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Amis Sacubitril/Valsartan is now becoming the class one recommendation for HFrEF. Some studies have shown the positive effect of Sacubitril/Valsartan on HFrEF cancer patients, while there is devoid of evidence about the effect of this drug in aged cancer patients with HFmrEF and HFpEF. We did this retrospective study to investigate the beneficial effect of Sacubitril/Valsartan on all three kinds of HF patients with cancer in the aged population. Method and results By searching the patients with a diagnosis of both cancer and heart failure over 65, the patients who had received treatment with Sacubitril/Valsartan were selected as the candidates for Sacubitril/Valsartan group, and the patients who had received conventional HF therapy without Sacubitril/Valsartan were chosen as the control group. Data were collected for up to 9 months. We filtered 38 patients and 50 patients valid for Sacubitril/Valsartan group and control group, respectively. After initiation of heart failure management, our study found a better cardiac condition in Sacubitril/Valsartan group, having better LVEF, LVFS, NT-proBNP in 3rd, 6th, 9th month (PConclusion Our study further indicated that Sacubitril/Valsartan can improve cardiac function and benefit cardiac remolding in aged cancer patients of all three kinds of HF. As we know, this is the first study to provide new evidence for the use of Sacubitril/Valsartan in aged cancer patients of all three kinds of HF.

A cocktail therapy comprising bismuth drugs and N-acetyl-l-cysteine is reported to suppress the replication of SARS-CoV-2 via the oral route. The broad-spectrum inhibitory activities of the combination upon key viral cysteine enzymes are verified.

Information on master's programs in the pharmaceutical sciences is lacking; this manuscript addresses this gap in the literature, by reporting on the results of an international survey performed in 2021 of master's programs in the pharmaceutical sciences offered at Schools/Colleges of Pharmacy. Ninety-six responses were received from universities from 23 countries, with the greatest number of responses obtained from India, followed by the United States and Japan. Master's programs in the pharmaceutical sciences are generally full time and 2 years in duration. Only 3% of programs were reported to be examination-based, while the remaining 97% had a research component with 70% of programs having a thesis defense with external and/or internal examiners. Master's programs tended to be larger in Asia and Europe than in North America; as well, programs in North America tended to have more international students. Didactic coursework was included in 96% of master's programs in North America, but only in 38% of Asian and 58% of European programs. The predominant placement of graduates from master's programs in Asia was in the pharmaceutical industry (70%); this contrasted with programs in Europe, Africa and North America where 28-36% enter careers in the pharmaceutical industry and higher percentages enter Ph.D. programs. The major challenge identified by programs was funding of faculty and of graduate students, although decreasing career opportunities was identified as a challenge in Asia and Africa.

This publication represents the first to report global information on characteristics and requirements of doctoral programs in the pharmaceutical sciences in schools/colleges of Pharmacy. Survey responses (140 responses) were received from doctoral programs in 23 countries, with the greatest number of responses obtained from Japan, followed by India and the United States. Program characteristics and requirements, and student and faculty information, including graduate placement, in programs in Asia, North America, Europe, Africa and Australia were compared. Survey responses indicated differences in entrance requirements for doctoral programs with minimum requirements being a bachelor's degree, pharmacy degree or master's degree, including a M.Phil. degree. Programs differed widely in size in all geographical areas, but there was a similar emphasis on core educational learning outcomes (core competencies) and Ph.D. graduation requirements including qualifying examinations, thesis defense with internal and external reviewers and requirements for peer-reviewed publications. Additionally, three-quarters of programs indicated that there was external review of their programs every 2-4 or 5-7 years. Female students and female faculty mentors represented about 50% of students/faculty in programs in most geographical areas. Placement of students after graduation indicated that the highest percentage went into the pharmaceutical industry in Asia (predominantly India) and North America, with a lower percentage in Europe, Africa and Australia.

Although Polygoni Multiflori Radix (PMR) has been widely used as a tonic and an anti-aging remedy for centuries, the extensively reported hepatotoxicity and potential kidney toxicity hindered its safe use in clinical practice. To better understand its toxicokinetics, the current study was proposed, aiming to evaluate the biodistributions of the major PMR components including 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucopyranoside (TSG), emodin, emodin-8-O-β-D-glucopyranoside (EMG) and physcion as well as their corresponding glucuronides following bolus and multiple oral administrations of PMR to rats. Male Sprague-Dawley rats received a bolus dose or 21 days of oral administrations of PMR concentrated granules at 4.12 g/kg (equivalent to 20.6 g/kg raw material). Fifteen minutes after bolus dose or the last dose on day 21, rats were sacrificed and the blood, liver, and kidney were collected for the concentration determination of both parent form and glucuronides of TSG, emodin, EMG, and physcion by HPLC-MS/MS. Among all the tested analytes, TSG, EMG, EMG glucuronides in liver and TSG, EMG, as well as all the glucuronides of these analytes in the kidney demonstrated the most significant accumulation after multiple doses. Moreover, the levels of the parent analytes were all significantly higher in liver and kidney in comparison to their plasma levels. Strong tissue binding of all four analytes and accumulation of TSG, EMG, and EMG glucuronides in the liver and TSG, EMG, as well as the glucuronides of all four analytes in the kidney after multiple dosing of PMR were considered to be associated with its toxicity.

Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with high metastasis and lethality. Arrestin domain-containing 4 (ARRDC4) is involved in inhibiting cancer glycolytic phenotypes. Brusatol (BR), extracted from Bruceae Fructus, exerts good anti-cancer effects against a number of cancers.In the present study, we aimed to explore the efficacy of BR on inhibiting CRC metastasis and elucidate the underlying mechanisms involving the upregulation of the ARRDC4 expression.Cell viability, colony formation, wound healing and transwell assay were used to detect the anti-proliferative and anti-metastatic effects of BR against CRC in vitro. Microarray analysis was performed to find out differential genes in CRC cells after treatment with BR. Analysis of the CRC patients tumor samples and GEPIA database were first conducted to identify the expression of ARRDC4 on CRC. Stable overexpression and knockdown of ARRDC4 CRC cells were established by lentiviral transfection. The role of ARRDC4 in mediating the anti-metastatic effects of BR on CRC was measured using qRT-PCR, western blotting, immunohistochemical and immunofluorescence analysis. Orthotopic xenograft and pulmonary metastasis mouse models of CRC were established to determine the anti-cancer and anti-metastatic effects of ARRDC4 and BR.BR markedly suppressed the cell proliferation, migration, invasion and inhibited tumor growth and tumor metastasis. Microarray analysis demonstrated that BR treatment markedly increased the gene expression of ARRDC4 in CRC cells. ARRDC4 was significantly repressed in CRC in the clinical samples and GEPIA analysis. ARRDC4 overexpression plus BR produced better inhibitory effects on CRC metastasis than BR treatment alone, while ARRDC4 knockdown could partially eliminate the inhibitory effects of BR against CRC metastasis. BR exerted anti-metastatic effects against CRC via upregulating ARRDC4 and inhibiting epithelial-mesenchymal transition (EMT) processing through modulating PI3K/Hippo pathway.This study reported for the first time that BR is a potent ARRDC4 agonist, and is worthy of further development into a new therapeutic strategy for CRC.

In this work, a series of novel 1,2,4-triazole derivatives with selenium-containing hydrophobic side chains were designed and synthesized based on the structure of lanosterol 14α-demethylase (CYP51). All compounds were characterized by HRMS

Introduction: As of 2020, breast cancer has become the leading cause of cancer incidence worldwide, and chemotherapy based on anthracycline is an important component of breast cancer treatment. Anthracycline-based drugs are known to cause cardiac toxicity and arrhythmia in breast cancer treatment. This is the first clinical quantitative analysis to accurately assess the incidences of arrhythmia and arrythmia subtypes and abnormal electrocardiogram (ECG) changes, providing data to support clinical drug use and drug monitoring. Methods: We systematically searched CNKI, VIP, Wanfang and other Chinese databases, PubMed, Embase, Web of Science, Cochrane Library and other English databases.The random effect model or fixed effect model was used to calculate the incidence of combined arrhythmias in breast cancer patients and the associated heterogeneity. STATA16 was used for statistical analysis. Results: A total of 37 articles were included in this study, including 5705 breast cancer patients treated with anthracyclines, of whom 2257 developed arrhythmias. Meta-analysis showed that the incidence of anthracycline-associated arrhythmias in breast cancer patients was 0.41 (0.37, 0.44). Subgroup analysis showed that the incidence of QT-QTc interphase change was 0.08 (0.05, 0.11), that of P wave change was 0.10 (0.05, 0.15), that of ST-T segment change was 0.19 (0.15, 0.23), and that of QT-QTc interphase change was 0.08 (0.05, 0.11). The incidence of low voltage abnormalities was 0.05 (0.03, 0.08). In addition, according to the subgroup analysis of arrhythmia subtypes, the incidence of conduction block was 0.04 (0.02, 0.05), the incidence of heart rate changes was 0.12 (0.10, 0.15), the incidence of premature beats was 0.09 (0.07, 0.11), and the incidence of atrial fibrillation was 0.04 (0.00, 0.12). Conclusion: The overall incidence of anthracycline-associated arrhythmias in breast cancer treatment was 0.41. ST-T segment was the most common ECG change. The results of this study are of great significance for guiding postoperative chemotherapy for and monitoring of breast cancer patients. Trial registration: The study has been registered in the international prospective register of systematic reviews(PROSPERO). Registration No.: CRD42022321213.

Xianyu Zhang, Min Mao, Zhong Zuo Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Zhong Zuo, Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, No. 1, Medical College Road, Yuzhong District, Chongqing, 400016, People’s Republic of China, Email zuozhong@hospital.cqmu.edu.cnPurpose: To establish an in vitro lipotoxicity model with mouse cardiomyocytes (MCMs) and investigate the molecular mechanism of the peroxisome proliferator-activated receptors (PPAR) signaling on mitochondrial energy metabolism disorder and cellular injury in diabetic cardiomyopathy (DCM).Methods: Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the differentially expressed genes (DEGs) of DCM. CCK-8 method was used to detect the proliferation inhibition effect of palmitate (PA) on MCMs. Oil red O staining and mRNA levels of CD36 were used to verify intracellular lipid accumulation. DCFH-DA method was used to determine the content of intracellular reactive oxygen species (ROS), and ATP levels were detected by the ATP Detection Kit. Transmission electron microscope (TEM) was used to observe the mitochondrial structure. Western blot was used to detect the expression levels of PPARα, PPARγ, P-mTOR, mTOR, PGC-1α, UCP2, and BNP. In addition, the expression of PPARγ was also detected by cellular immunofluorescence staining. BNP levels were detected by qRT-PCR and the ELISA Kit.Results: KEGG pathway analysis combined with GO analysis has shown that PPAR signaling played a significant regulatory role in mitochondrial biogenesis and fatty acid metabolism in DCM. Then, MCMs stimulated with PA for 24 h were selected as an in vitro lipotoxicity model. PA decreased cell viability, cell membrane shrinkage, and lipid accumulation. Meanwhile, PA-induced increase in cellular ROS led to ATP generation reduction and mitochondrial damage. Furthermore, the expression levels of p-mTOR- PPARα/γ were decreased, and the expressions of PGC-1α and UCP2 were increased. The levels of BNP were elevated, demonstrating PA impaired cardiomyocytes.Conclusion: Mitochondrial energy metabolism obstacle and cell injury appeared in cardiac lipotoxicity of DCM, associated with lipid accumulation and increased ROS, indicating a crosstalk with the PPAR pathway mediated mechanism.Keywords: diabetic cardiomyopathy, lipotoxicity, mitochondrial energy metabolism, cell damage, PPAR

Optical activity (OA) spectroscopy is a powerful tool to characterize molecular chirality, explore the stereo-specific structure and study the solution-state conformation of biomolecules, which is widely utilized in the fields of molecular chirality, pharmaceutics and analytical chemistry. Due to the considerably weak effect, OA spectral analysis has high demands on measurement speed and sensitivity, especially for organic biomolecules. Moreover, gas-phase OA measurements require higher resolution to resolve Doppler-limited profiles. Here, we show the unmatched potential of dual-comb spectroscopy (DCS) in magnetic optical activity spectroscopy (MOAS) of gas-phase molecules with the resolution of hundred-MHz level and the high-speed measurement of sub-millisecond level. As a demonstration, we achieved the rapid, high-precision and high-resolution MOAS measurement of the nitrogen dioxide $${\upsilon }_{1}$$ υ 1 +$${\upsilon }_{3}$$ υ 3 band and the nitric oxide overtone band, which can be used to analyze fine structure of molecules. Besides, the preliminary demonstration of liquid-phase chiroptical activity (as weak as 10−5) has been achieved with several seconds of sampling time, which could become a routine approach enabling ultrafast dynamics analysis of chiral structural conformations.

Background and purpose Altered drug pharmacokinetics is a significant concern in non-alcoholic steatohepatitis (NASH) patients. Although high-fat high-cholesterol (HFHC) diet-induced NASH (HFHC-NASH) rats could simulate the typical dysregulation of cholesterol in NASH patients, experimental investigation on the altered drug pharmacokinetics in this model are limited. Thus, the present study comprehensive investigates the nature of such altered pharmacokinetics using simvastatin as the model drug. Experimental approach Pharmacokinetic profiles of simvastatin and its active metabolite simvastatin acid together with compartmental pharmacokinetic modelling were used to identify the key factors involved in the altered pharmacokinetics of simvastatin in HFHC-NASH rats. Experimental investigations via in situ single-pass intestinal perfusion and intrahepatic injection of simvastatin were carried out. Histology, Ces1 activities and mRNA/protein levels of Oatp1b2/CYP2c11/P-gp in the small intestine/liver of healthy and HFHC-NASH rats were compared. Key results Reduced intestinal absorption and more extensive hepatic elimination in HFHC-NASH rats resulted in less systemic exposures of simvastatin/simvastatin acid. In the small intestine of HFHC-NASH rats, thicker intestinal wall with more collagen fibres, increased Ces1 activity and up-regulated P-gp protein decreased the permeability of simvastatin, accelerated the hydrolysis of simvastatin and promoted the efflux of simvastatin acid respectively. In the liver of HFHC-NASH rats, higher hepatic P-gp expression accelerated the hepatic elimination of simvastatin. Conclusion and implications Altered histology, Ces1 activity and P-gp expression in the small intestine/liver were identified to be the major contributing factors leading to less systemic exposure of drugs in HFHC-NASH rats, which may be applicable to NASH patients.

Although in-vivo bioequivalence (BE) study serves as a golden standard for establishing interchangeability of oral dosage forms, it remains challenging for products with high inter-subject variability such as mesalazine enteric-coated tablet to fulfil the BE criteria set by regulatory authorities. Mesalazine, as a BCS class IV drug, targets to be delivered to distal ileum or colon with a pH-sensitive polymer coating for the remission of ulcerative colitis. Through population pharmacokinetic (PK) analysis and in-vitro in-vivo correlation (IVIVC) modeling on the dissolution and BE data of a generic enteric-coated product (EM) and its reference Salofalk® 250 mg tablet (SM), we for the first time revealed the underlying mechanism of the high inter-subject variability for such delayed-release formulation. It was also noted that the in-vivo start time of absorption (T

Designing anode materials with high lithium specific capacity is crucial to the development of high energy-density lithium ion batteries. Herein, a distinctive lithium growth mechanism, namely, the restricted multilayered growth for lithium, and a strategy for lithium storage are proposed to achieve the balance between the ultra-high specific capacity and the need to avert uncontrolled dendritic growth of lithium. In particular, based on first-principles computation, we show that the Al2C monolayer with planar tetracoordinate carbon structure can be an ideal platform for realizing the restricted multilayered growth mechanism as a 2D anode material. Furthermore, the Al2C monolayer exhibits ultra-high specific capacity of lithium of 4059 mAh/g, yet with a low dif-fusion barrier of 0.039-0.17 eV as well as low open circuit voltage in the range of 0.002-0.34 V. These novel properties endow the Al2C monolayer a promising anode material for future lithium ion batteries. Our study offers a new way to design promising 2D anode materials with high specific capacity, fast lithium-ion diffusion, and safe lithium storage mechanism.

The processed lateral root of Aconitum carmichaelii Debx. is known as Fuzi, an extensively used Traditional Chinese Medicine to treat cardiovascular diseases, rheumatism arthritis, bronchitis, pains, and hypothyroidism, etc. Although Chinese Pharmacopeia regulates the safe clinical dosage of Fuzi at 3-15 g/person/day, such recommendation not only lacks bench evidence but also does not differentiate Fuzi with different processing types, such as Heishunpian and Paofupian.The current study aimed to 1) determine No-Observed-Adverse-Effect-Levels of Heishunpian and Paofupian in rats and 2) investigate the related toxicity mechanisms for their safe clinical use.After giving clinically relevant dosing regimen of Heishunpian/Paofupian to rats, we conducted toxicity assessments including ECG monitoring, histopathological changes and serum biomarkers to detect organ injury. Metabolomic study in the liver revealed changes in endogenous metabolite levels after two-week treatment of Fuzi preparations or its corresponding six toxic alkaloids mixtures.The NOAEL for both bolus and two-week treatments of Heishunpian and Paofupian in rats was designated to be 7.5 g/kg and 15 g/kg, respectively. Corresponding recommended doses in humans were 7.5-25 g/person/day for Heishunpian and 15-50 g/person/day for Paofupian. Metabolic profiles revealed more significant alterations in endogenous substances from rats receiving the two Fuzi preparations than their corresponding toxic alkaloids mixtures. Upregulation of bile acid pathway could be responsible for Fuzi induced liver injury.Compared to the current maximum recommended dose, our suggested upper limit of guided dose for Heishunpian was comparable, whereas that for Paofupian could be further elevated. Both C

We demonstrate three typical mode-locking processes of a nonlinear amplifying loop mirror (NALM) fiber laser via a general nonlinear Schrödinger equation-based (GNLSE) simulation model. First, the pulse evolutions in the NALM cavity were separately simulated under asymmetric and weakly asymmetric conditions. We found that the splitting ratio and positions of the gain fiber can result in a suitable phase bias between clockwise and counter-clockwise beams, enabling the realization of a self-starting low-threshold operating condition. To assess the roles of the splitting ratio and gain in the mode-locking process, we simulated three pulse formation processes: in the soliton, stretched-pulse, and dissipative soliton mode-locking regimes. The simulation results show that the splitting ratio, gain, and dispersion directly influence the mode-locking condition and pulse characteristics, thereby providing effective quantified guidance for high-quality pulse generation. Finally, an experimental NALM oscillation operating under stretched pulse conditions was established to investigate the impact of the splitting ratio and pump power on the pulse characteristics. The experimental results prove that the splitting ratio, gain, and dispersion can be used to manipulate the mode-locking threshold, self-starting threshold, nonlinear effects, and pulse characteristics.

Herein, we report the design, synthesis and evaluation of a novel series of diselenide and selenide derivatives as potent antifungal agents by exploiting the hydrophobic cleft of CYP51. Among all synthesized compounds, the most potent compound B01 with low cytotoxic and hemolysis effect exhibited excellent activity against C.alb., C.gla., C.par. and C.kru., as well as selected fluconazole-resistant strains. Moreover, compound B01 could reduce the biofilm formation of the FCZ-resistant C.alb. Subsequently, metabolic stability assays using liver microsomes demonstrated that compound B01 showed good profiles of metabolic stability. With superior pharmacological profile, compound B01 was advanced into in vivo bioactivity evaluation. In a murine model of systemic C.alb. infection, compound B01 significantly reduced fungal load of kidneys. Furthermore, compound B01 revealed relatively low acute toxicity and subacute toxicity in mice. In addition, docking study performed into C.alb. CYP51, showed the binding mode between C.alb. CYP51 and compound B01. Collectively, diselenides compound B01 can be further developed for the potential treatment of invasive fungal infections.

The concurrent use of conventional drugs and herbal medicines is becoming popular among patients with cancer. However, the potential risk of herb-drug interactions (HDI) remains under-addressed in the literature. Previous reviews have mainly focused on the prevalence of interactions, with less attention paid to the methods used by pharmacoepidemiological studies on evaluating HDI. This scoping review aims to summarize the existing pharmacoepidemiological studies that evaluate HDI using real-world data and to identify gaps to be addressed in future research.A comprehensive search was performed in nine English- and Chinese-language databases from their inception to May 2021. Gray literature and manual searches were conducted to identify additional studies. The recommended components of the pharmacoepidemiological studies and key findings related to HDI were summarized. The proportion (%) of patients with cancer at risk of HDI was estimated by combining data from eligible studies.Twenty-eight studies were included in the review. More than half of these studies were cross-sectional studies (n = 18, 64.3%), followed by retrospective cohort studies (n = 5, 17.9%) and prospective cohort studies (n = 2, 7.1%). The three cancer drugs most commonly studied for their interaction potential with herbs were tamoxifen (n = 11, 39.3%), cyclophosphamide (n = 6, 21.4%), and paclitaxel (n = 6, 21.4%). Most cross-sectional studies identified potential HDI using tertiary databases and primary literature searches. Conversely, prospective and retrospective studies mainly investigated actual clinical outcomes, such as adverse events and secondary cancer occurrences. Most interaction outcomes identified using real-world data did not lead to negative clinical consequences. Collectively, 45.4% of herbal medicine users of the included studies were found to be at risk of HDI. We infer from this review that the common limitations of these studies were limited sample size, lack of data on herbal medicine use and details of HDI, and lack of evidence of HDI. Based on the study limitations, several recommendations to enrich the data sources and optimize the study designs were proposed.There is a high demand for pharmacoepidemiological research on HDI, considering the increasing popularity of herbal medicine among patients with cancer. It is anticipated that emerging real-world data in this field can guide the development of safe and effective approaches to integrative oncology.

Dual-comb spectroscopy (DCS) is a powerful spectroscopic technique, which is developing for the detection of transient species in reaction kinetics on a short time scale. Conventionally, the simultaneous determination of multiple species is limited to the requirement of broadband spectral measurement at the cost of the measurement speed and spectral resolution owing to the inherent trade-off among these characteristics in DCS. In this study, a high-speed multi-molecular sensing is demonstrated and achieved through using a programmable spectrum-encoded DCS technique, where multiple narrow encoding spectral bands are reserved selectively and other comb lines are filtered out. As a dual-comb spectrometer with a repetition rate of 108 MHz is encoded spectrally over a spectral coverage range of 1520 to 1580 nm, the measurement speed is increased 6.15 times and single-shot absorption spectra of multiple molecules (C2H2, HCN, CO, CO2) at a time scale of 208 µs are obtained. Compared to conventional single-shot dual-comb spectra, encoded dual-comb spectra have improved short-term signal-to-noise ratios (SNRs) by factors of 3.65 with four encoding bands and 5.68 with two encoding bands. Furthermore, a fiber-Bragg-grating-based encoded DCS is demonstrated, which reaches 17.1 times higher average SNR than that of the unencoded DCS. This spectrum-encoded technique can largely improve the DCS measurement speed, and thus is promising for use in studies on multi-species reaction kinetics.

Updated data referring to efficacy and safety of crizotinib therapy have been presented. We reported a rare case of the 71-year-old elder heavy smoker with ALK-rearranged advanced lung adenocarcinoma. Within 7 months of crizotinib treatment, the giant lung tumor disappeared, and a complete response was achieved. The case illustrates exemplarily that crizotinib is effective and manageable as a first-line treatment in advanced NSCLC with ALK rearrangement. It also implies that the elder heavy smoker with such rare “god-given” ALK rearrangement might benefit more from ALK inhibitor.

The extrauterine adenomyoma is rare and it is extremely rare outside the pelvic cavity. Herein, we reported the first case of a single extrauterine adenomyoma occurring in the lesser omentum.This case involved a 55-year-old woman who had undergone subtotal gastrectomy and omentectomy for gastric carcinoma. During postoperational pathological examination, 1 lymph node-like mass was coincidentally found in the lesser omentum. The patient had a history of hysterectomy for uterine leiomyoma 8 years ago.The resected 17 "lymph nodes" from the lesser omentum were routinely checked for possible metastasis of gastric carcinoma. One of lymph node-like mass was microscopically showed that it was composed of benign smooth muscle components, endometrial glands and stroma by HE staining. Therefore, adenomyoma was initially considered.The lymph node-like mass was removed together with the lesser omentum during the subtotal gastrectomy and omentectomy for gastric carcinoma. No special intervention was performed for the adenomyoma.Immunohistochemical staining confirmed that smooth muscle tissue was diffusely and strongly positive for Desmin, smooth muscle actin, estrogen receptor, and progesterone receptor, and negative for CD117, Dog-1, S100, and CD34. Endometrial glands and stroma were positive for estrogen receptor and progesterone receptor, and the endometrium interstitium was also positive for CD10. The final diagnosis of extrauterine adenomyoma occurring in the lesser omentum was established.So far, to the best of our knowledge, total 53 cases of extrauterine adenomyoma have been reported in 45 English reports. The most common location for a single mass was pelvic cavity (37 cases), but rarely outside the pelvic cavity. This is the first case of a single extrauterine adenomyoma occurring in the lesser omentum.

Carboxylesterase (CES) plays an essential role in the hydrolysis of ester prodrugs. Our study explored the inhibitions of Radix Scutellariae flavones, including baicalein (B), baicalin (BG), wogonin (W), wogonoside (WG), oroxylin A (OXA) and oroxylin A-7-O-glucuronide (OAG), on CES-mediated hydrolysis of seven prodrugs (capecitabine, clopidogrel, mycophenolate mofetil, dabigatran etexilate, acetylsalicylic acid, prasugrel and irinotecan).In vitro screenings were developed by incubating the flavones with prodrugs in rat plasma, intestine S9 and liver S9. Docking simulations were conducted using AMDock v1.5.2. In vivo evaluations were performed in rats co-administered with the selected flavone and prodrug via oral gavage/intravenous administration for five consecutive days.The in vitro investigation showed that B and OXA demonstrated strongest inhibitions on the hydrolysis of irinotecan followed by dabigatran in rat plasma, intestine S9 and liver S9. Consistent results showed in the molecular docking analyses. Additionally, in rats receiving irinotecan, B/OXA intravenous and oral pre-treatments both led to reduction trends on the active metabolite SN-38 formation in plasma. Besides, significant decreases of SN-38/irinotecan plasma concentration ratios were found in the B/OXA oral pre-treatment group with quicker and stronger inhibition potential in OXA pre-treatment than that from B pre-treatment. OXA oral pre-treatment was also found to be able to significantly inhibit intestinal CES2 activities at 0.5 h and 5 h after irinotecan administration.Our current findings for the first time alert on potential CES-mediated HDIs between RS flavones and prodrugs, which provide a constructive information referring to rational drug combinations in clinical practice.

The emergence of SARS-CoV-2 variants of concern compromises vaccine efficacy and emphasizes the need for further development of anti-SARS-CoV-2 therapeutics, in particular orally administered take-home therapies. Cocktail therapy has shown great promise in the treatment of viral infection. Herein, we reported the potent preclinical anti-SARS-CoV-2 efficacy of a cocktail therapy consisting of clinically used drugs

Background Current guidelines indicate we can consider a bridging strategy that uses intravenous, reversible glycoprotein inhibitors for patients that required surgery following recent stent implantation. However, no strong clinical evidence exists that demonstrates the efficacy and safety of this treatment. Therefore, in this study, the efficacy and safety of a bridging strategy that uses intravenous platelet glycoprotein receptor inhibitors will be evaluated. Methods A meta-analysis was performed on preoperative bridging studies in patients undergoing coronary stent surgery. The primary outcome was the success rate of no major adverse cardiovascular events (MACE). The secondary outcomes were the success rate of no reoperations to stop bleeding. Results A total of 10 studies that included 382 patients were used in this meta-analysis. For the primary endpoint, the success rate was 97.7% (95% CI 94.4–98.0%) for glycoprotein IIb/IIIa inhibitors, 98.8% (95% CI 96.0–100%) for tirofiban (6 studies) and 95.8% (95% CI 90.4–99.4%) for eptifibatide (4 studies). For secondary endpoints, the success rate was 98.0% (95% CI 94.8–99.9%) for glycoprotein IIb/IIIa inhibitors, 99.7% (95% CI 97.1–100%) for tirofiban (5 studies), and 95.3% (95% CI 88.5–99.4%) for eptifibatide (4 studies). Conclusion The results of this study showed that the use of intravenous platelet glycoprotein IIb/IIIa inhibitors as a bridging strategy might be safe and effective for patients undergoing coronary stent implantation that require surgery soon after.

Traditional Chinese medicine (TCM) is becoming a popular complementary approach in pediatric oncology. However, few or no meta-analyses have focused on clinical studies of the use of TCM in pediatric oncology.We explored the patterns of TCM use and its efficacy in children with cancer, using a systematic review, meta-analysis and data mining study.We conducted a search of five English (Allied and Complementary Medicine Database, Embase, PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov) and four Chinese databases (Wanfang Data, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and VIP Chinese Science and Technology Periodicals Database) for clinical studies published before October 2021, using keywords related to "pediatric," "cancer," and "TCM."We included studies which were randomized controlled trials (RCTs) or observational clinical studies, focused on patients aged 19 years old who had been diagnosed with cancer, and included at least one group of subjects receiving TCM treatment.The methodological quality of RCTs and observational studies was assessed using the six-item Jadad scale and the Effective Public Healthcare Panacea Project Quality Assessment Tool, respectively. Meta-analysis was used to evaluate the efficacy of combining TCM with chemotherapy. Study outcomes included the treatment response rate and occurrence of cancer-related symptoms. Association rule mining (ARM) was used to investigate the associations among medicinal herbs and patient symptoms.The 54 studies included in this analysis were comprised of RCTs (63.0%) and observational studies (37.0%). Most RCTs focused on hematological malignancies (41.2%). The study outcomes included chemotherapy-induced toxicities (76.5%), infection rate (35.3%), and response, survival or relapse rate (23.5%). The methodological quality of most of the RCTs (82.4%) and observational studies (80.0%) was rated as "moderate." In studies of leukemia patients, adding TCM to conventional treatment significantly improved the clinical response rate (odds ratio [OR] = 2.55; 95% confidence interval [CI] = 1.49-4.36), lowered infection rate (OR = 0.23; 95% CI = 0.13-0.40), and reduced nausea and vomiting (OR = 0.13; 95% CI = 0.08-0.23). ARM showed that Radix Astragali, the most commonly used medicinal herb (58.0%), was associated with treating myelosuppression, gastrointestinal complications, and infection.There is growing evidence that TCM is an effective adjuvant therapy for children with cancer. We proposed a checklist to improve the quality of TCM trials in pediatric oncology. Future work will examine the use of ARM techniques on real-world data to evaluate the efficacy of medicinal herbs and drug-herb interactions in children receiving TCM as a part of integrated cancer therapy.

Introduction Camrelizumab is an antibody against programmed death protein 1 (PD-1) and is one of immune checkpoint inhibitors (ICI). ICI may lead to autoimmune myocarditis, which has a variety of clinical manifestations and usually has a poor prognosis. This article will discuss these clinical manifestations through 2 cases of ICI-related myocarditis caused by carrelizumab. Case report We reviewed the patients who received tumor treatment in our hospital from September 2019 to June 2020. A total of 155 patients received camrelizumab treatment. there were 2 cases of acute myocarditis, accounting for 1.29%, and 8 cases of new-onset arrhythmia. Here we present 2 cases of active myocarditis in a 69-year-old man with primary liver cancer and a 75-year-old man with non-small-cell lung cancer after treatment with camrelizumab. Management and outcome: The first patient presented with severe heart failure and died of malignant arrhythmia after being treated with glucocorticoid. The second patient presented with numbness of the extremities, weakness, and mild dyspnea. The symptoms gradually improved after treatment with glucocorticoid. The Naranjo scores of these two cases were 6 and 7, which suggested that myocarditis was probably caused by carrelizumab. Discussion ICI has been successfully used to treat a variety of malignant tumors with good results. However, blocking immune checkpoints by ICI may lead to autoimmune myocarditis with a poor prognosis. Early detection of cardiotoxicity may be possible through the patient's clinical manifestations and some commonly used cardiac examination methods.

Furmonertinib (AST2818) is a novel third-generation irreversible EGFR TKI and recently has been approved in China for the treatment of non-small cell lung cancer (NSCLC) with EGFR-sensitizing and T790M resistance mutations. In the current study, we developed a semi-mechanistic population pharmacokinetic model to characterize the nonstationary pharmacokinetics (PK) of the furmonertinib and its active metabolite AST5902 simultaneously. The PK data of furmonertinib and AST5902 were obtained from 38 NSCLC patients and 16 healthy volunteers receiving 20-240 mg furmonertinib in three clinical trials. A nonlinear mixed-effects modeling approach was used to describe the PK data. The absorption process of furmonertinib was described by a transit compartment model. The disposition of both furmonertinib and AST5902 was described by a two-compartment model. An indirect response model accounted for the autoinduction of furmonertinib metabolism mediated by CYP3A4. The model-based simulation suggested that furmonertinib clearance was increased in one cycle of treatment (orally once daily for 21 days) compared to baseline, ranging from 1.1 to 1.8 fold corresponding to the dose range of 20-240 mg. The concentration of furmonertinib was decreased over time whereas that of AST5902 was increased. Interestingly, the concentration of the total active compounds (furmonertinib and AST5902) appeared to be stable. The food intake, serum alkaline phosphatase and body weight were identified as statistically significant covariates. The mechanism of food effect on PK was investigated, where the food intake might increase the bioavailability of furmonertinib via increasing the splanchnic blood flow. Overall, a population PK model was successfully developed to characterize the nonstationary PK of furmonertinib and AST5902 simultaneously. The concentrations of total active compounds were less affected by the autoinduction of furmonertinib metabolism.

Pharmacokinetics (PK) is the study of the absorption, distribution, metabolism, and excretion (ADME) processes of a drug. Understanding PK properties is essential for drug development and precision medication. In this review we provided an overview of recent research on PK with focus on the following aspects: (1) an update on drug-metabolizing enzymes and transporters in the determination of PK, as well as advances in xenobiotic receptors and noncoding RNAs (ncRNAs) in the modulation of PK, providing new understanding of the transcriptional and posttranscriptional regulatory mechanisms that result in inter-individual variations in pharmacotherapy; (2) current status and trends in assessing drug–drug interactions, especially interactions between drugs and herbs, between drugs and therapeutic biologics, and microbiota-mediated interactions; (3) advances in understanding the effects of diseases on PK, particularly changes in metabolizing enzymes and transporters with disease progression; (4) trends in mathematical modeling including physiologically-based PK modeling and novel animal models such as CRISPR/Cas9-based animal models for DMPK studies; (5) emerging non-classical xenobiotic metabolic pathways and the involvement of novel metabolic enzymes, especially non-P450s. Existing challenges and perspectives on future directions are discussed, and may stimulate the development of new research models, technologies, and strategies towards the development of better drugs and improved clinical practice., Graphical abstract Understanding of DMPK properties is essential for drug development and precision medication. In this article, we provided an overview of recent research on DMPK with focuses on the regulatory mechanisms of pharmacokinetics, drug–drug interaction, mathematical modeling, non-classical metabolism and so on. Existing challenges and perspectives on future directions are also discussed.Image 1

Introduction: Piperine, the major bioactive component from black pepper, has gained increasing attention for its beneficial effects in the central nervous system (CNS). However, its related pharmacodynamics and brain pharmacokinetics, as well as its interaction with other CNS drugs are lacking, which may hinder its therapeutic and safe use. Areas covered: The current review provides an updated summary on CNS activities of piperine, including anti-epileptic, anti-depressive and neurodegeneration protection effect. The brain pharmacokinetic properties of piperine together with the approaches to enhance its aqueous solubility were summarized. Considering the wide use of black pepper and the well-reported alteration on CYP and transporters by piperine, interactions between piperine and CNS drugs are also illustrated for the first time. Expert opinion: Although the CNS beneficial effects of piperine have been extensively studied in preclinical models, clinical evidence on its CNS application is barely available, which may be attributed to its limited aqueous solubility, unclear pharmacokinetic properties in humans and potential toxicities during long-term use at higher doses. Although beneficial interactions between piperine and certain CNS drugs were often reported in preclinical studies, more mechanistic studies with clinically relevant doses should be conducted to provide guidance on their clinical combination use.

1. Donepezil (DPZ) is an acetylcholinesterase (AchE) inhibitor used in the mild to moderately severe Alzheimer’s disease. Among its major metabolites, 6-O-desmethyl DPZ (6-DDPZ), 5-O-desmethyl DPZ ...

Piperine (PIP) demonstrates extensive pharmacological effects. Recent studies reported that PIP enhanced osteogenic differentiation and inhibited osteoclast functions. Nevertheless, its effect has not been evaluated in vivo. In the current study, ovariectomised female mice and MC3T3-E1 cells were used to examine its effect on osteoblastogenesis. Oral administration of PIP significantly elevated bone mineral density and suppressed bone remodeling without dose dependence. The deterioration of trabecula and biomechanical properties were significantly improved. Moreover, new bone formation was also accelerated with increased mineral apposition rate. At the presence of PIP, the cell proliferation and alkaline phosphatase as well as mineralized nodules formation were significantly enhanced. The expression of osteogenic markers and Wnt/β-catenin signals were significantly up-regulated by the treatment of PIP. Conclusively, as an alternative supplement or functional food ingredient, PIP has the potential to treat osteoporosis induced by estrogen deficiency by enhancing osteogenic differentiation via Wnt/β-catenin signaling.

Gut microbiota alterations could influence the metabolism of administered drugs, leading to their altered pharmacokinetics and pharmacodynamics. Despite that metformin and berberine has individually demonstrated their impacts on hypoglycemic activities and gut microbiota alterations in diabetic mice, investigation regarding the impact of their combination treatment in diabetic treatment has never been conducted.Our current study was proposed aiming to investigate the effect of combination use of metformin with berberine on hypoglycemic activity and identify the possible intestinal bacteria involved in their microbiota-medicated drug-drug interactions in db/db mice.Pharmacodynamics interactions between metformin and berberine were evaluated in six groups of db/db mice (db, M250, B250, B125, B250+M250, and B125+M250) with its wild type (WT) as control to receive 14 days treatment of vehicle, metformin at 250 mg/kg, berberine at 250/125 mg/kg, and metformin (250 mg/kg) 2 h after dosing berberine (250/125 mg/kg).On day 13, insulin tolerance test (ITT) was conducted. On day 15, fasting serum samples were obtained for insulin concentration determination followed by intraperitoneal glucose tolerance test (ipGTT), homeostatic model assessment for insulin resistance (HOMA-IR) calculation, and feces collection for microbial 16S rRNA sequencing analyses. In addition, metformin steady state plasma concentrations on day 15 were measured by validated LC-MS/MS method.Combination treatment of metformin with berberine could further reduce in blood glucose in comparison to that of db/db diabetic control. Further microbial 16S rRNA sequencing analyses revealed that gut microbiota compositions were significantly changed with the abundance of Proteobacteria and Verrucomicrobia altered the most after metformin and berberine co-treatment compared to their monotherapy. In addition, steady state metformin concentrations in their combination treatment were significantly higher than that from metformin monotherapy.Co-administration of metformin (250 mg/kg) with berberine (125 mg/kg) could not only further improve insulin sensitivity, but also demonstrate different alterations on gut microbial communities than that of their individual treatment in db/db mice.

Natural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays. Characterization of the library in terms of physicochemical properties, structural diversity, and similarity to compounds in publicly available libraries indicates that the Canvass library contains many structural elements in common with approved drugs. The assay data generated were analyzed using a variety of quality control metrics, and the resultant assay profiles were explored using statistical methods, such as clustering and compound promiscuity analyses. Individual compounds were then sorted by structural class and activity profiles. Differential behavior based on these classifications, as well as noteworthy activities, are outlined herein. One such highlight is the activity of (−)-2(S)-cathafoline, which was found to stabilize calcium levels in the endoplasmic reticulum. The workflow described here illustrates a pilot effort to broadly survey the biological potential of natural products by utilizing the power of automation and high-throughput screening., Canvass, a crowd-sourced library of natural products, was evaluated through HTS in a spectrum of disease-relevant assays to survey the broad biological potential of natural products in drug discovery.

Background As a new noninvasive diagnostic technique, computed tomography (CT)-based fraction flow reserve (FFR) has been used to identify hemodynamically significant coronary artery stenosis. This meta-analysis used invasive FFR as the standard to evaluate the diagnostic performance of FFRCT. Methods We searched the PubMed, Cochrane library, and EMBASE for articles published between January 2009 and January 2021. The synthesized sensitivity and specificity of invasive FFR and FFRCT were analyzed at both the patient and vessel levels. We generated a summary receiver operating characteristic curve (SROC) and then calculated the area under the curve (AUC). Results We included a total of 23 studies, including 2,178 patients and 3,029 vessels or lesions. Analysis at each patient level demonstrated a synthesized sensitivity of 88%, specificity of 79%, LR+ of 4.16, LR-of 0.15, and AUC of 0.89 for FFRCT. Analysis at the level of each vessel or lesion showed a synthesized sensitivity of 85%, specificity of 81%, LR+ of 4.44, LR-of 0.19, and AUC of 0.87 for FFRCT. Conclusion Our research reveals that FFRCT has high diagnostic performance in patients with coronary artery stenosis, regardless of whether it is at the patient level or the vessel level.

Significance Small CAG (sCAG) RNAs are neurotoxic, but their role in polyglutamine degeneration remains to be fully elucidated. We observed that cellular expression of sCAGs is sufficient to induce neuronal DNA damage and discovered that the transcript level of NUDT16 was reduced in HD models. The NUDT16 protein has previously been linked to the DNA damage pathway. At the structural level, sCAGs form double-stranded CAG–CUG heteroduplex RNA with NUDT16 transcript which led to its gene silencing. We showed that the bisamidinium-based compound DB213 specifically interacts with duplex CAG RNA; consequently, both NUDT16 expression and DNA damage were rescued in HD mice. Our findings describe a pathogenic pathway that induces DNA damage in polyglutamine degeneration and demonstrate its therapeutic potential., DNA damage plays a central role in the cellular pathogenesis of polyglutamine (polyQ) diseases, including Huntington’s disease (HD). In this study, we showed that the expression of untranslatable expanded CAG RNA per se induced the cellular DNA damage response pathway. By means of RNA sequencing (RNA-seq), we found that expression of the Nudix hydrolase 16 (NUDT16) gene was down-regulated in mutant CAG RNA-expressing cells. The loss of NUDT16 function results in a misincorporation of damaging nucleotides into DNAs and leads to DNA damage. We showed that small CAG (sCAG) RNAs, species generated from expanded CAG transcripts, hybridize with CUG-containing NUDT16 mRNA and form a CAG-CUG RNA heteroduplex, resulting in gene silencing of NUDT16 and leading to the DNA damage and cellular apoptosis. These results were further validated using expanded CAG RNA-expressing mouse primary neurons and in vivo R6/2 HD transgenic mice. Moreover, we identified a bisamidinium compound, DB213, that interacts specifically with the major groove of the CAG RNA homoduplex and disfavors the CAG-CUG heteroduplex formation. This action subsequently mitigated RNA-induced silencing complex (RISC)-dependent NUDT16 silencing in both in vitro cell and in vivo mouse disease models. After DB213 treatment, DNA damage, apoptosis, and locomotor defects were rescued in HD mice. This work establishes NUDT16 deficiency by CAG repeat RNAs as a pathogenic mechanism of polyQ diseases and as a potential therapeutic direction for HD and other polyQ diseases.

Background Our current study aimed to evaluate the effect of an Glechoma hederacea extract (Hitrechol®) in normal rats and gallstone diseased mice to explore its underlying mechanisms. Normal rats and C57BL/6 mice with/without cholesterol gallstone were used in this study. Methods To monitor the effect of Hitrechol® on bile secretion, bile flow rates at 15 min interval until 2 h post-dosing in normal rats treated with vehicle and Hitrechol® were compared using multiple t-test with a p p Results Despite no significant impact on the bile flow rate, Hitrechol® TID treatment dramatically decreased size and amount of gallstone crystals and total cholesterol level (p ), as well as total bile acid (p ) and several types of bile acid (p ) levels in gallstone disease model mice. Hitrechol® TID treatment could significantly decrease the frequencies of hepatocyte necrosis and lipid aggregation notably as well as increase the antioxidant enzyme level (p ) in the liver. Conclusions Our findings for the first time demonstrated the beneficial effect of Hitrechol® against gallstone via its litholytic, liver-protective and antioxidant activities.

Concurrent use of simvastatin (SV) and Gardenia jasminoides J. Ellis (GJ) was adopted in patients with multi-morbidity, such as stroke rehabilitation patients with NASH. Although hepatotoxicity has been reported in both of them and NASH could alter the pharmacokinetics of drugs/herbs, the interaction between SV and GJ and the related hepatotoxicity remained uninvestigated under neither healthy nor NASH condition. The current study aimed to evaluate the potential hepatotoxicity resulted from the interactions between SV and GJ in both healthy and NASH rats. Both healthy and NASH rats received two-week SV (p. o., 8.66 mg/kg, once daily) and/or GJ (p.o., 325 mg/kg, twice daily). Pharmacokinetic profiles of SV, simvastatin acid (SVA, active metabolite of SV), and geniposide (major component in GJ); hepatic Cyp2c11/Oatp1b2/P-gp expression; and biomarker levels of liver function, lipid levels, and liver histology were compared to demonstrate the interactions in rats. To explore the mechanism of the interaction-mediated hepatotoxicity, hepatic genipin-protein adduct content and iNOS/COX-1/COX-2 expressions from related groups were compared. Moreover, liver histology of healthy/NASH rats at 90 days after discontinuation of two-week GJ in the absence and presence of SV was evaluated to estimate the long-term impact of the interactions. GJ reduced the systemic exposures of SV and SVA by up-regulating the hepatic P-gp expression in healthy but not NASH rats. Meanwhile, SV increased the systemic exposure of geniposide via inhibiting the activity of P-gp in both healthy and NASH rats. Although neither SV nor GJ induced hepatotoxicity in healthy rats, their co-treatment elevated serum ALT and AST levels, which may attribute to the aggravated genipin-protein adduct formation, inflammation infiltration, and iNOS/COX-1 expressions in the liver. In NASH rats, SV and/or GJ reduced serum ALT, AST, LDL/vLDL, and TC levels via alleviating hepatic inflammation infiltration and iNOS/COX-1 expressions. Moreover, in comparison to NASH rats, more severe fibrosis was observed in the livers of healthy rats at 90 days after discontinuation of two-week SV and GJ coadministration. Although interactions between SV and GJ induced short-term and long-term liver injuries in healthy rats, NASH condition in rats could lower such risk.

The outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global threat to human health. Using a multidisciplinary approach, we identified and validated the hepatitis C virus (HCV) protease inhibitor simeprevir as an especially promising repurposable drug for treating COVID-19. Simeprevir potently reduces SARS-CoV-2 viral load by multiple orders of magnitude and synergizes with remdesivir in vitro. Mechanistically, we showed that simeprevir not only inhibits the main protease (Mpro) and unexpectedly the RNA-dependent RNA polymerase (RdRp) but also modulates host immune responses. Our results thus reveal the possible anti-SARS-CoV-2 mechanism of simeprevir and highlight the translational potential of optimizing simeprevir as a therapeutic agent for managing COVID-19 and future outbreaks of CoV., Simeprevir, an HCV drug, suppresses SARS-CoV-2 replication by inhibiting two viral proteins and modulating host immune responses, thus providing novel insights in anti-CoV drug design.

In this paper, we report a scheme providing precise spectral analysis and surface imaging, simultaneously, based on a high-coherence dual-comb interferometer. With two tightly phase-locking frequency combs, we demonstrate a high-coherence dual-comb interferometer (DCI) covering 188 to 195 THz (1538.5 to 1595.7 nm) with comb-tooth resolution and a max spectral signal-to-noise ratio (SNR) of 159.7. The combination of the high-coherence dual-comb spectrometer and a reference arm simultaneously enables gas absorption spectroscopy and for the absolute distance information to be obtained in one measurement. As a demonstration, we measure the spectrum of CO2 and CO. From the same interferograms, we demonstrate that distance measurement, by time-of-flight (TOF), can be resolved with an rms precision of 0.53 μm after averaging 140 images and a measurement time of 1 s. Finally, we demonstrate that non-contact surface imaging, using 2D mechanical scanning, reaches lateral resolution of 40 μm. The longitudinal precision is 0.68 μm with a measurement time of 0.5 s. It verifies that DCS has the potential to be applied in standoff detection, environmental pollution monitors, and remote sensing.

An HERB-Drug Interaction (HDI) database is a structured data collection about HDI information extracted from scattered literatures for quick retrieving purpose. Our review summarized the currently available ten HDI databases, including those databases comprising HDI, on the market. Not only a detailed comparison on the scope of monographs included, nature of content extracted from the original literature, and user interfaces of these databases was performed, but also the number of references of fifty popular herbs in each HDI database was counted and presented in a heatmap to give users an intuitive understanding of the focuses of different HDI databases. Since it is well known that the development and maintenance of databases need continuous investment of capital and manpower, the sustainability of these databases is also reviewed and compared. Recently, artificial intelligence (AI) technologies, especially Natural Language Processing (NLP), have been applied to screen specific topics from massive articles and automatically identify the names of drugs and herbs in the literature. However, its application on the labour-intensive extraction and evaluation of HDI-related experimental conditions and results from literature remains limited due to the scarcity of these HDI data and the lack of well-established annotated datasets for these specific NLP recognition tasks. In view of the difficulties faced by current HDI databases and potential expansion of AI application in HDI database development, we propose a standardized format for data reporting and use of Concept Unique Identifier (CUI) for medical terms in the literature so as to accelerate the structured data collection. Significance Statement The worldwide popularity of botanical and/or traditional medicine products raised safety concerns due to potential HDI. However, the publicly available HDI databases are mostly outdated or incomplete. Through our review of the currently available HDI databases, a clear understanding of the key issues could be obtained and possible solutions to overcome the labour-intensive extraction as well as professional evaluation of information in HDI database development are proposed.

Purpose Dexmedetomidine (DEX) is a highly selective α2-adrenoceptor agonist with high protein binding of 94%. Critical illness may affect protein binding and the pharmacokinetic (PK) parameters of many drugs, including DEX. In critically ill patients receiving prolonged infusions of DEX, there is little information documenting the relationship between key pathophysiologic factors and DEX protein binding or PK parameters. The purpose of this study was to characterize the protein binding and PK profile of prolonged DEX infusion in critically ill patients. Methods Critically ill, adult intensive care unit patients at a university hospital in Hong Kong were studied. The association between the pathophysiologic changes of critical illness and protein binding was evaluated using a generalized estimating equation. A population pharmacokinetic model to establish the PK profile of DEX was developed, and key pathophysiologic covariate effects of severity of illness, organ dysfunction measures, and altered protein binding on DEX PK parameters in this critically ill population were evaluated. Findings A total of 22 critically ill patients and 1 healthy control were included. Mean protein binding of DEX in the critically ill patients was 90.4% (95% CI, 89.1–91.7), which was 4% lower than that in the healthy control. The PK data were adequately described by a 2-compartment model. The estimated population mean (relative standard error [RSE]) values of systemic clearance (CL), volume of distribution of the central compartment (V2), intercompartmental clearance (Q), and Vd in the peripheral compartment (V3) were 38.6 (11.7) L/h, 32.1 (46.1) L, 114.5 (58.3) L/h and 95.1 (30.6) L, respectively. The corresponding estimated interindividual variability expressed as CV% (RSE) was 52.4 (23.8) for CL, 172.9 (19.3) for V2, 123.7 (33.7) for Q, and 106 (39.9) for V3. No significant explanatory pathophysiologic covariates were identified. Implications Although a marginally significant reduction of protein binding in critically ill patients was demonstrated, the magnitude of the difference was unlikely to be of clinical significance. Higher alanine aminotransferase concentration was associated with decreased protein binding. No significant pathophysiologic covariates were associated with the observed PK parameters. The high interindividual variability of PK parameters supports the current practice of dose titration to ensure the desired clinical effects of DEX infusion in the intensive care unit setting.