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Hepatitis B virus (HBV) infection is a major global public health issue. Clinical cure (also known as functional cure) of chronic hepatitis B (CHB) is the ideal therapeutic goal recommended by the latest guidelines for the prevention and treatment of CHB in China and globally. Optimized treatment regimens with direct-acting antiviral agents ［e.g., nucleos(t)ide analogues］ or immunomodulators (e.g., pegylated interferon-α) sequentially or in combination tend to have low cure rates. Rapid development has been achieved in the research and development of drugs for the treatment of CHB. This article reviews the clinical study of new antiviral drugs for CHB, including the selection of subjects, study design, dosage, dose escalation, adverse events, and efficacy evaluation. It is necessary to introduce the knowledge of quantitative pharmacology to analyze the association of drug exposure in body with efficacy and adverse reactions, and exploratory indicators should be incorporated for comprehensive analysis. This review provides related experience and new ideas for the clinical research and development of new anti-HBV drugs.
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ObjectiveTo investigate the tolerance, pharmacokinetics, and antiviral activity of coblopasvir hydrochloride capsules in patients with hepatitis C. MethodsA total of 36 patients with hepatitis C who were admitted to The First Hospital of Jilin University from November 2016 to January 2017 were enrolled as subjects, and four dose groups (30 mg, 60 mg, 90 mg, and 120 mg) and one placebo group were established. The subjects were administered once daily for 3 consecutive days; tolerance was evaluated on D2 and D6, and follow-up was performed on D8 and D10. The subjects were enrolled based on single dose escalation, and a multiple-dose study was conducted under the premise of good tolerance to single dose. Liquid chromatography-tandem mass spectrometry was used to measure the plasma concentration of coblopasvir hydrochloride in human body, and WinNonlin 6.4 software was used to calculate main pharmacokinetic parameters. HCV RNA load was used to evaluate antiviral activity at different time points; a one-way analysis of variance was used for comparison between multiple groups, and the LSD t-test was used for further comparison between two groups. ResultsAfter coblopasvir hydrochloride capsules were administered orally once a day at a dose of 30-120 mg, the plasma concentration and exposure of coblopasvir hydrochloride increased with the increase in dose. There were no significant differences in plasma concentration and exposure between multiple-dose administration and single-dose administration in a fasting state, without accumulation in human body. After the oral administration of coblopasvir hydrochloride capsules once a day, the subjects with HCV genotype 1b had a reduction in HCV RNA load since baseline, with the lowest level at 120 hours, and there was a significant difference in antiviral activity between different dose groups (F=14.621, P＜0.000 1), among which the 60 mg group had a significantly greater reduction than the 30 mg group (P=0.025), while there was no significant difference between the 60 mg group and the 90/120 mg group (P＞0.05). There was no significant difference in HCV RNA load between different groups of patients with HCV genotype 2a (P＞0.05). Of all 36 subjects, 20 reported 34 cases of treatment-emergent adverse events, among which 19 cases were associated with coblopasvir hydrochloride, and no significant adverse events or serious adverse events were observed. ConclusionOral administration of coblopasvir hydrochloride capsules in a fasting state at a dose of 30-120 mg/d (for 3 consecutive days) has good safety and antiviral activity. Therefore, it has good application prospect in the treatment of HCV infection and provides a basis for dose selection in phrase 2 study.
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Objective To investigate the value of evaluation of pelvic floor ultrasound in the transvaginal modified patch repair and sacrospinous ligament fixation in uterine prolapse patients. Methods Thirty-two patients with uterine prolapse were included in the retrospective study from March 2016 to January 2017 in Hangzhou maternity and child health care hospital. All patients were detected by pelvic floor ultrasound before operation and cured by vaginal patch bilateral sacral spine ligament fixation treatment after. Of them, 8 cases were complicated with cystocele and 3 cases with anorectal prolapse, and all the complications were treated at the same time. The observations of the change of position, shape and activity of the implant by transvaginal at rest, on maxium Valsalva and contraction, and the transperineal pelvic ultrasound were performed to evaluate the change of pelvic floor function and compare the distance from the lowest point of the bladder, uterus and the rectal ampulla to reference line (the horizontal line at the lower margin of the pubic bone), area of levator hiatus and the thickness of the puborectalis muscle before and after operation. Results The patches were observed 2D and 3D postoperatively by pelvic ultrasound. The U-shaped hyperecho could be clearly shown around the cervix and activity of patches were clearly shown. The observation of 32 cases of patients with pelvic viscera situation by the transperineal 2D and 4D pelvic ultrasound: the distance from the lowest point of the bladder, uterus and the rectal ampulla to reference line and the thickness of the puborectalis muscle enlarged after operation (0.65±1.85 vs 0.15±1.85, 2.80±1.10 vs -1.00±1.50, 0.60±1.90 vs-0.55±1.55,0.51±0.24 vs 0.37±0.19)onmaxium valsalva,the area of levator hiatus decreased after operation (20.15±7.20 vs 29.00±9.50).The differences were both statistically significant (all P < 0.05). Uterine prolapse were not found after operation. In the 8 cases with cystocele, 5 cases were cured and 3 cases were improved. And all the 3 cases of patients with anorectal prolapse were all cured. Conclusion Combined application of transvaginal and transperineal pelvic ultrasound can clearly show the suspension of the patch after the treatment of modified patch repair and Sacrospinous ligament fixation, which provide valuable imaging information in the evaluation of preoperative pelvic functionand postoperative therapeutic effect.
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Objective To study the antileukemia immune response of IL-18 gene transfected dendritic cells(DCs) of chronic myelogeous leukemia(CML).Methods DCs were transfected with IL-18 gene by liposomes in CML.The expression of IL-18 in IL-18 transfected DCs was detected.The percentages of CD80+ and CD86+ cells in IL-18 tranfected DCs were determined by FCM.The proliferation of T cell,NK and specific CTL kill activity induced by IL-18 gene transfected DCs were detected.Results The quantity of IL-18 in IL-18 tranfected DCs was(596?34.1)pg/2?106cells/48 h,while the culture medium of mock-transduced DCs and DCs did not secrete detectable levels of IL-18.The percentages of CD80+ and CD86+ cells in IL-18 tranfected DCs were higher than that in mock-transfected DCs(P