Explore the vast range of titles available.

Article analyzes the main sorbitol detecting methods in animal biological fluids. Also it presents a brief methodology for conducting these studies. Respectively the main methods’ advantages and disadvantages are outlined. Upon the conclusion several proposes were made for veterinary practitioners. For example, some prospects for using methods duting laboratory examination.

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. In a phase 2a clinical trial in patients with nonalcoholic steatohepatitis, dual inhibition of sodium–glucose cotransporters 1 and 2 with 150 mg of licogliflozin led to reductions in serum alanine aminotranferase levels.

To evaluate the influence of renal function on the efficacy and safety of the sodium glucose cotransporter 2 inhibitor luseogliflozin (TS-071) in Japanese patients with type 2 diabetes mellitus (T2DM). Study 1 was a 52-week, Phase III study to evaluate the efficacy and safety of 2.5 mg/d luseogliflozin (or increased to 5 mg/d) in patients with T2DM with moderate renal impairment. During the initial 24 weeks, efficacy and safety of luseogliflozin were compared with placebo. Study 2 was a pooled analysis of four 52-week, Phase III studies of luseogliflozin, including Study 1, to evaluate the efficacy and safety of luseogliflozin in patients with various degrees of renal function. Patients were stratified into 3 groups by baseline estimated glomerular filtration rate (eGFR): normal renal function (≥90 mL/min/1.73 m2), mild impairment (≥60 to <90 mL/min/1.73 m2), and moderate impairment (≥30 to <60 mL/min/1.73 m2). Patients with moderate impairment were further divided into those with mild-moderate (≥45 to <60 mL/min/1.73 m2) and moderate-severe (≥30 to <45 mL/min/1.73 m2). In both studies, efficacy end points included changes in glycated hemoglobin (HbA1c) level, fasting plasma glucose (FPG) level, and body weight. The safety end points included adverse events (AEs) and laboratory parameters. In Study 1, HbA1c, FPG, and body weight significantly decreased at Week 24 in patients treated with luseogliflozin compared with patients treated with placebo, with the decrease in these parameters also observed with luseogliflozin at Week 52. The incidence of AEs was similar between groups. In Study 2, 1030 patients were included (normal, 275; mildly impaired, 598; and moderately impaired, 157). At Week 52, HbA1c, FPG, and body weight were significantly decreased from baseline in all groups. In between-group comparisons, the decreases in HbA1c and body weight were significantly smaller in patients with moderate impairment than in those with normal function; however, the HbA1c-lowering efficacy was reduced by nearly half, whereas the efficacy of body weight lowering was not so much diminished in the moderate impairment group. Furthermore, a scatter plot showed that changes in HbA1c were more influenced by baseline HbA1c than by baseline eGFR. The incidence of AEs during 52 weeks was similar among all groups, with the majority being mild. Luseogliflozin improved glycemic control and reduced body weight in all eGFR groups, and its efficacy on HbA1c lowering was reduced in those with moderate renal impairment. Luseogliflozin was well tolerated and safe, with no significant safety issues identified, regardless of baseline eGFR. The study is registered with Clinical Trials Information/JapicCTI of the Japan Pharmaceutical Information Center, and the study registry identification numbers are JapicCTI-111507, JapicCTI-111508, JapicCTI-111509, and JapicCTI-111543

Clinically available imaging tools for diagnosing infections rely on structural changes in the affected tissues. They therefore lack specificity and cannot differentiate between oncologic, inflammatory and infectious processes. We have developed 2-deoxy-2-[ 18 F]fluoro- d -sorbitol ( 18 F-FDS) as an imaging agent to visualize infections caused by Enterobacterales, which represent the largest group of bacterial pathogens in humans and are responsible for severe infections, often resulting in sepsis or death. A clinical study in 26 prospectively enrolled patients demonstrated that 18 F-FDS positron emission tomography (PET) was safe, and could detect and localize infections due to drug-susceptible or multi-drug-resistant Enterobacterales strains as well as differentiate them from other pathologies (sterile inflammation or cancer). 18 F-FDS is cleared almost exclusively through renal filtration and has also shown potential as a PET agent for functional renal imaging. Since most PET radionuclides have a short half-life, maximal clinical impact will require fast, on-demand synthesis with limited infrastructure and personnel. To meet this demand, we developed a kit-based solid phase method that uses commercially and widely available 2-deoxy-2-[ 18 F]fluoro- d -glucose as the precursor and allows 18 F-FDS to be produced and purified in one step at room temperature. The 18 F-FDS kit consists of a solid-phase extraction cartridge packed with solid supported borohydride (MP-borohydride), which can be attached to a second cartridge to reduce pH. We evaluated the effects of different solid supported borohydride reagents, cartridge size, starting radioactivity, volumes and flow rates in the radiochemical yield and purity. The optimized protocol can be completed in <30 min and allows the synthesis of 18 F-FDS in >70% radiochemical yield and >90% radiochemical purity. Mota et al. describe a protocol for the rapid, room-temperature, kit-based synthesis of 18 F-FDS for positron emission tomography imaging.

Luseogliflozin is a selective sodium glucose co-transporter 2 (SGLT2) inhibitor. To evaluate the cardiac safety of luseogliflozin, a thorough QT/QTc study was conducted in healthy Japanese subjects. The effects of moxifloxacin on QT prolongation in Japanese subjects were also evaluated. In this double-blind, placebo- and open-label positive-controlled, 4-way crossover study, 28 male and 28 female subjects received a single dose of luseogliflozin 5 mg (therapeutic dose), luseogliflozin 20 mg (supratherapeutic dose), placebo, and moxifloxacin 400 mg. Serial triplicate digital 12-lead electrocardiograms (ECGs) were recorded before and after dosing, and results were analyzed using the Fridericia correction (QTcF) method. Serial blood sampling was performed for pharmacokinetic analyses of luseogliflozin and moxifloxacin to analyze the relationship between QTcF interval and plasma concentration. The upper limits of the two-sided 90% confidence intervals (CIs) for baseline and placebo-adjusted QTcF intervals (ΔΔQTcF) in the 5 mg and 20 mg luseogliflozin groups were less than 10 ms at all time points. No correlation between plasma luseogliflozin concentrations and ΔΔQTcF was observed. In the moxifloxacin group, the lower limits of the two-sided 90% CIs for ΔΔQTcF were greater than 5 ms at all time points. A positive relationship was observed between plasma moxifloxacin concentration and change in ΔΔQTcF. Luseogliflozin was well tolerated at both dose levels. The majority of adverse events were mild in severity, and no serious or life-threatening adverse events occurred. Neither therapeutic (5 mg) nor supratherapeutic (20 mg) doses of luseogliflozin affected QT prolongation in healthy Japanese subjects.

The enzyme D-sorbitol dehydrogenase (SLDH) facilitates the conversion of D-sorbitol to L-sorbose. While current knowledge of this enzyme class predominantly centers on Gluconobacter oxydans , the catalytic properties of enzymes from alternative sources, particularly their substrate specificity and coenzyme dependency, remain ambiguous. In this investigation, we conducted BLASTp analysis and screened out a novel SLDH (Fpsldh) from Faunimonas pinastri A52C2. The SLDH was then identified and characterized. Analysis of the purified enzyme revealed its dependence on NAD + /NADP + and its specificity for L-sorbose production. Fpsldh demonstrated sustained catalytic activity over temperatures ranging from 27 to 37 ℃, with optimal performance observed at pH 8.0–10.0, and it exhibited no requirement for metal ions for activation. The K m of Fpsldh is 7.51 mM. Furthermore, a Bacillus licheniformis host expressing Fpsldh was engineered. The resultant whole-cell catalyst yielded 13.19 g/L of L-sorbose after 33.6 h of transformation, obviating the need for exogenous cofactors. This study enhances our understanding of the catalytic properties of the SLDH family and introduces a novel method for L-sorbose production, a compound of considerable commercial value. Key points •New D-sorbitol dehydrogenase from Faunimonas pinastri A52C2 is characterized. •Fpsldh is not PQQ but NAD + /NADP + -dependent. •Bacillus licheniformis expressing Fpsldh can produce 13.19 g/L L-sorbose within 33.6 h.

Background Older patients with type 2 diabetes mellitus (T2DM) have an increased risk of bone fracture independent of their bone mineral density (BMD), which is explained mainly by the deteriorated bone quality in T2DM compared to that in non-diabetic adults. Sodium-glucose co-transporter (SGLT) 2 inhibitors have been studied in several trials in T2DM, and the Canagliflozin Cardiovascular Assessment Study showed an increased fracture risk related to treatment with the SGLT2 inhibitor canagliflozin, although no evidence of increased fracture risk with treatment with other SGLT2 inhibitors has been reported. The mechanism of the difference in the fracture risk between the SGLT2 inhibitors is unknown, but the differences among the SGLT2 inhibitors in the selectivity of SGLT2 against SGLT1 may affect bone metabolism, since among the SGLT2 inhibitors the selectivity of canagliflozin is lowest. We will investigate whether the SGLT2 inhibitor luseogliflozin, which has the higher SGLT2 selectivity, affects bone metabolism by using high-resolution, peripheral quantitative computed tomography (HR-pQCT) which provides direct in vivo morphometric information about the bone microarchitecture. Methods/design This is a single-center, randomized, open-label, active-controlled, parallel pilot trial. Eligible participants are older (age ≥ 60 years) individuals with T2DM with HbA1c levels at 7.0–8.9%. A total of 24 participants will be allocated to either the luseogliflozin group (taking luseogliflozin) or the control group (taking metformin) in a 1:1 ratio to compare the groups’ changes in bone microarchitecture of the radius and tibia which are analyzed by HR-pQCT before and at 48 weeks after the administration of each medication. The laboratory data associated with glycemic control and bone metabolism will be collected every 12 weeks during the study. Recruitment began in June 2019. Discussion The reason that we use metformin as an active control is to avoid yielding differences in glycemic control between the luseogliflozin and control groups. Besides, metformin is considered to have a neutral effect on bone. This trial should reveal the effect of luseogliflozin on bone metabolism in older patients with T2DM. Trial registration The study was registered with the University Hospital Medical Information Network ( UMIN000036202 ) on 1 April 2019 and with the Japan Registry of Clinicla Trials ( jRCTs071180061 ) on 14 March 2019.

Epalrestat is an inhibitor of aldose reductase in the polyol pathway and is used for the management of diabetic neuropathy clinically. Our pilot experiments and accumulated evidences showed that epalrestat inhibited polyol pathway and reduced sorbitol production, and suggested the potential renal protection effects of epalrestat on diabetic nephropathy (DN). To evaluate the protective effect of epalrestat, the db/db mice were used and exposed to epalrestat for 8 weeks, both the physiopathological condition and function of kidney were examined. For the first time, we showed that epalrestat markedly reduced albuminuria and alleviated the podocyte foot process fusion and interstitial fibrosis of db/db mice. Metabolomics was employed, and metabolites in the plasma, renal cortex, and urine were profiled using a gas chromatography-mass spectrometry (GC/MS)-based metabolomic platform. We observed an elevation of sorbitol and fructose, and a decrease of myo-inositol in the renal cortex of db/db mice. Epalrestat reversed the renal accumulation of the polyol pathway metabolites of sorbitol and fructose, and increased myo-inositol level. Moreover, the upregulation of aldose reductase, fibronectin, collagen III, and TGF-β1 in renal cortex of db/db mice was downregulated by epalrestat. The data suggested that epalrestat has protective effects on DN, and the inhibition of aldose reductase and the modulation of polyol pathway in nephritic cells be a potentially therapeutic strategy for DN.

Introduction The renoprotective effects of luseogliflozin, a sodium‐glucose cotransporter 2 inhibitor, in patients with renal dysfunction are unexamined. We evaluated the efficacy of luseogliflozin in slowing renal function decline among patients with type 2 diabetes mellitus and moderate to severe renal dysfunction. Materials and Methods In a multicenter, randomized, open‐label, controlled clinical trial, patients with type 2 diabetes mellitus and an estimated glomerular filtration rate based on serum creatinine (eGFRcreat) of 15–45 mL/min/1.73 m2 were randomized into luseogliflozin or control groups. The primary endpoint was the change in eGFRcreat from baseline to 104 weeks. Secondary endpoints included eGFRcreat and eGFRcreat slope changes from 4 to 104 weeks (chronic eGFRcreat slope). Results Among 152 participants, eGFRcreat change from baseline to 104 weeks did not significantly differ between groups. The luseogliflozin group showed a significant decrease in eGFRcreat from 2 to 12 weeks compared to the control group; the largest decline occurred at 4 weeks (initial eGFR decline). There were no differences between groups thereafter. The chronic eGFRcreat slope was less negative in the luseogliflozin group compared to the control group (not significant). Conversely, subgroup analysis indicated that the difference in chronic eGFRcreat slope between groups was significantly greater (with a less negative or even positive slope observed in the luseogliflozin group compared to the control group) among patients with eGFRcreat <30 mL/min/1.73 m2, urinary albumin/creatinine ratio <30 mg/g creatinine, systolic blood pressure <130 mmHg, or females. Conclusions Although the primary endpoint did not reach statistical significance, luseogliflozin may provide renoprotective benefits in patients with type 2 diabetes mellitus and moderate‐to‐severe renal impairment, potentially by slowing eGFRcreat decline post‐initial decline. Luseogliflozin alleviated renal function decline (eGFR) after an initial decrease, showing renoprotective effects in patients with renal impairment. Luseogliflozin did not increase renal events, showing safety even in patients with moderate‐to‐severe renal impairment.

Luseogliflozin [Lusefi ® (Japan)] is an orally active second-generation sodium-glucose co-transporter 2 (SGLT2) inhibitor developed by Taisho Pharmaceutical for the treatment of patients with type 2 diabetes mellitus (T2DM). The drug has received its first global approval for this indication in Japan, either as monotherapy or in combination with other antihyperglycaemic agents. This article summarises the milestones in the development of luseogliflozin leading to this first approval for the treatment of T2DM.