Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension.

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 µCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.

Impact of dietary supplementation with N-carbamoyl-aspartic acid on serum metabolites and intestinal microflora of sows.

BACKGROUND: N-Carbamoyl-aspartic acid (NCA) is a critical precursor for de novo biosynthesis of pyrimidine nucleotides. To investigate the cumulative effects of maternal supplementation with NCA on the productive performance, serum metabolites and intestinal microbiota of sows, 40 pregnant sows (∼day 80) were assigned into two groups: (1) the control (CON) and (2) treatment (NCA, 50 g t-1 NCA). RESULTS: Results showed that piglets from the NCA group had heavier birth weight than those in the CON group (P < 0.05). In addition, maternal supplementation with NCA decreased the backfat loss of sows during lactation (P < 0.05). Furthermore,16S-rRNA sequencing results revealed that maternal NCA supplementation decreased the abundance of Cellulosilyticum, Fournierella, Anaerovibrio, and Oribacterium genera of sows during late pregnancy (P < 0.05). Similarly, on the 14th day of lactation, maternal supplementation with NCA reduced the diversity of fecal microbes of sows as evidenced by significantly lower observed species, Chao1, and Ace indexes, and decreased the abundance of Lachnospire, Faecalibacterium, and Anaerovorax genera, while enriched the abundance of Catenisphaera (P < 0.05). Untargeted metabolomics showed that a total of 48 differentially abundant biomarkers were identified, which were mainly involved in metabolic pathways of arginine/proline metabolism, phenylalanine/tyrosine metabolism, and fatty acid biosynthesis, etc. CONCLUSION: Overall, the results indicated that NCA supplementation regulated intestinal microbial composition of sows and serum differential metabolites related to arginine, proline, phenylalanine, tyrosine, and fatty acids metabolism that may contribute to regulating the backfat loss of sows, and the birth weight and diarrhea rate of piglets. © 2022 Society of Chemical Industry.

Effect of different dosages of sodium butyrate and niacin on growth, faecal microbiota and Vitamin B metabolism in weaned piglets.

AIMS: Our study aimed to evaluate the effects of different dosages of sodium butyrate and niacin on the growth performance, faecal Vitamin B and microbiota in weaned piglets. METHODS AND RESULTS: Seventy-two weaned piglets (Duroc × Landrace × Yorkshire, age of 21 days) were randomly assigned to one of six treatments (12 pigs/treatment); the control (CT) group was administered a basal diet. The groups in which concentration ratios of sodium butyrate to niacin were 100: 1, 100: 2, 100: 4, 100: 8 and 100: 16 (BN1, BN2, BN4, BN8 and BN16) were administered a basal diet supplemented with 2000 mg kg-1 sodium butyrate and 20, 40, 80, 160 or 320 mg·kg-1 niacin. After 14-day treatment, the samples were collected. The results showed that feed conversion rate (FCR) was reduced and average daily gain (ADG) was increased in BN2 (p < 0.05). The diarrhoea index of pigs decreased with the low supplement. Additionally, compared with the CT group, other groups significantly increased (p < 0.05) the abundance of Firmicutes (BN4, phylum), Lactobacillaceae (BN8, family), Megasphaera (BN8, genus) and Lactobacillus (BN8, genus). Furthermore, the sodium butyrate and niacin supplementation influence Vitamin B1, Vitamin B2, pyridoxine, niacin, nicotinamide and Vitamin B12 (p < 0.05). Correlation analysis of the association of micro-organisms with Vitamin B indicated that changes of Vitamin B metabolism have a potential correlation with alterations of faecal microbiota in weaned piglets. CONCLUSIONS: The results indicated that adding sodium butyrate and niacin in the diet could promote the performance and improve the faecal microbiota and Vitamin B metabolism in weaned piglets. SIGNIFICANCE AND IMPACT OF THE STUDY: Our study might provide clues to the research of correlations between faecal bacteria and faecal Vitamin B, and these findings will contribute to the direction of future research in weaned piglets.

Safety, tolerability, and pharmacokinetics of VV116, an oral nucleoside analog against SARS-CoV-2, in Chinese healthy subjects.

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmax increased in an approximately dose-proportional manner in the dose range of 25-800 mg. T1/2 was within 4.80-6.95 h. In MAD, the accumulation ratio for Cmax and AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmax and AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

Phase I dose escalation and pharmacokinetic study on the nanoparticle formulation of polymeric micellar paclitaxel for injection in patients with advanced solid malignancies.

Background Polymeric micellar paclitaxel (PM-paclitaxel) is a novel Cremophor EL-free, nanoparticle-encapsulated paclitaxel formulation administered through intravenous injection. The primary objective of this phase I trial was to determine the first cycle dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of PM-paclitaxel. Secondary objectives included the evaluation of the safety, antitumor activity, and pharmacokinetic (PK) profile of PM-paclitaxel in patients with advanced malignancies. Methods The PM-paclitaxel dose was escalated from 175 mg/m2 (level 1) to 435 mg/m2 (level 5). PM-paclitaxel was intravenously administered to patients for 3 h without premedication on day 1 of a 21-day cycle. Results Eighteen patients with confirmed advanced malignancies received PM-paclitaxel. DLT included grade 4 neutropenia (four patients) and grade 3 numbness (one patient), which occurred in one of the six patients who received 300 mg/m2 (level 3) PM-paclitaxel and all three patients who were treated with 435 mg/m2 PM-paclitaxel. Thus, the MTD of PM-paclitaxel was determined as 390 mg/m2 (level 4). Acute hypersensitive reactions were not observed. Partial response was observed in six of 18 patients (33.3%), three of whom had prior exposure to paclitaxel chemotherapy. The peak concentration and area under the curve values of paclitaxel increased with increasing dosage, indicating that PM-paclitaxel exhibits linear PKs. Conclusions PM-paclitaxel showed high MTD without additional toxicity, and exhibited desirable antitumor activity. The recommended dose of PM paclitaxel for phase II study is 300 mg/m2.

Proteomics analysis reveals a potential new target protein for the lipid-lowering effect of Berberine8998.

Berberine8998 is a newly synthesized berberine derivative with better lipid-lowering activity and improved absorption. The objective of this study was to investigate the effects of berberine8998 on serum cholesterol and lipid levels in vivo and to examine the mechanisms involved. Hamsters on high-fat diet (HFD) were administered berberine or berberine8998 (50 mg·kg-1·d-1, ig) for 3 weeks. Berberine8998 administration significantly lowered the total cholesterol, triglycerides and LDL-C levels in HFD hamsters. Bioinformatics revealed that berberine and berberine8998 shared similar metabolic pathways and fatty acid metabolism was the predominant pathway. Western blot validation results showed that peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) and long-chain fatty acid-CoA ligase 1 (ACSL1), two proteins involved in fatty acid metabolism, were expressed differently in the berberine8998 group than in the untreated group and the berberine treatment group. Biochemistry results showed that berberine8998 significantly lowered the non-esterified fatty acid (NEFA) levels, which may lead to a reduction in TG levels in the berberine8998 treatment group and the differences observed in proteomics analyses. Pharmacokinetic analysis conducted in rats. After administration of berberine or berberine8998 (50 mg/kg, ig), berberine8998 exhibited a remarkably improved absorption with increasing bioavailability by 6.7 times compared with berberine. These findings suggest that berberine8998 lowers cholesterol and lipid levels via different mechanisms than berberine, and its improved absorption makes it a promising therapeutic candidate for the treatment of hypercholesterolemia and obesity.

Population pharmacokinetic modeling and simulation of huperzine A in elderly Chinese subjects.

AIM: Our preliminary results show that huperzine A, an acetylcholinesterase inhibitor used to treat Alzheimer's disease (AD) patients in China, exhibits different pharmacokinetic features in elderly and young healthy subjects. However, its pharmacokinetic data in elderly subjects remains unavailable to date. Thus, we developed a population pharmacokinetic (PPK) model of huperzine A in elderly Chinese people, and identified the covariate affecting its pharmacokinetics for optimal individual administration. METHODS: A total of 341 serum huperzine A concentration records was obtained from 2 completed clinical trials (14 elderly healthy subjects in a phase I pharmacokinetic study; 35 elderly AD patients in a phase II study). Population pharmacokinetic analysis was performed using the non-linear mixed-effect modeling software Phoenix NLME1.1.1. The effects of age, gender, body weight, height, creatinine, endogenous creatinine clearance rate as well as drugs administered concomitantly were analyzed. Bootstrap and visual predictive checks were used simultaneously to validate the final population pharmacokinetics models. RESULTS: The plasma concentration-time profile of huperzine A was best described by a one-compartment model with first-order absorption and elimination. Age was identified as the covariate having significant influence on huperzine A clearance. The final PPK model of huperzine A was: CL (L/h)=2.4649(*)(age/86)((-3.3856)), Ka=0.6750 h(-1), V (L)=104.216. The final PPK model was demonstrated to be suitable and effective by the bootstrap and visual predictive checks. CONCLUSION: A PPK model of huperzine A in elderly Chinese subjects is established, which can be used to predict PPK parameters of huperzine A in the treatment of elderly AD patients.

Determination of the novel antiarrhythmic drug sulcardine sulfate in human plasma by liquid chromatography tandem mass spectrometry and its application in a clinical pharmacokinetic study.

Sulcardine sulfate (Sul), a novel antiarrhythmic agent, is currently in phase I and phase II clinical trials. To elucidate its clinical pharmacokinetic characteristics, a rapid and accurate liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed and validated for the quantification of Sul in human plasma. Plasma samples were precipitated by acetonitrile and isotope-labeled sulcardine was added as internal standard. The analysis was carried out on a Capcell Pak C18 MG III column (100 × 2.0 mm, 5 µm) with 0.1% formic acid in acetonitrile solution and water (17:83, v/v) as mobile phase. The linear range was 5.0-1000 ng/mL for Sul, with a lower limit of quantification of 5.0 ng/mL. The intra- and inter-batch CVs were within ±11.0% and the accuracies were 4.9-107.3%. Our method, for the first time, allows the rapid (only 3.0 min) and accurate quantification of Sul in human plasma. The method has been successfully applied in the pharmacokinetic study of Sul in a clinical trial following oral administration of Sul to healthy volunteers. Copyright © 2016 John Wiley & Sons, Ltd.

Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized, single-blind, crossover study.

AIM: To investigate the QT/QTc effects of orally administered moxifloxacin in healthy Chinese volunteers. METHODS: This was a single-blinded, randomized, single-dose, placebo-controlled, two-period cross-over study. A total of 24 healthy Chinese volunteers were enrolled, randomly assigned to two groups: one group received moxifloxacin (400 mg, po) followed by placebo with a 7-d interval, another group received placebo followed by moxifloxacin with a 7-d interval. On the days of dosing, 12-lead 24 h Holter ECGs were recorded and evaluated by an ECG laboratory blind to the treatments. Blood samples were collected to determine plasma concentrations of moxifloxacin. RESULTS: The orally administered moxifloxacin significantly prolonged the mean QTc at all time points except 0.5 h post-dose. The largest time-matched difference in the QTcI was 8.35 ms (90% CI: 5.43, 11.27) at 4 h post-dose. The peak effect on QTcF was 9.35 ms (90% CI: 6.36, 12.34) at 3 h post-dose. A pharmacokinetic-QTc model suggested a 2.084 ms increase in the QTc interval for every 1000 ng/mL increase in plasma concentration of moxifloxacin. In addition, the orally administered moxifloxacin was well tolerated by the subjects. CONCLUSION: Orally administered moxifloxacin significantly prolongs QTc, which supports its use as a positive control in ICH-E14 TQT studies in Chinese volunteers.

Pharmacokinetics of trantinterol and its metabolite in healthy elderly and young subjects.

OBJECTIVE: The aim of this study was to investigate and compare the pharmacokinetics of trantinterol and its active amphoteric carboxylic acid metabolite (1-carbonyl trantinterol) between the healthy elderly and young subjects. METHODS: This was a single-center, open-label, parallel-group study completed by 22 healthy subjects (≥65 years (the elderly group); 18-45 years (the young group); 9 males and 2 females per age group) receiving single oral dose of 50 µg trantinterol tablets. Blood samples were taken at intervals up to 48 hours post-dose. RESULTS: In both groups, maximum plasma concentration of trantinterol was researched at 0.9 hours, while the tmax of 1-carbonyl trantinterol differed slightly. Trantinterol Cmax and AUClast were higher in the elderly group than the young group, by 27% (90% CI, 0.95-1.69) and 77% (90% CI, 1.25-2.51), respectively. For 1-carbonyl trantinterol, Cmax, and AUClast were also higher, by 36% (90% CI, 1.04-1.78) and 71% (90% CI, 1.27-2.30), respectively, in the elderly group. The CL/F and V/F of trantinterol and 1-carbonyl trantinterol were significantly lower in the elderly group, while t1/2 of both did not show significant differences. CL/F of trantinterol and 1-carbonyl trantinterol were found to significantly correlate inversely with age, and positively with the baseline creatinine clearance. CONCLUSIONS: A single dose of 50 µg trantinterol was well tolerated. Significant changes in Cmax and AUC of trantinterol and 1-carbony trantinterol were seen in the elderly and may be clinically important.

A replicate designed bioequivalence study to compare two fixed-dose combination products of artesunate and amodiaquine in healthy chinese volunteers.

Artesun-Plus is a fixed-dose combination antimalarial agent containing artesunate and amodiaquine. The current study was conducted to compare the pharmacokinetic and safety profiles of Artesun-Plus and the WHO-designated comparator product Artesunate Amodiaquine Winthrop. To overcome the high intrasubject variability of artesunate, the study applied a two-sequence and four-period crossover (2 by 4), replicate study design to assess bioequivalence between the two products in 31 healthy male Chinese volunteers under fasting conditions. The results showed that the values of the geometric mean ratios of maximum concentration of drug in plasma (Cmax) and area under the concentration-time curve from time zero to the last blood sample collection (AUC0-last) for the artesunate component in the test and reference products were 95.9% and 93.9%, respectively, and that the corresponding 90% confidence intervals were 84.5% to 108.7% and 87.2% to 101.1%, while the geometric mean ratios for the amodiaquine component in the test and reference products were 95.0% and 100.0%, respectively, and the corresponding 90% confidence intervals were 86.7% to 104.1% and 93.5% to 107.0%. In conclusion, bioequivalence between the two artesunate and amodiaquine fixed-dose combination products was demonstrated for both components. The study also confirmed high intrasubject variability, especially for artesunate: the coefficients of variation (CV) of Cmax values for the test and reference products were 39.2% and 43.7%, respectively, while those for amodiaquine were 30.6% and 30.2%, respectively.

A novel automated multi-cycle magnetic solid-phase extraction coupled to LC-MS/MS to study the disorders of six functional B vitamins in patients with gastroenterology and hyperhomocysteinemia.

B vitamins are essential for human life and their disorders can cause a variety of diseases. Solid-phase extraction (SPE) coupled to LC-MS/MS is a preferred technique for determining multiple B vitamins, however, their complexity in real biological matrices makes it hard to achieve satisfactory recovery and accuracy when simultaneous detection. In this study, a novel automated multi-cycle magnetic SPE (MSPE) coupled to the LC-MS/MS method was established using a mixed-mode anion exchange magnetic adsorbent for the simultaneous extraction of six functional B vitamins, including methylmalonic acid, riboflavin, pantothenic acid, 4-pyridoxic acid, folic acid, and 5-methyltetrahydrofolate. After three consecutive MSPE cycles, the recoveries of all analytes were between 51.5% and 89.6%. The method exhibited excellent sensitivity and linearity, with a dynamic range of 200-fold (R > 0.99 for all analytes), exceptional accuracy (ranging between 95.4% and 105.6%) and precision (with RSDs ≤ 6.2%) without significant matrix effects or interferences. Compared to manual SPE method, the automated multi-cycle MSPE method has better feasibility and greater vitamin coverage. It shows a high correlation with the manual method for the detection of 5-methyltetrahydrofolate and folate (R > 0.99). A study of patients from the gastroenterology department showed that those undergoing surgery and those with malignancies may be at risk of folate deficiency. In addition, patients with hyperhomocystinemia had higher levels of methylmalonic acid and lower levels of 5-methyltetrahydrofolate, which correlated with homocysteine levels (R = 0.404 and -0.311, respectively) and showed dose-response relationships. This method is highly automated and cost-effective, with minimal systematic error, making it suitable for the analysis of clinical samples.

Phase I study on the pharmacokinetics and tolerance of ZT-1, a prodrug of huperzine A, for the treatment of Alzheimer's disease.

AIM: Huperzine A isolated from the Chinese herb Huperzia serrata (Thunb) Trev is a novel reversible and selective AChE inhibitor. The aim of this study was to evaluate the pharmacokinetics and tolerance of single and multiple doses of ZT-1, a novel analogue of huperzine A, in healthy Chinese subjects. METHODS: This was a double-blinded, placebo-controlled, randomized, single- and multiple-dose study. For the single-dose study, 9 subjects were randomly divided into 3 groups receiving ZT-1 (0.5, 0.75 or 1 mg, po) according to a Three-way Latin Square Design. For the multiple-dose study, 9 subjects receiving ZT-1 (0.75 mg/d, po) for 8 consecutive days. In the tolerance study, 40 subjects were randomly divided into 5 groups receiving a single dose of ZT-1 (0.5, 0.75, 1, 1.25 or 1.5 mg, po). Plasma and urine concentrations of ZT-1 and Hup A were determined using LC-MS/MS. Pharmacokinetic parameters, including Cmax, AUC0-72 h and AUC0-∞ were calculated. Tolerance assessments were conducted throughout the study. RESULTS: ZT-1 was rapidly absorbed and converted into huperzine A, thus the plasma and urine concentrations of ZT-1 were below the limit of quantification (<0.05 ng/mL). After single-dose administration of ZT-1, the mean tmax of huperzine A was 0.76-0.82 h; the AUC0-72 h and Cmax of huperzine A showed approximately dose-proportional increase over the dose range of 0.5-1 mg. After the multiple-dose administration of ZT-1, a steady-state level of huperzine A was achieved within 2 d. No serious adverse events were observed. CONCLUSION: ZT-1 is a pro-drug that is rapidly absorbed and converted into huperzine A, and ZT-1 is well tolerated in healthy Chinese volunteers.

Hair analysis, a reliable and non-invasive method to evaluate the contamination by clenbuterol.

The illegal use of clenbuterol has been an increasingly serious issue in today's livestock products industry. It becomes an important project to develop a reliable approach to detect its content in food animals. A simple and sensitive LC-MS/MS method was developed to detect clenbuterol residue in hair, with the low limit of quantitation (LLOQ) about 0.5ng/g. Hogs fed with 340µg/day of clenbuterol for 2 weeks were found a high clenbuterol residue in their hair approximately at 1-2 months after withdrawal. There remained 3.31ng/g clenbuterol in hog hair approximately 5 months after the last administration, focused on the tip of the hair (mainly in hogs with dark hair). An extensive contamination was observed in twenty investigated market hogs whose dark hair obviously had a higher clenbuterol residue than the light ones (p=0.017, t test). Volunteers (60.3 percent) from Xuhui district (Shanghai) were found to have a detectable amount of clenbuterol in their hair (>0.5ng/g). In conclusion, hair residue detection is a reliable method to evaluate the clenbuterol contamination in animals and humans. Meat supply in the Xuhui district might have serious potential safety risks which should be further investigated and discussed to determine the safety range of clenbuterol residue.

Dietary nucleotides influences intestinal barrier function, immune responses and microbiota in 3-day-old weaned piglets.

Nucleotides (NTs) play a pivotal role in the growth and development of the intestine. This study aimed to evaluate the effects of nucleotides supplementation on the intestinal barrier function, immune responses and microbiota in 3-day-old weaned piglets. Ninety-six piglets weaned at 3-days after birth were randomly assigned to 2 treatments (6 replicates/treatment, 8 piglets/replicate) according to the average body weight. The dietary treatments consisted of the control (CON; fed a basal artificial milk) and nucleotides groups (NT; fed a basal artificial milk with 0.035 % nucleotides, the contents of CMP, UMP, AMP, GMP, and IMP were 1:1:1:1:1, respectively). Diarrhea rates were recorded, and blood and intestinal samples were collected on day 35 of the piglets. The current study showed that NTs supplementation tended to decrease the diarrhea rate of weaned piglets (P < 0.10). NTs increased villus height and the villus height-to-crypt depth (V/C) ratio in the ileum (P < 0.05). Dietary NTs up-regulated protein expression of ZO-1 in ileal mucosa (P < 0.05), and the protein expression of Occludin tended to increase. Furthermore, NTs up-regulated the mRNA expression of Mucin (MUC)2, while the mRNA expression of MUC4 was down-regulated in the ileal mucosa (P < 0.05). Besides, supplementation with NTs increased the ileal mucosa genes expression of IL-21, INF-γ, IL-10, IL-4, IL-6 and TNF-α (P < 0.05). Furthermore, dietary NTs increased the protein expression of NF-κB, IL-6 and TNF-α (P < 0.05), and the proteins expression of Occludin and p-NF-κB tended to be up-regulated in the ileal mucosa (P < 0.10). Furthermore, NTs supplementation increased short chain fatty acid in the colonic (P < 0.05). And NTs supplementation reduced the Firmicutes/Bacteroidota ratio in the colon, at the genus level, NTs enriched the relative abundance of Prevotella, Faecalibacterium and Olsenella (P < 0.05). These data indicate that NTs could increase the villus height, increase the V/C, regulate the expression of tight junction protein and mucin, improve the intestinal barrier of piglets, regulate the secretion of cytokines, improve the biological immunity, increase the abundance of beneficial bacteria, and thus reduce the diarrhea of piglets.

Effects of Maternal Dietary Enteromorpha prolifera Polysaccharide Iron Supplement on Mineral Elements and Iron Level of Neonatal Piglets.

Iron plays a key role in maternal health during pregnancy and fetal growth. Enteromorpha polysaccharide-iron (EP-Fe) as an organic iron chelate may improve the iron transmission of mother and offspring, ameliorate the poor pregnancy outcomes of sows, and alleviate the growth restriction of piglets caused by iron deficiency. This study aimed to evaluate the effects of maternal dietary supplementation with EP-Fe on reproductive performance and placental iron transmission of sows, as well as growth performance of piglets. Sixty pregnant sows at the 95th day of gestation were randomly divided into control group and EP-Fe group (EP-Fe, 139 mg kg-1). Blood samples of sows and neonatal piglets, colostrum, and tissue samples were collected on the day of delivery. The animal experiment ended at the 21st day of post-delivery. Results showed that maternal dietary EP-Fe increased colostrum iron (P < 0.05) of sows, as well as final litter weight (P < 0.05) and average daily weight of piglets (P < 0.05) during days 1-21 of lactation, as well as iron and manganese content in umbilical cord blood (P < 0.05) and hepatic iron of neonatal piglets (P < 0.01), and decreased fecal iron (P < 0.001), serum calcium (P < 0.05), phosphorus (P < 0.05), and zinc (P < 0.01) in the parturient sow. RT-qPCR results showed that Fpn1 and Zip14 in placenta, as well as TfR1 and Zip14 in duodenum of neonatal piglets, were activated by maternal EP-Fe supplement. These findings suggest that maternal dietary EP-Fe could increase iron storage of neonatal piglets via improving placental iron transport and iron secretion in colostrum, thus enhancing the growth performance of sucking piglets.

Effect of visceral fat area on the accuracy of preoperative CT-N staging of colorectal cancer.

OBJECTIVE: To investigate the effect of visceral fat area (VFA) on the accuracy of preoperative CT-N staging of colorectal cancer. METHODS: We retrospectively reviewed the clinical and imaging data of 385 CRC patients who underwent surgical resection for colorectal cancer between January 2018 and July 2021. Preoperative CT-N staging and imaging features were determined independently by two radiologists. Using postoperative pathology as the gold standard, patients were divided into accurately and incorrectly staged groups, and clinical and imaging characteristics were compared between the two groups. VFA and subcutaneous fat area (SFA) at the L3 vertebral level, sex, age, BMI, tumor location, size, and tumor circumference ratio (TCR) were included. Logistic regression analysis was used to evaluate the independent factors influencing the accuracy of preoperative N staging of colorectal cancer. RESULTS: Of the 385 patients enrolled, 259 (67.27%) were in the preoperative N-stage accurate staging group, and 126 (32.73%) were in the incorrectly staged group. Univariate analysis showed that there were significant differences in BMI, tumor location, VFA, SFA, size and TCR between the two groups (P<0.05). Logistic regression analysis showed that VFA (95% CI: 1.277, 3.813; P=0.005) and TCR (95% CI: 1.649, 17.545; P=0.005) were independent factors affecting the accuracy of N staging. The optimal cutoff points for VFA and TCR in predicting incorrect staging were 110 cm2 and 0.675, respectively. CONCLUSIONS: Colorectal cancer patients with lower VFA and higher TCR and preoperative CT-N staging had an increased risk for diagnostic errors.

Safety and immunogenicity of a modified COVID-19 mRNA vaccine, SW-BIC-213, as a heterologous booster in healthy adults: an open-labeled, two-centered and multi-arm randomised, phase 1 trial.

BACKGROUND: We assessed the safety and immunogenicity of a core-shell structured lipopolyplex (LPP) based COVID-19 mRNA vaccine, SW-BIC-213, as a heterologous booster in healthy adults. METHODS: We conducted an open-labeled, two-centered, and three-arm randomised phase 1 trial. Healthy adults, who had completed a two-dose of inactivated COVID-19 vaccine for more than six months, were enrolled and randomized to receive a booster dose of COVILO (inactivated vaccine) (n = 20) or SW-BIC-213-25µg (n = 20), or SW-BIC-213-45µg (n = 20). The primary study endpoint was adverse events within 30 days post-boosting. The secondary endpoint was the titers of binding antibodies and neutralizing antibodies against the wild-type (WT) of SARS-CoV-2 as well as variants of concern in serum. The exploratory endpoint was the cellular immune responses. This trial was registered with http://www.chictr.org.cn (ChiCTR2200060355). FINDINGS: Between Jun 6 and Jun 22, 2022, 60 participants were enrolled and randomized to receive a booster dose of SW-BIC-213 (25 µg, n = 20, or 45 µg, n = 20) or COVILO (n = 20). The baseline demographic characteristics of the participants at enrollment were similar among the treatment groups. For the primary outcome, injection site pain and fever were more common in the SW-BIC-213 groups (25 µg and 45 µg). Grade 3 fever was reported in 25% (5/20) of participants in the SW-BIC-213-45µg group but was resolved within 48 h after onset. No fatal events or adverse events leading to study discontinuation were observed. For secondary and exploratory outcomes, SW-BIC-213 elicited higher and longer humoral and cellular immune responses than that in the COVILO group. INTERPRETATION: SW-BIC-213, a core-shell structured lipopolyplex (LPP) based mRNA vaccine, was safe, tolerable, and immunogenic as a heterologous booster in healthy Chinese adults. FUNDING: Shanghai Municipal Government, the Science and Technology and Economic Commission of Shanghai Pudong New Area, and mRNA Innovation and Translation Center of Shanghai.

Pharmacokinetics and tolerance of dehydroandrographolide succinate injection after intravenous administration in healthy Chinese volunteers.

AIM: Dehydroandrographolide succinate (DAS) is extracted from herbal medicine Andrographis paniculata (Burm f) Nees. DAS injection is used in China for the treatment of viral pneumonia and upper respiratory tract infections. The aim of this study is to investigate the pharmacokinetics and tolerance of DAS injection in healthy Chinese volunteers. METHODS: This was a single-center, randomized, single-dose, three-way crossover design study. Nine eligible subjects were randomly divided into 3 groups, and each group sequentially received 80, 160, or 320 mg of DAS infusion according to a three-way Latin square design. Plasma and urine samples were collected and determined using an LC-MS/MS method. Safety and tolerability were determined via clinical evaluation and adverse event monitoring. RESULTS: For the 80, 160, and 320 mg dose groups, the mean C(max) were 4.82, 12.85, and 26.90 mg/L, respectively, and the mean AUC(0-12) were 6.18, 16.95, and 40.65 mg·L(-1)·h, respectively. DAS was rapidly cleared, with a mean T(max) of 0.94-1.0 h and a t(1/2) of approximately 1.51-1.89 h. Approximately 10.1%-15.5% of the intravenous DAS dose was excreted unchanged in urine within 24 h in the 3 groups, and more than 90% of unchanged DAS was excreted between 0 and 4 h. The pharmacokinetic profile was similar between male and female subjects. No serious or unexpected adverse events were found during the study, but one mild adverse event (stomachache) was reported. CONCLUSION: This study shows that DAS has nonlinear pharmacokinetic characteristics. To guarantee the effective concentration, mul¬tiple small doses are recommended in clinical regimens.

Maternal pyrimidine nucleoside supplementation regulates fatty acid, amino acid and glucose metabolism of neonatal piglets.

Pyrimidine nucleosides (PN) are abundant in mammalian milk and mainly involved in glycogen deposition and lipid metabolism. To investigate the effects of maternal supplementation with pyrimidine nucleoside on glucose, fatty acids (FAs), and amino acids (AAs) metabolism in neonatal piglets. Forty pregnant sows were randomly assigned into the control (CON) group (fed a basal diet, n = 20) or the PN group (fed a basal diet supplemented with PN at 150 g/t, n = 20). Litter size, born alive and birth litter weight were recorded. The serum and placenta of sows, and jejunum and liver of neonatal piglets were sampled. The results indicated that supplementing sow diets with PN decreased birth mortality and increased the birth weight of piglets (P < 0.05). In addition, neonates from sows supplemented with PN had higher glucose levels in serum and liver compared with the CON group (P < 0.05). Moreover, maternal PN supplementation regulated the ratio of saturated FAs and polyunsaturated FAs, and AAs content in serum and liver of piglets (P < 0.05). Furthermore, an up-regulation of mRNA expression of genes related to glucose and AA transport were observed in the neonatal jejunum from the PN group (P < 0.05). Additionally, hepatic protein expressions of phosphorylated hormone-sensitive lipase (P-HSL), HSL, sterol regulatory element-binding transcription factor 1c (SREBP-1c), and phosphorylated protein kinase B (P-AKT) was higher in the piglets from the PN group than the CON group (P < 0.05). Together, maternal PN supplementation may regulate nutrient metabolism of neonatal piglets by modulating the gene expression of glucose and AA transporters in placenta and jejunum, and the gene and protein expression of key enzymes related to lipid metabolism in liver of neonatal piglets, which may improve the reproductive performance of sows.