Safety, pharmacokinetics, and efficacy of rifasutenizol, a novel dual-targeted antibacterial agent in healthy participants and patients in China with Helicobacter pylori infection: four randomised clinical trials.

BACKGROUND: Due to the rapid development of antimicrobial resistance, the efficacy of most Helicobacter pylori eradication therapies have progressively decreased to an unacceptable level. Rifasutenizol (TNP-2198) is a new molecular entity with a synergistic dual mechanism of action currently under clinical development for the treatment of microaerophilic and anaerobic bacterial infections. We aimed to evaluate the safety, pharmacokinetics, and efficacy of rifasutenizol in healthy Chinese participants and patients with H pylori. METHODS: We conducted four clinical trials of rifasutenizol capsules in healthy participants (aged 18-55 years) and patients with asymptomatic H pylori infection (aged 18-65 years) in a clinical trial centre in Jilin province, China. Trial 1 was a phase 1, double-blind, randomised, placebo-controlled, single ascending dose study, in which participants were enrolled into one of seven rifasutenizol dose groups (50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, or 1000 mg) and were randomly assigned in a 4:1 ratio to study drug or placebo. Trial 2 was a phase 1, double-blind, randomised, placebo-controlled, multiple ascending dose study, in which patients were enrolled into one of three rifasutenizol dose groups (200 mg, 400 mg, or 600 mg) and were randomly assigned in a 3:1 ratio to study drug or placebo. Trial 3 was a phase 2a, open-label, randomised, multiple-dose, dose-finding study in which patients enrolled into one of four cohorts were randomly assigned in a 1:1:1:1 ratio to a rifasutenizol dual or triple regimen. Trial 4 was a phase 2b, open-label, randomised, multiple-dose, regimen exploration study, in which patients enrolled into one of five cohorts were randomly assigned in a 2:2:1:1:2 ratio to a rifasutenizol dual therapy, triple therapy, or a control cohort. Block randomisation (block size 4 or 8) was used in all four trials. The key primary endpoints for trials 1, 2, and 3 were the tolerability, safety, and pharmacokinetics of rifasutenizol. For trial 4, the primary endpoint was the eradication rate of H pylori. These four trials were registered at ClinicalTrials.gov (NCT06081699, NCT06081712, NCT06076681, and NCT06076694) and chinadrugtrials.org.cn (CTR20190734, CTR20192553, CTR20212050, and CTR20220625) and are completed. FINDINGS: Between May 9, 2019, and Sept 14, 2022, 78 healthy participants (trial 1: n=10 per cohort in a 4:1 rifasutenizol:placebo ratio; and an additional eight for the food-effect cohort) and 168 patients with asymptomatic H pylori infection (trial 2: n=16 per cohort in a 3:1 rifasutenizol:placebo ratio; trial 3: n=10 per cohort; trial 4: n=10 or n=20 per cohort) were enrolled in the four clinical trials. Single doses of rifasutenizol (50-1000 mg) and multiple doses of rifasutenizol (200 mg to 600 mg, twice a day), either as monotherapy or co-administered with rabeprazole and amoxicillin, showed favourable safety and tolerability profiles. Most adverse events were mild, and no serious adverse events were reported. Rifasutenizol demonstrated a linear pharmacokinetic profile over the dose range of 50-800 mg, and there were no apparent pharmacokinetic interactions between rifasutenizol and the co-administrated drugs. Food intake slightly elevated the area under the plasma concentration-time curve (AUC) of rifasutenizol, and the geometric mean of AUC from time 0 to the last timepoint with a quantifiable concentration (AUC0-t) and AUC from time 0 to infinity (AUC0-∞) in the fed state were 1·334 and 1·396 times of those in the fasted state, respectively. There was mild accumulation after continuous administration of rifasutenizol, and the Rac(AUC) of rifasutenizol 400 mg in the dual and triple regiments in trial 3 were 1·37 and 1·49, respectively. In trial 3, the eradication rates of H pylori with 200 mg, 400 mg, or 600 mg of rifasutenizol in combination with rabeprazole, twice a day for 14 days, were 0% (95% CI 0-31), 30% (7-65), and 40% (12-74), respectively, identifying rifasutenizol 400 mg as the effective dose. In trial 4, H pylori eradication rates with the triple regimen in cohort A (400 mg rifasutenizol, 20 mg rabeprazole sodium, and 1 g amoxicillin) twice a day for 14 days was 95% (95% CI 74-100), and triple therapy (600 mg rifasutenizol, 20 mg rabeprazole sodium, and 1 g amoxicillin) three times a day for 7 days was 100% (69-100). INTERPRETATION: Rifasutenizol monotherapy and combination therapy was generally safe and well tolerated in healthy participants and patients with H pylori infection. A triple regimen of 400 mg rifasutenizol capsules, 20 mg rabeprazole sodium enteric-coated tablets, and 1 g amoxicillin capsules twice a day for 14 days showed promising efficacy as a new treatment regimen for H pylori infection. FUNDING: TenNor Therapeutics and National Natural Science Foundation of China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Apatinib Suppresses Gastric Cancer Stem Cells Properties by Inhibiting the Sonic Hedgehog Pathway.

The presence of gastric cancer stem cells (GCSCs) marks the onset of gastric carcinoma. The sonic hedgehog (SHH) pathway plays a vital role in the maintenance of GCSC characteristics. Apatinib has been approved in China for advanced gastric cancer (GC) treatment. However, whether apatinib can target GCSCs and affect the SHH pathway remains unclear. The present study aimed to investigate the underlying mechanism of apatinib's antitumor effects on GC. The expression levels of GCSC markers and number of CD133+ cells were significantly elevated in the sphere-forming cells. Apatinib effectively suppressed GCSC traits by inhibiting tumorsphere formation and cell proliferation, suppressing GCSC markers expression and CD133+ cell number, and inducing apoptosis. Apatinib downregulated the activation of the SHH pathway; while upregulation of the SHH pathway attenuated the inhibitory effects of apatinib on GCSCs. Moreover, apatinib treatment significantly delayed tumor growth and inhibited GCSC characteristics in the xenograft model. Our data suggested that apatinib exhibited inhibitory effects on GCSCs by suppressing SHH pathway both in vitro and in vivo, thus providing new insights into the therapeutic application of apatinib in GCSC suppression and advanced gastric cancer treatment.

Effectiveness and safety of acupuncture combined with Madopar for Parkinson's disease: a systematic review with meta-analysis.

OBJECTIVE: To evaluate the effectiveness and safety of acupuncture combined with Madopar for the treatment of Parkinson's disease (PD), compared to the use of Madopar alone. METHODS: A systematic search was carried out for randomised controlled trials (RCTs) of acupuncture and Madopar for the treatment of PD published between April 1995 and April 2015. The primary outcome was total effectiveness rate and secondary outcomes included Unified Parkinson's Disease Rating Scale (UPDRS) scores. Data were pooled and analysed with RevMan 5.3. Results were expressed as relative ratio (RR) with 95% confidence interval (CIs). RESULTS: Finally, 11 RCTs with 831 subjects were included. Meta-analyses showed that acupuncture combined with Madopar for the treatment of PD can significantly improve the clinical effectiveness compared with Madopar alone (RR=1.28, 95% CI 1.18 to 1.38, P<0.001). It was also found that acupuncture combined with Madopar significantly improved the UPDRS II (SMD=-1.00, 95% CI -1.71 to -0.29, P=0.006) and UPDRS I-IV total summed scores (SMD=-1.15, 95% CI -1.63 to -0.67, P<0.001) but not UPDRS I (SMD=-0.37, 95% CI -0.77 to 0.02, P=0.06), UPDRS III (SMD=-0.93, 95% CI -2.28 to 0.41, P=0.17) or UPDRS IV (SMD=-0.78, 95% CI -2.24 to 0.68, P=0.30) scores. Accordingly, acupuncture combined with Madopar appeared to have a positive effect on activities of daily life and the general condition of patients with PD, but was not better than Madopar alone for the treatment of mental activity, behaviour, mood and motor disability. In the safety evaluation, it was found that acupuncture combined with Madopar was associated with significantly fewer adverse effects including gastrointestinal reactions (RR=0.38, 95% CI 0.23 to 0.65, P<0.001), on-off phenomena (RR=0.27, 95% CI 0.11 to 0.66, P=0.004) and mental disorders (RR=0.24, 95% CI 0.06 to 0.92, P=0.04) but did not significantly reduce dyskinesia (RR=0.64, 95% CI 0.35 to 1.16, P=0.14). CONCLUSION: Acupuncture combined with Madopar appears, to some extent, to improve clinical effectiveness and safety in the treatment of PD, compared with Madopar alone. This conclusion must be considered cautiously, given the quality of most of the studies included was low. Therefore, more high-quality, multicentre, prospective, RCTs with large sample sizes are needed to further clarify the effect of acupuncture combined with Madopar for PD.

Genomic Analysis Reveals Multi-Drug Resistance Clusters in Group B Streptococcus CC17 Hypervirulent Isolates Causing Neonatal Invasive Disease in Southern Mainland China.

Neonatal invasive disease caused by group B Streptococcus (GBS) represents a significant public health care concern globally. However, data related to disease burden, serotype distribution, and molecular epidemiology in China and other Asian countries are very few and specifically relative to confined regions. The aim of this study was to investigate the genetic characteristics of GBS isolates recovered from neonates with invasive disease during 2013-2014 at Guangzhou and Changsha hospitals in southern mainland China. We assessed the capsular polysaccharide type, pilus islands (PIs) distribution and hvgA gene presence in a panel of 26 neonatal clinical isolates, of which 8 were recovered from Early Onset Disease and 18 from Late Onset Disease (LOD). Among 26 isolates examined, five serotypes were identified. Type III was the most represented (15 cases), particularly among LOD strains (n = 11), followed by types Ib (n = 5), V (n = 3), Ia (n = 2) and II (n = 1). We performed whole-genome sequencing analysis and antimicrobial susceptibility testing on the 14 serotype III isolates belonging to the hypervirulent Clonal Complex 17 (serotype III-CC17). The presence of PI-2b alone was associated with 13 out of 14 serotype III-CC17 strains. Genome analysis led us to identify two multi-drug resistance gene clusters harbored in two new versions of integrative and conjugative elements (ICEs), carrying five or eight antibiotic resistance genes, respectively. These ICEs replaced the 16 kb-locus that normally contains the PI-1 operon. All isolates harboring the identified ICEs showed multiple resistances to aminoglycoside, macrolide, and tetracycline antibiotic classes. In conclusion, we report the first whole-genome sequence analysis of 14 GBS serotype III-CC17 strains isolated in China, representing the most prevalent lineage causing neonatal invasive disease. The acquisition of newly identified ICEs conferring multiple antibiotic resistance could in part explain the spread of this specific clone among Chinese neonatal isolates and underlines the need for a constant epidemiological surveillance.

Behavioral Risk Profile of Men Who Have Sex with Men in Beijing, China: Results from a Cross-sectional Survey with Randomized Response Techniques.

BACKGROUND: Human immunodeficiency virus (HIV) is spreading rapidly among men who have sex with men (MSM) in China. Anonymous questionnaires or direct interviews have been frequently used to study their behavior. The aim of the study was to describe the behavioral risk profile of the MSM in Beijing using the randomized response techniques (RRTs). METHODS: A cross-sectional survey of sexual behavior among a sample of MSM was conducted in two HIV counseling and testing clinics in Beijing. The survey was carried out with an anonymous questionnaire containing sensitive questions on sexual behavior. To obtain the honest responses to the sensitive questions, three distinctive RRTs were used in the questionnaire: (1) Additive randomized response model for quantitative questions, (2) randomized response model for multiple choice questions, and (3) Simmons randomized response model for binomial questions. Formulae for the point estimate, variance, and confidence interval (CI) were provided for each specific model. RESULTS: Using RRTs in a sample of 659 participants, the mean age at first homosexual encounter was estimated to be 21.7 years (95% CI: 21.2-22.2), and each had sex with about three (2.9, 95% CI: 2.4-3.4) male partners on average in the past month. The estimated rate for consistent condom use was 56.4% (95% CI: 50.1-62.8%). In addition, condom was estimated to be used among 80.0% (95% CI: 74.1-85.9%) of the population during last anal sex with a male partner. CONCLUSIONS: Our study employed RRTs in a survey containing questions on sexual behavior among MSM, and the results showed that RRT might be a useful tool to obtain truthful feedback on sensitive information such as sexual behavior from the respondents, especially in traditional Chinese cultural settings.

Estimating the burden of invasive Group B Streptococcal disease in young infants in southern mainland China: an observational study.

OBJECTIVES: To estimate the incidence, case fatality ratio and serotypes associated with early-onset (EOD) and late-onset (LOD) invasive GBS disease in infants in southern mainland China. METHODS: During the six-month study period, infants aged ≤ 90 days with culture-confirmed GBS disease born in the study hospitals or elsewhere, but presenting to a study hospital, were enrolled. GBS-positive cultures were genotyped, serotyped and sequence typed. The incidence rate was calculated for infants born in the study hospitals, and case fatality ratio and causative serotypes identified for all enrolled GBS cases. RESULTS: Ten cases were enrolled: 2 EOD cases born in the study hospitals and 8 LOD cases born elsewhere. Incidence rate was 0.28 (95% confidence interval: 0.08-1.03, n = 2/7061 successfully followed-up consenting subjects); no cases resulted in fatality. In the 8 GBS isolates available for typing, 4 serotypes (Ia, Ib, III and V) and 5 multi-locus sequence types (1, 10, 12, 17 and 23) were identified. CONCLUSIONS: This is the first study specifically investigating the incidence of GBS invasive disease in infants in southern mainland China. Incidence and case fatality were low but further research is needed in larger, more diverse cohorts to estimate disease burden for the broader Chinese population.

Confirmatory factor analysis of the Child Feeding Questionnaire (CFQ) in Japanese elementary school children.

The validity of the Child Feeding Questionnaire (CFQ), one of the measures used to assess parental child feeding practices and attitudes, has been confirmed in American populations. We used confirmatory factor analysis to test the validity and factor structure of the translated version of the CFQ among parents of Japanese elementary school children. The structural equation modelling software Linear Structural Relationships (LISREL) was applied to explore the validity of the translated CFQ to examine child feeding behaviours and attitudes in a sample of 920 parents of Japanese elementary schoolchildren from schools in Koshu City in Yamanashi prefecture (grades 4-6), Japan. The confirmatory factor analysis suggested that after dropping the items with a low factor loading and adding three error covariances between items, the 7-factor model displayed acceptable fit and most items loaded as expected. Of the 24 direct factor-item correlations, 22 were greater than 0.50. Our study confirmed the validity of the translated CFQ to assess child feeding practices and attitudes among parents of elementary schoolchildren brought up in a Japanese eating culture.

[Cross-sectional investigation of prevalence of type 2 diabetes in Shanghai].

OBJECTIVE: To investigate the prevalence of type 2 diabetes and impaired glucose regulation among the permanent urban and rural inhabitants in Shanghai. METHODS: Questionnaire survey, physical examination, and laboratory testing were conducted among 14401 urban and rural inhabitants aged 15 - 74 in Shanghai selected by multistage cluster random sampling. The data about the prevalence of type 2 diabetes and impaired glucose regulation were collected and analyzed. RESULTS: The respondent rate of this investigation was 80.5% (11,589/14,401). The prevalence rates of type 2 diabetes, impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) were 8.6% (1000/11,589), 6.9% (802/11,589), and 1.0% (120/11,589) respectively (the standardized rates were 6.2%, 5.1% and 0.8%). The prevalence rates of type 2 diabetes, IGT, and IFG were significantly higher in those with overweight, obesity, central obesity, and hypertension. The prevalence rates of type 2 diabetes, IGT, and IFG in men were 8.9% (412/4621), 6.4% (296/4621), and 1.0% (47/4621) respectively, all not significantly different from those of the women, i.e. e., 8.4% (588/6968), 7.3% (506/6968), and 1.0% (73/6968) respectively (all P > 0.05). The prevalence rates of type 2 diabetes and IGT in the urban area were 11.2% (730/6500) and 6.4% (419/6500) respectively, both significantly higher than those in the rural area, i.e., 5.3% (270/5089) and 7.5% (383/5089) respectively (both P < 0.05). The prevalence rate of IFG in the urban area was 1.2% (77/6500), not significantly different from that in the rural area (0.8%, 43/5039, P > 0.05). The prevalence of type 2 diabetes, IGT, and IFG increased apparently with age, body mass index, waist hip ratio, and waist circumference. The ratios of undiagnosed type 2 diabetes in the urban area and rural area were 39.6% (289/730) and 69.3% (187/270) respectively (chi(2) = 74.07, P < 0.01). CONCLUSION: The prevalence rate of type 2 diabetes in Shanghai is higher than the mean national level and shows an increasing tendency. Screening of type 2 diabetes in rich rural areas should be emphasized.