Safety-Related Drug Withdrawals in China Between 1999 and 2021: A Systematic Investigation and Analysis.

INTRODUCTION: The Chinese National Medical Products Administration (NMPA) has emphasized proactive pharmacovigilance throughout the product life cycle in recent years. However, the safety-related withdrawal of drugs from the Chinese market has received less attention. OBJECTIVES: The primary aim of the study was to investigate the context of withdrawing a drug for safety reasons in China (between 1999 and 2021). METHODS: Withdrawn drugs were first identified from the Chinese NMPA and United States (US) Food and Drug Administration websites and the World Health Organization's (WHO's) consolidated list of products, WHO Drug Information, and WHO Pharmaceuticals Newsletter. We then searched the China National Knowledge Internet database, Chongqing VIP information database, Wanfang database, PubMed, and Google Scholar for drug withdrawal details. We used the Oxford Centre for Evidence-Based Medicine criteria to assess the levels of evidence that support withdrawing a drug. RESULTS: A total of 30 drugs were withdrawn from the Chinese market between 1999 and 2021. The number of withdrawals increased during the stable Chinese drug surveillance period (2012-2021). Evidence from case-series or case-control studies was primarily used to determine the withdrawals of 16 drugs (53.3%). Fifteen drugs were withdrawn from the markets of China and the US, including five drugs (5/15, 33.3%) that were withdrawn in the same year in China and the US. CONCLUSIONS: The promulgation of regulations and development of advanced passive and active systems have enhanced pharmacovigilance in China. High-quality evidence, coordination with other regulatory authorities, and communication and information sharing should be strengthened to optimize drug safety surveillance and risk management.

Real-World First-Line Treatment Patterns and Outcomes in Hormone Receptor-Positive Advanced Breast Cancer Patients: A Multicenter, Retrospective Study in China.

Background: Recent data on first-line treatment patterns administered to hormone receptor-positive (HR+) advanced breast cancer (ABC) patients in the real-world setting are limited. This study aimed to report the first-line treatment patterns and outcomes of HR+ ABC patients in China. Methods: This was a multicenter, noninterventional study. Eligible patients were cytologically or histologically confirmed to have HR+ ABC with ≥2 complete medical records and received first-line therapies between January 2015 and June 2019. Treatment patterns and outcomes were extracted from structured or unstructured electronic medical records. Progression-free survival (PFS) was analyzed with the Kaplan-Meier method. Results: In total, 1072 patients with HR+ ABC were enrolled at 6 treatment sites: 327 human epidermal growth factor receptor 2-positive (HER2+) patients, 696 HER2-negative (HER2-) patients and 49 HER2-unknown patients. Overall, 62.41% of patients received first-line chemotherapy (CT), 21.08% received targeted therapy (TT) and 15.49% received endocrine therapy (ET). For HR+/HER2+ patients, 65.14% received TT, 28.44% received CT, and 5.81% received ET. Compared with patients who received TT, patients who received CT alone, had a significantly worse median PFS (adjusted hazard ratio [HR] =2.59, 95% confidence interval [CI], 1.64-4.10, p<0.001). For HR+/HER2- patients, 77.01% received CT, 20.69% received ET and 1.15% received TT. Compared with patients who received ET, patients who received CT with maintenance therapy had a significantly prolonged median PFS (adjusted HR =0.57, 95% CI, 0.44-0.76, p<0.001). Among HR+/HER2- patients who received CT with maintenance treatment, those with maintenance ET had a longer median PFS than those with maintenance CT, but the difference was not significant (adjusted HR=0.92, 95% CI, 0.64-1.33, p=0.66). Conclusions: This real-world study demonstrates that CT remains the mainstream first-line treatment option for HR+ patients in China. Among patients with HR+/HER2+ ABC, the majority received first-line TT and experienced a PFS benefit. A high percentage of HR+/HER2- patients received CT as first-line therapy in clinical practice. PFS benefit was significantly longer in patients who received CT with maintenance therapy. Moreover, there was no obvious difference in PFS between maintenance ET and CT. Maintenance ET may be a better choice considering its lower toxicity and better quality of life.

Pathological response and predictive role of tumour-infiltrating lymphocytes in HER2-positive early breast cancer treated with neoadjuvant pyrotinib plus trastuzumab and chemotherapy (Panphila): a multicentre phase 2 trial.

PURPOSE: Panphila evaluated pyrotinib plus trastuzumab, docetaxel and carboplatin as neoadjuvant therapy for early breast cancer (BC), and investigated the predictive role of immune cell subpopulations. PATIENTS AND METHODS: In this multicentre phase 2 study, patients with human epidermal growth factor receptor 2-positive, stage T2-3N0-3M0 BC received pyrotinib 400 mg once daily plus docetaxel (75 mg/m2, day 1), carboplatin (6 mg/mL/min, day 1) and trastuzumab (8 mg/kg loading dose and 6 mg/kg maintenance dose, day 1) for 6 cycles of 21 days each. Simon's 2-stage design was adopted. The primary end-point was pathological complete response (pCR, ypT0/is ypN0) rate. Tumour-infiltrating lymphocytes (TILs) were assessed by haematoxylin and eosin staining and multiplex immunohistochemistry. RESULTS: In the modified intention-to-treat population (n = 69), 38 patients (55.1%) achieved pCR. In the safety population (n = 74), the most common grade ≥3 adverse events were diarrhoea (43.2%), anaemia (37.8%), vomiting (16.2%) and platelet count decrease (10.8%). No treatment-related deaths occurred. Analysis of single immune subpopulations revealed a significant association of pCR with higher baseline infiltration by stromal (s)-CD20+, s-CD8+ and s-CD4+ TILs. Unsupervised hierarchical clustering of stromal immune markers identified a group of patients characterised by high s-CD20+, s-CD8+, s-CD4+ and s-FOXP3+ immune cells infiltration, which was independently associated with pCR. CONCLUSION: Neoadjuvant pyrotinib plus trastuzumab-based chemotherapy exhibits promising efficacy and manageable toxicity in patients with human epidermal growth factor receptor 2-positive early BC, and thus phase 3 trials are warranted. Our findings also contribute to understanding the potential role of the immune microenvironment in response to neoadjuvant pyrotinib-based therapy.

Physical Violence against Children by Parents among Primary School Students from a Rural Area in Shandong Province, China.

Physical violence (PV) against children by parents is a worldwide public health concern. Fewer studies explored the prevalence of PV in rural areas of China. We conducted a cross-sectional survey among primary school students' parents in five rural schools located in a town of Shandong Province. Data about parental PV behaviors against their children during the past 3 months and possible risk factors of parental PV behaviors were collected. Logistic regression analyses were carried out to investigate the risk factors of parental PV behaviors against their children. Of the 978 parents investigated, the parental self-reported prevalence of PV against their children was 50.0%. Parents' favorable attitudes toward the use of corporal punishment to discipline children were found to be associated with their increased use of PV. The findings of higher prevalence of parental PV behaviors against children identified in this sample suggests the need for programs aimed at improving parents' parenting skills in this rural area of China.

Factors that Influence Chinese Parents' Intentions to Use Physical Violence to Discipline Their Preschool Children.

This study explored factors affecting parents' intentions to use physical violence (PV) to discipline their children in the future. The theory of planned behavior (TPB) guided selection of variables. A sample of 1337 preschool children's parents from nine kindergartens located in a county of Henan Province, China were selected by stratified random cluster sampling. Data on parents' attitudes, subjective norms, and perceived behavioral control over PV, intentions to engage in PV to discipline their preschool children in the future, self-reported PV behavior toward their children during the past three months, and demographic characteristics were collected via a paper-based questionnaire. Multivariable logistic regression analyses examined putative predictors of parents' intentions to use physically violent discipline. Nearly three-quarters of the sample said they definitely will not use violent discipline, while 23.4% either said they would use it, or did not rule it out. Logistic regression analysis showed that parents' lower level of perceived behavioral control over using violence (OR 4.17; 95% CI: 2.659, 6.551), attitudes that support PV (OR 2.23; 95% CI: 1.555, 3.203), and having been physically violent with their children during the past three months (OR 1.62; 95% CI: 1.032, 2.556) were significantly associated with parents' tendency either to include, or not exclude, the use of violent discipline. Parents' subjective norms regarding PV had no significant impact on their intentions (p > 0.05). The influence of TPB constructs varied according to parents' gender. Intervention programs that aim to reduce violent discipline should focus both on increasing parents' perceived behavioral control over PV and changing their attitudes toward physically violent practices, especially among mothers and parents who have already used PV to discipline their children.

Analysis of Suspension of Clinical Trials for Drug Registration in China.

Suspension is an important risk control measure during clinical trials. We investigated the use of this in China and identified common reasons for suspension by analyzing trends, hold issues, outcomes, background and design characteristics of suspended clinical drug trials from January 1, 2013 to December 1, 2019. A total of 298 clinical trials during the study timeframe were registered, accounting for 3.1% of all clinical drug trials. Numbers and proportion of clinical trials suspended based on benefit/risk factors have been increasing without holds on registrations by Center for Drug Evaluation. Reasons for suspension vary among trial phases, benefit and risk factors, protocol issues etc. 67% of trials that have been on hold for >1 year were still on hold at the time of this analysis. Children and the elderly were enrolled in 4.1% and 41% of the suspended trials, respectively. Strengthening regulation of pre-market pharmacovigilance through optimizing reporting and monitoring of safety information during clinical trial is thus needed. Establishing a closed-loop treatment mechanism for trial suspension is also important. Examination of potential risks, such as the quality of protocols, the ability of the institution to support the trial, and the adequacy of supplies of the investigational product is needed before beginning clinical trials. More careful evaluation at the drug registration phase will reduce the frequency of suspension and protect subjects after suspension occurs.

Erratum: Wang, H., et al. The Relationship between Parental Perception of Neighborhood Collective Efficacy and Physical Violence by Parents against Preschool Children: A Cross-Sectional Study in a County of China. Int. J. Environ. Res. Public Health 2019, 16, 2305.

The authors would like to correct the Cronbach's α for the measures in the "Methods" section of their previous paper [1] as follows: [...].

The Relationship between Parental Perception of Neighborhood Collective Efficacy and Physical Violence by Parents against Preschool Children: A Cross-Sectional Study in a County of China.

Children exposed to negative neighborhood environments are at high risk of experiencing violence. This study aimed to explore the effects of parental perception of neighborhood collective efficacy on parental physical violence (PV) to their preschool children in a county of China. A total of 1337 parents from nine kindergartens were recruited by the stratified random cluster sampling method. Data about parental PV behavior toward children during the past three months, parental perception of neighborhood collective efficacy, together with their attitudes towards the use of corporal punishment to discipline children, and demographic characteristics were collected. Their relationships were investigated by applying multivariable logistic regression models. Overall, 67.5% of the parents reported at least one form of PV during the past three months. The rates of minor PV (MPV) and severe PV (SPV) were 67% and 22.8%, respectively. The results of multivariate logistic regression showed that only social cohesion was associated with lower odds of parental PV and MPV behavior after controlling for covariates. The results suggest that neighborhood collective efficacy is associated with parental PV behavior against their children to some extent, but the effects differ according to the severity level of PV. Neighborhood social cohesion may have a positive role in reducing parental PV behavior in the county surveyed at present study.

[Association between obesity and age at spermarche among Chinese Han boys aged 11-18 years].

OBJECTIVE: To analyze the association between obesity and age at spermarche among Chinese Han boys aged 11-18 years . METHODS: The height, weight and status of the spermarche of Chinese Han boys aged 11-18 years were selected from the data of 2010 National Physical Fitness and Health Surveillance.The body mass index (BMI), prevalence of spermarche in each age group and ages at spermarche by BMI groups were calculated. Chi square test was used to analyze the differences of prevalences of spermarche among the boys with different BMIs across ages. U-test was used to compare the differences of age at spermarche between the boys who were obese and not. RESULTS: In the boys aged 12 and 17 years in urban areas and boys aged 13 years in rural areas, the differences of prevalences of spermarche among the normal weight, overweight and obesity groups were significant (P<0.05). The age at spermarche in the obesity group (13.90 years) was 0.1 years earlier than that in the non-obesity group (14.00 years) (P<0.05). CONCLUSION: Obesity may make the age at spermarche ahead of time.

An overview of developmental and reproductive toxicity risk assessment in China.

Development and reproductive toxicology (DART) studies in animals are integral parts of nonclinical safety evaluation of drugs. The State Food and Drug Administration (SFDA) of the People's Republic of China developed a new guideline on DART studies in 2006. This guideline is in broad agreement with ICH guideline S5A (1994), "Detection of Toxicity to Reproduction for Medical Products," and M3, "Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals." However, the new guideline on DART testing differs from ICH in some detailed requirements. This overview reviews some main specifications in China's guidelines on DART testing, and also briefly introduces the recommendations for conducting human clinical trials and marketing authorization in China.

The protective effect of vitamin E against oxidative damage caused by formaldehyde in the testes of adult rats.

AIM: To investigate the effect of formaldehyde (FA) on testes and the protective effect of vitamin E (VE) against oxidative damage by FA in the testes of adult rats. METHODS: Thirty rats were randomly divided into three groups: (1) control; (2) FA treatment group (FAt); and (3) FAt + VE group. FAt and FAt + VE groups were exposed to FA by inhalation at a concentration of 10 mg/m(3) for 2 weeks. In addition, FAt + VE group were orally administered VE during the 2-week FA treatment. After the treatment, the histopathological and biochemical changes in testes, as well as the quantity and quality of sperm, were observed. RESULTS: The testicular weight, the quantity and quality of sperm, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione (GSH) were significantly decreased whereas the level of malondialdehyde (MDA) was significantly increased in testes of rats in FAt group compared with those in the control group. VE treatment restored these parameters in FAt + VE group. In addition, microscopy with hematoxylin-eosin (HE) staining showed that seminiferous tubules atrophied, seminiferous epithelial cells disintegrated and shed in rats in FAt group and VE treatment significantly improved the testicular structure in FAt + VE group. CONCLUSION: FA destroys the testicular structure and function in adult rats by inducing oxidative stress, and this damage could be partially reversed by VE.

[Effects of programmed cell death on human dental follicle cells and changes of programmed cell death under different hydrostatic pressures].

OBJECTIVE: Tooth eruption requires the presence of the dental follicle (DF) around the unerupted tooth. This study is to investigate programmed cell death on human dental follicle cells and changes of programmed cell death under different hydrostatic pressures: 0, 50 and 100 kPa. METHODS: Human dental follicles from third mandibular molars were surgically removed from adolescents who need for orthodontics treatment after informed content, then trypsinized and cultured. Human dental follicle cells were divided into three groups according to different hydrostatic pressures: 0, 50 and 100 kPa and their programmed cell death were labeled by using TdT-medi-ated-dUTP nick and labeling (TUNEL). RESULTS: Dental follicle cells cultured were elongate shape and exhibited fibroblastic characteristics. Compared with 0 kPa, programmed cell death cells on human dental follicle cells were increased 0.23% and 31.65% under 50 kPa and 100 kPa hydrostatic pressures respectively. 100 kPa group increased significantly (P < 0.01). CONCLUSION: It suggested that programmed cell death occured in human dental follicle cells cultured in vitro and was influenced by different hydrostatic pressures. Hydrostatic pressure may improve tooth erup-tion through dental follicle.

Induction of liver cytochrome P450 1A2 expression by flutamide in rats.

AIM: To investigate the modulation of liver cytochrome P450 1A2 (CYP1A2) expression by giving flutamide to adult rats. METHODS: Rats were given 50, 100, and 200 mg/kg po of flutamide for 2 weeks. Liver CYP1A2 mRNA was measured using reverse transcription-polymerase chain reaction. CYP1A2 protein was detected using immunoblotting. CYP1A2 activity was assayed using high performance liquid chromatography, with caffeine as the CYP1A2 substrate. RESULTS: CYP1A2 mRNA levels after flutamide treatment at 100 mg/kg and 200 mg/kg were, respectively, 1.86 and 3.11-fold higher than those of the control. Correspondingly, CYP1A2 protein increased 1.78 and 2.89-fold and CYP1A2 activity increased approximately 1.65 and 2.83-fold, respectively, relative to controls. Flutamide treatment at 50 mg/kg had no significant effect on CYP1A2 mRNA, protein, or enzyme activity. CONCLUSION: Giving rats flutamide induced liver CYP1A2 expression in a dose-dependent manner.

[Clinical research on unilateral extraction for moderate crowding].

OBJECTIVE: To clinically investigate the results of unilateral extraction in the treatment of special moderate crowding cases. METHODS: 22 patients with harmonic profile and moderate crowding were selected and treated by unilateral extraction with Edgewise technique. The patients crowding was 6 - 9 mm and focused on one side of the arch. 22 patients with moderate crowding were treated by bilateral extraction as control. RESULTS: 22 patients have been treated successfully within 18 months. Crowding was completely resolved. Midline coincidence was basically maintained.Good intercuspation was achieved. There is no significant difference in dental arch symmetry between unilateral extraction and bilateral extraction (P > 0.05). CONCLUSION: Unilateral extraction can be successful in the treatment of special moderate crowding cases.

Effects of huperzine A on liver cytochrome P-450 in rats.

AIM: To predict possible drug interaction and assure safety medication of huperzine A (HupA). METHODS: The effects of HupA on activities and expressions of cytochrome P-450 (CYP) were examined. Liver microsomes and total mRNA were prepared from rats treated orally with 0, 0.1 (pharmacological dose), 1, or 2 mg/kg huperzine A for 2 weeks. Phenobarbital, 3-methylcholanthrene (3-MC), ethanol, and dexamethasone were used as positive controls. Total CYP protein was assayed by carbon monoxide difference spectrum. Activity of isoenzyme was detected with specific probe. Expression of CYP protein and mRNA was analyzed with Western blot and RT-PCR. RESULTS: No changes of isoenzyme expression and catalytic activities were found in rats treated with 0.1 mg/kg huperzine A. Huperzine A 1, 2 mg/kg parallelly increased CYP1A2 activity, protein and mRNA, although they were minor when contrasted with 3-MC. Huperzine A 1, 2 mg/kg got no effects on CYP2C11, CYP2B1/2, 2E1 and 3A. CONCLUSION: Activity and expression of liver CYP isoenzymes were not affected in rats treated with pharmacological dose of HupA, but HupA at toxicological dose may elicit a slight inductive response of CYP1A2. The CYP1A2 induction produced by HupA is related to transcription enhancement.

Acute effects of huperzine A and tacrine on rat liver.

AIM: To observe the acute effects of huperzine A and tacrine on rat liver. METHODS: Changes of liver coefficient, serum biochemistry, and histopathology were detected after single dose. In vitro cytotoxicity was assessed by determining extracellular and intracellular amount of lactate dehydrogenase in cultured hepatocytes. RESULTS: Both huperzine A and tacrine raised liver coefficient and increased serum aspartate aminotransferase and alanine aminotransferase. Tacrine induced liver histopathologic changes. The acute effects of huperzine A on liver could be redressed by atropine, while effects of tacrine on liver could not. Concentration-dependent in vitro cytotoxicity occurred with tacrine, but not with huperzine A. CONCLUSION: The acute effects of huperzine A on rat liver are not related to hepatotoxicity. The acute effects of tacrine on rat liver are related to hepatotoxicity.

Identification of cytochrome P450 1A2 as enzyme involved in the microsomal metabolism of Huperzine A.

Huperzine A is a reversible and selective cholinesterase inhibitor approved for the treatment of Alzheimer's disease. To identify which cytochrome P450 (CYP) isoenzymes are involved in the metabolism of Huperzine A, an in vitro study was performed with rat liver microsomes and immunoinhibition and chemical inhibition methods. Huperzine A metabolism was analyzed with high-performance liquid chromatography (HPLC) and expressed as Huperzine A disappearance rate. Result showed that 76.2% of Huperzine A metabolism was inhibited by CYP1A2 antibody and 17.8% by CYP3A1/2 antibody. Inhibitory effects produced by CYP2C11 and 2E1 antibodies were minor. The CYP1A2 substrate phenacetin showed an inhibitory effect of 70.3%. In conclusion, Huperzine A metabolism in rat liver microsomes is mediated primarily by CYP1A2, with a probable secondary contribution of CYP3A1/2. CYP2C11 and 2E1 are likely not involved in Huperzine A metabolism.