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BACKGROUND: Pregnant women have been excluded from vaccination of COVID-19 due to the lack of strong clinical evidence, which may place pregnant women at greater risk of contracting COVID-19. We conducted this study in China to investigate the maternal and neonatal safety of inactivated COVID-19 vaccination administered during the peri-pregnancy period. METHODS: This prospective observational cohort study enrolled pregnant women who received pregnancy care between January 1, 2021, and December 31, 2021. Pregnant women were categorized into vaccine group (n = 60) and control group (n = 60) based on whether they had received an inactivated COVID-19 vaccine within peri-pregnancy period. The primary outcomes were the incidence of maternal premature rupture of membranes (PROM) and neonatal adverse events, including induced labor/death, premature birth, low birth weight, and neonatal intensive care unit (NICU) admission and several secondary outcomes related to pregnant women and neonates. Inverse probability treatment weighting (IPTW) was employed to adjust for baseline covariates. Linear and logistic regression models were established after IPTW for continuous and binary outcomes, respectively. In sensitivity analysis, E-values were calculated and propensity score matching analysis and multivariate regression analysis used to demonstrate the robustness of IPTW results. Moreover, vaccination time subgroup analysis and medication subgroup analysis were conducted. RESULTS: Out of 120 neonates delivered, there was no significant difference in PROM (25.42 % vs. 19.67 %, p = 0.438) or neonatal adverse events (11.86 % vs. 4.92 %, p = 0.148) between the vaccine and control groups. Moreover, among the secondary outcomes only serum alanine transaminase (ALT) at first trimester had a statistically significant difference between the groups, ALT levels were significantly higher in the vaccine group during the first trimester (20.67 ± 20.34 vs. 13.05 ± 9.43; RR: 5.38; p = 0.04). In sensitivity analysis, the E-values calculated for the primary outcomes PROM and neonatal adverse events are 2.04 and 5.00 respectively. PSM analysis and multivariate regression analysis reached the same conclusion. The results of primary outcomes are both consistent across the vaccination time subgroup and medication subgroup. CONCLUSION: The sensitivity analysis illustrates the robustness of our results, so we can conclude that the vaccination of inactivated COVID-19 vaccine during the peri-pregnancy period is safe for both the pregnant woman and neonates no matter what time of vaccination and the use of medication. In addition, it is recommended to monitor ALT levels throughout the first trimester of pregnancy.

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In this paper, a new type of large-cavity two-anvil ultra-high pressure die structure is proposed to solve the problem that the large-scale of the two-anvil ultra-high pressure die is limited by the difficulty in machining the large-size tungsten carbide. The die is mainly composed of an internal split cylinder with an inner cone and its support ring and the external steel wire winding layer. The stress distribution and cavity dimensional stability of the split cylinder are studied by using the finite element method and compared with those of the integral cylinder. This suggests that although the cavity-dimensional stability of the split ultra-high pressure die is reduced, the split ultra-high pressure die has greater advantages in improving the pressure-bearing capacity, processing, and manufacturing.

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ETHNOPHARMACOLOGICAL RELEVANCE: Fuzi, the lateral roots of Aconitum carmichaelii Debx, plays an irreplaceable role in treating Yang deficiency and cold coagulation syndromes. However, Fuzi has a narrow margin of safety since its pharmacological constituents, Aconitum alkaloids, have potential cardiotoxicity and neurotoxicity. The current quality markers (Q-markers) for the control of Fuzi's efficacy and toxicity are 3 monoester-diterpenoid alkaloids, namely, benzoylaconine (BAC), benzoylhypaconine and benzoylmesaconine (BMA) and 3 diester-diterpenoid alkaloids, namely, aconitine (AC), hypaconitine and mesaconitine (MA). However, mounting evidence indicates that the current 6 Q-markers may not be efficacy- or toxicity-specific enough for Fuzi. AIM OF THE STUDY: The aim of this study was to explore and evaluate efficacy- or toxicity-specific potential quality markers (PQ-markers) of Fuzi. MATERIALS AND METHODS: PQ-markers were explored by analyzing 30 medicinal samples and alkaloids exposed in mouse. Pharmacokinetics of PQ-markers on C57BL/6J mice were determined. Anti-inflammatory effects of PQ-markers were evaluated by λ-carrageenan-induced paw edema model and lipopolysaccharide-induced RAW264.7 cell inflammatory model, while analgesic effects were assessed by acetic acid-induced pain model and Hargreaves test. Cardiotoxicity and neurotoxicity of PQ-markers were assessed by histological and biochemical analyses, while acute toxicity was evaluated by modified Kirschner method. RESULTS: After in vitro and in vivo explorations, 7 PQ-markers, namely, neoline (NE), fuziline (FE), songorine (SE), 10-OH mesaconitine (10-OH MA), talatizamine, isotalatizidine and 16ß-OH cardiopetalline, were found. In the herbal medicines, NE, FE, SE and 10-OH MA were found in greater abundance than many other alkaloids. Specifically, the amounts of NE, FE and SE in the Fuzi samples were all far higher than that of BAC, and the contents of 10-OH MA in 56.67% of the samples were higher than that of AC. In mouse plasma and tissues, NE, FE, SE, talatizamine, isotalatizidine and 16ß-OH cardiopetalline had higher contents than the other alkaloids, including the 6 current Q-markers. The pharmacokinetics, efficacy and toxicity of NE, FE, SE and 10-OH MA were further evaluated. The average oral bioavailabilities of NE (63.82%), FE (18.14%) and SE (49.51%) were higher than that of BMA (3.05%). Additionally, NE, FE and SE produced dose-dependent anti-inflammatory and analgesic effects, and their actions were greater than those of BMA. Concurrently, the toxicities of NE, FE and SE were lower than those of BMA, since no cardiotoxicity or neurotoxicity was found in mice after NE, FE and SE treatment, while BMA treatment notably increased the creatine kinase activity and matrix metalloproteinase 9 level in mice. The average oral bioavailability of 10-OH MA (7.02%) was higher than that of MA (1.88%). The median lethal dose (LD50) of 10-OH MA in mice (0.11 mg/kg) after intravenous injection was close to that of MA (0.13 mg/kg). Moreover, 10-OH MA produced significant cardiotoxicity and neurotoxicity, and notable anti-inflammatory and analgesic effects that were comparable to those of MA. CONCLUSIONS: Seven PQ-markers of Fuzi were found after in vitro and in vivo explorations. Among them, NE, FE and SE were found to be more efficacy-specific than BMA, and 10-OH MA was as toxicity-specific as MA.

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Bulleyaconitine A (BLA), a toxic Aconitum alkaloid, is a potent analgesic that is clinically applied to treat rheumatoid arthritis, osteoarthritis and lumbosacral pain. BLA-related adverse reactions occur frequently, but whether the underlying mechanism is related to its metabolic interplay with drug-metabolizing enzymes remains unclear. This study aimed to elucidate the metabolic characteristics of BLA and its affinity action and mechanism to drug-metabolizing enzymes to reveal whether BLA-related adverse reactions are modulated by enzymes. After incubation with human liver microsomes and recombinant human cytochrome P450 enzymes, we found that BLA was predominantly metabolized by CYP3A, in which CYP3A4 had an almost absolute advantage. In vitro, the CYP3A4 inhibitor ketoconazole noticeably suppressed the metabolism of BLA. In vivo, the AUC0-∞ values, cardiotoxicity and neurotoxicity of BLA in Cyp3a-inhibited mice were all obviously enhanced (P < 0.05) compared to those in normal mice. In the enzyme kinetics study, BLA was found to be a sensitive substrate of CYP3A4, and its characteristics were consistent with substrate inhibition (Km = 39.36 ± 10.47 µmol/L, Ks = 83.42 ± 19.65 µmol/L). BLA was further identified to be a competitive inhibitor of CYP3A4 with Ki = 53.64 µmol/L, since the intrinsic clearance (CLint) of midazolam, a selective CYP3A4 substrate, decreased significantly (P < 0.05) when incubated with BLA together in mouse liver microsomes. Overall, BLA is a sensitive substrate and competitive inhibitor of CYP3A4, and clinical adverse reactions of BLA may mechanistically related to the CYP3A4-mediated drug-drug interactions.

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OBJECTIVE: To observe the clinical efficacy and safety of electroacupuncture (EA) combined with herbal acupoint sticking in the treatment of Bell's palsy and provide optimizations for the clinic. METHODS: One hundred and two cases of Bell's palsy were randomized into an EA combined with herbal acupoint sticking group (group A, 50 cases) and an EA group (group B, 52 cases), EA at Cuanzhu (BL 2), Yangbai (GB 14), Taiyang (EX-HN 5), Quanliao (SI 18),Xiaguan (ST 7), Yingxiang (LI 20), etc. were applied in both groups and "facial paralys No.I " was applied at Yifeng (TE 17) in group A, once daily and 10 times totally were needed. The score of facial nerve function, clinical efficacy were compared before and after treatment. At 1 and 3 month follow up visit, the quality of life scale( WHOQOL-BREF) and the occurrence of complication were observed. RESULTS: The scores of facial nerve function in group A and group B were all significantly improved compared with those before treatment (48. 2+/- 2. 9 vs 25. 7 +/- 4. 9, 45. 9 +/- 6. 2 vs 25. 8 +/- 5. 5, both P0. 05). The occurrence of complication in group A (1 case) was significantly less than that in group B (8 cases, P 0. 05). CONCLUSION: Compared with EA, the combination of EA and acupoint sticking therapy for Bell's palsy cannot only improve the clinical efficacy and reduce the occurrence of complication but also reliable without any side effect.

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Sulfation and glucuronidation are the principal metabolic pathways of flavonoids, and extensive phase II metabolism is the main reason for their poor bioavailabilities. The purpose of this study was to compare the similarities and differences in the positional preference of glucuronidation versus sulfation in the mouse liver S9 fraction. The conjugating rates of seven monohydroxyflavones (HFs) (i.e., 2'-, 3'-, 4'-, 3-, 5-, 6-, and 7-HF), and five dihydroxyflavones (diHFs) (i.e., 6,7-, 4',7-, 3,7-, 5,7-, and 3,4'-diHF) were determined in three separate enzymatic reaction systems: (A) sulfation only, (B) glucuronidation only, or (C) simultaneous sulfation and glucuronidation (i.e., Sult-Ugt coreaction). In general, glucuronidation rates were much faster than sulfation rates. Among the HFs, 7-HF was the best substrate for both conjugation reactions, whereas 3-HF was rapidly glucuronidated but was not sulfated. As a result, the rank order of sulfation was very different from that of glucuronidation. Among the diHFs, regiospecific glucuronidation was limited to 7-OH and 3-OH positions, whereas regiospecific sulfation was limited to 7-OH and 4'-OH positions. Other positions (i.e., 6-OH and 5-OH) in diHFs were not conjugated. The positional preferences were essentially maintained in a Sult-Ugt coreaction system, although sulfation was surprisingly enhanced. Lastly, sulfation and glucuronidation displayed different regiospecific- and substrate-dependent characteristics. In conclusion, glucuronidation and sulfation shared the same preference for 7-OH position (of flavonoids) but displayed unique preference in other positions in that glucuronidation preferred the 3-OH position whereas sulfation preferred the 4'-OH position.

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The present study investigated the involvement of UDP-glucuronosyltransferase and sulfotransferase in the extensive liver and intestinal first-pass glucuronidation and sulfation of flavones in both mice and humans. Seven structurally similar mono- and di-hydroxyflavones were chosen as model compounds. Human liver, C57 mouse liver and intestinal S9 fraction, as well as C57 intestinal perfusion model were used. In human and C57 mouse, all selected flavones were found to be glucuronidated with the highest rates at the 7-OH group. In contrast, flavones with 3-OH group were not sulfated at all. Both glucuronidation and sulfation preferred 4'- and 7-OH in human and mouse in vitro and in situ. There were differences in glucuronidation and sulfation in human and mouse observed for all flavones and it is based on substitutional positions of the hydroxyl groups. The S9 fractions could accurately model glucuronidation (as the slope of correlation curve was 0.7988 for those flavones with 4'- or 7-OH) and sulfation (as the slope of correlation curve was 0.9834) in situ. Conclusively, the sulfation and glucuronidation of the flavones was regiospecific- and speciesdependent. Sulfation and glucuronidation in the mouse intestine in vitro were correlated well with those in situ.

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Hypaconitine (HA), an active and highly toxic constituent derived from Aconitum species, is widely used to treat rheumatism. Little is known about the hepatic cytochrome P450-catalyzed metabolism of HA. The present study investigated the metabolism of HA in vitro using male human liver microsomes (MHLMS). Chemical inhibitors of specific CYP enzymes, CYP-specific inhibitory monoclonal antibodies (mAbs), and cDNA-expressed CYP enzymes were used to confirm the enzyme subtypes involved in the metabolism. Liquid chromatography-high resolution mass spectrometry (LC-MS) was used to detect and identify metabolites. A total of 11 metabolites were identified in MHLMS incubations. The major metabolic pathways included demethylation (M1-M3), demethylation-dehydrogenation (M4-M6), hydroxylation (M7, M8), and didemethylation (M9-M11). M8 was identified as mesaconitine (MA), another active and highly toxic constituent of Aconitum. The results of chemical inhibition, monoclonal antibody inhibition, and cDNA-expressed CYP enzyme studies showed that the primary contributors toward HA metabolism were CYP3A4 and 3A5, with secondary contributions by CYP2C19, 2D6, and CYP2E1. CYP1A2 and 2C8 provided minor contributions.

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OBJECTIVE: To determine the concentration of ginsenoside Rb(2) and study the absorption characteristics of ginsenoside Rb(2) in Caco-2 cell monolayer. METHODS: LC-MS-MS was used to determine the concentration of ginsenoside Rb(2), and the apparent permeability coefficient (P(app)) of ginsenoside Rb(2) was calculated. RESULTS: P(app(AP-BL)) was 3.27 x 10(-7) cm.s(-1), P(app(BL-AP)) was 3.16 x 10(-6) cm.s(-1), and the efflux ratio (P(app(BL-AP))/P(app(AP-BL))) was 9.63. CONCLUSION: The absorption characteristics of ginsenoside Rb(2) in Caco-2 cell model have been demonstrated.

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