Objective To evaluate the bioequivalence and safety of ezetimibe tablets in healthy Chinese subjects.Methods The study was designed as a single-center,randomized,open-label,two-period,two-way crossover,single-dose trail.Subjects who met the enrollment criteria were randomized into fasting administration group and postprandial administration group and received a single oral dose of 10 mg of the subject presparation of ezetimibe tablets or the reference presparation per cycle.The blood concentrations of ezetimibe and ezetimibe-glucuronide conjugate were measured by high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS),and the bioequivalence of the 2 preparations was evaluated using the WinNonlin 7.0 software.Pharmacokinetic parameters were calculated to evaluate the bioequivalence of the 2 preparations.The occurrence of all adverse events was also recorded to evaluate the safety.Results The main pharmacokinetic parameters of total ezetimibe in the plasma of the test and the reference after a single fasted administration:Cmax were(118.79±35.30)and(180.79±51.78)nmol·mL-1;tmax were 1.40 and 1.04 h;t1/2 were(15.33±5.57)and(17.38±7.24)h;AUC0-t were(1 523.90±371.21)and(1 690.99±553.40)nmol·mL-1·h;AUC0-∞ were(1 608.70±441.28),(1 807.15±630.00)nmol·mL-1·h.The main pharmacokinetic parameters of total ezetimibe in plasma of test and reference after a single meal:Cmax were(269.18±82.94)and(273.93±87.78)nmol·mL-1;Tmax were 1.15 and 1.08 h;t1/2 were(22.53±16.33)and(16.02±5.84)h;AUC0_twere(1 463.37±366.03),(1 263.96±271.01)nmol·mL-1·h;AUC0-∞ were(1 639.01±466.53),(1 349.97±281.39)nmol·mL-1·h.The main pharmacokinetic parameters Cmax,AUC0-tand AUC0-∞ of the two preparations were analyzed by variance analysis after logarithmic transformation.In the fasting administration group,the 90％CI of the log-transformed geometric mean ratios were within the bioequivalent range for the remaining parameters in the fasting dosing group,except for the Cmax of ezetimibe and total ezetimibe,which were below the lower bioequivalent range.The Cmax of ezetimibe,ezetimibe-glucuronide,and total ezetimibe in the postprandial dosing group was within the equivalence range,and the 90％CI of the remaining parameters were not within the equivalence range for bioequivalence.Conclusion This test can not determine whether the test preparation and the reference preparation of ezetimibe tablets have bioequivalence,and further clinical trials are needed to verify it.

Perihilar cholangiocarcinoma(PHC)is a common malignancy of biliary tract,for which surgery is the most effective treatment.However,its prognosis is not satisfactory even after surgical resection.In recent years,there have been some new advances in the surgical treatment of PHC.In this paper,we reviewed the existing literatures,demonstrated the current situation of preoperative biliary drainage,liver hyperplasia,hepatic resection,liver transplantation and minimally invasive surgery in the treatment of PHC,and prospected the future research direction.

Objective To investigate the effect of varying blood pressure stratification on renal function in the diabetic population.Methods A prospective cohort study was conducted,enrolling 9 489 diabetic patients from a total of 101 510 Kailuan Group employees who underwent health examinations between July 2006 and October 2007.The follow-up period was(8.6±4.0)years.Participants were categorized into four groups based on their baseline blood pressure levels:normal blood pressure(systolic blood pressure<120 mmHg and diastolic blood pressure<80 mmHg),elevated blood pressure(systolic blood pressure 120-130 mmHg and diastolic blood pressure<80 mmHg),stage 1 hypertension(systolic blood pressure 130-140 mmHg and/or diastolic blood pressure 80-90 mmHg),and stage 2 hypertension(systolic blood pressure≥140 mmHg and/or diastolic blood pressure≥90 mmHg).The incidence density of chronic kidney disease(CKD)was compared among these groups.A multivariate Cox proportional hazards regression model was employed to assess the effects of different blood pressure levels on renal function in diabetic patients,with the stability of the results confirmed using a multivariate time-dependent Cox proportional hazards model.Sensitivity analysis was conducted after excluding cases of cardiovascular disease(CVD)during follow-up,and cases using antihypertensive and antidiabetic medications at baseline.Results(1)At baseline,stage 1 hypertension patients demonstrated statistically significant higher differences with age and body mass index(BMI)compared to normal blood pressure group(P<0.05).(2)By the end of the follow-up,2 294 cases of CKD were identified,including 1 117 cases of estimated glomerular filtration rate(eGFR)decline and 1 575 cases of urinary protein.The incidences density of CKD,eGFR decline and urinary protein for stage 1 hypertension group were 39.4,16.3 and 25.5 per thousand person-years,respectively,all of which were statistically significant different from normal blood pressure group(log-rank test,P<0.01).(3)Multivariate Cox regression analysis revealed that,compared to the normal blood pressure group,stage 1 hypertension was associated with a 29%increased risk of CKD(HR=1.29,95%CI 1.09-1.52)and a 40%increased risk of eGFR decline(HR=1.40,95%CI 1.08-1.80)in diabetic individuals.Conclusion Stage 1 hypertension significantly increases the risk of CKD and eGFR decline in diabetic individuals,with a particularly notable effect on the risk of eGFR decline.

Humans ; Child ; Metabolic Diseases/therapy*

Objective: To identify the risk factors in mortality of pediatric acute respiratory distress syndrome (PARDS) in pediatric intensive care unit (PICU). Methods: Second analysis of the data collected in the "efficacy of pulmonary surfactant (PS) in the treatment of children with moderate to severe PARDS" program. Retrospective case summary of the risk factors of mortality of children with moderate to severe PARDS who admitted in 14 participating tertiary PICU between December 2016 to December 2021. Differences in general condition, underlying diseases, oxygenation index, and mechanical ventilation were compared after the group was divided by survival at PICU discharge. When comparing between groups, the Mann-Whitney U test was used for measurement data, and the chi-square test was used for counting data. Receiver Operating Characteristic (ROC) curves were used to assess the accuracy of oxygen index (OI) in predicting mortality. Multivariate Logistic regression analysis was used to identify the risk factors for mortality. Results: Among 101 children with moderate to severe PARDS, 63 (62.4%) were males, 38 (37.6%) were females, aged (12±8) months. There were 23 cases in the non-survival group and 78 cases in the survival group. The combined rates of underlying diseases (52.2% (12/23) vs. 29.5% (23/78), χ²=4.04, P=0.045) and immune deficiency (30.4% (7/23) vs. 11.5% (9/78), χ²=4.76, P=0.029) in non-survival patients were significantly higher than those in survival patients, while the use of pulmonary surfactant (PS) was significantly lower (8.7% (2/23) vs. 41.0% (32/78), χ²=8.31, P=0.004). No significant differences existed in age, sex, pediatric critical illness score, etiology of PARDS, mechanical ventilation mode and fluid balance within 72 h (all P>0.05). OI on the first day (11.9(8.3, 17.1) vs.15.5(11.7, 23.0)), the second day (10.1(7.6, 16.6) vs.14.8(9.3, 26.2)) and the third day (9.2(6.6, 16.6) vs. 16.7(11.2, 31.4)) after PARDS identified were all higher in non-survival group compared to survival group (Z=-2.70, -2.52, -3.79 respectively, all P<0.05), and the improvement of OI in non-survival group was worse (0.03(-0.32, 0.31) vs. 0.32(-0.02, 0.56), Z=-2.49, P=0.013). ROC curve analysis showed that the OI on the thind day was more appropriate in predicting in-hospital mortality (area under the curve= 0.76, standard error 0.05,95%CI 0.65-0.87,P<0.001). When OI was set at 11.1, the sensitivity was 78.3% (95%CI 58.1%-90.3%), and the specificity was 60.3% (95%CI 49.2%-70.4%). Multivariate Logistic regression analysis showed that after adjusting for age, sex, pediatric critical illness score and fluid load within 72 h, no use of PS (OR=11.26, 95%CI 2.19-57.95, P=0.004), OI value on the third day (OR=7.93, 95%CI 1.51-41.69, P=0.014), and companied with immunodeficiency (OR=4.72, 95%CI 1.17-19.02, P=0.029) were independent risk factors for mortality in children with PARDS. Conclusions: The mortality of patients with moderate to severe PARDS is high, and immunodeficiency, no use of PS and OI on the third day after PARDS identified are the independent risk factors related to mortality. The OI on the third day after PARDS identified could be used to predict mortality.
Female ; Male ; Humans ; Child, Preschool ; Infant ; Child ; Critical Illness ; Pulmonary Surfactants/therapeutic use* ; Retrospective Studies ; Risk Factors ; Respiratory Distress Syndrome/therapy*

We aimed to investigate the relationship of dietary zinc intake with new-onset hypertension among Chinese adults. A total of 12,177 participants who were free of hypertension at baseline from the China Health and Nutrition Survey were included. Dietary intake was assessed by three consecutive 24-h dietary recalls combined with a household food inventory. Participants with systolic blood pressure ≽ 140 mmHg or diastolic blood pressure ≽ 90 mmHg or diagnosed by a physician or under antihypertensive treatment during the follow-up were defined as having new-onset hypertension. During a median follow-up duration of 6.1 years, 4269 participants developed new-onset hypertension. Overall, the association between dietary zinc intake and new-onset hypertension followed a J-shape (P for non-linearity < 0.001). The risk of new-onset hypertension significantly decreased with the increment of dietary zinc intake (per mg/day: hazard ratio (HR) 0.93; 95% confidence interval (CI) 0.88-0.98) in participants with zinc intake < 10.9 mg/day, and increased with the increment of zinc intake (per mg/day: HR 1.14; 95% CI 1.11-1.16) in participants with zinc intake ≽ 10.9 mg/day. In conclusion, there was a J-shaped association between dietary zinc intake and new-onset hypertension in general Chinese adults, with an inflection point at about 10.9 mg/day.
Adult ; Humans ; Cohort Studies ; Zinc ; Diet ; Hypertension/epidemiology* ; Eating ; China/epidemiology*

Objective: To investigate the clinical and biological characteristics of familial platelet disorder (FPD) with germline Runt-related transcription factor (RUNX) 1 mutations. Methods: Patients diagnosed with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) with RUNX1 mutations from February 2016 to December 2021 in Wuhan No.1 Hospital underwent pedigree analysis and were screened for gene mutations (somatic and germline). Patients diagnosed with FPD with germline RUNX1 mutations were enrolled and evaluated in terms of clinical characteristics and biological evolution. Bioinformatics analysis was used to assess the pathogenicity of mutations and to analyze the effect of mutated genes on the function of the corresponding protein. Results: Germline RUNX1 mutations were detected in three out of 34 patients suffering from MDS/AML who had RUNX1 mutations. A pedigree of FPD with RUNX1 (RUNX1-FPD) c.562A>C and RUNX1 c.1415T>C mutations was diagnosed, and the mutations were of patrilineal origin. Bioinformatics analysis indicated that the locus at positions 188 and 472 in the AML-1G type of RUNX1 was highly conserved across different species, and that variations might influence functions of the proteins. The mutations were evaluated to be highly pathogenic. Of the nine cases with germline RUNX1 mutations: two patients died due AML progression; one case with AML survived without leukemia after transplantation of hemopoietic stem cells; four patients showed mild-to-moderate thrombocytopenia; two cases had no thrombocytopenia. During the disease course of the proband and her son, mutations in RUNX1, NRAS and/or CEBPA and KIT appeared in succession, and expression of cluster of differentiation-7 on tumor cells was enhanced gradually. None of the gene mutations correlated with the tumor were detected in the four cases not suffering from MDS/AML, and they survived until the end of follow-up. Conclusions: RUNX1-FPD was rare. The mutations c.562A>C and c.1415T>C of RUNX1 could be the disease-causing genes for the family with RUNX1-FPD, and these mutations could promote malignant transformation. Biological monitoring should be carried out regularly to aid early intervention for family members with RUNX1-FPD.
Humans ; Female ; Germ-Line Mutation ; Core Binding Factor Alpha 2 Subunit/genetics* ; Pedigree ; Blood Platelet Disorders/complications* ; Leukemia, Myeloid, Acute/genetics*

The aim of this study was to compare crocins in the fruit of Gardenia jasminoides and Gardenia jasminoides var. radicans. Acchrom XCharge C_(18) column(4.6 mm×250 mm, 5 μm) was used for separation, with mobile phase of acetonitrile and 0.1% formic acid for gradient elution. The detection wavelength was set at 440 nm with a flow rate of 1.0 mL·min~(-1), and the column temperature was 30 ℃. The high performance liquid chromatography(HPLC) fingerprint of crocin in Gardenia species was established by testing 20 batches of G. jasminoides and 8 batches of G. jasminoides var. radicans samples from different sources, and UHPLC-ESI-Orbitrap-MS/MS technology and reference substances were used to predict and identify the common peaks. The results showed that 20 common chromatographic peaks from the samples were selected and the structures of 16 common peaks were predicted by mass spectrum. Four common peaks(crocin Ⅰ, Ⅱ, Ⅲ, and Ⅳ) were identified by the comparison with reference substances. The content of crocin Ⅰ, Ⅱ, Ⅲ, and Ⅳ was determined simultaneously under the same chromatographic condition, and both the system suitability and the methodological investigation results met the requirements of content determination. The relative similarity of HPLC fingerprint of 28 samples to the reference fingerprint was above 0.98. The results of cluster analysis(CA) showed that G. jasminoides and G. jasminoides var. radicans were separately grouped into one group. In the 20 batches of G. jasminoides, the content of crocin Ⅰ, Ⅱ, Ⅳ, and Ⅲ was between 3.58-9.58, 0.230-1.452, 0.014 5-0.135, and 0.301-1.12 mg·g~(-1), respectively, and the total content was between 4.12-12.25 mg·g~(-1). In the 8 batches of G. jasminoides var. radicans, the content of crocin Ⅰ, Ⅱ, Ⅳ, and Ⅲ was between 5.84-11.48, 0.308-0.898, 0.010 6-0.025 5, and 0.675-1.34 mg·g~(-1), respectively, and the total content was between 6.97-13.72 mg·g~(-1). The existing results showed that there is a certain similarity between G. jasminoides and G. jasminoides var. radicans in the composition of crocin, which needs further proved by more batches of samples. The method established in this paper provides references for the quality control of G. jasminoides, G. jasminoides var. radicans, and related products.
Carotenoids/analysis* ; Chromatography, High Pressure Liquid/methods* ; Fruit/chemistry* ; Gardenia/chemistry* ; Tandem Mass Spectrometry

A comprehensive quality control method was established to provide references for quality control and evaluation of substance benchmarks of Danggui Sini Decoction(DSD). The HPLC separation was performed on a Kromasil 100 C-8 column(4.6 mm×250 mm, 5 μm) with acetonitrile(A)-0.05% phosphoric acid in water(B) as mobile phase in a gradient elution mode at the flow rate of 1 mL·min~(-1). The column temperature was 25 ℃ and the detection wavelength was set at 275 nm. Under these conditions, the content of seven components, including paeoniflorin, liquiritin, cinnamic acid, cinnamaldehyde, ammonium glycyrrhetate, ligustilide, and asarinin was simultaneously determined. Under the same chromatographic conditions, the HPLC fingerprint method for analysis of 15 batches of DSD was established. The content determination of aristolochic acid I, using the same test solution as the content determination item, was performed on an ACQUITY UPLC BEH C_(18) column(2.1 mm×50 mm, 1.7 μm) with methanol(A)-water(including 0.1% formic acid and 5 mmol·L~(-1) ammonium formate)(B) as the mobile phase in a gradient elution mode at the flow rate of 0.4 mL·min~(-1) and the column temperature of 40 ℃ by LC-MS/MS. The MS conditions included electrospray ionization(ESI) as an ion source, positive ion ionization, selective reaction monitoring(SRM), the parent ion of 359.3, and the daughter ion of 297.8. The results of the methodological investigation all met the requirements of content determination/fingerprint determination. As a result, the content ranges of paeoniflorin, liquiritin, cinnamic acid, cinnamaldehyde, ammonium glycyrrhetate, ligustilide, and asarinin were 5.419 8-11.267 3, 1.023-3.669 8, 0.145 6-0.444 1, 0.099 1-0.321 9, 3.159 1-7.731 9, 0.146 4-0.471 7, and 0.237 3-0.401 0 mg·g~(-1), respectively. Twenty-two common peaks were selected and 10 of them were identified by the comparison with the reference substances. The fingerprint similarity of 15 batches of DSD was in the range of 0.91-0.996 and the content of aristolochic acid I in DSD was 300.03-638.13 ng·g~(-1). The method established in this study is reliable and easy to operate and has great practical value, which can be used for overall quality control of substance benchmarks for DSD.
Ammonium Compounds ; Benchmarking ; Chromatography, High Pressure Liquid/methods* ; Chromatography, Liquid ; Drugs, Chinese Herbal/chemistry* ; Quality Control ; Tandem Mass Spectrometry/methods* ; Water

This study aimed to explore the correlation of the content of 15 non-crocin components of Gardeniae Fructus with its external properties(shape and color). The fruit shape was quantified according to the length/diameter measured by ruler and vernier calliper and the chromaticity values L~*, a~*, b~*, and ΔE~* of all samples were determined by chroma meter. Chromatographic separation was conducted on a Welch Ultimate XB C_(18) column(4.6 mm×250 mm, 5 μm) under gradient elution with acetonitrile solution(A) and 0.1% formic acid aqueous solution(B) as the mobile phase at a flow rate of 1.0 mL·min~(-1). The column temperature was 30 ℃ and the detection wavelength was 238 nm. The high-performance liquid chromatography(HPLC) method was established for simultaneous determination of the content of eight iridoid glycosides, six phenolic acids, and one flavonoid in 21 batches of Gardeniae Fructus samples. The correlation of the content of the 15 components with shapes and chromaticity values in each sample was analyzed by multivariate statistical analysis. According to the circulation situation and traditional experience, 21 batches of Gardeniae Fructus samples were divided into three categories, namely 14 batches of Jiangxi products(small and round, red and yellow), 4 batches of Fujian products(oval, red) and 3 batches of Shuizhizi(Gardenia jasminoides, longest, reddest). The Gardeniae Fructus samples were sequenced as Jiangxi products(1.71) < Fujian products(1.99) < Shuizhizi(2.55) in terms of the length/diameter average, Jiangxi products(17.7) < Fujian products(19.7) ≈ Shuizhizi(19.6) in terms of average value of a~*(red and green), Jiangxi products(24.4) > Fujian products(19.2) ≈ Shuizhizi(19.3) in terms of b~*(yellow and blue), and Jiangxi products(49.8) > Fujian products(48.0) ≈ Shuizhizi(47.8) in terms of L~*(brightness). The total content of the 15 components, 8 iridoid glycosides, 6 phenolic acids, and rutin in Jiangxi products was in the ranges of 65.53-99.64, 52.15-89.16, 6.10-11.83, and 0.145-1.81 mg·g~(-1), respectively. The total amount of the 15 components, 8 iridoid glycosides, 6 phenolic acids, and rutin in Fujian products was in the ranges of 69.33-94.35, 63.52-85.19, 5.39-8.41, and 0.333-0.757 mg·g~(-1), respectively. In Shuizhizi, the total content of the 15 components, 8 iridoid glycosides, 6 phenolic acids, and rutin was in the ranges of 77.35-85.98, 68.69-76.56, 7.30-9.05, and 0.368-0.697 mg·g~(-1), respectively. Pearson correlation analysis revealed that Gardeniae Fructus with leaner and longer fruit shape possessed lower content of total phenolic acids(the sum of the six phenolic acids) and rutin, but the correlation with iridoid glycosides was not high. Additionally, the higher content of total phenolic acids and rutin denoted the yellow coloration of Gardeniae Fructus, and the higher content of cryptochlorogenic acid, chlorogenic acid, and rutin meant the brighter color of Gardeniae Fructus. However, the higher content of geniposide and neochlorogenic acid and the lower content of deacetyl asperulosidic acid methyl ester led to the red coloration of Gardeniae Fructus. The results indicated that the morphological characters of Gardeniae Fructus were closely related to its chemical components. The more round shape and the yellower color reflected the higher content of phenolic acids and flavonoid, and Gardeniae Fructus with redder color had higher content of geniposide. OPLA-DA showed that the length/diameter and the content of six iridoid glycosides(gardoside, shanzhiside, gardenoside, genipin 1-gentiobioside, 6β-hydroxy geniposide, and deacetyl asperulosidic acid methyl ester), two phenolic acids(neochlorogenic acid and cryptochlorogenic acid) and rutin could be used as markers to distinguish three types of samples. This study provided experimental data for the scientific connotation of "quality evaluation through morphological identification" of Gardeniae Fructus.
Chromatography, High Pressure Liquid/methods* ; Drugs, Chinese Herbal/analysis* ; Esters/analysis* ; Flavonoids/analysis* ; Fruit/chemistry* ; Gardenia/chemistry* ; Iridoids/analysis* ; Rutin/analysis*