Comparison of visual outcomes and optical aberrations after SMILE with intraoperative Kappa angle adjustments between small and large Kappa angles.

This study compares postoperative visual outcomes and optical aberrations after Small Incision Lenticule Extraction (SMILE) in patients with both small (S-Kappa: Kappa angle < 0.2 mm) and large Kappa (L-Kappa: Kappa angle ≥ 0.2 mm) angles. The evaluated aberrations include total higher-order aberrations (HOAs), horizontal coma (HC), vertical coma (VC), and spherical aberrations (SA), with procedures incorporating intraoperative Kappa angle adjustments. We retrospectively analyzed patient records undergoing SMILE utilizing linear mixed models (LMM). We assessed adjusted mean uncorrected distance visual acuity (UDVA), Strehl ratio (SR), total HOAs, VC, and SA at pupils of 3 mm and 6 mm for both S-Kappa and L-Kappa. The disparities between S-Kappa and L-Kappa were evaluated by LMM's adjusted mean differences. The differences in optical metrics were also assessed in eyes grouped by myopia levels: low, moderate, and high. A sensitivity analysis was conducted on a threshold of Kappa angle at 0.3 mm. Eight-five patients (169 eyes) were analyzed, and no significant pre-operative difference was found in UDVA (p = .222) or spherical equivalent (p = .433). Post-operative differences were found in SR at 3 mm pupil size (-0.06, p = .022), total HOA 3 mm (0.15, p = .022), HC 3 mm (0.04, p = .042), VC 3 mm and 6 mm (-0.08, p = .041; 0.04, p = .041). The stratified analysis for high myopia revealed significant differences in UDVA (-0.04, p = .037), HC 3 mm (0.07, p = .03), VC 6 mm (-0.21, p = .001), and SA 3 mm and 6 mm (0.07, p = .037; -0.09, p = .037). Sensitivity analysis showed no significant difference using a 0.3 mm Kappa threshold. While some optical aberrations exhibited statistical differences between S-Kappa and L-Kappa, their clinical significance is limited. Thus, a large Kappa angle might not substantially influence post-operative optical aberrations when intraoperative Kappa angle adjustments are implemented.

Trimatch comparison of the prognosis of hypochloremia, normolchloremia and hyperchloremia in patients with septic shock.

BACKGROUND: Septic shock is a lethal disease, and identifying high-risk patients through noninvasive and widely available biomarkers can help improve global outcomes. While the clinical impact of chloride levels on critically ill patients remains unclear, this study aims to investigate the association between hypochloremia and mortality following ICU admission among septic shock patients. METHODS: This is an analysis of data stored in the databases of Medical Information Mart for Intensive Care IV (MIMIC-IV). The initial chloride levels were classified ashypochloremia, normal chloraemia, and hyperchloraemia. A multivariate logistic regression model was applied, adjusting for age, lactate, pH, PO2, urine volume, RDW, creatinine, and liver disease, to assess the association between the three categories of chloride levels and mortality. RESULTS: Of 3726 patients included in the study, 470 patients (12.6%) had hypochloremia on ICU admission. During the follow-up period, 1120 (33.5%) patients died. Hypochloremia was significantly associated with increased mortality and the incidence of AKI after adjusting for several variables. CONCLUSIONS: Hypochloremia is independently associated with higher hospital mortality, AKI incidence among septic shock patients. However, further high-quality research is necessary to establish the precise relationship between hypochloremia and septic shock prognosis.

Two-Level Self-Thickening Mechanism of a Novel Acid Thickener with a Hydrophobic-Associated Structure during High-Temperature Acidification Processes.

Two acid thickeners, ADMC and ADOM, were prepared by aqueous solution polymerization using acrylamide (AM) and methacryloyloxyethyl trimethyl ammonium chloride (DMC) as raw materials, with or without the introduction of octadecyl polyoxyethylene ether methacrylate (OEMA). It was characterized by FTIR, 1H NMR, and the fluorescence spectra of pyrene. The double-layer thickening mechanism of ADOM was proved by comparing the thickening and rheological properties of ADMC and ADOM tested by a six-speed rotary viscometer and a HAKKE MARSIV rheometer during the acidification process. The results showed that the synthetic product was the target product; the first stage of the self-thickening ADOM fresh acid solution during high-temperature acidification was mainly affected by Ca2+ concentration, and the second stage of self-thickening was mainly affected by temperature. The residual viscosity of the 0.8 wt% ADOM residual acid solution was 250, 201.5, and 61.3 mPa·s, respectively, after shearing at 90, 120, and 150 °C for 60 min at a shear rate of 170 s-1. The thickening acid ADOM with a hydrophobic association structure has good temperature resistance and shear resistance, which can be used for high-temperature deep-well acid fracturing. In addition, no metal crosslinking agent was introduced in the system to avoid damage to its formation, and ADOM exhibited good resistance to Ca2+, which could provide ideas for the reinjection of the acidizing flowback fluid. It also has certain advantages for environmental protection.

A stimuli-responsive hydrogel for reversible information storage, encryption and decryption.

Smart hydrogel materials, known for their sensitivity to external stimuli, exhibit a reversible dynamic response and find applications in diverse fields, particularly in information storage. Despite significant efforts in this domain, developing a hydrogel with high-resolution, repeatable recording, and robust information encryption/decryption capabilities still remains a challenge. In this study, we synthesized a polymer hydrogel, namely polyvinyl alcohol-n-isopropylacrylamide-octadecyl polyoxyethylene ether acrylate hydrogel (PPNS), which features multiple hydrogen bonds through copolymerization, by using N-isopropylacrylamide, polyvinyl alcohol, and octadecyl polyoxyethylene ether acrylate (SGA15) as raw materials. The PPNS hydrogel demonstrated outstanding high-resolution, repeatable recording capabilities, enabling reversible recording, encryption, and decryption of information using anhydrous ethanol as the inducer. Varying the SGA15 monomer concentration revealed that the PPNS-2% hydrogel, prepared with 2% SGA15, outperformed the other hydrogels in terms of information recording and encryption/decryption when immersed in anhydrous ethanol and deionized water. Furthermore, the PPNS-2% hydrogel exhibited the ability to undergo multiple information cycles while maintaining excellent mechanical properties even after 25 cycles. Notably, ethanol served as a specialized ink for inscribing different patterns on the hydrogel surface for information recording. The recorded information could be erased through water wiping or ethanol volatilization, enabling reversible information recording, encryption, and decryption. Due to their responsive and dynamic nature of PPNS hydrogels are positions them as promising candidates for use as innovative information storage platforms.

The Effectiveness of Student-Led Ward Round Training on Knowledge Acquisition, Critical Thinking Ability, and Self-Confidence of Acute Upper Gastrointestinal Bleeding for Nursing Students.

Introduction: Nursing knowledge, critical thinking ability, and self-perceived confidence are imperative to nursing skills in professional nursing practice. Therefore, nurse educators are required to use teaching strategies that will help promote their knowledge, critical thinking, and self-confidence in complex contents such as the nursing of acute upper gastrointestinal bleeding (AUGIB). Purpose: This study compares the effect of student-led and instructor-led ward-round training methods on knowledge acquisition, critical thinking ability, and self-perceived confidence during AUGIB sessions. Methods: Forty nursing students in the first year of the Emergency Nursing Residency Program were randomly divided into a student-led ward round training group (SG) and an instructor-led ward round training group (IG) with a ratio of 1:1. A knowledge quiz, critical thinking ability test, and self-perceived confidence questionnaire were performed before and after the ward round training to assess both groups of students for their knowledge acquisition, critical thinking ability, and self-perceived confidence improvement. Feedback questionnaires were conducted after the training to evaluate students' perspectives and interests concerning the teaching module. Results: The scores of the post-training quiz were significantly higher than that of the pre-training quiz in both the SG (44.10±2.92 vs 31.10±4.27, p<0.001) and IG (32.35±2.21 vs 30.55±2.24, p=0.01). In the post-training quiz, scores achieved by the students from the SG (44.10±2.92) were significantly higher than those achieved by the students from the IG (32.35±2.21, p< 0.001). The level of self-perceived confidence improved significantly after ward round training in the SG (p< 0.001). However, there was no statistically significant difference in the IG with respect to the change from pre- to post-training (p=0.43).The students' critical thinking ability improved significantly in the SG (14.95±2.58 vs 7.10±1.79, p<0.001), while no significant improvement was found in the IG (7.91±2.28 vs 6.52±2.21, p=0.07) after ward round training. Conclusion: The teaching method of SWRT improves nursing students' knowledge acquisition, critical thinking ability, and self-perceived confidence in AUGIB.

Semi-mechanistic population pharmacokinetics analysis reveals distinct CYP2C19 dependency in the bioactivation of vicagrel and clopidogrel to active metabolite M15-2.

AIMS: Vicagrel is a novel antiplatelet drug used to mitigate clopidogrel resistance due to CYP2C19 polymorphism. This study aimed to develop a semi-mechanistic population pharmacokinetic (PopPK) model to characterize the pharmacokinetic (PK) profile of M15-2, the active metabolite of vicagrel and clopidogrel, and to evaluate the influence of CYP2C19 polymorphisms and other covariates in healthy subjects and patients with acute coronary syndrome (ACS) after oral administration. METHODS: The analysis utilized data from 213 subjects, including 178 healthy subjects and 35 patients, from five clinical trials. PopPK modeling and simulation were used to estimate PopPK parameters and evaluate the impact of covariates. RESULTS: The M15-2 PK profiles were well characterized by a model incorporating transit compartments, two-compartment parent models and two-compartment M15-2 models for both vicagrel and clopidogrel. The parameter estimates indicated the dose fraction of vicagrel that formed M15-2 was approximately 20-fold that of clopidogrel. Covariate analysis identified a significant effect of CYP2C19 on M15-2 apparent clearance (CL/F) and apparent volume of distribution (V3/F) for clopidogrel but only CL/F for vicagrel. The analysis suggested that the nonlinear PK of M15-2 for clopidogrel was due the first-step bioactivation of clopidogrel to 2-oxoclopidogrel. CONCLUSION: The model illustrated the bioactivation of vicagrel is more efficient and less dependent on CYP2C19 than that of clopidogrel. M15-2 is formed in a linear process from vicagrel, versus a nonlinear and less predictable process from clopidogrel. Advantages in both PK and pharmacogenetics suggest that vicagrel may reduce the complexity of currently recommended CYP2C19-based dosage adjustment for clopidogrel.

Antiplatelet effect, safety, and pharmacokinetics of vicagrel in patients with coronary artery disease undergoing percutaneous coronary intervention.

AIMS: Vicagrel, a novel antiplatelet prodrug to overcome the residual high platelet reactivity of clopidogrel induced by inactive metabolism and cytochrome P450 (CYP) 2C19 polymorphisms, provides favourable antiplatelet inhibition in healthy volunteers. However, its antiplatelet effect and safety in patients with coronary artery disease (CAD) are unclear. METHODS AND RESULTS: This was a multicentre, randomized, double-blind, triple-dummy, dose-exploring phase II trial comparing the antiplatelet activity and safety of vicagrel at different doses vs. those of clopidogrel in patients with CAD undergoing percutaneous coronary intervention (PCI). The primary endpoint was inhibition of adenosine diphosphate (ADP)-induced platelet aggregation (%IPA) after loading and maintenance doses (LD/MD) at 28 days. Safety endpoints included adverse events (AEs) and Bleeding Academic Research Consortium-defined any bleeding. Pharmacokinetic (PK) profiles and the influence of CYP2C19 polymorphisms were explored in subgroup analysis. Two hundred and seventy-nine patients diagnosed with stable CAD (51.97%), unstable angina (40.86%), and myocardial infarction (7.17%) were randomized to receive vicagrel 20/5 mg (LD/MD), 24/6 mg, or 30/7.5 mg or clopidogrel 300/75 mg in combination with aspirin. %IPAs on Day 28 were 30.19%, 35.02%, 45.61%, and 32.55% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, respectively, and were comparable across all groups (P = 0.0694). The plasma concentration of the vicagrel active metabolite M15-2 had a similar area under curve and Tmax to those of clopidogrel. There were no significant differences in AEs (4.35%, 0%, 1.45%, and 5.56% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, P = 0.6667) or any bleeding (13.04%, 14.06%, 11.59%, and 11.11% for vicagrel 20/5, 24/6, and 30/7.5 mg and clopidogrel, respectively, P = 0.95) across four groups. %IPAs and PK profiles of vicagrel did not vary significantly among different CYP2C19 metabolizers. CONCLUSION: Vicagrel had comparable antiplatelet effect and safety to clopidogrel in patients with CAD undergoing PCI.

Long-term sequelae of different COVID-19 variants: The original strain versus the Omicron variant.

Although Omicron appears to cause less severe acute illness than the original strain, the potential for large numbers of patients to experience long COVID is a major concern. Little is known about the recovery phase in cases of Omicron, highlighting the importance of dynamically monitor long COVID in those patients. Subjects of the current study were patients available for a three-month follow-up who were admitted from January 13 to May 22, 2020 (period of the original strain) and from January 1 to May 30, 2022 (period of Omicron). Twenty-eight-point-four percent of patients infected with the original strain had long-term symptoms of COVID-19 and 5.63% of those infected with the Omicron strain had such symptoms. The most common symptom was a cough (18.5%), followed by tightness in the chest (6.5%), in patients infected with the original strain. Fatigue (2.4%) and dyspnea (1.7%) were the most commonly reported symptoms in patients infected with the Omicron strain. The respiratory system is the primary target of SARSCoV-2. Supportive treatment is the basis for the treatment of respiratory symptoms in patients with COVID-19. Quality sleep and good nutrition may alleviate fatigue and mental issues. Further knowledge about a long-term syndrome due to Omicron needs to be discussed and assembled so that healthcare and workforce planners can rapidly obtain information to appropriately allocate resources.

Pharmacokinetics, mass balance, and metabolism of [14C]vicagrel, a novel irreversible P2Y12 inhibitor in humans.

Vicagrel, a novel irreversible P2Y12 receptor inhibitor, is undergoing phase III trials for the treatment of acute coronary syndromes in China. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of vicagrel in six healthy male Chinese subjects after a single oral dose of 20 mg [14C]vicagrel (120 µCi). Vicagrel absorption was fast (Tmax = 0.625 h), and the mean t1/2 of vicagrel-related components was ~38.0 h in both plasma and blood. The blood-to-plasma radioactivity AUCinf ratio was 0.55, suggesting preferential distribution of drug-related material in plasma. At 168 h after oral administration, the mean cumulative excreted radioactivity was 96.71% of the dose, including 68.03% in urine and 28.67% in feces. A total of 22 metabolites were identified, and the parent vicagrel was not detected in plasma, urine, or feces. The most important metabolic spot of vicagrel was on the thiophene ring. In plasma pretreated with the derivatization reagent, M9-2, which is a methylated metabolite after thiophene ring opening, was the predominant drug-related component, accounting for 39.43% of the radioactivity in pooled AUC0-8 h plasma. M4, a mono-oxidation metabolite upon ring-opening, was the most abundant metabolite in urine, accounting for 16.25% of the dose, followed by M3-1, accounting for 12.59% of the dose. By comparison, M21 was the major metabolite in feces, accounting for 6.81% of the dose. Overall, renal elimination plays a crucial role in vicagrel disposition, and the thiophene ring is the predominant metabolic site.

Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y12 inhibitor.

AIMS: We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects. METHODS: CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open-label, 2-period cross-over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7. RESULTS: After a loading dose, the AUC0-t of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC0-t of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28-fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs. CONCLUSIONS: CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs.

Platelet inhibitory activity, tolerability, and safety of vicagrel, a novel thienopyridine P2Y12 inhibitor.

Vicagrel is a new antiplatelet pro-drug based on clopidogrel sulfur lactone metabolites. The purpose of the study was to evaluate the safety, tolerability, and pharmacodynamics (PD) of vicagrel in healthy Chinese subjects.This study was designed as a single-center, randomized, double-blind, placebo-controlled, single oral ascending dose study. Fifty nine subjects were assigned to 6 vicagrel dose cohorts (5, 10, 20, 40, 60, and 75 mg), and 8 subjects were assigned to 75 mg clopidogrel. Within each vicagrel dose cohort, the 10 subjects (9 in the 75 mg cohort) were randomized 4:1 to receive vicagrel or placebo. Platelet function was assessed using VerifyNow P2Y12. ΔP2Y12 reaction units (ΔPRU) and percent inhibition platelet aggregation (%IPA) were used to evaluate the PD of vicagrel.Although the number of adverse events (AEs) increased with vicagrel dose, none were considered serious, suggesting that vicagrel is safe and well-tolerated. The ΔPRU and %IPA patterns suggest that inhibition of ADP-induced platelet aggregation increased in a dose-dependent manner across the 10 to 40 mg dose range. The inhibitory effect was nearly complete at 4 hours (mean %IPA 87.9%-93.0%, mean ΔPRU 206.6-240.0) for doses of 40 to 75 mg of vicagrel. In contrast, for 5 mg vicagrel and 75 mg clopidogrel, there were no measurable effects on platelet aggregation throughout the study.The results suggest that vicagrel at 40 to 75 mg inhibits ADP-induced platelet aggregation, with a fast onset of action and significantly greater potency than clopidogrel. These findings indicate that vicagrel may be a highly effective and well-tolerated antiplatelet agent.

Rheological properties of an ultra-high salt hydrophobic associated polymer as a fracturing fluid system.

Herein, a novel ultra-high salt hydrophobic associated polymer, UUCPAM, was prepared using acrylamide, acrylic acid, 2-acrylamide-2-methyl propane sulfonic acid and the hydrophobic monomer UUC. Polymerization exothermic test results indicated that the increase in the hydrophobic monomer content led to an increase in the exothermic time, which is considerably conducive to the formation of hydrophobic structures. The scanning electron microscopy and transmission electron microscopy studies showed that the polymer had complex network structures and that this phenomenon was considerably obvious in NaCl solution. The fluorescence probe experiment verified that the critical association concentration of this polymer decreased with an increase in the hydrophobic monomer. Rheology studies indicated that the polymer had good temperature and shear resistance in NaCl solution. Moreover, the apparent viscosity of the polymer remained above 80 mPa s when 0.3 wt% UUCPAM was added at 170 s-1 in 20 000 mg L-1 NaCl solution at 90 °C. The storage modulus that indicated strong elasticity increased with an increase in the polymer concentration. Meanwhile, the number of hydrophobic micro-zones increased, thus forming dense network structures. Therefore, the polymer was found to have excellent salt resistance and extensive application prospects.

Pharmacokinetics and pharmacokinetic/pharmacodynamic relationship of vicagrel, a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy Chinese subjects following single oral dosing.

BACKGROUND AND OBJECTIVES: Vicagrel, a novel thienopyridine antiplatelet agent, is an analogue of clopidogrel in development for the treatment of acute coronary syndromes. This study investigated the pharmacokinetic properties of vicagrel after single oral dosing with a direct comparison with clopidogrel in healthy Chinese subjects in the first two phase I clinical studies. The relationship between the exposure to the active metabolite and the platelet reactivity was also assessed for vicagrel. METHODS: Study A was a single-ascending-dose study of vicagrel (5-75 mg) compared with clopidogrel (75 mg) in 67 healthy volunteers. Study B was a randomized, two-period, crossover, loading-dose study of vicagrel 20 mg compared with clopidogrel 300 mg in 12 healthy subjects. Plasma concentrations of three common metabolites of vicagrel and clopidogrel, the active thiol metabolite H4, the inactive thiol metabolite H3, and the S-methylated form of H3 (SM3, the major metabolite of vicagrel), were determined using a validated UHPLC-MS/MS method. The relationship between the AUC0-t of active H4 and the P2Y12 reaction units at 4 h after administration of vicagrel was investigated. Blood concentrations of vicagrel were determined after a single oral administration of vicagrel 25 mg to two healthy Chinese subjects. RESULTS: In the single-ascending-dose study, vicagrel was metabolized rapidly with the median tmax for the three metabolites, namely, H4, H3, and SM3, ranging from 0.25-1.75 h. The pharmacokinetics of the three metabolites for vicagrel were linear across the dose range of 5-75 mg, with the mean Cmax and AUCs for H4 and H3 increasing in an approximately 1:1 dose-proportional manner and for SM3 increasing in a <1:1 dose-proportional manner. The median tmax for active H4 in the vicagrel 5 mg group was slightly shorter than that in the clopidogrel 75 mg group (0.50 versus 0.75 h). The mean AUC0-t for H4 in the vicagrel 5 mg group was similar to that in the clopidogrel 75 mg group (11.7 versus 11.8 ng∙h/mL). The AUC0-t of active H4 was apparently associated with the P2Y12 reaction units at 4 h for vicagrel. In the loading-dose study, for active H4, the median tmax was slightly shorter (0.50 versus 0.75 h) and the mean AUC0-t was 29% higher in the vicagrel 20 mg group than those in the clopidogrel 300 mg group. After a single oral administration of vicagrel 25 mg to 2 subjects, vicagrel was detected in blood but in very low concentrations. CONCLUSIONS: Vicagrel was rapidly and extensively metabolized, and the levels of the parent drug in circulation were very low. The pharmacokinetics of the three metabolites of vicagrel were linear and predictable across the dose range of 5-75 mg. The AUC of active H4 was apparently associated with the P2Y12 reaction units for vicagrel. For active H4, vicagrel 5 mg produced similar exposure (AUC) with more rapid appearance compared with clopidogrel 75 mg, and vicagrel 20 mg produced even slightly higher exposure (AUC) with more rapid appearance compared with clopidogrel 300 mg in humans. TRIAL REGISTRATION: CTR20150346, CTR20160379.

Evaluation of Tolerability, Pharmacokinetics and Pharmacodynamics of Vicagrel, a Novel P2Y12 Antagonist, in Healthy Chinese Volunteers.

Background: Vicagrel is a novel anti-platelet drug and hydrolyzed to the same intermediate as clopidogrel via esterase, instead of CYP2C19. Here we report the first clinical trial on the tolerability, pharmacokinetics and pharmacodynamics of different doses of vicagrel, and comparison with clopidogrel in healthy Chinese volunteers. Methods: This study was conducted in two parts. Study I was a dose-escalating (5-15 mg) study. For each dose, 15 participants were randomized into three groups (total n = 45); nine participants were given vicagrel, three were given clopidogrel, and three were given a placebo. Study II was conducted to assess interactions between vicagrel and aspirin in 15 healthy participants. The plasma concentrations of the metabolites of vicagrel and clopidogrel were determined using a LC-MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y12 assay. Results: Vicagrel (5-15 mg per day) dosing for 10 days or addition of aspirin was well tolerated in healthy volunteers. The exposure of the active metabolite increased proportionally across the dose range and was higher (~10-fold) than clopidogrel. The levels of IPA dosing 75 mg clopidogrel were between the responses of 5 mg and 10 mg vicagrel. After a single loading dose of vicagrel (30 mg) and a once-daily maintenance dose (7.5 mg) for 8 days, the maximum inhibition of platelet aggregation was similar to that seen with the combined use of vicagrel and aspirin (100 mg/day). Conclusion: Oral vicagrel demonstrated a favorable safety profile and excellent anti-platelet activity, which could be a promising P2Y12 antagonist as anti-platelet drug and can be further developed in phase II/III studies, and marketing for the unmet medical needs of cardiovascular diseases. The study was registered at http://www.chictr.org.cn (ChiCTR-IIR-16009260).

Development and validation of a sensitive and rapid UHPLC-MS/MS method for the simultaneous quantification of the common active and inactive metabolites of vicagrel and clopidogrel in human plasma.

Vicagrel, an analog of clopidogrel, is a novel thienopyridine P2Y12 antagonist in clinical development in China for the treatment of acute coronary syndromes. Vicagrel and clopidogrel are prodrugs requiring metabolic activation to produce a pharmacologically active thiol metabolite (H4) in vivo. The formation of H4 from vicagrel in humans is promising more efficient and consistent than that from clopidogrel. After oral dosing of vicagrel or clopidogrel to humans, the active thiol metabolite H4 and two inactive metabolites closely related to H4 formation (the thiol metabolite H3 and the S-methylated metabolite SM3) were observed in plasma; SM3 was the most abundant drug-related component of vicagrel in circulation. In this study, a sensitive, rapid, and reliable UHPLC-MS/MS method was developed for the simultaneous determination of derivatized H3 (MP-H3), derivatized H4 (MP-H4), and SM3 in human plasma to investigate the pharmacokinetics of vicagrel in healthy subjects compared with clopidogrel. After extracted from 50µL of plasma by simple protein precipitation, the analytes and stable isotope-labeled internal standards were separated on an Acquity UPLC BEH C18 column (100mm×2.1mm, 1.7µm). The mobile phase was acetonitrile-water-formic acid (45:55:0.0275, v/v/v) delivered at a flow rate of 0.45mL/min under isocratic elution. The total chromatographic run time was 6min. MP-H3, MP-H4, and SM3 were separated from their corresponding isomers under the chromatographic conditions. Mass spectrometric detection was conducted in multiple reaction monitoring mode on an AB Sciex Qtrap 5500 System using a positive electrospray ionization interface. The calibration curves were linear in the following ranges: 0.100-200ng/mL for MP-H3 and MP-H4 and 1.00-1000ng/mL for SM3. The intra- and inter-day accuracy and precision for each analyte at all concentrations were within acceptable limits (±15%). The validated method was successfully applied to compare the pharmacokinetics of vicagrel and clopidogrel after a single oral administration to healthy subjects in the first-in-human study of vicagrel.

Glycerol-3-phosphate metabolism plays a role in stress response in the red alga Pyropia haitanensis.

Glycerol-3-phosphate (G3P) has been suggested as a novel regulator of plant defense signaling, however, its role in algal resistance remains largely unknown. The glycerol kinase (also designated as NHO1) and NAD-dependent G3P dehydrogenase (GPDH) are two key enzymes involved in the G3P biosynthesis. In our study, we cloned the full-length cDNA of NHO1 (NHO1Ph ) and GPDH (GPDHP h ) from the red alga Pyropia haitanensis (denoted as NHO1Ph and GPDHP h ) and examined their expression level under flagellin peptide 22 (flg22) stimulation or heat stress. We also measured the level of G3P and floridoside (a downstream product of G3P in P. haitanensis) under flg22 stimulation or heat stress. Both NHO1Ph and GPDHP h shared high sequence identity and structural conservation with their orthologs from different species, especially from red algae. Phylogenetic analysis showed that NHO1s and GPDHs from red algae were closely related to those from animals. Under flg22 stimulation or heat stress, the expression levels of NHO1Ph and GPDHP h were up-regulated, G3P levels increased, and the contents of floridoside decreased. But the floridoside level increased in the recovery period after heat stress. Taken together, we found that G3P metabolism was associated with the flg22-induced defense response and heat stress response in P. haitanensis, indicating the general conservation of defense response in angiosperms and algae. Furthermore, floridoside might also participate in the stress resistance of P. haitanensis.

[Advances on the genome of algae].

Algae possess complex and diverse biology and evolutionary history. They play an important role in the ecosystem. A mass of unique genes and biological processes also make them attractive. The application of high-throughput sequencing approaches to algal research has greatly contributed to the development of algal genomics and transcriptomics, as well as enriched the gene information of algae. In this article, we summarize the advances of algal genomics and transcriptomics, describe and compare the characteristics of different algae genomes, and introduce the application of expression sequence tags (ESTs), microarray and RNA sequencing technique to algal transcriptomics research. Furthermore, the advances of algal gene expression and small RNA are also reviewed in detail. At last, we discuss the challenges and future development of this area.

Comparative pharmacokinetic and bioavailability studies of three salvianolic acids after the administration of Salviae miltiorrhizae alone or with synthetical borneol in rats.

Salviae miltiorrhizae is one of the most commonly used herbal plants in the treatment of numerous ailments including cardiovascular diseases for hundreds of years. According to the theory of traditional Chinese herbal medicine, S. miltiorrhizae is always used in combination with borneol to obtain better pharmacological effects. The purpose of this study was to investigate the effects of borneol on the pharmacokinetic and bioavailability of S. miltiorrhizae. The pharmacokinetics studying on rosmarinic acid, salvianolic acid A and salvianolic acid B which are the main active compounds of S. miltiorrhizae in rat plasma, was achieved using a optimal high-performance liquid chromatographic technique coupled with liquid-liquid extraction method. After administration of either single salvianolic acids or salvianolic acids in combination with borneol, plasma concentrations of rosmarinic acid, salvianolic acid A and salvianolic acid B of male Sprague-Dawley rats were determined at different time points (5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300, and 360 min). In comparison with salvianolic acid extract alone, there were statistically significant differences in pharmacokinetic parameters of rosmarinic acid, salvianolic acid B and salvianolic acid A, and the bioavailability of the three salvianolic acids increased by different degrees when the salvianolic acid extract and borneol were administered together. These results indicated that borneol could enhance the intestinal absorption, decrease the distribution and inhibit the metabolism of salvianolic acids.

[Intestinal absorption properties of three components in salvianolic acid extract and the effect of borneol on their absorption in rats].

This study aimed to investigate the effects of concentration, intestinal section and borneol on the intestinal absorption of salvianolic acids. The experiment not only studied the intestinal absorption properties of three concentrations of rosmarinic acid, salvianolic acid B and salvianolic acid A at duodenum, jejunum and ileum, but also of salvianolic acids compatible with borneol at different concentrations using single-pass intestinal perfusion model in rat with phenol red as the marker. The results showed that salvianolic acids was stable under weak-acid condition and affected by metabolism enzyme; The Peff and Ka significantly different among three concentrations of rosmarinic acid and salvianolic acid B, whose intestinal absorption were saturated in high concentration, suggesting that the transport mechanisms of rosmarinic acid and salvianolic acid B were similar to active transport or facilitated diffusion; However, there was inconspicuousness in the Peff and Ka of salvianolic acid A at different concentrations, whose absorption was not saturated in high concentration, indicating that the transport mechanisms of salvianolic acid A was passive diffusion; The Peff and Ka in the ileum obviously higher than those in the duodenum and jejunum, namely the ileum was the best absorption section; When concentration of borneol increased, the enhancing effect of intestinal absorption of salvianolic acids increased, but significantly decreased when borneol increased to some degree. The enhancing effect of medium borneol concentration was the optimum. This implied that borneol can enhance the intestinal absorption of salvianolic acids, and the capacity of enhancing effect was influenced by the concentration of borneol.