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.

Long-term sorbitol consumption affects the hippocampus and alters cognitive function in aged mice.

The systemic effects of the artificial sweetener sorbitol on older adult individuals have not been elucidated. We assessed the effects of sorbitol consumption on cognitive and gingival health in a mouse model. Aged mice were fed 5% sorbitol for 3 months before their behavior was assessed, and brain and gingival tissues were collected. Long-term sorbitol consumption inhibited gingival tissue aging in aged mice. However, it caused cognitive decline and decreased brain-derived neurotrophic factor (BDNF) in the hippocampus. Sorbitol consumption did not affect homeostatic function; however, it may exert effects within the brain, particularly in the hippocampus.

In Situ Live Imaging of Gut Microbiota.

Most studies of gut microbiota have focused on relationships between a specific disease and the presence/abundance of one or a few bacterial species/genera. Whether the spatial and temporal distribution of gut microbiota, as a whole, affects or correlates with health is unknown, largely due to the absence of tools for dynamically monitoring the overall gut microbiota landscape inside living subjects. Here, we describe a novel, noninvasive, live imaging method for gut microbiota using 2-deoxy-2-[18F]fluoro-d-sorbitol (18F-FDS), a compound that specifically labeled gut bacteria in mice and hamsters following oral administration. Positron emission tomography-computed tomography (PET-CT) scanning showed that the radiolabel signal was concentrated in the gut (especially the large intestine), was absent when mice gut microbiota was depleted by antibiotic treatment, and was restored after transplanting antibiotic-treated mice with a fecal or probiotic bacterial mixture. Thus, 18F-FDS images microbiota, not gut tissue. The tissue distribution of 18F-FDS was the highest in the gut (∼3-fold higher than average), in contrast to 2-deoxy-2-[18F]fluoro-d-glucose, which concentrated in brain and many other organs. 2-[18F]fluoro-aminobenzoic acid, another bacterium-specific radioactive tracer, was unsuited for gut microbiota imaging due to unexpected stomach retention following oral administration. When similar gut microbiota imaging was done with hamsters, the spatial resolution increased significantly over that with mice, suggesting that even higher spatial resolution can be achieved with humans or large animals. Thus, our work establishes a new tool for noninvasive, live imaging of gut microbiota; the new tool may enable exploration of relationships between gut microbiota landscape and diseases in clinical settings. IMPORTANCE Gut microbiota dysbiosis correlates with many diseases, but such correlations derive mostly from relationships between one or a few bacteria and a particular disease. Since microbiota resemble complex forest ecosystems more closely than individual patches of trees, the overall landscape (spatial and temporal distribution) of gut bacteria may also affect/reflect disease development. Such a possibility has not been explored due to a lack of tools for directly visualizing natural landscape patterns of gut microbiota. The present work identified 2-deoxy-2-[18F]fluoro-d-sorbitol as a gut microbiota-specific radioactive tracer and developed a novel PET-CT scan-based imaging method that enables noninvasive, real-time imaging of the overall gut bacterial landscape. The method showed increased spatial resolution when hamsters replaced mice, suggesting that even higher spatial resolution could be achieved with larger animals such as humans. This novel technology establishes the feasibility of investigating spatial-temporal distribution dynamics of gut microbiota with many human diseases.

Protective effect of SGL5213, a potent intestinal sodium-glucose cotransporter 1 inhibitor, in nonalcoholic fatty liver disease in mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic disease. SGL5213, which is minimally absorbed and is restricted to the intestinal tract, is a potent intestinal sodium-glucose cotransporter 1 (SGLT1) inhibitor. In this study, we investigated the protective effect of SGL5213 in a rodent model of NAFLD. METHODS: Using a rodent model of NAFLD, we compared SGL5213 efficacy with miglitol, which is an α-glucosidase inhibitor. We used a high-fat and high-sucrose diet-induced NAFLD model. RESULTS: SGL5213 and miglitol improved obesity, liver dysfunction, insulin resistance, and the NAFLD severity. To further investigate the effects of SGL5213, we analyzed the mRNA expression of genes involved in lipid metabolism, inflammation, and liver fibrosis, and cecal pH levels. SGL5213 and miglitol treatment significantly decreased mRNA expression of factors involved in inflammation and liver fibrosis. SGL5213 treatment significantly decreased cecal pH levels, which did not occur with miglitol. CONCLUSIONS: SGL5213 had a protective effect on the pathogenesis of NAFLD in a rodent model. We considered that inhibiting glucose absorption and increasing glucose content in the gastrointestinal tract with SGL5213 might have contributed to the protective effect in NAFLD. SGL5213 is a promising therapeutic agent for NAFLD with obesity and insulin resistance.

Smoflipid Is Better Than Lipofundin for Long-Term Neurodevelopmental Outcomes in Preterm Infants.

Neurodevelopmental morbidities developed more commonly in low-birth-weight premature infants. We sought to determine the effects of different lipid emulsions on the neurodevelopmental outcomes of children born prematurely. This retrospective cross-sectional study had two intervention legs, Lipofundin® MCT/LCT (LIPO) versus Smoflipid® (SMOF), which are mainly differentiated by fish oil. Data of premature neonates born between 2001 and 2015 from the research database of Chang Gung Memorial Hospital with corresponding individual medical records up to July 2020 were analyzed. Long-term neurodevelopmental outcomes were defined by the international classification of disease codes -9 or -10. The prevalence of diseases was compared between LIPO and SMOF groups at five and five years old and further analyzed by stratification of 1500 g birth weight. The LIPO and SMOF groups each included 1120 neonates. Epilepsy, cerebral palsy, developmental disorder and attention-deficit hyperactivity disorder (ADHD) were significantly decreased at age two years in the SMOF group, and epilepsy, language delay (LD), ADHD and autism spectrum disorder (ASD) were significantly decreased in the SMOF group at age five years. In children with birth weight < 1500 g, ADHD was decreased in the SMOF group at ages two and five years, and ASD was decreased in the SMOF group at age five years. In children with birth weight ≥ 1500 g, epilepsy, LD and ADHD were decreased in the SMOF group at age two years. LD was decreased in the SMOF group at age five years. We conclude that lipid emulsions with fish oil improve the neurodevelopmental outcomes of children born prematurely.

Different renoprotective effects of luseogliflozin depend on the renal function at the baseline in patients with type 2 diabetes: A retrospective study during 12 months before and after initiation.

AIMS: The safety and efficacy, particularly, the factors associated with the renal prognosis, were assessed over 12 months after the initiation of luseogliflozin therapy in Japanese patients with type 2 diabetes and renal impairment. METHODS: In total, 238 patients treated with luseogliflozin (2.5 mg, once daily) were studied as the safety analysis set. Two hundred and two subjects whose medication was continued over 12 months were investigated as the full analysis set. The subjects were divided into 3 groups based on the estimated glomerular filtration rate (eGFR): high eGFR (n = 49), normal eGFR (n = 116) and low eGFR (n = 37) groups. RESULTS: The body weight, systolic blood pressure, HbA1c and urinary protein excretion gradually decreased from baseline in all eGFR groups. While the eGFR was significantly reduced from baseline in the high and normal eGFR groups, the eGFR did not significantly differ over time in the low eGFR group. There was no marked difference in the frequency of adverse events that were specific for SGLT2 inhibitors among the 3 groups in the safety analysis set. CONCLUSIONS: Luseogliflozin can preserve the renal function in the medium term in patients with type 2 diabetes and renal impairment without an increase in specific adverse events.

Synergistic PXT3003 therapy uncouples neuromuscular function from dysmyelination in male Charcot-Marie-Tooth disease type 1A (CMT1A) rats.

Charcot-Marie-Tooth disease 1 A (CMT1A) is caused by an intrachromosomal duplication of the gene encoding for PMP22 leading to peripheral nerve dysmyelination, axonal loss, and progressive muscle weakness. No therapy is available. PXT3003 is a low-dose combination of baclofen, naltrexone, and sorbitol which has been shown to improve disease symptoms in Pmp22 transgenic rats, a bona fide model of CMT1A disease. However, the superiority of PXT3003 over its single components or dual combinations have not been tested. Here, we show that in a dorsal root ganglion (DRG) co-culture system derived from transgenic rats, PXT3003 induced myelination when compared to its single and dual components. Applying a clinically relevant ("translational") study design in adult male CMT1A rats for 3 months, PXT3003, but not its dual components, resulted in improved performance in behavioral motor and sensory endpoints when compared to placebo. Unexpectedly, we observed only a marginally increased number of myelinated axons in nerves from PXT3003-treated CMT1A rats. However, in electrophysiology, motor latencies correlated with increased grip strength indicating a possible effect of PXT3003 on neuromuscular junctions (NMJs) and muscle fiber pathology. Indeed, PXT3003-treated CMT1A rats displayed an increased perimeter of individual NMJs and a larger number of functional NMJs. Moreover, muscles of PXT3003 CMT1A rats displayed less neurogenic atrophy and a shift toward fast contracting muscle fibers. We suggest that ameliorated motor function in PXT3003-treated CMT1A rats result from restored NMJ function and muscle innervation, independent from myelination.

The effect of luseogliflozin on bone microarchitecture in older patients with type 2 diabetes: study protocol for a randomized controlled pilot trial using second-generation, high-resolution, peripheral quantitative computed tomography (HR-pQCT).

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.

Head Circumference Growth Is Enhanced by SMOFlipid in Preterm Neonates.

BACKGROUND: Suboptimal fat intake during the early postnatal weeks significantly affects brain growth and maturation. Studies to date have focused on the quantity rather than the quality of fat intake. OBJECTIVE: We hypothesized that early nutrition of premature neonates should also include optimization of the type of fat intake, and thus those receiving SMOFlipid, a balanced multicomponent lipid emulsion, would have improved head growth as measured by head circumference (HC) at discharge. STUDY DESIGN: We retrospectively reviewed HC in infants weighing <1,500 g who were hospitalized for two or more weeks during a 20-month period, in which all preterm infants received fat as Lipofundin, and the following 20-month period, in which all such infants received SMOFlipid.Lipids were dosed up to 3 g/kg/day and reduced as enteral nutrition progressed. Parenteral fish oil (Omegaven) was permitted as rescue therapy during both periods. RESULTS: Period 2 infants had better head growth (0.79 [0.69,0.90] vs. 0.75 [0.64,0.86] cm/week; p = 0.0158). More infants reached discharge with an HC of ≥50 percentile (51 vs. 31%; p = 0.0007), and fewer infants had an HC of ≤3 percentile (11 vs. 14%; p = 0.023). Median length of stay was reduced by more than 1 week.A multivariable regression was performed using the weekly increase in HC as the dependent variable, and the time epoch, birth weight, gestational age, hospitalization days, and gender as independent variables. Only the time epoch and days of hospitalization were significant (both p < 0.0001). CONCLUSION: Our data offer preliminary evidence of improved brain growth in those receiving a balanced lipid emulsion as compared with a soybean oil emulsion.

Effects of sorbitol and lactate on erythropoietin production in HepG2 cells.

Promotion of erythropoietin (EPO) production is important for erythropoiesis as well as cell viability. The most effective inducing factor for EPO production is hypoxia. Hypoxia inducible factor (HIF), a regulator of EPO production, is increased under hypoxic conditions and is also affected by various regulators such as sirtuin1 (SIRT1). SIRT1 is regulated by the cytoplasmic redox state, which is thought to affect EPO production. Therefore, we investigated the effects of sorbitol and lactic acid, which serve as substrates for cellular respiration and bring cells into a reduced state, on EPO production in HepG2 cells. The addition of low-concentration sorbitol to HepG2 cells produced a mildly reduced state similar to that of hypoxia and increased NAD+, SIRT1, and HIF-α, and EPO mRNA expression. On the other hand, lactate suppressed EPO mRNA expression at all concentrations. Inhibition of lactate production from pyruvate abolished the effect of low sorbitol concentrations on EPO mRNA expression. When low-concentration sorbitol and a reducing agent were administered simultaneously, the effect of increasing EPO mRNA expression disappeared. It was suggested that SIRT1 and EPO production increased under conditions where lactate production was not suppressed, even under mildly reduced conditions similar to hypoxia.

Effect of single dose administration activated charcoal containing sorbitol on serum sodium concentration and hydration status in dogs.

OBJECTIVE: To assess the administration of a commercially available activated charcoal suspension with sorbitol (ACS) on serum sodium concentrations and hydration status in healthy dogs. DESIGN: Prospective study. SETTING: Private referral hospital. ANIMALS: Nine healthy adult dogs. INTERVENTIONS: Dogs were administered 1 mg/kg maropitant (Cerenia; Pfizer Animal Health, New York, NY) intravenously 1 hour prior to charcoal administration. Dogs were administered a single dose of 2 g/kg ACS. MEASUREMENTS AND MAIN RESULTS: Blood samples and body weights were obtained prior to charcoal administration and 2, 4, 6, 8, 10, and 12 hours post ACS administration. Venous sodium, potassium, chloride, blood urea nitrogen, creatinine, lactate, packed cell volume, and total plasma protein were measured at each time interval. All dogs returned 2-4 weeks after ACS administration for a 12 hour period of water restriction and to serve as their own control group. The same measurements were repeated during water restriction period as following ACS administration. The increase in serum sodium concentration was significantly higher following ACS administration when compared to control period (P = 0.0002). All dogs administered ACS experienced a significant degree of weight loss (P = 0.0371) when compared to the control period. Following administration of ACS, the hematocrit of the dogs administered ACS was found to be significantly increased (P = 0.0001), when compared to the control period. CONCLUSION: Patients that are administered a single dose of ACS are at risk of developing dehydration and secondary hypernatremia as observed in the dogs during the study period. Patients receiving ACS should have electrolytes monitored and would benefit from fluid therapy as previously recommended.

Risk of reduced intestinal absorption of myo-inositol caused by D-chiro-inositol or by glucose transporter inhibitors.

Background: D-chiro-inositol (DCI) and glucose transporter inhibitors may inhibit myo-inositol (MI) transporters, and the aim is to clinically evaluate their effect on MI absorption. Research design and methods: Fasting 18 healthy volunteers received orally 6000 mg MI, 6000 mg MI with 1000 mg DCI, and 6000 mg MI with SelectSIEVE® Apple PCQ and Sorbitol, Maltodextrin and Sucralose (PCQ-SMS), in three different phases with a washout period of 7 days. At each phase, blood samples were collected before administration, and every 60 minutes until 540 minutes after administration. MI plasma levels (µmol/L) were quantified by gas chromatography-mass spectrometry; maximum plasma concentration (Cmax), time to reach it (Tmax), and the area under the time-concentration curve of MI (AUC 0-540) were evaluated. Results: The Cmax of MI alone (Tmax = 180min) was 1.29-fold higher than those of MI with DCI (Tmax = 180min) (p < 0.001) and 1.69-fold higher than those of MI with PCQ-SMS (Tmax = 240min) (p < 0.001). The AUC 0-540 was reduced by 19.09% in MI plus DCI (p = 0.0118) and by 31.8% in MI plus PCQ-SMS (p < 0.001) as compared to MI alone. Conclusions: DCI, glucose transporter inhibitors and sugars, such as sorbitol and maltodextrin, seem to inhibit MI absorption, decreasing MI plasma concentration as compared to MI alone.

Comparison of two small bowel distending agents for enterography in pediatric small bowel imaging.

OBJECTIVE: To evaluate the ability of pediatric patients with known or suspected inflammatory bowel disease to ingest a new oral distending agent at CT or MR enterography (CTE/MRE), and to determine the impact on small bowel (SB) distension and diagnostic confidence. MATERIALS AND METHODS: The study design is that of retrospective review of pediatric patients who underwent CTE or MRE from January 2014 to June 2016. Patients ingested low-concentration barium suspension or flavored beverage containing sorbitol and mannitol. The need for nasogastric tube (NGT) administration, amount ingested, emesis, distal extent of contrast, SB distension, terminal ileum (TI) transverse dimension, and diagnostic confidence in TI disease were assessed. Three radiologists each blindly reviewed a subset of the studies. RESULTS: Of the total 591 scans in 504 patients, 316 scans used low-concentration barium suspension and 275 scans flavored beverage. Nearly all consumed the entire amount (97% vs. 96%). Low-concentration barium suspension exams required NGT more often (7% [23/316] vs. 1% [3/275]; p < 0.0003), and tended to have more emesis (3% [9/316] vs. 1% [3/275]; p = 0.13). Diagnostic confidence score was nearly identical (p = 0.94). Qualitative and quantitative analyses showed no difference in SB distension, except for distension of mid-ileum (flavored beverage > low-concentration barium suspension; p = 0.02). Flavored beverage exams demonstrated a slight increase in distal extent of luminal distension (p = 0.02). CONCLUSIONS: A new flavored beverage distends small bowel as well as low-concentration barium suspension, with decreased requirement for NGT insertion and improved distal extent of luminal distension, and without any decrease in diagnostic confidence in the presence or the absence of TI disease.

Effects of prebiotic mixtures on growth performance, intestinal microbiota and immune response in juvenile chu's croaker, Nibea coibor.

Prebiotics has been known to be growth promoter and immunostimulant in aquatic animals. In this study, we investigated the effects of prebiotics on growth performance, intestinal microbiota, short-chain fatty acids (SCFAs) production and immune response of the marine fish, juvenile chu's croaker (Nibea coibor). The fish were fed IG (including 0.5% inulin and 0.5% GOS), GS (0.5% GOS and 0.5% D-sorbitol), IGS (0.33% inulin, 0.33% GOS and 0.33% D-sorbitol) or control diets for 8 weeks. The results showed that the growth performance of the fish was promoted by IG and GS, but not by IGS. The intestinal microbiota in NDC (non-digestible carbohydrates, NDC)-supplemented groups was clearly separated from that of the control, and the highest Shannon and Simpson diversity indices were observed in the IGS group. In the intestine of the croaker, Proteobacteria, Firmicutes, and Bacteroidetes were dominant; among them, 24 taxa revealed a significant difference among groups. Most of these bacteria are able to produce SCFAs, which were significantly increased in all NDC-supplemented groups. Moreover, NDCs were found to activate the immune system of the fish by modulating the serum complements, cytokine levels, lysozyme activities and antioxidant capacity. Furthermore, the results of this study revealed correlations among intestinal microbiota, SCFAs production, innate immunity, antioxidant capacity and digestive enzymes in the croaker fed NDCs. Taken together, our results demonstrated that NDC mixtures might promote growth performance, antioxidant capacity and immune responses of the croaker through modulating the composition of intestinal microbiota and the subsequent SCFAs production, which suggest that NDCs were efficient feed additives for marine fish.

Effect of sugar-free chewing gum on plaque and gingivitis among 14-15-year-old school children: A randomized controlled trial.

AIM: The aim of the study was to find out the effect of sugar-free chewing gums (xylitol and sorbitol) on plaque and gingivitis among 14-15-year-old school children. MATERIALS AND METHODS: A single center, double-blind, randomized controlled trial was conducted on 14-15-year-old children. Sample size was determined to be 48. Participants were randomly allocated to test group (xylitol [n = 12], sorbitol [n = 12]) and control group (no gum, n = 24). Duration of the study was 14 days. Baseline assessment of plaque, gingival, and bleeding score, followed by oral prophylaxis. Selected children received daily two chewing gum (1.1 g each) to chew for 20 min postbreakfast and postlunch. Follow-up was done on 15th day. Analysis was done using independent t-test, ANOVA, and post hoc test. Significance level was kept at P < 0.05. RESULTS: There was a significant reduction in plaque, gingival, and bleeding score in test group (P < 0.05) compared to control group. CONCLUSION: Sugar-free gum (xylitol and sorbitol) significantly reduced the plaque, gingival, and bleeding score.

The effects of licogliflozin, a dual SGLT1/2 inhibitor, on body weight in obese patients with or without diabetes.

BACKGROUND: There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium-glucose co-transporter (SGLT) 1/2, on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity. METHODS: Patients with obesity (BMI, 35-50 kg/m2 ) were enrolled into a 12-week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two-part study, comprising a single-dose cross-over study (N = 12; 2.5 - 300 mg) and a 14-day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE24 ) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP-1, PYY3-36 , and GIP), insulin and glucagon. RESULTS: Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC0-4h ) and suppressed insulin by 90% (P < 0.01; incremental AUC0-4h ). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24-hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP-1 by 54% (P < 0.001) and PYY3-36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12-week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%-43% with licogliflozin vs 9%-11% with placebo in the 12-week study) were among the other gastrointestinal events reported. CONCLUSION: Licogliflozin treatment (1-84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.

A pharmacological composition for induction of a reversible torpor-like state and hypothermia in rats.

AIMS: To initiate a state of artificial torpor we suggested a pharmacological multi-targeting strategy for simulation of the physiological pattern of natural hibernation including a significant reduction in heart rate, respiratory rate, body temperature and oxygen consumption as well as a decline in brain activity known as torpor. MATERIALS AND METHODS: We have developed a composition which initiates a pharmacologically induced torpor-like state (PITS-composition), made up of eight therapeutic agents, inert gas xenon and lipid emulsion served as a drug vehicle. KEY FINDINGS: After a single intravenous injection to rats, PITS-composition causes a rapid decline in heart rate followed by a steady decrease in body temperature from about 38.5 °C to 31.5 °C, at ambient temperature of 22 °C-23 °C. The hypothermic state may continue on average for 16-17 h with the subsequent spontaneous return of heart rate and body temperature to the initial values. In the open field test at torpor the motility, rearing and grooming were suppressed but 4-8 days later they were restored. SIGNIFICANCE: Suspended animation states, including natural hibernation or pharmacologically induced synthetic torpor are of special attention of medicine, since it may improve survival rate after cardiac arrest, brain hemorrhage and ischemia, and during long-term space traveling. The suggested here multi-targeting strategy made possible to develop the pharmacological composition able, after a single intravenous injection, to initiate long, stable and reversible hypothermia and torpor at room temperature. After the torpor, animals were able to spontaneously restore both physiological parameters, and behavioral reactions.

The effect of a mixture of 2.7% sorbitol-0.54% mannitol solution on blood coagulation: an invitro, observational healthyvolunteer study using rotational thromboelastometry (ROTEM).

BACKGROUND: We investigated the effect of irrigation fluid on coagulation according to the hemodilution level using rotational thromboelastometry (ROTEM). METHODS: Venous blood was taken from 12 healthy volunteers and divided into four specimen tubes that were diluted to various levels (0%, 10%, 20%, and 40%) using an irrigation fluid composed of 2.7% sorbitol and 0.54% mannitol. RESULTS: Significant prolongation of clotting time was observed in the 40% diluted sample using both INTEM (P = 0.009) and EXTEM (P = 0.001) assays. However, the clot formation time was prolonged significantly in the 10%, 20%, and 40% diluted samples using both INTEM (P < 0.001) and EXTEM (P = 0.002, P < 0.001, and P < 0.001, respectively) assays. A significant decrease of α-angle of INTEM and EXTEM were observed in the 10% (P < 0.001), 20% (P < 0.001 and P = 0.001, respectively), and 40% (P < 0.001) groups compared with the 0% dilution group. The maximum clot firmness (MCF) of INTEM decreased significantly in the 20% (P < 0.001) and 40% (P < 0.001) diluted samples. In the MCF of EXTEM and FIBTEM assays, 10% (P = 0.009 and P = 0.015, respectively), 20% (P = 0.001), and 40% (P < 0.001) samples showed a significant decrease compared with the 0% sample. Nevertheless, most of the ROTEM values were within the reference range, except the 40% sample. CONCLUSIONS: Blood became hypocoagulable when it was diluted in vitro with a fluid composed of 2.7% sorbitol and 0.54% mannitol.

Effects of Sorbitol on the Pharmacokinetics of Lamivudine Solution and the FDA's Decision to Increase the Dose of Lamivudine Solution for Pediatric Patients.

The article by Adkison et al. described sorbitol effects on lamivudine exposures. The results indicate a plausible mechanism for lower lamivudine exposures in pediatric patients receiving the solution formulation with concomitant medications containing sorbitol. In this commentary, we discuss lower lamivudine exposures in pediatric patients receiving the solution formulation, the impact of sorbitol on lamivudine exposures, and the US Food and Drug Administration's (FDA's) decision to increase the dose of the lamivudine solution for all pediatric patients.