Pharmacokinetics, Pharmacodynamics and Safety of Janagliflozin in Chinese Type 2 Diabetes Mellitus Patients with Renal Impairment.

BACKGROUND: Janagliflozin is a novel sodium-glucose cotransport-2 inhibitor. Despite its remarkable effect in glycemic control, no systematic research has evaluated the effect of renal impairment (RI) on its pharmacokinetics and pharmacodynamics. METHODS: Here, patients with T2DM (n = 30) were divided into normal renal function (eGFR ≥ 90 mL/min/1.73 m2), mild RI (eGFR between 60 and 89 mL/min/1.73 m2), moderate RI-I (eGFR between 45 and 59 mL/min/1.73 m2), and moderate RI-II (eGFR between 30 and 44 mL/min/1.73 m2) groups. They were administered 50 mg janagliflozin orally, and plasma and urine samples were collected for the determination of janagliflozin concentration. RESULTS: Following oral administration, janagliflozin was rapidly absorbed, with the time to Cmax of 2-6 h for janagliflozin and 3-6 h for its metabolite XZP-5185. Plasma exposure levels were similar for janagliflozin in T2DM patients with or without RI but decreased for the metabolite XZP-5185 in T2DM patients with eGFR between 45 and 89 mL/min/1.73 m2. Janagliflozin significantly promoted the excretion of urinary glucose, even in patients with reduced eGFR. Janagliflozin was well tolerated in patients with T2DM with or without RI, and no serious adverse events (SAEs) occurred during this trial. CONCLUSIONS: The exposure levels of janagliflozin in T2DM patients were slightly increased with worsening of RI (i.e., 11% increase in the AUC in patients with moderate RI compared with the normal renal function group). Despite worsening of renal function, janagliflozin exerted a significant pharmacologic effect and was well tolerated, even in patients with moderate RI, implying a promising role in the treatment of patients with in T2DM. REGISTRATION: China Drug Trial register ( http://www.chinadrugtrials.org.cn/I ) identifier no.: CTR20192721.

Melt milling as manufacturing method for solid crystalline suspensions.

Production of submicron particles (0.1-1 µm) has been identified by the pharmaceutical industry as a key technology to enhance the bioavailability of poorly water-soluble drugs. However, nanosuspensions derived from commonly applied wet milling suffer from long-term stability issues, making further downstream processing necessary. In previous works, the formulation as a long-term stable solid crystalline suspension (SCS) was introduced, for which the crystalline drug is ground in a (molten) hydrophilic carrier matrix. The model formulation of the antimycotic Griseofulvin and the sugar alcohol Xylitol was reused for comparative purposes. Due to process limitations regarding the degree of comminution, the present work demonstrates the application of fine grinding in the framework of SCS manufacturing. A custom-built mill with annular gap geometry successfully yielded particles in the targeted submicron range. A process optimization study lead to improved energy utilization during grinding, which reduced the necessary grinding time and, thereby, the thermal exposition of the drug. Investigation of solid-state properties of the SCS, via differential scanning calorimetry and x-ray powder diffraction, showed no alteration even for extended grinding times. In dissolution experiments, the melt-milled SCS outperformed its predecessors, although mostly agglomerates were found by SEM imaging in the solidified product. In conclusion, melt milling is a valuable tool to overcome low aqueous solubility.

Effectiveness of casein phosphopeptide-amorphous calcium phosphate and xylitol chewing gums on salivary pH, buffer capacity, and Streptococcus mutans levels: An interventional study.

AIM: The aim of the study is to compare the anticariogenic effectiveness of Casein phosphopeptide- Amorphous Calcium phosphate (CPP-ACP) and xylitol chewing gums based on salivary pH, buffer capacity, and Streptococcus mutans levels. MATERIALS AND METHODS: A group of twenty individuals in the age group of 18-25 years were randomly divided into two Groups A and B. Test arm A received xylitol gums and test arm B received CPP-ACP gums and they were instructed to use the gums thrice daily for 2 weeks. Unstimulated salivary samples were collected before they began the use of the gums for baseline values, 24 h after beginning the usage of chewing gums and at the end of 14 days. The samples were analyzed for pH, buffer capacity, and S. mutans levels. RESULTS: A statistically significant reduction of salivary S. mutans levels, improvement in salivary pH, and buffer capacity were displayed in both groups 24 h and 14 days after the intervention when compared with baseline. Group B showed more statistically significant improvement in pH than group A after 24 h (P = 0.028) and at the end of 2 weeks (P = 0.041). CONCLUSION: CPP-ACP has better ability than xylitol in improving the pH of saliva. Both CPP-ACP and xylitol gums individually have remarkable ability in bringing down S. mutans levels while simultaneously improving the pH and buffer of saliva.

Pharmacokinetics and Plasma Cellular Antioxidative Effects of Flavanols After Oral Intake of Green Tea Formulated with Vitamin C and Xylitol in Healthy Subjects.

This study aimed to test whether green tea formulated with vitamin C and xylitol (GTVX) could improve absorption of flavanols and total antioxidant activity (TAC) of plasma compared with green tea only (GT) in healthy subjects. The total radical-trapping antioxidant parameter method was used to measure the TAC of plasma. Cmax, Tmax, and area under the curve (AUC) of flavanols in plasma after consumption of GTVX were 5980.58 µg/mL, 2.14 h, and 18,915.56 h·µg/mL, respectively, indicating that GTVX showed significantly higher AUC than GT (13,855.43 µg/mL). The peak TACs occurred at 3 and 0.5 h after intake of GT and GTVX, respectively. The TAC of plasma was found to be significantly higher in GTVX than in GT at each time point. This study suggests that formulating green tea with vitamin C and xylitol could increase the absorption of flavanols in green tea, enhancing cellular antioxidative effects.

Green tea formulations with vitamin C and xylitol on enhanced intestinal transport of green tea catechins.

The effect of green tea formulated with vitamin C and xylitol on intestinal cell transport of gallated and nongallated catechin was studied. The transport of catechins from both apical to basolateral and basolateral to apical directions was measured. The effect of vitamin C (4, 10, 20 ppm), xylitol (11, 27.5, 55 ppm), and combinations of both on the intestinal transport rate of catechins was examined. The efflux value (Pb→a/Pa→b) of (-)-epigallocatechin (EGC), (-)-epigallocatechin gallate (EGCG), (-)-epicatechin (EC), and (-)-epicatechin gallate (ECG) was 0.26, 0.22, 1.22, and 0.17, respectively, indicating that EC appeared to be less absorbed compared with other catechins. The addition of xylitol (11, 27.5, 55 ppm) and vitamin C (4, 10, 20 ppm) and in combination enhanced transport rate of nongallated catechins such as EC and EGC. For EC, vitamin C was revealed to be the most effective on intestinal transport, implying the inhibition of the efflux transport mechanism of EC. Intestinal transport of gallated catechins significantly increased from catechins formulated with vitamin C and xylitol in a dose-dependent manner compared to the catechin-only formulation. Results provide a potential strategy to enhance the delivery and bioavailability of catechins in humans by modulating green tea formulation with vitamin C and xylitol.

A bolus infusion of xylitol solution in the treatment of cow ketosis does not cause a surge in insulin secretion.

When a solution of xylitol was rapidly administered intravenously (bolus infusion) to healthy cattle or those with ketosis, different results were obtained. In healthy cattle, a temporary surge in insulin secretion was observed, whereas in ketotic cattle no such surge was found, but instead a moderate level of secretion continued for a lengthy period. No significant difference in the areas under the insulin curve (AUC) was found between healthy cattle and ketotic cattle up to 120 min after xylitol infusion. These results clearly demonstrated that a bolus infusion of xylitol solution in ketotic cattle does not cause a temporary surge in insulin secretion unlike in healthy animals, but rather results in a continuous, gradual rise in secretion.

Dissolution of xylitol from a food supplement administered with a novel slow-release pacifier: preliminary results.

AIM: The aim of the study was to monitor the pattern of release and salivary xylitol concentrations during sucking of a slow-release pacifier used to deliver a novel food supplement. METHODS: The food supplement tablet contained 300 mg xylitol and 0.5 x 10(10) colony-forming units of Bifidobacterium lactis Bb-12 (Bb-12). The reference tablet contained 300 mg xylitol and was used by 10 adults (mean age 32 years) in the study. Whole saliva samples were collected with 2.5 min intervals during pacifier sucking. The salivary xylitol concentrations were determined using an enzyme assay kit. RESULTS: All subjects showed salivary xylitol concentrations exceeding 1% at least at one collection point. The xylitol and xylitol-Bb-12 tablets showed similar dissolving with no clear concentration peaks (comparison of saliva collection times; p = 0.139). CONCLUSION: Xylitol released from the food supplement, delivered with the novel pacifier, may result in salivary xylitol concentrations high enough to inhibit mutans streptococci in vivo.

Xylitol concentration in saliva and dental plaque after use of various xylitol-containing products.

The study consisted of two sets of experiments, one in saliva and one in dental plaque. The xylitol concentration in saliva was determined enzymatically in 12 children (mean age 11.5 years) after a standardised use of various xylitol products: (A) chewing gums (1.3 g xylitol), (B) sucking tablets (0.8 g xylitol), (C) candy tablets (1.1 g xylitol), (D) toothpaste (0.1 g xylitol), (E) rinse (1.0 g xylitol), and (F) a non-xylitol paraffin. Unstimulated saliva was sampled 1, 3, 8, 16 and 30 min after use. The concentration in dental plaque was determined after mouthrinses with contrasting amounts of xylitol (LX = 2.0 g, HX = 6.0 g, and control) and supragingival plaque was collected and pooled after 5, 15 and 30 min. The mean xylitol concentration in saliva at baseline was approximately 0.1 mg/ml. All xylitol-containing products resulted in significantly increased levels (p < 0.05) immediately after intake and remained elevated for 8-16 min in the different groups. The highest mean value in saliva was obtained immediately after use of chewing gums (33.7 +/- 16.4 mg/ml) and the lowest was demonstrated after using toothpaste (8.2 +/- 4.9 mg/ml). No significant differences were demonstrated between chewing gums (A), sucking tablets (B), candy (C) and rinses (E). In dental plaque, the mean values were 8.6 +/- 5.4 and 5.1 +/- 4.0 mg/ml 5 min after HX and LX rinses. Concerning the higher concentration, the values remained significantly elevated (p < 0.05) during the entire 30-min follow-up. In conclusion, commonly advocated xylitol-containing products gave elevated concentrations of xylitol in unstimulated whole saliva and dental plaque for at least 8 min after intake.

Bronchoscopic assessment of airway retention time of aerosolized xylitol.

BACKGROUND: Human airway surface liquid (ASL) has abundant antimicrobial peptides whose potency increases as the salt concentration decreases. Xylitol is a 5-carbon sugar that has the ability to lower ASL salt concentration, potentially enhancing innate immunity. Xylitol was detected for 8 hours in the ASL after application in airway epithelium in vitro. We tested the airway retention time of aerosolized iso-osmotic xylitol in healthy volunteers. METHODS: After a screening spirometry, volunteers received 10 ml of nebulized 5% xylitol. Bronchoscopy was done at 20 minutes (n = 6), 90 minutes (n = 6), and 3 hours (n = 5) after nebulization and ASL was collected using microsampling probes, followed by bronchoalveolar lavage (BAL). Xylitol concentration was measured by nuclear magnetic resonance spectroscopy and corrected for dilution using urea concentration. RESULTS: All subjects tolerated nebulization and bronchoscopy well. Mean ASL volume recovered from the probes was 49 +/- 23 microl. The mean ASL xylitol concentration at 20, 90, and 180 minutes was 1.6 +/- 1.9 microg/microl, 0.6 +/- 0.6 microg/microl, and 0.1 +/- 0.1 microg/microl, respectively. Corresponding BAL concentration corrected for dilution was consistently lower at all time points. The terminal half-life of aerosolized xylitol obtained by the probes was 45 minutes with a mean residence time of 65 minutes in ASL. Corresponding BAL values were 36 and 50 minutes, respectively. CONCLUSION: After a single dose nebulization, xylitol was detected in ASL for 3 hours, which was shorter than our in vitro measurement. The microsampling probe performed superior to BAL when sampling bronchial ASL.

In vitro testing of xylitol as an anticariogenic agent.

A number of studies involving xylitol chewing gum have demonstrated that xylitol is both noncariogenic and anticariogenic. The ability of xylitol to act as an anticariogenic agent most likely is due to its ability to be transported into caries-causing oral bacteria and inhibiting fermentation either by depleting the cell of high-energy phosphate or by poisoning the glycolytic system. In vitro tests were conducted to determine the concentration of xylitol required to inhibit the growth of three strains of oral streptococcus (S. mutans, S. salivarius, and S. sanguis). All three strains were inhibited significantly at xylitol concentrations of 12.5% and higher; however, only S. mutans was inhibited significantly at a xylitol concentration of 1.56%.

Release of cariostatic agents from a new buffering fluoride- and xylitol-containing lozenge to human whole saliva in vivo.

A new buffering lozenge (sucking tablet) was developed for patients susceptible to dental caries and erosion, in particular for those with reduced salivary secretion. As active ingredients this lozenge comprises of a combination of xylitol, fluoride, calcium, phosphate, zinc and buffering compounds. To test the lozenge's activity in vivo, the release of ingredients was monitored in 19 healthy subjects for 22 min after sucking the lozenge was completed. In subjects with a normal salivary secretion rate the lozenge caused only a slight stimulation of saliva flow, but a significant elevation both in salivary pH and buffer effect was observed. Furthermore, fluoride, calcium and phosphate were effectively released into whole saliva with peak values 2-4 min after use. The same salivary parameters were also quantitated after 1 month's regular use (3 lozenges/day) but no consistent long-term changes were found. Salivary mutans streptococci and total anaerobic microflora did not change significantly during the long-term use. The results show that the buffering fluoride- and xylitol-containing lozenge, which also releases calcium and phosphate, is active in vivo but its serviceability as a remineralizing agent, in particular for elderly patients with reduced salivary flow rate, has to be analysed separately.

Are sodium lauryl sulfate-containing toothpastes suitable vehicles for xylitol?

The hypothesis to be tested in this study was that toothpastes containing sodium lauryl sulfate (SLS) is unsuitable vehicles for xylitol. The bacteriostatic (and cariostatic) effect of xylitol is assumed to be caused by intracellular accumulation of xylitol-5-P in plaque bacteria. Experiments were designed to investigate whether presence of SLS would affect the uptake of xylitol by interacting with the bacterial membranes and thus inhibit xylitol-5-P formation. It was shown in an in vitro study that even very low concentrations of the strong anionic detergent SLS inhibited uptake of xylitol and xylitol-5-phosphate formation by dental plaque totally. The mild nonionic detergent ethoxylated stearyl alcohol (30x EO) had no such effect. In vivo experiments with toothpastes containing xylitol and either the strong or the mild detergent, showed that xylitol in toothpaste with SLS was not available for the plaque bacteria and gave no adaptation to xylitol, whereas in the presence of 30x EO it was available, and a xylitol adaptation was observed. Glucose metabolism, which was also studied for the plaque samples, was not significantly affected by presence of any of the 2 detergents, indicating that the amounts of xylitol in toothpastes were presumably too low to give clinical significant effects, even when mild detergents are used.

Amino acid efflux in response to chemotactic and osmotic signals in Bacillus subtilis.

We observed a large efflux of nonvolatile radioactivity from Bacillus subtilis in response to the addition of 31 mM butyrate or the withdrawal of 0.1 M aspartate in a flow assay. The major nonvolatile components effluxed were methionine, proline, histidine, and lysine. In studies of the release of volatile radioactivity in chemotaxis by B. subtilis cells that had been labeled with [3H]methionine, the breakdown of methionine to methanethiol can contribute substantially to the volatile radioactivity in fractions following addition of 0.1 M aspartate. However, methanol was confirmed to be released after aspartate addition and, in lesser quantities, after aspartate withdrawal. Methanol and methanethiol were positively identified by derivitization with 3,5-dinitro-benzoylchloride. Amino acid efflux but not methanol release was observed in response to 0.1 M aspartate stimulation of a cheR mutant of B. subtilis that lacks the chemotaxis methylesterase. The amino acid efflux could be reproduced by withdrawal of 0.1 M NaCl, 0.2 M sucrose, or 0.2 M xylitol and is probably the result of changes in osmolarity. Chemotaxis to 10 mM alanine or 10 mM proline resulted in methanol release but not efflux of amino acids. In behavioral studies, B. subtilis tumbled for 16 to 18 s in response to a 200 mosM upshift and for 14 s after a 20 mosM downshift in osmolarity when the bacteria were in perfusion buffer (40 mosM). The pattern of methanol release was similar to that observed in chemotaxis. This is consistent with osmotaxis in B. subtilis away from an increase or decrease in the osmolarity of the incubation medium. The release of methanol suggests that osmotaxis is correlated with methylation of a methyl-accepting chemotaxis protein.

[Carbohydrate substitutes: comparative study of intestinal absorption of fructose, sorbitol and xylitol]. / Zuckeraustauschstoffe: Vergleichende Untersuchung zur intestinalen Resorption von Fructose, Sorbit und Xylit.

BACKGROUND: The carbohydrate substitutes fructose, sorbitol and xylitol are gaining more and more importance in the production of dietary food. But they can provoke gastrointestinal side-effects. In a randomized double blind study the rate of malabsorption of these sugars was compared and the concomitant symptoms were recorded. SUBJECTS AND METHODS: 25 healthy controls received 25 g of each sugar within 3 consecutive days. The intestinal absorption was determined by H2-exhalation tests and the clinical symptoms were recorded. RESULTS: The rate of malabsorption was 84% for sorbitol, 36% for fructose and 12% for xylitol (p < 0.01 for sorbitol versus fructose and xylitol). 57% of the participants with pathological H2-test after sorbitol and 56% after fructose reported symptoms, while all of the 3 malabsorbers of xylitol were symptomatic. CONCLUSIONS: There is an advantage to administering xylitol and fructose with regard to the intestinal absorption and concomitant symptoms as compared with sorbitol. H2-exhalation tests appear to be a reliable diagnostic tool to detect carbohydrate malabsorption and should find broader application in patients suffering from non-specific abdominal complaints.

Kinetics of acetaminophen after single- and multiple-dose oral administration as a gradient matrix system to healthy male subjects.

The in vivo characteristics of two formulations of a recently developed controlled-release system, the Gradient Matrix System (GMS-1 and GMS-2), with acetaminophen as a model drug compound have been determined in healthy volunteers both after separate single- and multiple-dose administration. Values for the mean residence time (MRT) were increased from 5.2 h for an oral solution to 10.2 and 13.3 h for two GMS formulations after single dosing. Peak plasma concentrations were lower for the two GMS formulations after single dosing compared to the oral solution. The bioavailability, relative to the oral solution, was 91 per cent and 84 per cent for the two GMS formulations tested. After multiple dosing of one of the GMS formulations over 5 days, no change in AUC compared to the single dose AUC occurred. Steady state was reached within 2-3 days of twice daily dosing of the GMS formulation. The peak-trough-fluctuation (per cent PTF) was 44 per cent. No signs of dose dumping were observed in fasted subjects. A plateau-like plasma drug concentration profile at steady state was maintained with the GMS formulation.

Pharmacokinetics of butyric acid derivative with xylitol.

The short chain fatty acids, especially butyric acid salts have interesting biological properties. In some cases, transformed cells can recover a normal phenotype and in animal, butyrate salts increase antitumor resistance. Butyrate may be considered as possibly useful for antitumor therapy. But these products exhibit two essential disadvantages which restrict their clinical use in man: high concentrations required to achieve therapeutic effects and rapid excretion with short half life. In order to optimize the clinical use of butyrate, we studied a n-butyric acid ester obtained with xylitol selected for its physiological and metabolic inertia. Structure determination of tributyryl xylitol was carried out by mass and NMR spectrometry (MW = 344). The low toxicity and the antitumor effects of this ester, especially in association with Corynebacterium parvum and interferon, confirm its therapeutic interest. The slow excretion of this prodrug should make butyrate clinical use easier by preventing extensive systemic metabolism and metabolic side-effects due to cations of butyrate salts.

Uptake of 14C-xylitol by xylitol-cultured Streptococcus sobrinus ATCC 27352 and Streptococcus mitis ATCC 36249 in vitro.

The effect of three successive cultures in the presence of 6% xylitol on the uptake of 14C-xylitol was studied using resting cells of Streptococcus sobrinus ATCC 27352 and Streptococcus mitis ATCC 36249. In the case of S. mitis, the three successive cultures did not alter the growth inhibition observed in the presence of xylitol. In the case of S. sobrinus, however, growth inhibition decreased. The 14C-xylitol uptake experiments also demonstrated that uptake of xylitol by S. sobrinus was decreased by culture in the presence of xylitol. Previous 14C-xylitol uptake levels were, however, re-established by culturing S. sobrinus in the presence of glucose alone. Culture in the presence of xylitol did not affect 14C-xylitol uptake in the case of S. mitis. These results show that S. sobrinus and S. mitis differ in the ways they handle of exogenous xylitol, and that uptake of xylitol by S. sobrinus could be reversibly regulated by addition xylitol to the growth medium.