increase in eGFR. Luseogliflozin was shown to reduce serum uric acid by enhancing urinary uric acid excretion in association with increased urinary glucose. Treatment with luseogliflozin resulted in increased serum uric acid in some patients, which may be due to reduced glomerular filtration of uric acid via the tubuloglomerular feedback. SGLT2 inhibitors reduced serum uric acid desirably in patients with type 2 diabetes mellitus with low HbA1c and high serum uric acid.

Luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, reverses cerebrovascular dysfunction and cognitive impairments in 18-mo-old diabetic animals.

Diabetes mellitus (DM) is a leading risk factor for age-related dementia, but the mechanisms involved are not well understood. We previously discovered that hyperglycemia induced impaired myogenic response (MR) and cerebral blood flow (CBF) autoregulation in 18-mo-old DM rats associated with blood-brain barrier (BBB) leakage, impaired neurovascular coupling, and cognitive impairment. In the present study, we examined whether reducing plasma glucose with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) luseogliflozin can ameliorate cerebral vascular and cognitive function in diabetic rats. Plasma glucose and HbA1c levels of 18-mo-old DM rats were reduced, and blood pressure was not altered after treatment with luseogliflozin. SGLT2i treatment restored the impaired MR of middle cerebral arteries (MCAs) and parenchymal arterioles and surface and deep cortical CBF autoregulation in DM rats. Luseogliflozin treatment also rescued neurovascular uncoupling, reduced BBB leakage and cognitive deficits in DM rats. However, SGLT2i did not have direct constrictive effects on vascular smooth muscle cells and MCAs isolated from normal rats, although it decreased reactive oxygen species production in cerebral vessels of DM rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.NEW & NOTEWORTHY This study demonstrates that luseogliflozin, a sodium-glucose cotransporter-2 inhibitor, improved CBF autoregulation in association with reduced vascular oxidative stress and AGEs production in the cerebrovasculature of 18-mo-old DM rats. SGLT2i also prevented BBB leakage, impaired functional hyperemia, neurodegeneration, and cognitive impairment seen in DM rats. Luseogliflozin did not have direct constrictive effects on VSMCs and MCAs isolated from normal rats. These results provide evidence that normalization of hyperglycemia with an SGLT2i can reverse cerebrovascular dysfunction and cognitive impairments in rats with long-standing hyperglycemia, possibly by ameliorating oxidative stress-caused vascular damage.

SGLT-1-specific inhibition ameliorates renal failure and alters the gut microbial community in mice with adenine-induced renal failure.

Sodium-dependent glucose cotransporters (SGLTs) have attracted considerable attention as new targets for type 2 diabetes mellitus. In the kidney, SGLT2 is the major glucose uptake transporter in the proximal tubules, and inhibition of SGLT2 in the proximal tubules shows renoprotective effects. On the other hand, SGLT1 plays a role in glucose absorption from the gastrointestinal tract, and the relationship between SGLT1 inhibition in the gut and renal function remains unclear. Here, we examined the effect of SGL5213, a novel and potent intestinal SGLT1 inhibitor, in a renal failure (RF) model. SGL5213 improved renal function and reduced gut-derived uremic toxins (phenyl sulfate and trimethylamine-N-oxide) in an adenine-induced RF model. Histological analysis revealed that SGL5213 ameliorated renal fibrosis and inflammation. SGL5213 also reduced gut inflammation and fibrosis in the ileum, which is a primary target of SGL5213. Examination of the gut microbiota community revealed that the Firmicutes/Bacteroidetes ratio, which suggests gut dysbiosis, was increased in RF and SGL5213 rebalanced the ratio by increasing Bacteroidetes and reducing Firmicutes. At the genus level, Allobaculum (a major component of Erysipelotrichaceae) was significantly increased in the RF group, and this increase was canceled by SGL5213. We also measured the effect of SGL5213 on bacterial phenol-producing enzymes that catalyze tyrosine into phenol, following the reduction of phenyl sulfate, which is a novel marker and a therapeutic target for diabetic kidney disease DKD. We found that the enzyme inhibition was less potent, suggesting that the change in the microbial community and the reduction of uremic toxins may be related to the renoprotective effect of SGL5213. Because SGL5213 is a low-absorbable SGLT1 inhibitor, these data suggest that the gastrointestinal inhibition of SGLT1 is also a target for chronic kidney diseases.

Assessment of the Response Profile to Hyaluronic Acid Plus Sorbitol Injection in Patients with Knee Osteoarthritis: Post-Hoc Analysis of a 6-Month Randomized Controlled Trial.

In a previous randomized trial, the non-inferiority of two hyaluronic acid injections (Synolis VA versus Synvisc-One) was assessed in patients with knee OA, with a response rate of 79% for Synolis VA. To assess whether a responder profile could be established for this treatment modality, we used the Synolis VA arm of a published 6-month prospective, multicenter, comparative, randomized, double-blinded trial. At baseline and during the study, pain and function were assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire. Ninety-six subjects from the intention-to-treat trial were included in the analysis. The 6-month change of WOMAC Pain with Synolis VA was not associated with any baseline clinical data. However, the change in WOMAC Function was significantly associated with its baseline level, even after adjustment for potential confounding variables (p = 0.028), i.e., a poorer physical function at baseline was associated with a better response. In conclusion, in addition to the high absolute response rate to Synolis VA, the probability of success is even increased if administered in patients with more limited physical function at baseline. Further research with other potential confounding clinical variables is warranted in order to better applicate the concept of personalized medicine.

Regional Distribution of Cardiologists and Prescription Patterns of Sodium-Glucose Transporter-2 Inhibitors in Japan.

The clinical evidence is accumulating since 2015 that anti-diabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors have the beneficial effect of cardiovascular and, recently, renal protection. Although it is not well analyzed how the transfer of this new evidence into daily practice has expedited, we hypothesize that the recent usage of the drugs is positively associated with several certified cardiologists in each region.The 2016 annual and 2016-2017 increased number of SGLT2 inhibitor tablets, based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan, were divided by the estimated number of patients with type 2 diabetes mellitus for each of the 47 prefectures. Then, regression analyses were performed to investigate the potential association of the number of certified cardiologists with the drug prescription.The 2016 prescription of ipragliflozin, dapagliflozin, luseogliflozin, canagliflozin, and empagliflozin was 2.7- to 4.4-fold different between prefectures. The 2016-2017 increased prescription volume also varied among prefectures by as large as 7.3-fold for ipragliflozin. Regression analysis revealed that the annual and increased prescription volume of all the SGLT2 inhibitors except luseogliflozin were higher in regions with more certified cardiologists (P < 0.05), even after adjusting for regional parameters.In conclusion, the regional number of certified cardiologists was positively associated with a 2016 annual of and 2016-2017 increase in SGLT2 inhibitor prescription amount, implying an early adopter role of clinical experts in healthcare delivery.

Investigations of Dianhydro-D-glucitol adsorbed on AuNPs surface: In silico and in vitro approach based on anticancer activity studies against A549 lung cancer cell lines.

The adsorption behavior of a lung cancer agent, Dianhydro-D-glucitol (DIS) on gold nanoparticles (AuNPs) was studied using surface-enhanced Raman scattering techniques. The stabilized geometry, inter- and intra-molecular hydrogen bond, and harmonic vibrational wavenumbers of DIS and DIS adsorbed on AuNPs (DISA) surface have been investigated with the help of the density functional theory (DFT) method. The stability of the molecules arising from stereoelectronic interactions, leading to its bioactivity, has been confirmed using natural bond orbital (NBO) analysis, which was further substantiated by the narrow HOMO LUMO energy gap obtained for DISA, from frontier molecular orbital analysis as well as electronic spectral analysis. The molecular electrostatic potential analysis along with local and global reactivity descriptors predicts the reactive site of the molecules. Molecular docking study was performed to obtain information about protein-ligand reactions for DIS and DISA, with different cancer proteins. This study enlightens the potential of SERS agents for targeted drug delivery and photothermal. The in vitro cytotoxic effects of DPH and DPHA molecules on lung cancer cell lines were analyzed using the MTT assay and the SERS method.

Non-Inferiority of a Single Injection of Sodium Hyaluronate Plus Sorbitol to Hylan G-F20: A 6-Month Randomized Controlled Trial.

INTRODUCTION: Several viscosupplement treatments are available for patients suffering from painful osteoarthritis (OA) of the knee, but few comparative clinical trials have been conducted. The primary objective of the trial was to demonstrate the non-inferiority of Synolis VA (80 mg hyaluronic acid and 160 mg sorbitol) (Group HA1) to Synvisc-One (48 mg hylan GF-20) (Group HA2) at Day 168 in terms of pain relief efficacy in patients with knee OA (Kellgren and Lawrence radiological stage II or III) in whom oral treatment with analgesics, NSAIDs or weak opioids provided insufficient clinical responses or were poorly tolerated. METHODS: This was a prospective, multicentre, comparative, randomized, double-blinded trial comparing the two previously indicated viscosupplements, HA1 and HA2. The average VAS pain score (1-100) was 62.5 at baseline (Day 0). The patients were randomized into two parallel groups at Day 0 and followed until Day 168. They received one injection of either HA1 or HA2. The primary end point was the evolution of the Western Ontario and McMaster University (WOMAC) pain index at D168 in the groups. One of the secondary end points was the daily assessment of this index by the patient for 7 days following the injection and thereafter at Day 14. The other secondary end points were the WOMAC pain, stiffness, function and total scores assessed at Day 28, Day 84 and Day 168. At Day 168, efficacy and satisfaction were assessed by the evaluator and by the patient using a Likert scale (7 points). Moreover, the number of strict responders in each group was evaluated according to the The Osteoarthritis Research Society International (OARSI) Standing Committee for Clinical Trials Response Criteria Initiative and the Outcome Measures in Rheumatology (OMERACT) criteria (OMERACT-OARSI). The per protocol (PP) population was used for the primary analysis. RESULTS: A total of 202 patients were randomized. The patients were predominantly female (66%). The median age of the whole population was 65 years, and the median body mass index was 27.4 kg/m2. No statistically significant differences between the two treatment groups were observed for any of the demographic criteria. At Day 168, 197 had had no protocol violations (94 in the HA1 group and 103 in the HA2 group). The WOMAC pain score decreased in the two groups: - 29.2 ± 24.1 (SD) in the HA1 group and - 31.6 ± 25.5 (SD) in the HA2 group, confirming the non-inferiority of Synolis VA (P = 0.57 for the difference between groups). Regarding the secondary end points, no significant difference was observed at Day 14, Day 28, Day 84 or Day 168 for all the outcomes except stiffness at Day 28 (P = in favour of treatment received in HA2). The rate of responders was comparable between the two groups: 79% for HA1 and 77% for HA2. Both products were well tolerated. Serious adverse events were reported by four patients in the HA1 group and 3 in the HA2 group. CONCLUSION: In this trial, we confirmed the non-inferiority of Synolis VA compared to Synvisc-One at Day 168 according to the WOMAC pain score. Safety was satisfying and comparable in the two groups. TRIAL REGISTRATION: 2017-A00034-49.

Effect of Luseogliflozin on Heart Failure With Preserved Ejection Fraction in Patients With Diabetes Mellitus.

Background Effects of sodium-glucose cotransporter 2 inhibitors on reducing hospitalization for heart failure have been reported in randomized controlled trials, but their effects on patients with heart failure with preserved ejection fraction (HFpEF) are unknown. This study aimed to evaluate the drug efficacy of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus and HFpEF. Methods and Results We performed a multicenter, open-label, randomized, controlled trial for comparing luseogliflozin 2.5 mg once daily with voglibose 0.2 mg 3 times daily in patients with type 2 diabetes mellitus suffering from HFpEF (left ventricular ejection fraction >45% and BNP [B-type natriuretic peptide] concentrations ≥35 pg/mL) in a 1:1 randomization fashion. The primary outcome was the difference from baseline in BNP levels after 12 weeks of treatment between the 2 drugs. A total of 173 patients with diabetes mellitus and HFpEF were included. Of these, 83 patients were assigned to receive luseogliflozin and 82 to receive voglibose. There was no significant difference in the reduction in BNP concentrations after 12 weeks from baseline between the 2 groups. The ratio of the mean BNP value at week 12 to the baseline value was 0.79 in the luseogliflozin group and 0.87 in the voglibose group (percent change, -9.0% versus -1.9%; ratio of change with luseogliflozin versus voglibose, 0.93; 95% CI, 0.78-1.10; P=0.26). Conclusion In patients with type 2 diabetes mellitus and HFpEF, there is no significant difference in the degree of reduction in BNP concentrations after 12 weeks between luseogliflozin and voglibose. Registration URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000018395.

Investigation and Management of Stool Frequency and Consistency Associated With SGLT1 Inhibition by Reducing Dietary Carbohydrate: A Randomized Trial.

Treatment with licogliflozin, a dual sodium-glucose co-transporter (SGLT)1/2-inhibitor, is associated with increased stool frequency and loose stools, attributed to SGLT1 inhibition. To investigate the effect of carbohydrate content and supplements on licogliflozin-induced stools, a randomized, open-label, two-part (N = 24/part), three-period crossover study was carried out in overweight or obese adults. Significantly higher (P < 0.01) change from baseline in 3-day total number of bowel movements was observed following 3 days of licogliflozin treatment (50 mg q.d.) together with a 50% carbohydrate meal compared with a 25% and 0% carbohydrate meal. The number of stools with Bristol Stool Chart score of 6 or 7 was also significantly lower following a 0% carbohydrate meal. Supplementation with psyllium 6 g or calcium carbonate 1 g had no effect on stool changes following treatment. Licogliflozin was generally safe and well-tolerated. Loose stool associated with licogliflozin treatment and ingestion of meals can be managed by reducing the carbohydrate content of meals taken with licogliflozin.

Licogliflozin, a Novel SGLT1 and 2 Inhibitor: Body Weight Effects in a Randomized Trial in Adults with Overweight or Obesity.

OBJECTIVE: The aim of this study was to explore the dose response of licogliflozin, a dual inhibitor of sodium/glucose cotransporter 1 (SGLT1) and 2 (SGLT2), by evaluating change in body weight in adults with overweight or obesity. METHODS: This dose-response analysis evaluated change in body weight following 24 weeks with four once-daily and twice-daily licogliflozin doses (2.5-150 mg) versus placebo (primary end point). A further 24-week analysis evaluated the efficacy and safety of two once-daily licogliflozin doses in maintaining initial weight reduction. RESULTS: Licogliflozin once daily or twice daily produced a significant dose-response signal for weight loss versus placebo (P < 0.0001). However, mean adjusted percent changes in body weight after 24 weeks were modest, ranging from -0.45% to -3.83% (in the 50 mg twice daily group [95% CI: -5.26% to -2.48%]; n = 75). Responder analysis of ≥ 5% weight loss at week 24 revealed significant differences versus placebo, which were most pronounced with highest doses of 50 mg twice daily (45.3%) and 150 mg once daily (42.9%) (both P < 0.01). While weight loss was greater at higher doses, gastrointestinal adverse events were also more frequent. The 50-mg once-daily dose had perhaps the best balance between efficacy and tolerability. CONCLUSIONS: Licogliflozin produced significant reductions in body weight versus placebo. However, the magnitude of weight reduction was modest.