Stability of glycosylated complexes loaded with Epigallocatechin 3-gallate (EGCG).

The application of Epigallocatechin-3-gallate (EGCG) in food industry was limited by its low stability in aqueous solutions and poor bioavailability in vivo. The novel EGCG glycosylated arachin nanoparticles (Ara-CMCS-EGCG) and EGCG glycosylated casein nanoparticles (Cas-CMCS-EGCG) were prepared to improve the stability and bioavailability of EGCG. The effect of different variables on the storage stability and the slow-release behavior of novel glycosylation complexes in nanoparticle background solution and artificial gastrointestinal fluid were investigated. The results showed that the DPPH scavenging activity of Ara-CMCS-EGCG and Cas-CMCS-EGCG were stable in temperature (25 âˆ¼ 70 °C). EGCG could enhance the crosslinking effect of molecular particles in glycosylation complexes solution. The glycosylated protein nanoparticles were stable to acid-base and enzymolysis in simulated gastrointestinal fluid. The release rate of EGCG in simulated intestinal fluid was higher than that in simulated gastric fluid. The glycosylated protein carrier can not only release EGCG slowly, but also significantly improve the stability and bioavailability of EGCG in simulated gastrointestinal fluid.

Preparation and characterization of high embedding efficiency epigallocatechin-3-gallate glycosylated nanocomposites.

Glycosylated protein nano encapsulation was an efficient encapsulation technology, but its embedding rate for EGCG was not high, and the research on the embedding mechanism was relatively weak. Based on this, this study compared the embedding effect of glycosylated peanut globulin and glycosylated casein on EGCG. The embedding mechanism of EGCG with glycosylated protein was discussed by ultraviolet, fluorescence, infrared and fluorescence microscopy. Results revealed that the highest encapsulation efficiency of EGCG was 93.89 ± 1.11%. The neutral pH value and 0.3 mg/mL EGCG addition amount were suitable for EGCG glycosylated nanocomposites. The hydrogen bond between EGCG hydroxyl group and tyrosine and tryptophan of glycosylated protein is mainly non covalent. The encapsulation effect of EGCG glycosylated nanocomposites could be quenched by changing the polar environment and spatial structure of the group. The fluorescence characteristic and dispersibility of EGCG glycosylated peanut globin were higher than EGCG glycosylated casein. This study might provide a theoretical basis for EGCG microencapsulation technology and EGCG application in tea beverage and liquid tea food systems.

Seladelicatulasine A-G, C27 steroidal glycosides with cholinesterase inhibitory activities from Selaginella delicatula.

Seven undescribed C27 steroidal glycosides, Seladelicatulasine A-G, including six cholestanol glycosides and one spirostanol glycoside, were isolated from Selaginella delicatula. Their structures were elucidated by 1D/2D NMR spectra and HRESIMS analyses. The absolute configurations of the sugars were determined by enzymatic hydrolysis and GC/MS analyses. These cholestanol glycosides were isolated from the family Selaginellaceae for the first time. Seladelicatulasine F is characterized as a rare B-5,6-secosteroid. In addition, all the compounds were evaluated for their inhibitory activities against cholinesterase (AChE/BChE) and monoamine oxidase (MAO-A/MAO-B). These steroidal glycosides displayed selective inhibition activities on cholinesterase. Seladelicatulasine A, B and E inhibited the AChE activity with IC50 values of 0.31, 0.09, and 0.04 µM, respectively. Seladelicatulasine A and F showed the strongest inhibition activity on BChE with IC50 values of 0.37 and 0.65 µM, respectively.

Pictalignans D-F, three new neolignan derivatives from Selaginella picta.

Three new neolignan derivatives (1-3), together with three known isolariciresinol derivatives (4-6) were isolated from Selaginella picta. Their structures were elucidated by spectroscopic methods (1D/2D NMR, HRESIMS and CD). All isolated compounds were assayed on the neuroprotective activity against the injury of HT-22 cells induced by L-Glutamate in vitro. All compounds displayed potent protective effect on HT-22 cells.

New adenine analogues and a pyrrole alkaloid from Selaginella delicatula.

Phytochemical study on the n-BuOH extract of Selaginella delicatula lead to the isolation, characterization and structure elucidation of two new adenine analogues, delicatulines A (1) and B (2), one new pyrrole alkaloid (4), and five known compounds (3, 5-8). These new substances all contain an aliphatic chain in their parent nucleus, which were unusual to find in plants. In the present study, they were identified from Selaginellaceae for the first time. The structures and absolute configurations of these new compounds were determined by a combination of NMR and CD spectroscopic analyses. Compounds 1, 3 and 4 were evaluated for their inhibitory activities on HBV surface antigen and HBV DNA in HepAD38 cells. The results showed that these compounds had only weak or no inhibitive effects on HBV.

Abietane diterpenoids from Lycopodium complanatum.

Five new abietane diterpenoids (complanatins A-E, 1-5) have been isolated from the club moss Lycopodium complanatum, along with two known abietane diterpenoids (xanthoperol and sugiol). Their structures were determined by comprehensive analysis of 1D, 2D NMR, CD and HRESIMS data. The cytotoxic effects of five compounds (1-4, 7) were evaluated in three human lung cancer cell lines (MSTO-211H, NCI-H2052 and NCI-H226). Compounds 3 and 4 exhibited cytotoxic activities against the three cell lines. In addition, a plausible biogenetic pathway of compounds 1-7 was proposed.

New neolignans from Selaginella picta and their protective effect on HT-22 cells.

Three new compounds, pictalignans A (1), B (2), C (3), along with three known analogues, syringaresinol (4), 3,3',5-trimethoxy-4',7-epoxy-8,5'-neoligan-4',9,9'-triol (5), 4,9-dihydroxy-4',7-epoxy-8',9'-dinor-8,5'-neolignan-7'-oic acid (6) were isolated from the 75% aqueous ethanol extract of Selaginella picta. Their structures were established by physicochemical properties and spectroscopic methods, and absolute configurations of new compounds were elucidated by experimental and calculated ECD spectra. Compounds 1-3 are neolignans with additional one or two C6-C3 structural units attached to hydroxypropyl group, which are extremely rare in nature. All new compounds exhibited moderate protective effect against the injury of HT-22 cells induced by L-Glutamate in vitro, and compound 1 showed better protective effect than positive drug with the concentrations of 10 µM to 15 µM.

A new neolignan from Selaginella moellendorffii Hieron.

A new neolignan, selamoellenin A (1), was isolated from the whole plants of Selaginella moellendorffii Hieron. The structure was elucidated on the basis of comprehensive spectroscopic methods (1D/2D NMR and HRMS). Compound 1 was evaluated for its protective effect against high glucose-induced human umbilical vein endothelial cells (HUVECs) damage in vitro.

Optimization of conditions for Cu(II) adsorption on D151 resin from aqueous solutions using response surface methodology and its mechanism study.

An experimental study on the removal of Cu(II) from aqueous solutions by D151 resin was carried out in a batch system. The response surface methodology (RSM)-guided optimization indicated that the optimal adsorption conditions are: temperature of 35 °C, pH of 5.38, and initial Cu(II) concentration of 0.36 mg/mL, and the predicted adsorption capacity from the model reached 328.3 mg/g. At optimum adsorption conditions, the adsorption capacity of Cu(II) was 321.6 mg/g, which obtained from real experiments what were in close agreement with the predicted value. The adsorption isotherms data fitted the Langmuir model well, and the correlation coefficient has been evaluated. The calculation data of thermodynamic parameters (ΔG, ΔS, and ΔH) confirmed that the adsorption process was endothermic and spontaneous in nature. The desorption study revealed that Cu(II) can be effectively eluted by 1 mol/l HCl solution, and the recovery was 100%. Moreover, the characterization was undertaken by infrared (IR) spectroscopy.

Adsorption performance and mechanism for removal of Cd(II) from aqueous solutions by D001 cation-exchange resin.

The adsorption and desorption properties of D001 resin for Cd(II) has been investigated. Batch studies were carried out with various pH, contact time, temperature and initial concentrations, and then column studies were conducted. The results showed that the optimal adsorption condition was at pH value of 3.0 in HAc-NaAc medium. The resin exhibited a high Cd(II) uptake of 185.8 mg/g at 298 K. The apparent activation energy Ea is 5.05 kJ/mol and the sorption thermodynamic parameters are ΔH = 21.1 kJ/mol, ΔS = 0.122 kJ/(mol K) and ΔG298K = -15.3 kJ/mol, which indicated that the adsorption process was spontaneous and endothermic. Compared with the Freundlich isotherm, the sorption of Cd(II) obeys the Langmuir isotherm better. The Thomas model was delineated here to predict the breakthrough curves based on the experimental column study data. Furthermore, the resin could be regenerated through the desorption of the Cd(II) anions using 1 mol/L HCl solution and could be reused to adsorb again. The infrared spectroscopic technique was undertaken. Compared with other absorbents, D001 resin was relatively low cost and was effective in removing Cd(II) ions.

Preparation and application of acrylic acid grafted polytetrafluoroethylene fiber as a weak acid cation exchanger for adsorption of Er(III).

In this work, a weakly acidic ion exchange fiber (PTFE-g-AA) has been prepared by 60Co irradiation grafting with acrylic acid (AA) onto the polytetrafluoroethylene (PTFE) fiber. The grafted fiber was characterized by FTIR, SEM and TGA technique. The exchange capacity of the PTFE-g-AA fiber is 3.87 mmol/g. The adsorbent material was employed for Er(III) uptaking by batch and column experiments. Kinetics studies showed that the adsorption process obeyed pseudo-second-order kinetics. The adsorption isotherms followed both the Freundlich model and Langmuir model. The maximum adsorption capacity of the PTFE-g-AA fiber for Er(III) was evaluated to be 142.0mg/g for the Langmuir model. It was found that 0.75 M HCl-0.25 M NaCl solution provided effectiveness of the desorption of Er(III) from the PTFE-g-AA fiber. Various thermodynamic parameters such as standard enthalpy (DeltaH(0)), standard entropy (DeltaS(0)) and standard free energy (DeltaG(0)) were evaluated. The adsorption of Er(III) on the PTFE-g-AA fiber was found to be endothermic in nature. The Thomas model was successfully applied to experimental data to predict the breakthrough curves and to determine the characteristics parameters of the column useful for process design.

Pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western subjects.

PURPOSE: To compare the pharmacokinetics of carisbamate (RWJ-333369) in healthy Japanese and Western adults, and to comparatively assess carisbamate safety and tolerability between the two populations. METHODS: An open-label study was conducted in 24 Japanese and 24 Caucasian healthy subjects. Subjects received a single oral dose of 250 mg carisbamate on day 1 followed by a 3-day washout period; twice-daily dosing of 250 mg carisbamate on days 5-8; subsequently, 500 mg on days 9-12 and a single dose of 500 mg on day 13. Plasma samples were collected for a pharmacokinetic analysis on days 1, 8, and 13. Plasma and urine samples were analyzed for carisbamate and its urinary metabolites by liquid-chromatography-mass-spectrometry. RESULTS: Following a single dose, carisbamate Cmax and area under the curve (AUC) geometric mean ratios were 16.4% and 28.8% higher in Japanese than in Caucasians, respectively; these differences were statistically significant and their 90% confidence intervals (CIs) fell outside of the 80-125% limits, which are considered not to be of clinical significance. With dose-body weight normalization, Cmax and AUC were similar in Japanese and Caucasian subjects and the 90% CIs were within the 80-125% boundaries. Carisbamate was well tolerated, and its mean oral clearance and half-life were similar in both groups, ranging from 35.1-41.4 ml/h/kg and 11.5-12.8 h. DISCUSSION: Carisbamate plasma exposure (AUC) and C(max) in Japanese subjects is approximately 20-25% higher than in Caucasians due to a higher mg/kg dose. After body weight normalization, carisbamate pharmacokinetics was similar between Japanese and Caucasian subjects following single and multiple dosing, and showed the same dose proportionality.

Pharmacokinetics, safety, and tolerability of the new antiepileptic carisbamate in the elderly.

PURPOSE: To evaluate the effect of age on the disposition of two different oral formulations of carisbamate (RWJ-333369), a novel neuromodulator under investigation. METHODS: The disposition of carisbamate was studied in eight men and eight women in each of the three age groups: 18-55, 65-74, and >or= 75 years (N=48). Subjects received single (100mg immediate-release [IR] tablets or 250 mg controlled-release [CR] tablets) or repeated administration (up to 500 mg IR BID or 1250 mg CR QD) of carisbamate in a randomized, double-blind, placebo-controlled, parallel-group, single-center study. RESULTS: After either single or repeated IR administration, no apparent differences were observed between the two elderly and the non-elderly groups. Following single-dose CR administration, the two elderly age groups had higher exposure compared with non-elderly subjects, but the difference decreased for all doses tested after repeated administration. There was no effect of age on plasma protein binding of carisbamate. Renal clearance decreased with age for both formulations, but this decrease had no effect on the total clearance of the drug because of its limited renal elimination. CONCLUSION: Age had no effect on pharmacokinetics of carisbamate IR formulation. The small effect observed after single-dose CR carisbamate diminished after repeated dosing. The drug was generally safe and well tolerated.

An interaction study between the new antiepileptic and CNS drug carisbamate (RWJ-333369) and lamotrigine and valproic acid.

PURPOSE: To characterize possible pharmacokinetic interactions between the new antiepileptic drug carisbamate (RWJ-333369) and valproic acid (VPA) or lamotrigine (LTG) following multiple dosing in healthy subjects. METHODS: Two open-label, sequential-design studies were conducted in 24 healthy adults. In Study 1, subjects received carisbamate alone (5 days 250 mg q12h; 5 days 500 mg q12h), then VPA alone (7 days 300 mg q12h; 7 days 500 mg q12h), and then a combination of VPA (500 mg q12h) and carisbamate (5 days 250 mg q12h; 5 days 500 mg q12h). In Study 2, subjects received carisbamate alone as in Study 1, then LTG alone (14 days 25 mg q12h; 14 days 50 mg q12h), and then combination of LTG (50 mg q12h) and carisbamate (3 days 250 mg q12h; 14 days 500 mg q12h). RESULTS: Coadministration of VPA or LTG had minimal effect on carisbamate mean C(max) and AUC(ss) values. Mean VPA-C(max) and AUC(ss) values were approximately 15% lower when given concomitantly with carisbamate. However, the 90% confidence intervals (CIs) for the C(max) and AUC(ss) ratio with/without carisbamate were within the 80-125% equivalence range, C(max) 82-89%; AUC(ss) 81-88%. Mean LTG C(max) and AUC(ss) values were approximately 20% lower when given concomitantly with carisbamate. The 90% CIs with and without carisbamate for LTG C(max) and AUC(ss) were 79-86% and 75-81%, respectively. This modest change is not considered clinically significant. CONCLUSIONS: There were no clinically significant interactions between carisbamate and VPA or LTG. Concomitant administration of carisbamate with VPA or LTG was generally safe and well tolerated.

Pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369 following single and multiple dosing to humans.

PURPOSE: To characterize the pharmacokinetics of the new antiepileptic and CNS drug RWJ-333369 following single and multiple oral doses to healthy subjects, including the effect of food on bioavailability. METHOD: Two studies were conducted. The first study had a randomized, double-blind, placebo-controlled, sequential, ascending-dose crossover design. Subjects were divided into four dose groups (100, 250, 500, and 750 mg) of 10 to 11 subjects each. RWJ-333369 or placebo was administered for two 7-day periods, separated by a 14-day washout. In the second study RWJ-333369 (750 mg) was administered to 12 healthy subjects under fasted and fed conditions. Plasma and urine samples were analyzed for RWJ-333369 by liquid chromatography-mass spectroscopy. Safety was assessed throughout the studies. RESULTS: Mean (range) pharmacokinetic parameters in the above studies were: oral clearance (CL/F) 3.4-4.2 L/h, half-life (t(1/2)) 10.6-12.8 h, and renal clearance (CLr) 0.042-0.094 L/h, indicating that RWJ-333369 is eliminated primarily by metabolism. These parameters were not significantly different (p > 0.05) for the four dose groups and for single and multiple dosing. C(max) and AUC increased proportionally with dose and decreased with food by 11% and 5%, respectively. CONCLUSIONS: Following single and repetitive (q12h) doses of 100-750 mg, RWJ-333369 had linear pharmacokinetics; food did not alter pharmacokinetics to a clinically relevant extent. RWJ-333369 is extensively metabolized and has a low CL/F that equals < 5% of the liver blood flow. Thus, orally administered RWJ-333369 has no hepatic first-pass effect. The 12-h half-life will enable bid dosing with an immediate-release oral formulation.

Pharmacokinetic interaction study between the new antiepileptic and CNS drug RWJ-333369 and carbamazepine in healthy adults.

PURPOSE: To characterize the possible pharmacokinetic interaction between the new antiepileptic and CNS drug RWJ-333369 and carbamazepine (CBZ) following multiple dosing in healthy subjects. METHODS: In an 8-week, open-label, sequential design study, 24 healthy adults received multiple-dose RWJ-333369 alone (5 days 250 mg q12h; 5 days 500 mg q12h), then after a 4-day washout, multiple-dose CBZ alone (3 days 100 mg q12h; 3 days 200 mg q12h; 22 days 300 mg q12h), and then combination of CBZ (300 mg q12h), and RWJ-333369 (5 days 250 mg q12h; 5 days 500 mg q12h). RESULTS: At steady-state following multiple dosing, RWJ-333369 peak plasma concentration (C(max)) and area under the concentration-time-curve within the dosing interval (AUCss) increased in proportion to dose. The C(max) and AUCss of CBZ were similar when given alone or concomitantly with RWJ-333369. The 90% confidence intervals for the ratio of CBZ C(max) and AUCss with/without RWJ-333369 were: 94-104% and 95-104%, respectively (well within the equivalence range of 80-125%). When RWJ-333369 was administered with CBZ, its mean (SD) oral clearance increased from 3.2 L/h to 4.9 L/h and consequently its mean half-life was shortened from 10.4 (1.9) h to 7.4 (1.2) h, and mean AUCss and C(max) were reduced by 37% and 30%, respectively. CONCLUSIONS: There was no effect of multiple-dose RWJ-333369 on CBZ pharmacokinetics. CBZ induced RWJ-333369 clearance, resulting in shortened half-life and decreased exposure (AUCss) and C(max). Concomitant administration of RWJ-333369 with CBZ was generally safe and tolerated.

Steady-state pharmacokinetics of galantamine are not affected by addition of memantine in healthy subjects.

To evaluate the effect of multiple doses of memantine on the pharmacokinetics of galantamine and to assess the safety and tolerability of galantamine with adjunctive memantine treatment, an open-label, single-center, drug interaction study was conducted in 16 healthy adults. Subjects received an 8-mg dose of galantamine extended release once daily during week 1 and a 16-mg dose of galantamine extended release once daily during week 2. During weeks 3 and 4, they received a 16-mg dose of galantamine extended release once daily and a 10-mg dose of memantine twice daily, except on days 1 and 2 of week 3, when memantine was given as 10 mg once daily. The pharmacokinetic profile and parameters of galantamine at steady state were similar after administration of a 16-mg dose of galantamine once daily alone and after administration with a 10-mg dose of memantine twice daily. Galantamine 16 mg once daily with adjunctive memantine 10 mg twice daily was well tolerated and safe in healthy subjects.

Comparison of in vitro and in vivo inhibition potencies of fluvoxamine toward CYP2C19.

A previous study suggested that fluvoxamine inhibition potency toward CYP1A2 is 10 times greater in vivo than in vitro. The present study was designed to determine whether the same gap exists for CYP2C19, another isozyme inhibited by fluvoxamine. In vitro studies examined the effect of nonspecific binding on the determination of inhibition constant (K(i)) values of fluvoxamine toward CYP2C19 in human liver microsomes and in a cDNA-expressed microsomal (Supersomes) system using (S)-mephenytoin as a CYP2C19 probe. K(i) values based on total added fluvoxamine concentration (K(i,total)) and unbound fluvoxamine concentration (K(i,ub)) were calculated, and interindividual variability in K(i) values was examined in six nonfatty livers. K(i,total) values varied with microsomal protein concentration, whereas the corresponding K(i,ub) values were within a narrow range (70-80 nM). In vivo inhibition constants (K(i)iv) were obtained from a study of the disposition of a single oral dose (100 mg) of the CYP2C19 probe (S)-mephenytoin in 12 healthy volunteers receiving fluvoxamine at 0, 37.5, 62.6, and 87.5 mg/day to steady state. In this population, the ratio of (S)-4-hydroxy-mephenytoin formation clearances (uninhibited/inhibited) was positively correlated with fluvoxamine average steady-state concentration with an intercept of 0.85 (r(2) = 0.88, p < 0.001). The mean (+/-S.D.) values of K(i)iv based on total and unbound plasma concentrations were 13.5 +/- 5.6 and 1.9 +/- 1.1 nM, respectively. Comparison of in vitro and in vivo K(i) values, based on unbound fluvoxamine concentrations, suggests that fluvoxamine inhibition potency is roughly 40 times greater in vivo than in vitro.

Inhibition-based metabolic drug-drug interactions: predictions from in vitro data.

There has been a growing interest in predicting in vivo metabolic drug-drug interactions from in vitro systems. High-throughput screening methods aimed at assessing the potential of drug candidates for drug interactions are widely used in industry. However, at present, there is no consensus on methodologies that would yield reliable quantitative predictions, because a number of issues remain unsolved, such as estimations of inhibition constants in vitro and inhibitor concentration around the enzyme site in vivo. In the present review, different approaches to estimation of inhibitor concentration around the enzyme site are summarized; also, the problems associated with estimation of in vitro K(i) values due to incubation conditions and environment differences between in vitro and in vivo are presented. A new approach based on comparisons of in vitro and in vivo inhibition potencies by calculation of in vivo inhibition constants is discussed. Examples of predictions of in vivo drug interactions based on mechanism-based inactivation are described. Unresolved issues that would allow further refinement of existing prediction models are also evaluated.