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The effect of extended thromboprophylaxis in improving the prognosis of adult patients with coronavirus disease 2019 (COVID-19) after discharge remains debatable. This meta-analysis was aimed to determine the advantages and disadvantages of extended thromboprophylaxis in these patients.Different databases such as PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies that evaluated the effects of extended thromboprophylaxis in post-discharge patients with COVID-19 until 13 June 2022. The primary efficacy outcome was defined by the composite outcome of thromboembolism and all-cause mortality, and the safety outcome was defined by bleeding events. The odds ratios (ORs) and 95 % confidence intervals (CIs) of efficacy and safety outcomes were calculated using fixed- or random-effects model. Interaction analysis was performed to assess and compare observational studies and randomised controlled trials (RCTs). A sensitivity analysis was performed after excluding studies of poor quality.Eight studies involving 10,148 patients were included. The results confirmed that extended thromboprophylaxis, primarily prophylactic use of anticoagulants for35 days, was significantly associated with reduced composite outcome in high-risk post-discharge patients with COVID-19 (OR: 0.52; 95 % CI: 0.41-0.67, P = 0.000). Interaction analysis revealed that the effect estimates were consistent between the RCT and observational studies (PIn post-discharge patients with COVID-19 at high risk of thromboembolism, extended thromboprophylaxis, primarily prophylactic use of anticoagulants for35 days, can significantly reduce the risk of thrombosis and all-cause mortality without increasing the risk of major bleeding events.PROSPERO CRD42022339399.

Sceptridium ternatum is a medicinal herb with multiple health benefits. However, its antioxidant activity and active components have not been clarified. In this study, the antioxidant capacity of S. ternatum was comprehensively investigated using multiple colorimetric methods and 1,1-diphenyl-2-picrylhydrazyl-high-performance liquid chromatography analysis. First, the phenolic content, flavonoid content, and radical scavenging ability of S. ternatum were parallelly determined using colorimetric methods performed in 96-well microplates. The flavonoid content, rather than the phenolic content, was highly correlated with its antioxidant activity. Sceptridium ternatum was shown to be a rich source of flavonoids, with a highest flavonoid yield of 3.44 ± 0.11 mg/g. Subsequently, 1,1-diphenyl-2-picrylhydrazyl-high-performance liquid chromatography experiment and quadrupole time-of-flight mass spectrometry analyses were carried out for rapid screening of the individual antioxidants. A total of 14 O-glycosyl flavonoids with quercetin or kaempferol aglycone have been characterized. Particularly, quercetin 3-O-rhamnoside-7-O-glucoside exhibited the most potent antioxidant ability. Its half-maximal effective concentrations for scavenging 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis (3-ethylbenzthiazoline-6-sulfonic acid) radicals were 70.55 ± 2.69 and 106.90 ± 1.76 µg/mL, respectively, which were comparable with those of l-ascorbic acid. Our results indicated that the combined colorimetric and chromatographic methods provided a practical strategy for the discovery of bioactive compounds from natural products.

Deferoxamine, deferiprone, and deferasirox are used for the treatment of systemic iron overload, although they possess limitations due to lack of oral activity, lower efficacy, and side effects. These limitations led to a search for an orally active iron chelator with an improved therapeutic index. The lower efficacy of deferiprone is due to rapid glucuronidation, leading to the formation of a nonchelating metabolite. Here, we demonstrate that the influence of metabolism can be reduced by introducing a sacrificial site for glucuronidation. A log P-guided investigation of 20 hydroxpyridinones led to the identification of CN128. The Fe(III) affinity and metal selectivity of CN128 are similar to those of deferiprone, the log P value is more lipophilic, and its iron scavenging ability is superior. Overall, CN128 was demonstrated to be safe in a range of toxicity assessments and is now in clinical trials for the treatment of β-thalassemia after regular blood transfusion.

BACKGROUND: Total parenteral nutrition (TPN) is an essential treatment for patients who undergo abdominal surgery. Due to the gap of knowledge background between clinicians and pharmacists, the participation of the latter may improve TPN standardization. However, the impact on clinical outcome is unknown. In this study, we evaluated the impact of appropriacy and efficacy of TPN prescription, after a pharmacist-led TPN standardization program introduced. METHODS: A pharmacist-led TPN standardization program was introduced in the Zhejiang Cancer Hospital and the clinical outcomes were assessed. The TPN standardization program includes a pre-established standard multidisciplinary evaluation standard, a computerized TPN management system and regular evaluations of TPN prescription performed by pharmacists. Any concerns were identified and improved via discussed with doctors. To evaluate the effect of pharmacists’ intervention in nutritional status and postoperative complications, an observational before-and-after cohort study was performed. All patients admitted in hospital with colorectal cancer (CRC) and receiving abdominal surgery in June 2019 (pre-intervention cohort) and June 2020 (post-intervention cohort) were retrospectively analyzed. Nutritional status of patients was evaluated using the levels of postoperative serum albumin, prealbumin, total protein, and their decrease extent. Surgical or TPN-related complications and recovery time were collated as the clinical outcomes. RESULTS: There were no significant differences in the basic clinical information of the two cohorts, suggesting that the two groups are comparable. The average postoperative prealbumin levels were elevated in 2020 compared to 2019 (192.3±5.5 mg/L for 2019 and 229.5±4.8 mg/L for 2020, P

Opioid-tolerant patients are more likely to deviate from recommended treatments and to experience inadequate analgesia than opioid-naive ones. The aim of this study was to examine whether pharmacist-led management could help improve treatment adherence and quality of life.Eligible patients were randomized in a 1:1 ratio to control group and intervention group. The control group received routine education and support, while the intervention group received additional individualized pharmacist-led care. The primary endpoint was treatment adherence in the per-protocol analysis, as evaluated by blinded assessors. An interim analysis was planned when 30% patients completed the study. Alpha was divided into the interim analysis (0.015) and the final analysis (0.035).In the interim analysis (97 and 87 patients in the control and intervention groups, respectively), the primary endpoint was met. Pharmacist-led intervention significantly increased treatment adherence (93.3 vs. 79.8%; OR: 2.25; 95% CI 1.02, 4.94; P = 0.013), quality of life (0.81 ± 0.17 vs. 0.72 ± 0.25; P = 0.008), and reporting of adverse events (82.7 vs. 61.9%; OR: 1.88; 95% CI 1.16, 3.07; P = 0.004). The two groups did not differ in pain control rate (66.7 vs. 57.1%; OR: 1.25; 95% CI 0.87, 1.78; P = 0.218), breakthrough pain-free rate (66.7 vs. 61.9%; OR: 1.12; 95% CI 0.78, 1.59; P = 0.532) and pain score (1.97 ± 1.04 vs. 2.15 ± 1.24; P = 0.522).Pharmacist-led management improved treatment adherence, quality of life, and the reporting of adverse events in opioid-tolerant patients with cancer pain.ClinicalTrials.gov, NCT03455023.

Objective This study aims to investigate the impact of intervention of multidisciplinary team incorporating pharmacists for management of opioid-naive patients with moderate to severe cancer pain. Methods A retrospective cohort study was conducted to compare pre- and post-multidisciplinary intervention groups in opioid-naive patients with moderate to severe cancer pain. Primary outcome was the proportions of appropriate pain assessment and opioid titration. Secondary outcomes were pain intensity (PI), length of hospital stay, opioid escalation index percentage (OEI%) and incidences of opioid-related adverse events. Results A total of 400 patients were included in the study (pre-intervention, n = 200; post-intervention, n = 200). Continuous improvement in pain assessment and titration was recorded after intervention. Though no substantial differences existed between groups in PI on the day of discharge, post-intervention group was associated with reduced length of hospital stay as well as decreased proportion of subjects with OEI% >5%. As for safety, significant decreases in constipation and vomiting were seen. Conclusion Findings suggest that interventions of multidisciplinary team incorporating pharmacists could improve cancer pain management for opioid-naive patients. Pharmacists should be considered as an important member of a multidisciplinary team in good pain management.

Hepatocellular carcinoma (HCC), one of the most dangerous malignancies with an increasing incidence and a high mortality rate, represents a major international health problem. HCC progression is known to involve genome-wide alteration of epigenetic modifications, leading to aberrant gene expression patterns. The activity of CYP2C19, an important member of the cytochrome P450 superfamily, was reported to be compromised in HCC, but the underlying mechanism remains unclear. To understand whether epigenetic modification in HCC is associated with a change in CYP2C19 activity, we evaluated the expression levels of CYP2C19 and its transcription factors by quantitative real-time polymerase chain reaction using mRNA extracted from both primary hepatocytes and paired tumor versus nontumor liver tissues of patients infected with hepatitis B virus (HBV). DNA methylation was examined by bisulfite sequencing and methylation-specific polymerase chain reaction. Our results indicated that CYP2C19 could be regulated by e-box methylation of the constitutive androstane receptor (CAR). Decreased CYP2C19 expression in tumorous tissues of HBV-infected patients with HCC was highly correlated with suppressed expression and promoter hypermethylation of CAR. Our study demonstrates that aberrant CAR methylation is involved in CYP2C19 regulation in HBV-related HCC and may play a role in liver tumorigenesis.

Human cytochrome P450 3A4 (CYP3A4) is the most abundant phase I drug-metabolizing enzyme in the liver, and approximately 50% of drugs on the market are metabolized by CYP3A4. Therefore, many in vitro studies relied on recombinant CYP3A4 as screening tool to evaluate potential drug-drug interactions (DDIs) in vivo. However, limited information regarding recombinant CYP3A4 with high catalytic activity is available. So, the present study aimed to obtain recombinant CYP3A4 with high catalytic activity and to characterize its functions in vitro. To enhance the catalytic activities of heterologously expressed CYP3A4, the enzyme was fused to cytochrome b5 (b5) tail-to-head, and the fused enzyme was inserted together with NADPH–P450 reductase (POR) into a single plasmid to achieve a simultaneous expression in sf9 cells. Here, substrate binding affinities, enzymatic activities and applications in in vitro DDIs of the fused enzyme were investigated. The dissociation constant Kd of POR-cyt b5CYP3A4 was 8.3 ± 0.87 μmol/L, the Clint (Clint=Vmax/Km) was 8.57 mL/min/g protein for POR-cyt b5CYP3A4 in the metabolism of testosterone and 150.3 mL/min/g protein for midazolam. In addition, the inhibitory constant Ki of ketoconazole on testosterone metabolism was 0.013 ± 0.0038 μmol/L. The present results suggested significantly increased substrate binding affinity and enzymatic activity for the fused enzyme. Thus, the construct could be helpful for studying drug metabolisms and DDIs investigation associated with CYP3A4 in vitro. In addition, simultaneous expression of the fused enzyme and POR could provide more reproducible results based on a more stable molar ratio of CYP3A4/POR/b5.

Luteolin (3',4',5,7-tetrahydroxyflavone) and apigenin (4',5,7-trihydroxyflavone) are two common flavones and major bioactive components in Flos Chrysanthemi extract (FCE). Although FCE contains approximately equal amounts of luteolin (6.5%, w/w) and apigenin (5.4%, w/w), luteolin showed a much lower exposure than apigenin when FCE was orally administered to rats. The aim of the present study is to elucidate the mechanisms that caused the pharmacokinetic difference between luteolin and apigenin in rats. The results of an in situ rat intestinal single-pass perfusion model showed that the permeability of luteolin (k(a), 7.96×10⁻² min⁻¹ and P(eff), 4.87×10⁻³ cm/min) was about 50% that of apigenin (k(a), 18.5×10⁻² min⁻¹ and P(eff), 10.8×10⁻³ cm/min), which agreed with the observation that oral bioavailability of luteolin (30.4%) from FCE was significantly lower than that of apigenin (51.1%). On the other hand, luteolin was much more unstable than apigenin during the incubation with primary rat hepatocytes, and methylated metabolites of luteolin were detected after incubation. In addition, further metabolism of methylated luteolin also contributed to the faster elimination of luteolin. In conclusion, luteolin and apigenin are very similar in structure, however, one-hydroxyl difference gives them different characteristics in absorption and metabolism, which results in much lower exposure of luteolin than apigenin when FCE is orally administered to rats.

Scope The study aimed to investigate the regioselectivity of methylation of luteolin (3′,4′,5,7-tetrahydroxyflavone) in human in vitro and in vivo. Methods and results Recombinant human catechol-O-methyltransferase (COMT) and human liver S9 were utilized to study the kinetics of meta (3′)- and para (4′)- methylation of luteolin, and urine samples from volunteers after giving a luteolin-containing formulation were collected to determine the ratio of para-/meta-production. The results showed luteolin favored a para-methylation, with a ratio of of para-/meta-production in CLint (1.43 in recombinant human COMT and 1.47 in human liver S9), which was contrary to the known substrates of COMT. However, the result of urine sample assay showed a preference of meta-methylation with a ratio of of para-/meta-production (0.460 ± 0.126). To elucidate the mechanism for different preference of methylation of luteolin in vitro and in vivo, metabolism stability of the meta- and para-methylated luteolin was evaluated in human liver microsomes and recombinant human CYP450s, which revealed that para-methylated luteolin was more easily demethylated by human CYP1A2 and CYP3A4/5 than meta-methylated luteolin. Conclusion Luteolin was a rare substrate of human COMT favoring a para-methylation, but further demethylation by human CYP1A2 and CYP3A4/5 caused a preference of accumulation in meta-methylated luteolin in vivo.

Flos Chrysanthemi (the flower of Chrysanthemum morifolium Ramat.) is widely used in China as a food and traditional Chinese medicine for many diseases. Luteolin and apigenin are two main bioactive components in Flos Chrysanthemi, and chrysoeriol and diosmetin are two methylated metabolites of luteolin in vivo by cathechol-O-methyltransferase (COMT). However, there was lack of pharmacokinetic information of chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract (FCE). The present study aimed to develop an HPLC-UV method for simultaneous determination of rat plasma concentration of luteolin, apigenin, chrysoeriol and diosmetin and utilize it in pharmacokinetic study of the four compounds after orally giving FCE to rats. The method was successfully validated and applied to the pharmacokinetic study when oral administration of FCE to rats with or without co-giving a COMT inhibitor, entacapone. Chrysoeriol and diosmetin were detected in rat plasma after oral administration of FCE and their concentrations were significantly decreased after co-giving entacapone. Furthermore, AUC of luteolin was significantly increased by entacapone, while that of chrysoeriol was decreased by entacapone, which revealed COMT might play an important role in the disposition of luteolin in rats after dosing of FCE. In conclusion, a sensitive, accurate and reproducible HPLC-UV method for simultaneous determination of luteolin, apigenin, chrysoeriol and diosmetin in rat plasma were developed, pharmacokinetics of chrysoeriol and diosmetin combined with luteolin and apigenin were characterized after oral administration of FCE to rats, which gave us more information on pharmacokinetics and potential pharmacological effects of FCE in vivo., Graphical abstract