[Overview of the application of knowledge graphs in the medical field].

With the booming development of medical information technology and computer science, the medical services industry is gradually transiting from information technology to intelligence. The medical knowledge graph plays an important role in intelligent medical applications such as knowledge questions and answers and intelligent diagnosis, and is a key technology for promoting wise medical care and the basis for intelligent management of medical information. In order to fully exploit the great potential of knowledge graphs in the medical field, this paper focuses on five aspects: inter-drug relationship discovery, assisted diagnosis, personalized recommendation, decision support and intelligent prediction. The latest research progress on medical knowledge graphs is introduced, and relevant suggestions are made in light of the current challenges and problems faced by medical knowledge graphs to provide reference for promoting the wide application of medical knowledge graphs.

The impacts of race and regimens on the efficacy and safety of paclitaxel and platinum combination treatment for patients with advanced non-small cell lung cancer.

PURPOSE: Paclitaxel-platinum chemotherapy is the first-line treatment for advanced non-small cell lung cancer (NSCLC) patients. This study quantitatively evaluated the factors influencing the efficacy and safety of the paclitaxel-platinum regimen to provide the necessary reference for the development of clinical practice and clinical trials. METHODS: A literature search was performed using public databases. The parametric survival function was used to analyze the overall survival (OS) time course of patients treated with the paclitaxel-platinum regimen. The random effects model in the single-arm meta-analysis was used to analyze the objective response rate (ORR) and the incidence of grade 3-4 adverse events (AEs) under the predefined subgroups according to race and the regimen. RESULTS: A total of 31 studies consisting of 3365 participants were included in the analysis. Race was the most important determinant of efficacy and safety in the paclitaxel-platinum regimen, with the median survival time and ORR in East Asians and non-East Asians being 12.2 months (95% CI: 10.5-14.4 months) and 37% (95% CI: 32-41%) and 8.4 months (95% CI: 6.5-11.0 months) and 28% (95% CI: 25-32%), respectively. The incidence of grade 3-4 AEs such as leukopenia and neutropenia was about three times higher in East Asians compared to non-East Asians. CONCLUSIONS: The efficacy and safety of the paclitaxel-platinum regimen can vary between East Asian and non-East Asian populations and between different treatment schedules. The results of this study can provide a reliable and precise external control for the future evaluation of new treatment options for advanced NSCLC.

Analysis of Time-Course, Dose-Effect, and Influencing Factors of Antidepressants in the Treatment of Acute Adult Patients With Major Depression.

OBJECTIVE: Model-based meta-analysis was used to describe the time-course and dose-effect relationships of antidepressants and also simultaneously investigate the impact of various factors on drug efficacy. METHODS: This study is a reanalysis of a published network meta-analysis. Only placebo-controlled trials were included in this study. The change rate in depression rating scale scores from baseline was used as an efficacy indicator because a continuous variable is more likely to reflect subtle differences in efficacy between drugs. RESULTS: A total 230 studies containing 64 346 patients were included in the analysis. The results showed that the number of study sites (single or multi-center) and the type of setting (inpatient or noninpatient) are important factors affecting the efficacy of antidepressants. After deducting the placebo effect, the maximum pure drug efficacy value of inpatients was 18.4% higher than that of noninpatients, and maximum pure drug efficacy value of single-center trials was 10.2% higher than that of multi-central trials. Amitriptyline showed the highest drug efficacy. The remaining 18 antidepressants were comparable or had little difference. Within the approved dose range, no significant dose-response relationship was observed. However, the time-course relationship is obvious for all antidepressants. In terms of safety, with the exception of amitriptyline, the dropout rate due to adverse events of other drugs was not more than 10% higher than that of the placebo group. CONCLUSION: The number of study sites and the type of setting are significant impact factors for the efficacy of antidepressants. Except for amitriptyline, the other 18 antidepressants have little difference in efficacy and safety.

Population pharmacokinetics of moxifloxacin and its concentration-QT interval relationship modeling in Chinese healthy volunteers.

Moxifloxacin (MX) is an 8-methoxyquinolone antimicrobial drug, which is often used as a positive control in thorough QT (TQT) studies. In the present study we established the population pharmacokinetics model of MX and the relationship of MX concentrations with the QT and various corrected QT (QTc) intervals, and compared the results with other ethnicities. The MX data used for modeling were obtained from a published TQT interval prolongation study of antofloxacin with MX as the positive control. In this four-period crossover study, 24 adult Chinese healthy volunteers received either 200 or 400 mg of oral antofloxacin once daily, 400 mg of MX, or a placebo. Population concentration-effect models were used to investigate the relationship between MX concentrations and QT interval prolongation, baseline-adjusted QTc (ΔQTc), or ΔQTc adjusted with time-matched placebo corrections (ΔΔQTc). The influencing factors of MX PK and the concentration-QTc relationship were determined through covariate screening. Simulation studies were conducted in R2.30 by using the final model with the estimated population mean and intra-individual and inter-individual variability. The estimated pharmacokinetic parameters and the estimated slope of the MX concentration-QT/ΔQTc/ΔΔQTc relationship were described using models and were compared to results for other ethnicities from the literature. We showed that the population pharmacokinetic parameter estimates for total plasma clearance (CL/F), the volume of distribution of central compartment (Vc/F), the distributional clearance in plasma (Q), the volume of distribution of peripheral compartment (Vp/F), and the absorption rate constant (Ka) were 8.22 L/h, 104 L, 3.98 L/h, 37.7 L, and 1.81 1/h, respectively. There was no significant covariate included in the final model. QT interval prolongation of MX estimates ranging from 9.77 to 12.91 ms at the mean average maximum concentration of MX (4.36 µg/mL) and a mean slope ranging from 2.33 to 2.96 ms per µg/mL. In conclusion, no ethnic differences were observed for the MX pharmacokinetic parameters and QT interval prolongation.

A Network-Based Pharmacology Study of the Herb-Induced Liver Injury Potential of Traditional Hepatoprotective Chinese Herbal Medicines.

Herbal medicines are widely used for treating liver diseases and generally regarded as safe due to their extensive use in Traditional Chinese Medicine practice for thousands of years. However, in recent years, there have been increased concerns regarding the long-term risk of Herb-Induced Liver Injury (HILI) in patients with liver dysfunction. Herein, two representative Chinese herbal medicines: one-Xiao-Chai-Hu-Tang (XCHT)-a composite formula, and the other-Radix Polygoni Multiflori (Heshouwu)-a single herb, were analyzed by network pharmacology study. Based on the network pharmacology framework, we exploited the potential HILI effects of XCHT and Heshouwu by predicting the molecular mechanisms of HILI and identified the potential hepatotoxic ingredients in XCHT and Heshouwu. According to our network results, kaempferol and thymol in XCHT and rhein in Heshouwu exhibit the largest number of liver injury target connections, whereby CASP3, PPARG and MCL1 may be potential liver injury targets for these herbal medicines. This network pharmacology assay might serve as a useful tool to explore the underlying molecular mechanism of HILI. Based on the theoretical predictions, further experimental verification should be performed to validate the accuracy of the predicted interactions between herbal ingredients and protein targets in the future.

Pharmacokinetic and pharmacodynamic interactions of aspirin with warfarin in beagle dogs.

1. Warfarin and aspirin are widely used in a wide spectrum of thromboembolic and atherothrombotic diseases. Despite the potential efficacy of warfarin-aspirin therapy, the safety and side effect of combined therapy remains unclear. 2. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic interactions between warfarin and aspirin in beagles after single and multiple doses. 3. Coadministration of aspirin had no significant effects on the area under the plasma concentration time curve (AUC(0-t)) and maximum plasma concentration (Cmax) of R- and S-warfarin after a single dose of warfarin, but significantly increase the AUC(0-t) and Cmax and dramatically decrease the clearance (CL) of R- and S-warfarin after multiple dose of warfarin. Accordingly, there was a slight increase in the AUEC(0-t) and Emax of activated partial thromboplastin time (aPTT), prothrombin time (PT) and international normalized ratio (INR) after multiple dose of warfarin. 4. Coadministration of warfarin had no markedly effects on the AUC(0-t) and Cmax of aspirin and its metabolite salicylic acid after single or multiple dose of aspirin. Meanwhile, the AUEC(0-t) and Emax of inhibition of platelet aggregation (IPA) were not significantly affected by warfarin. 5. Our animal study indicated that coadministration of aspirin with warfarin can cause significant pharmacokinetic and pharmacodynamic drug-drug interactions in beagles. However, more studies are urgently needed to assess related information of warfarin-aspirin drug interactions in healthy volunteers or patients.

Advantage of population pharmacokinetic method for evaluating the bioequivalence and accuracy of parameter estimation of pidotimod.

OBJECTIVE: This study was aimed at exploring the accuracy of population pharmacokinetic method in evaluating the bioequivalence of pidotimod with sparse data profiles and whether this method is suitable for bioequivalence evaluation in special populations such as children with fewer samplings. Methods In this single-dose, two-period crossover study, 20 healthy male Chinese volunteers were randomized 1 : 1 to receive either the test or reference formulation, with a 1-week washout before receiving the alternative formulation. Noncompartmental and population compartmental pharmacokinetic analyses were conducted. Simulated data were analyzed to graphically evaluate the model and the pharmacokinetic characteristics of the two pidotimod formulations. Various sparse sampling scenarios were generated from the real bioequivalence clinical trial data and evaluated by population pharmacokinetic method. RESULTS: The 90% confidence intervals (CIs) for AUC0-12h, AUC0-∞, and Cmax were 97.3 - 118.7%, 96.9 - 118.7%, and 95.1 - 109.8%, respectively, within the 80 - 125% range for bioequivalence using noncompartmental analysis. The population compartmental pharmacokinetics of pidotimod were described using a one-compartment model with first-order absorption and lag time. In the comparison of estimations in different dataset, the estimation of random three- and< fixed four-point sampling strategies can provide results similar to those obtained through rich sampling. The nonlinear mixed-effects model requires fewer data points. Moreover, compared with the noncompartmental analysis method, the pharmacokinetic parameters can be more accurately estimated using nonlinear mixed-effects model. CONCLUSIONS: The population pharmacokinetic modeling method was used to assess the bioequivalence of two pidotimod formulations with relatively few sampling points and further validated the bioequivalence of the two formulations. This method may provide useful information for regulating bioequivalence evaluation in special populations.

Population pharmacokinetics of adefovir dipivoxil tablets in healthy Chinese volunteers.

AIM: To develop a population pharmacokinetic model of adefovir dipivoxil in healthy volunteers and evaluate the effect of individual factors on the pharmacokinetics of adefovir dipivoxil. METHODS: Plasma concentration data collected from 32 healthy Chinese subjects in a Phase I clinical study was pooled. Subjects received a single oral dose of 10 mg, 20 mg, or 30 mg adefovir dipivoxil, or multiple doses of 10 mg once a day for 9 days. Plasma concentrations of adefovir dipivoxil were measured using a validated liquid chromatography-mass spectrometric method. A nonlinear mixed-effect model was used to analyze the plasma concentration data of adefovir dipivoxil in healthy volunteers and to calculate the relevant parameters as well as inter- and intra-individual variability. RESULTS: The time course of adefovir dipivoxil concentration is best described by a first-order absorption and first-order elimination two-compartment model with lag time. The final estimate of total body clearance (CL) is 56.9 L/h and 78.7 L/h for single and multiple dosing regimen, respectively; the volume distribution of the central compartment (V2) is 106 L; inter-compartmental clearance (Q) is 220 L/h; volume distribution of the peripheral compartment (V3) is 498 L and 800 L for single and multiple dosing regimen, respectively; absorption rate is 0.509 h-1; and lag time is 0.315 hours. The inter-individual variabilities of CL and V2 were 22.4% and 58.9%, respectively. The proportional error of residual variability is 14.1% and the additive error is 0.30 ng/L. The final pharmacokinetic model was evaluated using a bootstrap method. CONCLUSIONS: A nonlinear mixed effect model for oral adefovir dipivoxil formulations was developed in healthy Chinese subjects. A multiple dosing regimen may significantly increase the body clearance and volume distribution of the peripheral compartment compared to a single dosing regimen. *These authors contribute equally to this work.

Random sparse sampling strategy using stochastic simulation and estimation for a population pharmacokinetic study.

The purpose of this study was to use the stochastic simulation and estimation method to evaluate the effects of sample size and the number of samples per individual on the model development and evaluation. The pharmacokinetic parameters and inter- and intra-individual variation were obtained from a population pharmacokinetic model of clinical trials of amlodipine. Stochastic simulation and estimation were performed to evaluate the efficiencies of different sparse sampling scenarios to estimate the compartment model. Simulated data were generated a 1000 times and three candidate models were used to fit the 1000 data sets. Fifty-five kinds of sparse sampling scenarios were investigated and compared. The results showed that, 60 samples with three points and 20 samples with five points are recommended, and the quantitative methodology of stochastic simulation and estimation is valuable for efficiently estimating the compartment model and can be used for other similar model development and evaluation approaches.

Exploring the anti-hepatocellular carcinoma effects of Xianglian Pill: Integrating network pharmacology and RNA sequencing via in silico and in vitro studies.

BACKGROUND: Liver cancer represents a most common and fatal cancer worldwide. Xianglian Pill (XLP) is an herbal formula holding great promise in clearing heat for treating diseases in an integrative and holistic way. However, due to the complex constituents and multiple targets, the exact molecular mechanisms of action of XLP are still unclear. PURPOSE: This study is focused on hepatocellular carcinoma (HCC), the most common type of liver cancer. The aim of this study is to develop a fast and efficient model to investigate the anti-HCC effects of XLP, and its underlying mechanisms. MATERIALS AND METHODS: HepG2, Hep3B, Mahlavu, HuH-7, or Li-7 cells were employed in the studies. The ingredients were analyzed using liquid chromatography tandem mass spectrometry (LC-MS). RNA sequencing combined with network pharmacology was used to elucidate the therapeutic mechanism of XLP in HCC via in silico and in vitro studies. An approach was constructed to improve the accuracy of prediction in network pharmacology by combining big data and omics. RESULTS: First, we identified 13 potential ingredients in the serum of XLP-administered rats using LC-MS. Then the network pharmacology was performed to predict that XLP demonstrates anti-HCC effects via targeting 94 genes involving in 13 components. Modifying the database thresholds might impact the accuracy of network pharmacology analysis based on RNA sequencing data. For instance, when the matching rate peak is 0.43, the correctness rate peak is 0.85. Moreover, 9 components of XLP and 6 relevant genes have been verified with CCK-8 and RT-qPCR assay, respectively. CONCLUSION: Based on the crossing studies of RNA sequencing and network pharmacology, XLP was found to improve HCC through multiple targets and pathways. Additionally, the study provides a way to optimize network pharmacology analysis in herbal medicine research.

Limited sampling strategy models for estimating the AUC of gliclazide in Chinese healthy volunteers.

The aim of this work is to reduce the cost of required sampling for the estimation of the area under the gliclazide plasma concentration versus time curve within 60 h (AUC0-60t ). The limited sampling strategy (LSS) models were established and validated by the multiple regression model within 4 or fewer gliclazide concentration values. Absolute prediction error (APE), root of mean square error (RMSE) and visual prediction check were used as criterion. The results of Jack-Knife validation showed that 10 (25.0 %) of the 40 LSS based on the regression analysis were not within an APE of 15 % using one concentration-time point. 90.2, 91.5 and 92.4 % of the 40 LSS models were capable of prediction using 2, 3 and 4 points, respectively. Limited sampling strategies were developed and validated for estimating AUC0-60t of gliclazide. This study indicates that the implementation of an 80 mg dosage regimen enabled accurate predictions of AUC0-60t by the LSS model. This study shows that 12, 6, 4, 2 h after administration are the key sampling times. The combination of (12, 2 h), (12, 8, 2 h) or (12, 8, 4, 2 h) can be chosen as sampling hours for predicting AUC0-60t in practical application according to requirement.

Reduning injection for fever, rash, and ulcers in children with mild hand, foot, and mouth disease: a randomized controlled clinical study.

OBJECTIVE: To assess the efficacy and safety of Reduning injection for fever, rash, and ulcers in children with mild hand, foot, and mouth disease (HFMD). METHODS: A stratified-block randomized, double-blind, parallel-controlled, and multicenter clinical trial was conducted with 360 patients in five hospitals across China: Quanzhou Children's Hospital, Shijiazhuang No. 5 Hospital, Shanghai Public Health Centre, Hunan Provincial Children's Hospital, and Kaifeng Children's Hospital. Patients were randomized into three groups with 120 in each. Group A was treated with Western Medicine, group B with Reduning injection, a Chinese herbal medicine, and group C with both Reduning injection and Western Medicine. Results were compared for treatment efficacy and safety on HFMD. The clinical outcomes were observed as follows: fever and onset time of antifebrile effect (time to bring the body temperature down > or = 0.5 degrees C after medication); cumulative time for fever recovery (body temperature recovering to normal and lasting more than 24 h without medication); cumulative time for rash disappearance (without new rashes or ulcers appearing and the original ones fading away); and cumulative time for mouth ulcer disappearance. RESULTS: For the onset time of the antifebrile effect, there was no statistical difference between groups A and B (P > 0.05) and groups B and C (P > 0.05). However, there was a statistical difference between groups A and C (P < 0.05), and the effect in group C was the best. For the cumulative time for rash disappearance, there was no statistical difference between groups A and B (P > 0.05). There were statistical differences between groups A and C, and groups B and C (P < 0.05), and the effect in group C was the best. For the cumulative time for mouth ulcers disappearance, there were no statistical differences among the three groups (P > 0.05). CONCLUSION: Reduning injection with Western Medicine for symptomatic treatment is most effective for mild HFMD. No adverse reactions were observed.

A review of research on eligibility criteria for clinical trials.

The purpose of this paper is to systematically sort out and analyze the cutting-edge research on the eligibility criteria of clinical trials. Eligibility criteria are important prerequisites for the success of clinical trials. It directly affects the final results of the clinical trials. Inappropriate eligibility criteria will lead to insufficient recruitment, which is an important reason for the eventual failure of many clinical trials. We have investigated the research status of eligibility criteria for clinical trials on academic platforms such as arXiv and NIH. We have classified and sorted out all the papers we found, so that readers can understand the frontier research in this field. Eligibility criteria are the most important part of a clinical trial study. The ultimate goal of research in this field is to formulate more scientific and reasonable eligibility criteria and speed up the clinical trial process. The global research on the eligibility criteria of clinical trials is mainly divided into four main aspects: natural language processing, patient pre-screening, standard evaluation, and clinical trial query. Compared with the past, people are now using new technologies to study eligibility criteria from a new perspective (big data). In the research process, complex disease concepts, how to choose a suitable dataset, how to prove the validity and scientific of the research results, are challenges faced by researchers (especially for computer-related researchers). Future research will focus on the selection and improvement of artificial intelligence algorithms related to clinical trials and related practical applications such as databases, knowledge graphs, and dictionaries.

Discovery and Validation of Traditional Chinese and Western Medicine Combination Antirheumatoid Arthritis Drugs Based on Machine Learning (Random Forest Model).

The combination of traditional Chinese medicine (TCM) and Western medicine is a promising method for treating rheumatoid arthritis (RA). Combining the two fully exploits the advantages of Western and TCM to treat RA and has the potential to greatly improve the therapeutic effect on RA. In this study, we developed a combination drug training set by using 16 characteristic variables based on the characteristics of small molecules of TCM ingredients and Food and Drug Administration-certified combination drug data downloaded from the DrugCombDB database. Furthermore, we compared the prediction and classification abilities of five models: the k-nearest neighbors, naive Bayes, support vector machine, random forest, and AdaBoost algorithms. The random forest model was selected as the classification and prediction model for Western and TCM and Western combination drugs. We collected data for 41 small molecules of TCM ingredients from the Traditional Chinese Medicine Systems Pharmacology database and 10 small molecule drugs commonly used in anti-RA treatment from the DrugBank database. Combinations of Western and TCM for anti-RA treatment were screened. Finally, the CellTiter-Glo method was used to determine the synergy of these combinations, and the 15 most predicted drug combinations were carried out experimental verification. Myricetin, rhein, nobiletin, and fisetin had high synergy with celecoxib, and rhein had high synergy with hydroxychloroquine. The preliminary findings of this study can be further applied for practical clinical anti-RA combined treatment strategies and serve as a reference for clinical treatment of RA with integrated Western and TCM.

Efficacy of Lianhua Qingwen for children with SARS-CoV-2 Omicron infection: A propensity score-matched retrospective cohort study.

BACKGROUND: Lianhua Qingwen Granules or Capsules (LHQW) has accumulated much research evidence in the fight against the coronavirus disease 2019 (COVID-19) epidemic. However, there are still few data on its efficacy and safety in children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. PURPOSE: To evaluate the efficacy and safety of LHQW in children with SARS-CoV-2 Omicron infection. METHODS: We conducted a single-center, propensity-score matched retrospective cohort study of children with SARS-CoV-2 Omicron infection in Shanghai New International Expo Center mobile cabin hospital between April 1st and June 1st, 2022. Eligible patients received either LHQW granules/capsules plus supportive care (LHQW group) or supportive care alone (control group). The primary outcome was the negative conversion time of nucleic acid. Secondary outcomes included the negative conversion rate of nucleic acid, the length of hospital stay, clinical disease progression, and cycle threshold [Ct] values for SARS-CoV-2 open reading frame [ORF1ab] or nucleocapsid [N] genes. RESULTS: Overall, 2808 patients were enrolled, and 346 patients in each group were included in the analysis. Among the propensity-score matched groups, LHQW treatment was associated with an accelerated negative conversion time of nucleic acid (median: 5 d vs. 6 d, Hazard ratio: 1.25, 95% CI: 1.08 - 1.46, Log-rank p < 0.001), a higher negative conversion rate of nucleic acid (Day 2 - 6: 2.9% vs. 0.6%, p = 0.036; 29.8% vs. 5.5%, p < 0.001; 42.5% vs. 24.3%, p < 0.001; 51.4% vs. 31.5%, p < 0.001; 63.3% vs. 55.2%, p = 0.030), shorter hospital stay (median: 10 d vs. 11 d, Hazard ratio: 1.50, 95% CI: 1.29 - 1.74, Log-rank p < 0.001), and lower rates of asymptomatic infection progressing to mild (37.9% vs. 46.5%, p = 0.021). CONCLUSION: Our study suggested that LHQW treatment was associated with faster clinical recovery in children with SARS-CoV-2 Omicron infection.

Dose findings of antofloxacin hydrochloride for treating bacterial infections in an early clinical trial using PK-PD parameters in healthy volunteers.

AIM: To find an appropriate dose regimen of the novel antibacterial agent antofloxacin for a phase II clinical trial using a population pharmacokinetic (PPK) study in healthy volunteers and the minimum inhibitory concentration (MIC) as pharmacodynamic (PD) parameters. METHODS: Twenty-four healthy volunteers were enrolled in a double-blind crossover study and received antofloxacin (200 or 400 mg/d, po) for consecutive 5 d with 10 d washout between two separate periods. Blood concentrations were analyzed using HPLC with a UV-Vis detector. The values of area under the curve (AUC) with covariates were obtained from a PPK model, and the MICs came from the previous in vitro studies. The dose regimen was determined for the phase II clinical trial according to the ratio (>20) of AUC/MIC, and the efficacy of the dose was evaluated by the trial. RESULTS: A two-compartment model best described the time-concentration data with first-order absorption. The PPK parameter estimates for CL, V(c), Q, V(p) and K(A) are 8.34 L/h, 142 L, 15.9 L/h, 52.2 L and 4.64 1/h, respectively. The covariates sex for K(A), weight for CL, weight for V(c) and interoccasion variability were included in the final model. The AUC/MIC was calculated based on the PPK model and the MIC of antofloxacin for Escherichia coli, Klebsiella pneumonia, Staphylococcus aureus and Staphylococcus epidermidis were determined in previous researches. The 400 mg loading dose with 200 mg/d maintenance dose was recommended and confirmed by the phase II trial. CONCLUSION: The ratio of AUC from the PPK model vs MIC as the PD parameter can be applied in a dose-finding trial of antofloxacin in treatment of bacterial infections. The PPK model suggests that sex and body weight may be considerations in regards to individual therapy, which should be investigated in larger clinical trials and serve as a potential reference for clinical therapies.

Characteristic analysis of clinical trials for new traditional Chinese medicines in mainland China from 2013 to 2021.

Objective: Based on the clinical trials registered on the platform for the registry and publicity of clinical drug trials of the National Medical Products Administration (NMPA), the registration and approval of clinical trials of traditional Chinese medicines (TCMs) in mainland China from 2013 to 2021 were reviewed. Methods: Clinical trials of new TCMs published in Chinese were retrieved from the platform for the registry and publicity of clinical drug trials. The number of registered trials and approved trials, status of clinical trials, therapeutic area of clinical trials for the treatment of diseases, type of trial design, sample size, sponsors, and leading clinical trial centers were evaluated. Results: From 2013 to 2021, a total of 965 clinical trials of new drugs applied in TCM were registered on the aforementioned NMPA platform, comprising 117 phase I trials, 586 phase II trials, 174 phase III trials, 40 phase IV trials, and 48 other clinical trials. The treatment fields included the respiratory system, alimentary tract and metabolism, genetic system and reproductive hormones, and cardiovascular system. Among the 760 phase II and phase III trials, 98.9% were randomized, 95.4% were double-blind, and 98.2% were parallel controlled trials, and the proportion of placebo-controlled trials increased year by year from 2013 to 2021. From 2013 to 2021, 123 new TCMs were approved in mainland China. Conclusion: From 2015 to 2021, the number of registered clinical trials of new TCMs remained low. The approval rate was also low, but the clinical trial design was greatly improved.

Whether Immunostimulants Are Effective in Susceptible Children Suffering From Recurrent Respiratory Tract Infections: A Modeling Analysis Based on Literature Aggregate Data.

Immunostimulants are gradually being used in the prevention and treatment of recurrent respiratory tract infections in susceptible children, but their drug effects have not been quantified. The purpose of this study was to confirm the efficacy of immunostimulants in the prevention and treatment of recurrent respiratory tract infections in susceptible children. A model-based meta-analysis was used to describe the time course of placebo and immunostimulants in the prevention of respiratory tract infections in children. The cumulative number of respiratory tract infections was used as an indicator of efficacy. A meta-analysis was used to analyze the incidence of drug-related adverse events. Fourteen articles with 2400 pediatric subjects were finally included in the analysis. The results showed that the cumulative number of respiratory tract infections increased linearly with time, with the incidence of respiratory tract infections in the placebo group being 0.65 (95% confidence interval [CI], 0.55-0.75) per month. OM-85 BV and pidotimod reduced the incidence of respiratory tract infections by 0.21 (95%CI, 0.16-0.26) and 0.19 (95%CI, 0.17-0.21) compared to placebo per month, respectively. Pidotimod and OM-85 BV can effectively reduce the incidence of respiratory tract infections in susceptible children, with no significant increase in the incidence of drug-related adverse events when compared with placebo (risk ratio values were 1.07 [95%CI, 0.66-1.71] and 1.31 [95%CI, 0.54-3.19], respectively). This study provides quantitative support for the application of immunostimulants for the prevention of recurrent respiratory tract infections in children.

Naoxintong Capsule for Secondary Prevention of Ischemic Stroke: A Multicenter, Randomized, and Placebo-Controlled Trial.

OBJECTIVE: To examine whether the combination of Naoxintong Capsule with standard care could further reduce the recurrence of ischemic stroke without increasing the risk of severe bleeding. METHODS: A total of 23 Chinese medical centers participated in this trial. Adult patients with a history of ischemic stroke were randomly assigned in a 1:1 ratio using a block design to receive either Naoxintong Capsule (1.2 g orally, twice a day) or placebo in addition to standard care. The primary endpoint was recurrence of ischemic stroke within 2 years. Secondary outcomes included myocardial infarction, death due to recurrent ischemic stroke, and all-cause mortality. The safety of drugs was monitored. Results were analyzed using the intention-to-treat principle. RESULTS: A total of 2,200 patients were enrolled from March 2015 to March 2016, of whom 143 and 158 in the Naoxintong and placebo groups were lost to follow-up, respectively. Compared with the placebo group, the recurrence rate of ischemic stroke within 2 years was significantly lower in the Naoxintong group [6.5% vs. 9.5%, hazard ratio (HR): 0.665, 95% confidence interval (CI): 0.492-0.899, P=0.008]. The two groups showed no significant differences in the secondary outcomes and safety, including rates of severe hemorrhage, cerebral hemorrhage and subarachnoid hemorrhage (P>0.05). CONCLUSION: The combination of Naoxintong Capsule with standard care reduced the 2-year stroke recurrence rate in patients with ischemic stroke without increasing the risk of severe hemorrhage in high-risk patients. (Trial registration No. NCT02334969).

Interpreting the Molecular Mechanisms of Yinchenhao Decoction on Hepatocellular Carcinoma through Absorbed Components Based on Network Pharmacology.

To investigate the mechanisms through which Yinchenhao decoction (YCHD) inhibits hepatocellular carcinoma (HCC), we analyzed YCHD ingredients absorbed into the bloodstream by using network pharmacology. We conducted a weighted gene coexpression network analysis on gene expression data collected from the Gene Expression Omnibus and The Cancer Genome Atlas databases to derive an HCC gene set; moreover, we used four online prediction system databases to predict the potential targets of YCHD ingredients absorbed into the bloodstream. We discovered that YCHD directly interfered with 17 HCC-related disease targets. Subsequent gene ontology enrichment analyses of these 17 disease targets revealed that YCHD exhibited effects through 17 biological processes, 7 molecular functions, and 9 cellular components. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated 14 pathways through which YCHD inhibits HCC. We observed similar trends in how the 17 small molecules interfered with the key target set. We surmised that YCHD inhibits HCC by regulating inflammatory and metabolic pathways. Network pharmacological analysis of YCHD ingredients absorbed into the bloodstream may provide new insights and serve as a new method for discovering the molecular mechanisms through which YCHD inhibits HCC.