The purpose of this study was to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of frunexian (formerly known as EP-7041 and HSK36273) injection, a small molecule inhibitor of activated coagulation factor XI (FXIa), in healthy Chinese adult volunteers. This study was a randomized, placebo- and positive-controlled, sequential, ascending-dose (0.3/0.6/1.0/1.5/2.25 mg/kg/h) study of 5-day continuous intravenous infusions of frunexian. Frunexian administration exhibited an acceptable safety profile with no bleeding events. Steady state was rapidly reached with a median time ranging from 1.02 to 1.50 h. The mean half-life ranged from 1.15 to 1.43 h. Frunexian plasma concentration at a steady state and area under the concentration-time curve exhibited dose-proportional increases. The dose-escalation study of frunexian demonstrated its progressively enhanced capacities to prolong activated partial thromboplastin time (aPTT) and inhibit FXIa activity. The correlations between PK and PD biomarkers (aPTT/baseline and FXI clotting activity/baseline) were described by the two Emax models, with the EC50 values of 8940 and 1300 ng/mL, respectively. Frunexian exhibits good safety and PK/PD properties, suggesting it is a promising candidate for anticoagulant drug.
Anticoagulants , Blood Coagulation , Adult , Humans , Partial Thromboplastin Time , Healthy Volunteers , China , Double-Blind Method , Dose-Response Relationship, Drug
The traditional charcoal technique was used to determine the changes in the key aroma compounds of Tan mutton during the roasting process. The results showed that the samples at the different roasting time were distinguished using GC-MS in combination with PLS-DA. A total of 26 volatile compounds were identified, among which 14 compounds, including (E)-2-octenal, 1-heptanol, hexanal, 1-hexanol, heptanal, 1-octen-3-ol, 1-pentanol, (E)-2-nonenal, octanal, 2-undecenal, nonanal, pentanal, 2-pentylfuran and 2-methypyrazine, were confirmed as key aroma compounds through the odor activity values (OAV) and aroma recombination experiments. The OAV and contribution rate of the 14 key aroma compounds were maintained at high levels, and nonanal had the highest OAV (322.34) and contribution rate (27.74%) in the samples after roasting for 10 min. The content of α-helix significantly decreased (P < 0.05), while the ß-sheet content significantly increased (P < 0.05) during the roasting process. The content of random coils significantly increased in the samples roasted for 0-8 min (P < 0.05), and then no obvious change was observed. At the same time, ß-turn content had no obvious change. Correlation analysis showed that the 14 key aroma compounds were all positively correlated with the content of α-helix and negatively correlated with the contents of ß-sheet and random coil, and also positively correlated with the content of ß-turn, except hexanal and 2-methypyrazine. The results are helpful to promoting the industrialization of roasted Tan mutton.
The key aroma compounds and water distribution of the beef at different roasting times (0, 3, 6, 9, 12, 15, and 18 min) were identified and analyzed. The results showed that the L * value increased considerably before peaking and then decreased. On average, a * values decreased significantly first and then kept stable, while b * values increased first and then decreased. A total of 47 odorants were identified in all samples, including 14 alcohols, 18 aldehydes, 6 ketones, 1 ester, 3 acids, 4 heterocyclic compounds, and 1 other compound. Among them, 11 key aroma compounds were selected and aldehydes and alcohols predominantly contributed to the key aroma compounds. The fluidity of the water in the beef during the roasting process was decreased, and the water with a high degree of freedom migrated to the water with a low degree of freedom. The correlation analysis showed that water content and L * were negatively correlated with key aroma compounds of the samples, while M 21 was positively correlated with key aroma compounds.
Taking the eutectic point as the final freezing temperature, the differences of flavor substances of in hand grab mutton (HGM) frozen at three rates of 0. 26 cm/h (-18°C), 0.56 cm/h (-40°C) and 2.00 cm/h (-80°C) were determined and analyzed. The results showed that the flavor of HGM decreased significantly after freezing. With the increase of freezing rate, the contents of aldehydes, alcohols, ketones, acids, esters, others, free amino acids and 5'-nucleotides were higher, and the content of specific substances was also generally increased. All samples from unfrozen and frozen HGM could be divided into four groups using an electronic nose based on different flavor characteristics. Seven common key aroma components were determined by relative odor activity value (ROAV), including hexanal, heptanal, octanal, nonanal, (E)-oct-2-enal, (2E,4E)-deca-2,4-dienal and oct-1-en-3-ol. The higher the freezing rate, the greater the ROAVs. Taste activity values calculated by all taste substances were far <1, and the direct contribution of the substances to the taste of HGM was not significant. The equivalent umami concentration of HGM frozen at -80°C was the highest. These findings indicated that higher freezing rate was more conducive to the retention of flavor substances in HGM, and the flavor fidelity effect of freezing at -80°C was particularly remarkable.
