Effect of a high-fat meal on the relative bioavailability of HMPL-689 in Chinese healthy volunteers.

The aim of this study was to investigate the effect of a high-fat meal on the single-dose pharmacokinetics (PK) and tolerability of HMPL-689 in Chinese healthy volunteers. In this study, 34 eligible male volunteers received a single 30-mg dose of HMPL-689 capsules following an overnight fast or a high-fat breakfast prior to dosing. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety and tolerability were assessed throughout the study. Total 32 healthy male volunteers were completed in the study. The GMRs of AUC0-t , AUC0-∞ , and Cmax and their 90% CIs were 1.12 (1.09, 1.15), 1.12 (1.09, 1.15), and 0.64 (0.58, 0.70), respectively, in healthy male subjects after oral administration of HMPL-689 following intake of a high-fat diet versus under fasting state. The 90% CI of Cmax GMR fell outside the acceptable equivalent range (0.8-1.25). In addition, the median Tmax of HMPL-689 was 1.0 and 4.0 h under the fasting and the fed conditions. The study indicated that intake of a high-fat diet had an impact on the in vivo PK profile of HMPL-689 in healthy Chinese male subjects, which could obviously reduce the oral absorption rate of HMPL-689 and had little effect on the extent of oral absorption (AUC).

Leymus chinensis resists degraded soil stress by modulating root exudate components to attract beneficial microorganisms.

Phytoremediation is an effective means to improve degraded soil nutrients and soil structure. Here, we investigated the remediation effects of Leymus chinensis on the physicochemical properties and structure of degraded soil after 3 years of cultivation and explored the bacterial and fungal drivers in root exudates by metabolomics and high-throughput sequencing. The results showed that root exudates increased soil organic matter (SOM), total nitrogen (TN), total phosphorus (TP) and soil aggregates, and organic acids in root exudates reduced pH and activated insoluble nutrients into forms that are available to plants, such as available nitrogen (NH4 +-N), nitrate nitrogen (NO3 --N), and available phosphorus (AP). The cultivation of L. chinensis restored the diversity and richness of soil microorganisms and recruited potential beneficial bacteria and fungi to resist degraded soil stress, and L. chinensis also regulated the abundances of organic acids, amino acids and fatty acids in root exudates to remediate degraded soils. Spearman correlation analysis indicated that glutaric acid, 3-hydroxybutyric acid and 4-methylcatechol in root exudates attracted Haliangium, Nitrospira and Mortierella to the rhizosphere and dispersed the relative abundance of the harmful microorganisms Fusicolla and Fusarium. Our results demonstrate that L. chinensis enhances soil fertility, improves soil structure, promotes microbial diversity and abundance, and recruits potentially beneficial microorganisms by modulating root exudate components.

Biochemical Process and Microbial Evolution in the Conversion of Corn Straw Combined with Coal to Biogas.

The combined anaerobic fermentation of coal and straw can increase the production of biogas. To explore the mechanism of adding corn straw to increase methane production, coal with different metamorphic degrees and corn straw were collected for biogas production simulation experiments under different substrate ratios. The changes in liquid products, the structure of lignocellulose in corn straw, and microbial evolution were monitored. The results showed that the combined fermentation of bituminous coal A with corn straw and bituminous coal C with corn straw at a mass ratio of 2:1 each ((AC-2) and (CC-2)) and that of bituminous coal B and corn straw at a mass ratio of 3:1 (BC-3) had the best gas production, and methane yields reached 17.28, 12.51, and 14.88 mL/g, respectively. The fermentation liquid had organic matter with more types and higher contents during the early and peak stages of gas production, and fewer types of organic matter were detected in the terminal stage. The degradation of lignocelluloses in the corn straw of AC-2 was higher. With the increase in fermentation time, the carbohydrates in the fermentation system increased and the degradation rate of cellulose decreased gradually. The abundance of genes related to nitrate reduction gradually increased, while that of sulfate reduction was on the contrary. Bacteria in the cofermentation system mainly metabolized carbohydrates. During cofermentation with high metamorphic coal, corn straw would be preferentially degraded. The structure of the archaea community changed from Methanosarcina and Methanothrix to Methanobacterium.

Leymus chinensis Adapts to Degraded Soil Environments by Changing Metabolic Pathways and Root Exudate Components.

Phytoremediation is a promising remediation strategy for degraded soil restoration. Root exudates are the main carrier substances for information communication and energy transfer between plant roots and soil, which play non-negligible roles in the restoration process. This work investigated the adaptation of Leymus chinensis root exudates to different degraded levels of soil and the mechanism of rhizosphere restoration in a 3-year degraded soil field study. We found that the soil quality at each degradation level significantly increased, with the soil organic matter (SOM) content slightly increasing by 1.82%, moderately increasing by 3.27%, and severely increasing by 3.59%, and there were significant increases in the contents of available nutrients such as available phosphorus (AP), ammonia nitrogen (AN), and nitrate nitrogen (NN). The physiological activities indicated that root tissue cells also mobilize oxidative stress to respond to the soil environment pressure. A total of 473 main components were obtained from root exudates by gas chromatography-time-of-flight mass spectrometry (GC-TOFMS), including acids, alcohols, carbohydrates, and other major primary metabolites. OPLS-DA revealed that soil degradation exerted an important influence on the metabolic characteristics of root exudates, and the numbers of both up- and downregulated metabolic characteristic peaks increased with the increase in the degree of degradation. Forty-three metabolites underwent clear changes, including some defense-related metabolites and osmotic adjustment substances that were significantly changed. These changes mainly mobilized a series of lipid metabolism pathways to maintain the fluidity of membrane function and help plants adapt to unfavorable soil environmental conditions. The PPP energy metabolism pathway was mobilized in response to slight degradation, and TCA energy pathways responded to the environmental pressure of severe soil degradation.

Amino Acid-Mediated Synthesis of the ZIF-8 Nanozyme That Reproduces Both the Zinc-Coordinated Active Center and Hydrophobic Pocket of Natural Carbonic Anhydrase.

The zeolitic imidazolate framework-8 (ZIF-8) nanozyme has been synthesized using hydrophobic amino acid (AA) to regulate crystal growth. The as-synthesized ZIF-8 reproduces both the structural and functional properties of natural carbonic anhydrase (CA). Structurally, Zn2+/2-methylimidazole coordinated units mimic very well the active center of CA while the hydrophobic microdomains of the adsorbed AA simulate the CA hydrophobic pocket. Functionally, the nanozymes show excellent CA-like esterase activity by giving specific enzyme activity of 0.22 U mg-1 at 25 °C in the case of Val-ZIF-8. More strikingly, such nanozymes are superior to natural CA by having excellent hydrothermal stability, which can give highly enhanced esterase activity with increasing temperature. The specific enzyme activity of Val-ZIF-8 at 80 °C is about 25 times higher than that at 25 °C. In addition, AA-ZIF-8 also shows an excellent catalytic efficiency toward carbon dioxide (CO2) hydration. This study puts forward the important role of hydrophobic microdomains in biomimetic nanozymes for the first time and develops a facile and mild method for the synthesis of nanozymes with controlled morphology and size to achieve excellent catalytic efficiency.

Safety and tolerability of high-dose ulinastatin after 2-hour intravenous infusion in adult healthy Chinese volunteers: A randomized, double-blind, placebo-controlled, ascending-dose study.

Ulinastatin, is a broad-spectrum protease inhibitor purified from human urine, inhibits endogenous proteases such as trypsin, α-chymotrypsin, hyaluronidase, and plasmin. It is widely being used at increasingly higher doses for the treatment of acute or chronic pancreatitis, severe infection, and acute organ failure. We aimed to evaluate the safety and tolerability of high-dose ulinastatin in healthy volunteers in our single center, randomized, double-blind, placebo-controlled, single-dose escalation study. Fifty-one healthy Chinese subjects were enrolled in 9 dose cohorts (3×105 U, 6×105 U, 12×105 U, 20×105 U, 30×105 U, 45×105 U, 60×105 U, 70×105 U, or 80×105 U of ulinastatin) and randomized to UTI or matching placebo (n = 1). Each dose cohort was composed of 3-7 subjects. All subjects were required to have 2 h of intravenous infusion. Safety and tolerability were assessed throughout the study via monitoring of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and interviews with the subjects about adverse events. Fifty-one subjects (35 men and 16 women) completed the study. A total of 13 AEs were reported by 10 subjects: 11 adverse events in the ulinastatin groups and 2 adverse events in the placebo group. Twelve of the adverse events were possibly related to the study drug. The most common drug-related adverse events included dizziness, pain at injection site, and a decrease in white blood cell count. All adverse events were of mild severity; none were serious. In conclusion, 2 hours of intravenous infusion of ulinastatin (3×105 to 80×105 U) was well tolerated by healthy Chinese subjects.

Pharmacokinetics and tolerability of Tenofovir disoproxil fumarate 300 mg once daily: an open-label, single- and multiple-dose study in healthy Chinese subjects.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been approved worldwide for the treatment of adults with chronic hepatitis B and, in combination with other antiretroviral agents, HIV-1 infection. Although its use for the treatment of HIV has been approved by the Chinese State Food and Drug Administration, there are no data on the pharmacokinetic profile of TDF in Chinese individuals. OBJECTIVES: This study aimed to investigate the pharmacokinetic properties and tolerability of TDF in healthy Chinese subjects. METHODS: This open-label, single- and multiple-dose study was conducted in healthy Chinese volunteers. Subjects received TDF 300 mg once daily, administered as a single dose (day 1) and multiple doses (days 4-10). Multiple plasma samples were collected over time, and the concentrations of TDF were determined using LC-MS/MS. Pharmacokinetic parameters were estimated using a noncompartmental model. Tolerability was determined using clinical evaluation and monitoring of adverse events (AEs). RESULTS: Fourteen volunteers were enrolled (7 men, 7 women; mean age, 24.6 years). TDF was rapidly absorbed; median Tmax was 0.75 hour, and t½ was ~21 hours with single dosing. The mean ratio of AUC0-τ steady state/AUC0-24 single dose was 1.55. The pharmacokinetic properties of TDF were consistent between the single dose and multiple doses, and between men and women. No serious AEs were reported, and there were no discontinuations due to AEs. CONCLUSIONS: There was an accumulation of approximately 55% in tenofovir exposure in healthy Chinese between multiple dose and single dose. TDF exhibited a pharmacokinetic profile similar to that of healthy Western subjects in a historical comparison. TDF was generally well tolerated in these healthy Chinese subjects. ClinicalTrials.gov identifier: NCT01480622.

Tablets based on compressed zein microspheres for sustained oral administration: design, pharmacokinetics, and clinical study.

In our previous study, we reported a novel tablet based on compressed zein microspheres as a universal drug delivery system using the hydrophobic protein zein, which shows zero-order release in the presence of pepsin. However, this formulation had difficulty with disintegration under physiological conditions within 48 h, and thus could not be used directly for oral administration. In the present study, a formulation of ivermectin (IVM) tablets based on compressed zein microspheres was improved as a new dosage form. The plasma disposition pharmacokinetics of IVM tablets based on compressed zein microspheres after oral administration was studied over a 7-day period with six dogs (Canis familiaris), using a commercial IVM tablet (5 mg/piece, Yilijia(®) ) as a control. Clinical efficacy was tested using 270 dogs presented as veterinary patients for the treatment of demodicidosis. A formulation with disintegration time within 15 min could be obtained. The acquired C( max), T(max), and AUC were 9.89 ± 0.34 ng/mL, 11.33 ± 2.63 h, and 883.87 ng h/mL for IVM tablets based on compressed zein microspheres and 9.64 ± 1.05 ng/mL, 7.26 ± 2.09 h, and 666.30 ng h/mL for Yilijia(®), respectively. The bioavailability of the tablets based on compressed zein microspheres was 132.65% that of Yilijia( ®). Efficacy for the dogs in all the IVM tablets based on compressed zein microspheres-treated groups reached 100% at 7, 14, and 21 days post administration.