States Food And Drug Administration Research Articles

Simultaneous Quantification of Vancomycin, Linezolid and Voriconazole in Human Plasma by UHPLC–MS/MS: Application in Therapeutic Drug Monitoring

Abstract Objective Individual differences challenge the treatment of vancomycin, linezolid and voriconazole in severe infections. This study aimed to build a simple and economical method for simultaneous determination of the three antibiotics in human plasma by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC–MS/MS) and provided a reference for therapeutic drug monitoring (TDM) of infected patients. Methods The plasma samples were precipitated by acetonitrile and detected and separated on a shim-pack GIST C18 column following the gradient elution within 5 min. Mass quantification was performed on multiple reaction monitoring mode under positive electrospray ionization. Results The linear ranges of vancomycin, linezolid and voriconazole were 1.00–100.00, 0.10–15.00 and 0.10–20.00 μg·mL−1, respectively, with good linearity (R2 > 0.99). The accuracy and precision, matrix effect, extraction recovery and stability were validated, and the results all meet the acceptance criteria of China Food and Drug Administration (CFDA) guidelines. Conclusion The UHPLC–MS/MS method was established and validated for the simultaneous determination of vancomycin, linezolid and voriconazole in human plasma and successfully applied to routine TDM for individualized treatment.

[Chinese expert consensus on the analytical validation of tumor comprehensive genomic profiling next generation sequencing testing (2024 edition)].

In hospital laboratories-developed testing is of great significance for the clinical testing products that has not been approved by the National Medical Product Administration and is urgently needed to meet clinical practice needs. With the development of cancer precision medicine in recent years, comprehensive genomic profiling (CGP) has become an important means and method for the detection of drug targets, precise molecular typing, and immunotherapy biomarkers in cancer patients. However, there is still a lack of unified understanding and consensus on clinical testing standards and application specifications for laboratory-developed testing in the hospitals. The Molecular Pathology Collaboration Group of the Cancer Experts Committee of the Chinese Anti-Cancer Association and the Molecular Pathology Group of the Pathology Branch of the Chinese Medical Association initiated the expert consensus on relevant specifications for analytical validation of CGP next-generation sequencing (NGS) testing in Chinese hospitals. Combined with domestic clinical practice, refer to domestic and foreign literatures, from the background of the laboratory-developed testing, analytical validation scenarios, evaluation indicators and variation ranges, sample types and quantities covered by analytical validation, clinical performance and drug efficacy determination, and site personnel for analytical validation, quality control, inter-laboratory quality evaluation and document management, etc. After the discussion by the expert group, 12 expert consensuses were formed to provide reference for the analytical validation and clinical application of tumor CGP NGS testing in Chinese hospitals, so as to promote the laboratory-developed testing applications in Chinese hospitals.

Increased levels of villus-derived exosomal miR-29a-3p in normal pregnancy than uRPL patients suppresses decidual NK cell production of interferon-γ and exerts a therapeutic effect in abortion-prone mice

ObjectiveRecurrent pregnancy loss (RPL) patients have higher absolute numbers of decidual natural killer (dNK) cells with elevated intracellular IFN-γ levels leading to a pro-inflammatory cytokine milieu, which contributes to RPL pathogenesis. The main objective of this study was twofold: first to explore the regulatory effects and mechanisms of villus-derived exosomes (vEXOs) from induced abortion patients or RPL patients at the level of intracellular IFN-γ in dNK cells; second to determine the validity of application of vEXOs in the treatment of unexplained RPL (uRPL) through in vitro experiments and mouse models.MethodsExosomes were isolated from villus explants by ultracentrifugation, co-cultured with dNK cells, and purified by enzymatic digestion and magnetically activated cell sorting. Flow cytometry, enzyme-linked immunosorbent assays, and RT-qPCR were used to determine IFN-γ levels. Comparative miRNA analysis of vEXOs from induced abortion (IA) and uRPL patients was used to screen potential candidates involved in dNK regulation, which was further confirmed by luciferase reporter assays. IA-vEXOs were electroporated with therapeutic miRNAs and encapsulated in a China Food and Drug Administration (CFDA)-approved hyaluronate gel (HA-Gel), which has been used as a clinical biomaterial in cell therapy for > 30 years. In vivo tracking was performed using 1,1-dioctadecyl-3,3,3,3-tetramethylindotricarbocyaine iodide (DiR) labelling. Tail-vein and uterine horn injections were used to evaluate therapeutic effects of the engineered exosomes in an abortion-prone mouse model (CBA/J × DBA/2 J). Placental growth was evaluated based on placental weight. IFN-γ mRNA levels in mouse placentas were measured by RT-qPCR.ResultsIFN-γ levels were significantly higher in dNK cells of uRPL patients than in IA patients. Both uRPL-vEXOs and IA-vEXOs could be efficiently internalized by dNK cells, whereas uRPL-vEXOs could not reduce the expression of IFN-γ by dNK cells as much as IA-vEXOs. Mechanistically, miR-29a-3p was delivered by vEXOs to inhibit IFN-γ production by binding to the 3′ UTR of IFN-γ mRNA in dNK cells. For in vivo treatment, application of the HA-Gel effectively prolonged the residence time of vEXOs in the uterine cavity via sustained release. Engineered vEXOs loaded with miR-29a-3p reduced the embryo resorption rate in RPL mice with no signs of systemic toxicity.ConclusionOur study provides the first evidence that villi can regulate dNK cell production of IFN-γ via exosome-mediated transfer of miR-29a-3p, which deepens our understanding of maternal–fetal immune tolerance for pregnancy maintenance. Based on this, we developed a new strategy to mix engineered vEXOs with HA-Gel, which exhibited good therapeutic effects in mice with uRPL and could be used for potential clinical applications in uRPL treatment.Graphical

Metabolomics-Based Effects of a Natural Product on Remyelination After Cerebral Ischemia Injury Via GABABR–pCREB–BDNF Pathway

Background Yi-Qi-Tong-Luo Granules (YQTLs) is a natural compound of Traditional Chinese Medicine authorized by China Food and Drug Administration (CFDA). These granules are employed in the convalescent stage of cerebral infarction and render notable clinical efficacy. This study aims to uncover the underlying mechanisms of YQTLs on remyelination after cerebral ischemia injury. Materials and Methods We established cerebral ischemia model in rats using microsphere-induced multiple cerebral infarction (MCI). We evaluated the pharmacological effects of YQTLs on MCI rats, through Morri’s water maze test, open field test, hematoxylin and eosin staining, and glycine silver immersion. We employed liquid chromatography mass spectrometry metabolomics to identify differential metabolites. Enzyme-linked immunosorbent assay was utilized to measure the release of neurotrophins, while immunofluorescence staining was used to assess oligodendrocyte precursor cells differences and myelin regeneration. We used Western blotting to validate the protein expression of remyelination-associated signaling pathways. Results YQTLs significantly improves cognitive function following cerebral ischemia injury. Pathological tissue staining revealed that YQTLs administration inhibits neuronal denaturation and neurofibrillary tangles. We identified 141 differential metabolites among the sham, MCI, and YQTLs-treated MCI groups. Among these metabolites, neurotransmitters were identified, and notably, gamma-aminobutyric acid (GABA) showed marked improvement in the YQTLs group. The induction of neurotrophins, such as brain-derived neurotrophic factor (BDNF) and PDGFAA, upregulation of olig2 and MBP expression, and promotion of remyelination were evident in YQTLs-treated MCI groups. Gamma-aminobutyric acid B receptors (GABABR), pERK/extracellular regulated MAP kinase, pAKT/protein kinase B, and pCREB/cAMP response element-binding were upregulated following YQTLs treatment. Conclusion YQTLs enhance the binding of GABA to GABABR, thereby activating the pCREB/BDNF signaling pathway, which in turn increases the expression of downstream myelin-associated proteins and promotes remyelination and cognitive function.

Review time of oncology drugs and its underlying factors: an exploration in China.

Introduction: How the launch delay of drugs and other factors of interest can influence the length of the review period by drug agencies is still unknown, and understanding this can help better strike the trade-off related to review speed. Methods: We included all new oncology drug applications submitted to China's National Medical Product Administration (NMPA) between 1 January 2018 and 31 December 2021, and ultimately succeeded in achieving marketing approval. For each drug, the length of the NMPA review process and other major characteristics were collected, including the registration class, approval class, priority review designation, and launch delay relative to the United States, as well as the number of patients enrolled, comparator, and primary endpoint of the pivotal trials supporting the approval. Linear regression model was employed to analyze the effects of factors of interest on the NMPA review time. Results: From 2018 to 2021, NMPA received 137 oncology applications that were ultimately approved. Half of the approvals [76 (55.5%)] were first licensed in the US, leaving a median launch delay of 2.71years (IQR, 1.03-5.59) in China. In the pivotal studies, the median enrollment was 361 participants (IQR, 131-682), and the use of control groups [90 (65.7%)] and surrogate endpoints [101 (73.7%)] was prevalent. The median review time was 304days (IQR, 253-376). Multivariate analysis for log-transformed review time showed that larger enrollment ( 92) was associated with a drop of 20.55% in review time (coefficient = -0.230; 95% CI, -0.404 to -0.055; p = 0.010); and a short delay (0 delay 1.95years) was associated with a drop of 17.63% in review time (coefficient = -0.194; 95% CI, -0.325 to -0.062; p = 0.004). Discussion: The short launch delay relative to the US was one important driver to the review speed of NMPA, which might suggest its latent regulatory reliance on the other global regulator during the post-marketing period when new information on the drug's clinical benefit was still lacking.

[Guidelines for pharmaceutical care of endocrine therapeutics for breast cancer(2023 edition)].

Endocrine therapy is one of the primary treatment methods for hormone receptor-positive breast cancer patients. As of June 1 2023, the National Medical Product Administration has approved 56 drugs related to endocrine therapy in patients with HR+ /HER-2- breast cancer (including generic drugs that have passed the consistency evaluation), including 44 endocrine drugs which can be categorized according to their mechanisms of action into selective estrogen receptor modulators, selective estrogen receptor down-regulators, aromatase inhibitors, luteinizing hormone-releasing hormone analogs, and progestogens and 12 targeted drugs for combined with endocrine therapy, including CDK4/6 inhibitors, mTOR inhibitors, and HDAC inhibitors. The different pharmacological characteristics, mechanisms of action, and long-term medication factors of breast cancer endocrine therapy-related drugs can directly affect patients' medication adherence and medication safety. To standardize the pharmaceutical care of endocrine therapy drugs for breast cancer and promote rational use in clinical settings, the Oncology Specialty Pharmacist Subcommittee, in conjunction with multidisciplinary experts nationwide, has developed the "Guidelines for pharmaceutical care of endocrine therapy drugs for breast cancer (2023 edition)". The guidelines is based on clinical evidence-based evidence, relevant regulations of pharmaceutical management, and pharmaceutical care practices. The Delphi method and expert interviews were used to formulate the guidelines. The GRADE approach was used for assessing the certainty of evidence. This guideline mainly focuses on endocrine therapy for HR+ /HER-2- breast cancer patients. Due to space constraints, HER-2 positive targeted drugs were not included in the guideline. It covers 6 dimensions and 22 key problems of pharmaceutical care in the whole process of drug therapy, providing a scientific basis for pharmacists to carry out pharmaceutical care of such drugs.

Exploring the potential mechanism of Xuebijing injection against sepsis based on metabolomics and network pharmacology

Sepsis is a major contributor to the death of critically ill patients globally, in which metabolic disturbance is observed. Xuebijing injection (XBJ), a well-known traditional Chinese medicine, has received approval by the State Food and Drug Administration (SFDA) of China owing to its satisfactory clinical therapeutic effect. Nowadays, it has been applied clinically to the treatment of sepsis, but its effect on metabolic disorders remains unclear. In the present study, we sought to explore its underlying mechanism by employing a combination of network pharmacology and metabolomics. Initially, its protective effects were validated using a sepsis rat model created through cecal ligation puncture (CLP). Subsequently, the metabonomic strategy was utilized to discriminate the differential metabolic markers. Meanwhile, a comprehensive view of the potential ingredient-target-disease network was constructed based on a network pharmacology analysis. Next, the network diagram was constructed by integrating the results of network pharmacology and metabonomics. Finally, qRT-PCR together with Western blot was used to validate the expression levels of the associated genes. Based on our findings, we identified 34 differential metabolites in the sepsis group and 26 distinct metabolites in the XBJ group, with 8 common biological metabolites predominantly associated with arginine and proline metabolism. Through comprehensive analysis, we identified 21 genes that regulate metabolites, and qRT-PCR validation was conducted on six of these genes in both liver and kidney tissues. Additionally, XBJ demonstrated the capability to inhibit the activation of the NF-kB signaling pathway in both liver and kidney tissues, leading to a reduction in the occurrence of inflammatory responses. In summary, our study has validated the complexity of the natural compounds within XBJ and elucidated their potential mechanisms for addressing CLP-induced metabolic disturbances. This work contributes to our understanding of the bioactive compounds and their associated targets, providing insights into the potential molecular mechanisms involved.

Cost-effectiveness analysis of anlotinib as a third-line or further treatment for advanced non-small cell lung cancer in China.

The health expenditure on treatment of advanced non-small cell lung cancer (NSCLC) is enormous, especially in third-line or further therapy. Cost-effectiveness analysis for the treatment of advanced NSCLC is particularly important. Anlotinib has been approved by the China Food and Drug Administration (CFDA) for the third-line or further treatment of advanced NSCLC. The price of anlotinib in China fell in 2022. Thus, this study evaluated the cost-effectiveness of anlotinib in the third-line or further treatment of patients with advanced NSCLC based on the newest price from the Chinese health-care system perspective. A Markov model was developed to compare the lifetime costs and effectiveness of anlotinib and a placebo in the third-line or further treatment of patients with advanced NSCLC based on outcome data from the ALTER 0303 phase-3 randomized clinical trial, which included 437 patients with advanced NSCLC and investigated the efficacy of anlotinib. The lifetime costs and quality-adjusted life years (QALYs) were estimated. One-way and probabilistic sensitivity analyses were performed to evaluate the model uncertainty. Anlotinib provided an additional 0.1161 QALYs compared to the placebo. The corresponding incremental cost was ¥22,729. The incremental cost-effectiveness ratio (ICER) of anlotinib compared to the placebo was ¥195,768 per QALY. From the perspective of the Chinese health-care system, anlotinib was found to be cost-effective compared to the placebo in the third-line or further treatment of patients with advanced NSCLC at a willingness-to-pay (WTP) threshold of ¥242,928 per QALY. Moreover, 1-way sensitivity analysis found that the results were sensitive to the utility of progressive disease (PD). The lower this parameter was, the higher the probability of ICER for anlotinib not being cost-effective. The cost-effectiveness acceptability curves showed that the base-case analysis results were relatively stable. Considering the clinical efficacy, safety, and cost-effectiveness of anlotinib, it may be a valuable third-line or further treatment for advanced NSCLC in China.

Comparison of CHOP‐like with or without Tucidinostat in the first‐line treatment of Peripheral T‐cell lymphoma: a retrospective propensity score‐matched study

Introduction: Peripheral T cell lymphoma (PTCL) is a group of highly heterogeneous malignancies with a high rate of disease relapse or progression.Tucidinostat (formerly known as chidamide(C)),a novel histone deacetylase inhibitor, has shown promising results in T-cell lymphomas by multiple mechanisms and is currently approved by the Chinese FDA for relapsed/refractory PTCL.In this retrospective study,we compared the efficacy of Tucidinostat with CHOP-like (C+CHT) and CHOP-like (CHT) alone in newly diagnosed PTCL. Methods: We reviewed 132 patients with PTCL diagnosed at the Shanxi Provincial Cancer Hospital Hematology Oncology Center from January 2015 to July 2021,of whom 109 patients were diagnosed with newly diagnosed PTCL,with last follow-up as of November 2022.Those in the C+CHT group who achieved complete remission received Tucidinostat maintenance therapy.The two groups of patients were subjected to 1:1 propensity score matching, according to whether the Prognostic index for PTCL-NOS(PIT) ≥2, pathological subtype, age＞60 years, and gender (matching tolerance = 0.024),36 pairs (n = 72) were matched. The primary study endpoint of this study was progression-free survival (PFS), and the secondary study endpoints were overall survival (OS), objective remission rate (ORR) at the end of the first-line chemotherapy regimen, CR rate and adverse events (AEs). Results: After matching,no statistical difference was found in baseline characteristics between C+CHT (n = 36) and control (n = 36) groups (all P > 0.05).The ORR for C+CHT group and control group were 72.2% and 52.8% (p = 0.088), with the CR rate of 44.4% and 33.3% (p = 0.334). After median follow-up of 18.7 (range 1.0–82.8) months, the median PFS in C+CHT group and control group were 17.2 and 5.0 months, respectively; the 2-year PFS was 67.9% and 25.3%, respectively; the median OS was 43.7 and 18.5 months, respectively; and the 2-year survival rate was 65.6% and 35.7%, respectively. Compared with control group, C+CHT group displayed significantly longer PFS(HR = 0.553, 95% CI: 0.319–0.959,p = 0.035, Figure 1A) and OS(HR = 0.483, 95% CI: 0.251–0.930, p = 0.029, Figure 1B). Cox analyses further verify that the effect values were basically consistent with the matching results (PFS HR = 0.552, OS HR = 0.469). Common grade 3–4 hematological AEs in the C+CHT group were leukopenia (55.9%), neutropenia (52.9%), thrombocytopenia (26.5%), and anemia (20.6%), the incidence of AEs was comparable to that of the control group. Common non-hematological AEs, the incidences of elevated AST and ALT were higher in the C+CHT group than in the control group(p = 0.028 and p = 0.021, respectively), but they were mainly grade 1 AEs, which could be resolved with supportive treatment. Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Novel Proline Derivatives for Treating COVID-19.

COVID-19 is a contagious disease. Paxlovid, a combination of Nirmatrelvir and Ritonavir, was granted emergency use authorization by the United States Food and Drug Administration (FDA) for the treatment of COVID-19 on December 22, 2021. These are peptidomimetic coronavirus main protease inhibitors. Nirmatrelvir is a proline derivative. The present patent describes similar proline- like compounds, their preparation, use, pharmaceutical composition, and treatment.

A mass balance study of [14C]SHR6390 (dalpiciclib), a selective and potent CDK4/6 inhibitor in humans.

SHR6390 (dalpiciclib) is a selective and effective cyclin-dependent kinase (CDK) 4/6 inhibitor and an effective cancer therapeutic agent. On 31 December 2021, the new drug application was approved by National Medical Product Administration (NMPA). The metabolism, mass balance, and pharmacokinetics of SHR6390 in 6 healthy Chinese male subjects after a single oral dose of 150mg [14C]SHR6390 (150µCi) in this research. The Tmax of SHR6390 was 3.00h. In plasma, the t 1/2 of SHR6390 and its relative components was approximately 17.50h. The radioactivity B/P (blood-to-plasma) AUC0-t ratio was 1.81, indicating the preferential distribution of drug-related substances in blood cells. At 312h after administration, the average cumulative excretion of radioactivity was 94.63% of the dose, including 22.69% in urine and 71.93% in stool. Thirteen metabolites were identified. In plasma, because of the low level of radioactivity, only SHR6390 was detected in pooled AUC0-24h plasma. Stool SHR6390 was the main component in urine and stool. Five metabolites were identified in urine, and 12 metabolites were identified in stool. Overall, faecal clearance is the main method of excretion.

Sodium Oligomannate Electrostatically Binds to Aβ and Blocks Its Aggregation.

GV-971 (sodium oligomannate) is a China Food and Drug Administration (CFDA)-approved drug for treating Alzheimer's disease, and it could inhibit Aβ fibril formation in vitro and in mouse studies. To elucidate the mechanisms for understanding how GV-971 modulates Aβ's aggregation, we conducted a systematic biochemical and biophysical study of Aβ40/Aβ42:GV-971 systems. The integrating analysis of previously published data and our results suggests that the multisite electrostatic interactions between GV-971's carboxylic groups and Aβ40/Aβ42's three histidine residues might play a dominant role in driving the binding of GV-971 to Aβ. The fuzzy-type electrostatic interactions between GV-971 and Aβ are expected to protect Aβ from aggregation potentially through breaking the histidine-mediated inter-Aβ electrostatic interactions. Meanwhile, since GV-971's binding exhibited a slight downregulation effect on the flexibility of Aβ's histidine-colonized fragment, which potentially favors Aβ aggregation, we conclude that the dynamics alteration plays a minor role in GV-971's modulation on Aβ aggregation.

Research Progress of Immunotherapy for Gastric Cancer.

Gastric cancer (GC) is one of the most common gastrointestinal tract cancers worldwide, which has high incidence and mortality rates and poor prognosis. Although multidisciplinary comprehensive therapies consisting of surgery, chemotherapy, radiotherapy, and targeted therapy have made great progress in GC treatment, a satisfactory curative effect still cannot be achieved in many circumstances, and the 5-year survival of patients with GC remains to be very low. In China, about 75% of patients with GC are diagnosed in the advanced stage and thus miss the opportunity of surgical resection. Although the conventional treatment of GC has improved the survival time of advanced patients to a certain extent, the clinical efficacy has encountered a bottleneck and cannot bring higher survival benefits to patients. With the development of immunologic and molecular biologic technologies, immunotherapy has gradually become a new essential treatment for GC, which has attracted extensive attention in the field of oncology. The US Food and Drug Administration (USFDA) and China Food and Drug Administration (CFDA) have approved a variety of immune-related drugs for the treatment of GC, and all of which have achieved good efficacy. In this review, we summarize the recent development in nonspecific enhancer therapy, adoptive immunocell therapy, tumor vaccine therapy, oncolytic virus therapy, and immune checkpoint inhibitor therapy, and their roles in the treatment of GC.

Stem Cell Therapy for the Treatment of Crohn's Disease; Current Obstacles and Future Hopes.

Crohn's disease (CD) is an autoimmune disease of the gastrointestinal tract, characterized by relapsing and remitting courses. The disease is debilitating in nature with three prominent phenotypic clinical presentations; fistulizing, stenosing, and inflammatory. Stem cells offer new hope for CD patients by modifying the immune response and progression of the healing process. This mini-review discusses the role of stem cells in treating CD, their effectiveness as a new therapy and their current limitations. The author conducted a literature review on recent randomized controlled trials and cohort studies concerned with the topic in question using the following keywords (Crohn's Disease, perianal fistula, Stem cell therapy, mesenchymal stem cells, remission). Clinical trials show that the stem cells are more effective in the CD-associated complex perianal fistula than the CD enteritis. At present, there are no standardized guidelines regarding dose of stem cells used, number of doses administered, route of administration, type of stem cells used. Only one group of researchers proposed a standardized procedure for injecting mesenchymal stem cells in complex perianal fistula, according to their own experience in clinical trials. Moreover, mesenchymal stem cells and their related types (placental, adipose tissue, umbilical tissue, etc.) are the safest and effective in clinical trials. Currently, the commercially available mesenchymal stem cells preparation (Darvadstrocel (Cx601)) is the only one approved by The United States Food and Drug Administration (FDA) for clinical use in refractory CD associated complex perianal fistula. Stem cell therapy (SCT) shows promise in inducing remission in refractory Crohn's colitis, and perianal fistula, but further research is required before SCT could be applied to clinical practice guidelines.

Off-label dose direct oral anticoagulants and clinical outcomes in Asian patients with atrial fibrillation: A new evidence of Asian dose

AimThis study aimed to evaluate the label compliance of DOACs in the Chinese AF population and explore the relationship between inappropriate DOACs dosage and clinical results. Methods and resultsThis is a retrospective multicenter cohort study conducted in 14 centers in China. According to the China Food and Drug Administration(CFDA) label and the recommendations of international guidelines, we divided patients into on-label dosage and off-label dosage. We then compared the clinical results after propensity score matching. We collect demographic information through the hospital information system and obtain clinical events through follow-up of patients or their families. Clinical results include major, minor, total bleeding, thrombosis, and all-cause death. 4191 patients with non-valvular AF (NVAF) were included, and approximately 55.6% and 1.7% of AF patients received off-label underdose and off-label overdose of DOACs, respectively. Compared with the on-label dose, DOACs with off-label underdose were associated with a significantly reduced risk of major bleeding (P = 0.004, OR = 0.23,95% CI: 0.08–0.69) and all-cause death (P<0.001, OR = 0.49,95% CI: 0.33–0.73). However, there was no significant difference in thrombotic events (P = 0.865 OR = 1.06,95% CI: 0.54–2.07) and minor bleeding (P = 0.465, OR = 1.10,95% CI: 0.85–1.43) risk. ConclusionsAbout 57.3% of Asian AF patients received an off-label dose of DOACs in daily practice. Off-label underdose DOACs were associated with significantly lower risks of major bleeding, all-cause death, and similar risks of minor bleeding, thrombotic events compared with on-label dose DOACs. Further prospective randomized trials are needed to determine the optimal dose of DOACs in Asian patients with AF at high bleeding risk.

Analysis of the problems of drug sampling and testing programme under tripartite system reform in China.

To ensure that quality medicines are available to the populace. To provide a new perspective for drug sampling and testing using a risk-based approach globally, and provide a reference for improving the efficiency of the drug sampling and testing programme in China. This study used a combination of theoretical analysis and problem analysis. First, we analysed the high-risk drugs that should be given attention to theoretically in the drug sampling testing programme based on the healthcare reform in China. Second, this study leveraged on data on the sampling and testing of drugs extracted from self-constructed data by the China Food and Drug Administration (CFDA). The integrated and structured data sets were used to conduct an innovative analysis that identifies the actual content of the drug sampling and testing programme and contrasts them with the theoretical content to understand the problems. This study used quantitative and qualitative approaches for data analysis. Following analysis, we discovered that there is still a big gap between the reality of drug sampling and testing in China and the ideal state of the objective requirements of healthcare reforms. The major sources of risk are the retail pharmacies or hospital pharmacies in the distribution chain of drugs; however, the CFDA sampled mostly drugs from drug manufacturers. Additionally, the CFDA did not sample adequate essential medicines, bid-winning drugs (especially those with large price drops in centralized procurement), biological productsand other high-risk drug varieties. The high-risk drugs produced by companies or enterprises with a history of noncompliance, especially bid-winning enterprises in centralized procurement, were not sampled. We suggest that the major content of drug sampling and testing in China should focus on the link of drug utilization, varieties of drugs with large price drops in centralized procurementand bid-winning enterprises with a history of noncompliance.

Clinical effectiveness of Qilong capsule in patients with ischemic stroke: A prospective, multicenter, non-randomized controlled trial

BackgroundThe Qilong capsule (QLC) is a Chinese patented medicine characterized by an equal emphasis on replenishing Qi and activating blood circulation. In 2000, China's FDA approved the use of QLC for ischemic stroke (IS). However, there is not yet much high-quality evidence of the clinical effectiveness of QLC combined with conventional treatment (CT) for IS with Qi deficiency and blood stasis syndrome. PurposeIn this study, we conducted a prospective, multicenter, non-randomized controlled trial at 7 hospitals in China to investigate the clinical effectiveness of QLC combined with CT for IS with Qi deficiency and blood stasis syndrome. MethodsParticipants aged 35 to 80 years old diagnosed as IS with Qi deficiency and blood stasis syndrome in TCM were recruited. Participants were treated with QLC (intervention group) or non-QLC (control group). The intervention course of QLC was 12 weeks. All participants in two groups received standard treatment. All participants returned for in-person follow-up visits at the 12th week and 24th week. Primary outcome measures included a modified Rankin Scale (mRS), the National Institute of Health Stroke Scale (NIHSS), and the Barthel Index (BI). Secondary outcome measures included TCM syndromes (Qi deficiency syndrome score, blood stasis syndrome score), psychological index (self-rating depression scale, SDS; self-rating anxiety scale, SAS), blood lipid index, blood coagulation index, homocysteine, and favorable functional outcome (mRS 0 – 3). Multiple imputations were used for any missing data. Propensity score matching (PSM) was used to deal with any confounding factors (age, gender, scale score, etc.). Rank alignment transformation variance analysis (ART ANOVA) and generalized linear mixed model (GLMM) were introduced to improve the scientific and accuracy of repeated measurement data. All statistical calculations were carried out with R 3.6.1 statistical analysis software. ResultsA total of 2468 participants were screened from November 2016 to January 2019. Finally, 2302 eligible participants were included in the analysis. There were 1260 participants in the intervention group (QLC group) and 1042 participants in the control group (non-QLC group). After PSM matching, sub-samples of 300 participants in the QLC group and 300 participants in the non-QLC group were finally formed. The final results of clinical effectiveness are the same results shared by the total samples and sub-samples after PSM. In the 24th week after treatment, QLC combined with CT proved to be significantly better than CT alone in reducing the scores of mRS (p < 0.05), NIHSS (p < 0.001), Qi deficiency syndrome (p < 0.01), and blood stasis syndrome (p < 0.001), SAS (p < 0.05), as well as in improving BI score (p < 0.05). The favourable functional outcome (mRS score of 0 to 3 at week 12) was statistically different between QLC and non-QLC group in the sub-samples (p < 0.01, 97% vs 91.7%). The results of the ART ANOVA showed that the improvement of mRS (p < 0.01), BI (p < 0.05) and NIHSS (p < 0.001) in QLC group was better than non-QLC group when the interaction effect was considered. The results of GLMM showed that the reduction of mRS and NIHSS scores of patients in the QLC group were better than those of the non-QLC group (p < 0.001). The BI score of the QLC group in the sub-samples after PSM increased more than the non-QLC group (p < 0.001). There was no evidence showing that QLC can cause serious adverse reactions (ADRs) in treating patients with IS. ConclusionQLC combined with CT was better than CT alone in reducing mRS score, NIHSS score, Qi deficiency syndrome score, blood stasis syndrome score, and SAS score, as well as improving BI score after treatment. Further high-quality RCTs are needed to confirm the positive results. The study protocol was embedded in a registry study that registered in the Clinical Trials USA Registry (registration No. NCT03174535).

Effectiveness and safety of sacubitril/valsartan for patients with hypertension and heart failure in the real-world setting: A retrospective study in China.

Hypertension (HP) is associated with heart failure (HF). Sacubitril/valsartan (sac/val) has been approved for primary HP by China Food and Drug Administration (CFDA) in June 2021. The present study aimed to provide evidence on the effectiveness and safety of sac/val in Chinese patients complicated with HP and HF. This retrospective study was conducted on adult patients diagnosed with HP and HF and treated with sac/val between July 2020 and December 2020. The potential risk factors for the discontinuation events caused by sac/val-related adverse events (AEs) were explored. The data, including blood pressure (BP), cardiac indicators, corresponding values on echocardiographic parameters, unplanned visits, and AEs throughout 3-12 months, were collected. A total of 446 eligible patients were included in this study. The discontinuation events of sac/val were mainly attributed to its AEs (hypotension, hyperkalemia, and deterioration in kidney function). Univariate analysis revealed that history of chronic kidney disease, atrial fibrillation, higher values of serum creatinine, serum uric acid, serum N-terminal pro B-type natriuretic peptide, and lower estimated glomerular filtration rate were potential risk factors for discontinuation. Patients who maintained sac/val therapy throughout 3-12 months showed significantly improved values of clinical BP, cardiac indicators, and echocardiographic parameters compared to those at baseline (p < 0.0001). Sac/val was effective on BP and improved cardiac function in patients complicated with HP and HF. The physicians should focus on patients with renal dysfunction to take timely precautions to improve tolerability for sac/val.

Registered Clinical Trials Comprising Pregnant Women in China: A Cross-Sectional Study.

Background: In this study, an investigation was conducted on clinical drug trials comprising pregnant women in China that provided data on the quantity, properties, source of funding, and geographical distribution regarding registration and post-marketing studies. Methods: We conducted a cross-sectional descriptive study of clinical trials of pregnant women in China on 30 December 2021, and it was registered on the official Drug Clinical Trial Information Management Platform (ChiCTR) (http://www.chinadrugtrials.org.cn) established by the State Food and Drug Administration of China (Chinese FDA). Results: This study encompassed 72 registered trials (0.46%, 72/15,539) for data analysis. Of these trials, 43.1% of trials were started between 2013 and 2016, and nearly half of the trials (48.6%) were completed. Industries were listed as the primary sponsor for 95.8% trials. Economically developed eastern China and northern China, accounting for 69.5% of the 72 registered trials, were the most frequently identified study locations. Regarding study designs of these trials, more than half of the trials (70.8%) were randomized, 61.1% were a parallel assignment, 33.3% were phase 3, and half of the trials (54.2%) were open label. In total, 23 trials met the requirements after excluding trials of cancer and/or of postmenopausal women, accounting for 0.15% of the 15,539 registered trials in the ChiCTR websites. Of the 72 clinical trials, 54 drugs for 18 indications were included. Of these indications, the highest proportion of the trials is osteoporosis (27.8%), followed by cancer (22.2%), assisted reproduction (13.9%), and other indications (13.9%). Conclusion: This survey revealed a significant shortage of the development, evaluation, and safety trials of pregnancy-related drugs in China. Modifying or adding legislation and providing financial incentives may therefore encourage pharmaceutical companies to conduct additional clinical trials on pregnant women.

Functional food for alleviation of nutritional amemia in China: an analysis on official registration data

Objective To analyze the status quo of functional food for improving nutritional anemia officially registered in China for providing evidences to relevant research and development of enterprises and governmental supervision. Methods From the website of China Food and Drug Administration (CFDA) and State Administration for Market Regulation (SAMR), we extracted the information on 228 functional food products (FFPs) for improving nutritional anemia officially registered in China from March 1996 through February 2010. Dosage form, function claim, composition of traditional Chinese medicine, content of iron-compound, and content measurement of functional/marker components of the FFPs were analyze with general descriptive analysis, visual data analysis, factor analysis and principal component analysis using Ucinet 6 and SPSS 22.0. Social network mapping was performed to display the utilization frequency of the 73 traditional Chinese medicine and its extracts and other bioactive compounds which were included in the ingredients of the three or more of the FFPs. Results Of the 228 FFPs in 7 dosage forms, 117 (51.3%) are oral liquids. The main raw materials were listed the ingredients of 197 (86.4%) of the FFPs. Angelica sinensis and its extract, Astragalus membranaceus and its extract, donkey-hide gelatin, Chinese-date and its extract, and iron and its compound are among the components locating in central region of the social network map constructed. Traditional Chinese medicine raw material and medicine food homology raw material were listed in the ingredients of 157 FFPs. Among 14 top traditional Chinese medicine raw material most frequently used in the FFPs, seven common factors (Angelica sinensis and Astragalus mongholicus, Poria cocos and Chinese yam, prepared rehmannia root and Codonopsis pilosula, Paeonia Lactiflora, mulberry, longan, Lycium chinensis and black-bone chicken) were identified, contributing a cumulative variance of 72.378. Among the 165 FFPs with iron-compound in the ingredients, 130 (78.8%) contain traditional Chinese medicine raw material. The top 5 iron-compounds utilized in the 165 FFPs are ferrous lactate (in 46 FFPs), ferrous gluconate (43), heme chloride (30), ferrous fumarate (9), and ehylenediaminetetraacetic acid ferric sodium (8), respectively. Of the 70 FFPs approved by the Ministry of Health of the People′s Republic of China, 42 (60.0%) indicated the contents of functional/marker components in the products′ registration information; all the 158 FFPs approved by CFDA and SAMR indicated the contents of functional/marker components in the products′ registration information, with the top 3 most frequently listed functional/marker components of iron (in the ingredients of 76% of the 158 FFPs), polysaccharide (29.5%), and total saponins (22%). Conclusion For the officially registered FFPs for improving nutritional anemia, the combination and types of utilized traditional Chinese medicine raw material is relatively identical and there is lack of known specific correlation between the utilized traditional Chinese medicine raw material and the implied effect of functional/marker components.