Clinical efficacy and safety of TCM prescriptions combined with nucleoside(acid)analogues in treating chronic hepatitis B:a meta-analysis

Objective There are many clinical reports on traditional Chinese medicine(TCM)combined with nucleoside(acid)analogues(NAs)for the treatment of chronic hepatitis B(CHB),but its efficacy and safety are not completely clear.This meta-analysis aims to evaluate the clinical efficacy and safety thus providing evidence for clinical applications.Methods We searched Chinese databases the China National Knowledge Infrastructure(CNKI),Wanfang Data,and China Science and Technology Journal Database(VIP),as well as English databases Pub Med and Cochrane Library,from time of establishment to April 14,2021.Literature quality was evaluated according to the bias risk assessment criteria of Cochrane Collaboration network.Rev Man 5.3 and Stata 12.0 software were used to perform this research.Results A total of 23 articles,3282 patients,and 25 TCM prescriptions were included in this study.NAs plus TCM remarkably improved the clinical total effective rate[Odds ratio(OR)=3.92,P<0.00001],TCM syndrome score(Mean difference=-3.73,P<0.00001),hepatitis B virus(HBV)DNA negative conversion rate(OR=1.49,P=0.0001),hepatitis Be antigen(HBe Ag)negative conversion rate(OR=2.03,P<0.00001),alanine aminotransferase levels[Std mean difference(SMD)=-0.95,P<0.00001],and aspartate aminotransferase levels(SMD=-0.70,P=0.0004).Adverse reaction rates did not increase in the combined treatment group(OR=0.97,P=0.84).A comprehensive analysis of the 25 TCM prescriptions suggested that the combination of spleen-strengthening prescriptions with NAs showed better effects than other prescriptions.Conclusion TCM in combination with NAs,demonstrated better clinical efficacy against CHB than NAs alone.In addition,the combination of spleen-strengthening prescriptions and NAs was identified as the best therapeutic strategy.However,more randomized controlled trials of high quality are needed to provide more reliable clinical basis for the application of TCM.

Application of nucleoside analogues to liver transplant recipients with hepatitis B

Hepatitis B is a common yet serious infectious disease of the liver, affecting millions of people worldwide. Liver transplantation is the only possible treatment for those who advance to end-stage liver disease. Donors positive for hepatitis B virus(HBV) core antibody(HBc Ab) have previously been considered unsuitable for transplants. However, those who test negative for the more serious hepatitis B surface antigen can now be used as liver donors, thereby reducing organ shortages. Remarkable improvements have been made in the treatment against HBV, most notably with the development of nucleoside analogues(NAs), which markedly lessen cirrhosis and reduce post-transplantation HBV recurrence. However, HBV recurrence still occurs in many patients following liver transplantation due to the development of drug resistance and poor compliance with therapy. Optimized prophylactic treatment with appropriate NA usage is crucial prior to liver transplantation, and undetectable HBV DNA at the time of transplantation should be achieved. NA-based and hepatitis B immune globulin-based treatment regimens can differ between patients depending on the patients' condition, virus status, and presence of drug resistance. This review focuses on the current progress in applying NAs during the perioperative period of liver transplantation and the prophylactic strategies using NAs to prevent de novo HBV infection in recipients of HBc Ab-positive liver grafts.

Current prodrug strategies for improving oral absorption of nucleoside analogues

Nucleoside analogues are first line chemotherapy in various severe diseases:AIDS(acquired immunodeficiency disease syndrome),cytomegalovirus infections,cancer,etc.However,many nucleoside analogues exhibit poor oral bioavailability because of their high polarity and low intestinal permeability.In order to get around this drawback,prodrugs have been utilized to improve lipophilicity by chemical modification of the parent drug.Alternatively,prodrugs targeting transporters present in the intestine have been applied to promote the transport of the nucleoside analogues.Valacyclovir and valganciclovir are two classic valine ester prodrugs transported by oligopeptide transporter 1.The ideal prodrug achieves delivery of a parent drug by attaching a non-toxic moiety that is stable during transport,but is readily degraded to the parent drug once at the target.This article presents advances of prodrug approaches for enhancing oral absorption of nucleoside analogues.

Effects of two novel nucleoside analogues on different hepatitis B virus promoters

AIM： To explore the effects of the nucleoside analogues β-L-D4A and β-LPA on hepatitis B virus （HBV） promoters. METHODS： Four HBV promoters were amplified by polymerase chain reaction （PCR） and subcloned into the expression vector pEGFP-1. The four recombinants controlled by HBV promoters were confirmed by restriction analysis and sequencing. Human hepatoma HepG2 cells transfected with the recombinant plasmids were treated with various concentrations of β-L-D4A and β-LPA. Then, enhanced green fluorescent protein （EGFP）-positive cells were detected by fluorescence microscopy and using a fluorescence activated cell sorter RESULTS： Four HBV promoters were separately obtained and successfully cloned into pEGFP-1, Expression of EGFP under the control of the surface promoter （Sp） and the X promoter （Xp） was inhibited by β-L-D4A in a dosedependent manner, while expression of EGFP under the control of the core promoter （Cp） and Xp was inhibited by β-LPA in a dose-dependent manner. CONCLUSION： The two novel nucleoside analogues investigated here can inhibit the activities of HBV promoters in a dose-dependent manner. These findings may explain the mechanisms of action by which these two novel compounds inhibit HBV DNA replication.

Design, synthesis and in vitro evaluation of L-amino acid esters prodrugs of acyclic nucleoside phosphonates as anti-HBV agent

A series of novel L-amino acid esters prodrugs of acyclic nucleoside phosphonates was synthesized and their anti-HBV activity was evaluated in HepG2 2.2.15 cells. Compound 1d exhibited more potent anti-HBV activity and lower cytotoxicity than those of adefovir dipivoxil with EC50 and CC50 values of 0.207 μmol/L and 2530 μmol/L, respectively.

Structure and Anti-HIV Activity of Betulinic Acid Analogues

Firstly discovered in 1980s, human immunodeficiency virus （HIV） continues to affect more and more people. However, there is no effective drug available for the therapy of HIV infection. Betulinic acid existing in various medicinal herbs and fruits exhibits multiple biological effects, especially its outstanding anti-HIV activity, which has drawn the attentions of many pharmacists. Among the derivatives of betulinic acid, some compounds exhibited inhibitory activities at the nanomolar concentration, and have entered phase II clinical trials. This paper summarizes the current investigations on the anti-HIV activity of betulinic acid analogues, and provides valuable data for subsequent researches.

Effectiveness of 0.1% topical salicylic acid on blepharoconjunctivitis affecting glaucoma patients treated with topical prostaglandin analogues:a prospective randomized trial

AIM: To evaluate the efficacy of 0.1% topical salicylic acid（TSA） to treat iatrogenic chronic blepharoconjunctivitis in patients with primary open angle glaucoma（POAG）, treated with topical prostaglandin analogues（TPAs）.METHODS: Totally 60 patients were randomly distributed into 3 equal size groups, two of which treated with 0.1% TSA（OMKASA;） and 0.1% topical clobetasone butyrate（TCB; VISUCLOBEN;） respectively, and one consisting of untreated controls. The parameters taken into account at baseline（T0） and after 30 d（T1） of therapy were: conjunctival hyperemia, lacrimal function tests [Schirmer I test and break up time（BUT）] and intraocular pressure（IOP）.RESULTS: Conjunctival hyperemia showed a substantial improvement in both treated groups（P<0.001） but not among controls. Similarly, lacrimal function tests displayed an improvement of Schirmer I test in both treated groups（P<0.05） and an extension of BUT only in the group treated with 0.1% TSA（P<0.05）. The IOP increase was statistically significant only in those patients treated with 0.1% TCB（P<0.001）.CONCLUSION: The 0.1% TSA has proved to be an effective anti-inflammatory treatment of blepharoconjunctivitis affecting glaucoma patients on therapy with TPAs, leading to a sizeable decrease of inflammation as well as both quantitative and qualitative improvement of tear film. Furthermore, differently from 0.1% TCB, it does not induce any significant IOP increase.

Syntheses of Nucleoside Derivatives Containing Fmocor Trityl-protected Amino Acids

Facile direct esterification reactions between 2′,3′-O-isopropylidene-nucleosides and Fmoc- or trityl-protected amino acids %via% N,N-dicyclohexyl-carbodiimide(DCC) mediated condensation are described. These reactions offer a mild and convenient method to synthesize aminoacylated nucleoside derivatives.

Interaction between N-Phospho-Amino Acids and Nucleoside in Aqueous Medium

Nucleosides were phosphorylated with different N- (O, O-diisopropyl) phosphoryl amino acids to give nucleoside mono phosphates in aqueous solution. 2', 3', and 5'-isomers had been confirmed by comparison with authentic samples on the basis of HPLC analysis. The conversion percentage of nucleoside indicated that N- (O, O-diisopropyl) phosphoryl aspartic acid reacted with adenosine and guanosine at a much higher rate than other kinds of N- phosphoryl amino acids. while phosphorylation of cytidine and uridine was relatively easy by using N- (O, O-diisopropyl) phosphoryl threonine. The result could give some clue to the prebiotic code origin of nucleic acid and protein.

Interaction between N-phosphoryl-α-,β-and γ-amino acids and nucleosides

The reactions of four different N-（O,O＇-diisopropyl） phosphoamino acids （DIPP-aa）, such as N-phosphoryl-L-α-alanine （DIPP- L-α-Ala）, N-phosphoryl-D-α-alanine （DIPP-D-α-A1a）, N-phosphoryl-β-alanine （DIPP-β-A1a） and N-phosphoryl-γ-amino butyric acid （DIPP-γ-Aba）, and four nucleosides, adenosine （A）, guanosine （G）, cytidine （C） and uridine （U）, were studied by electrospray ionization tandem mass spectrometry （ESI-MS/MS） and HPLC/ESI-MS. DIPP-L-α-A1a and DIPP-D-α-A1a produced the same phosphorylated nucleosides, dinucleotides and phosphoroligopeptide. However, DIPP-β-A1a and DIPP-γ-Aba gave no relevant products.

LYSOPHOSPHATIDIC ACID ACTIVATES NUCLEAR NUCLEOSIDE TRIPHOSPHATASE IN RAT HEPATOCYTES

Objectives.To observe if lysophosphatidic acid(LPA)can influence nuclear nucleoside triphos-phatase(NTPase)activity of isolated hepatocyte from rat,and to investigate the possible mechanisms by which LPA affects the NTPase.Method.Isolated and cultured hepatocytes from rat liver were exposed to LPA(1×10 -9 ,1×10 -8 and5×10 -8 mol/L)with or without inhibitors of protein kinase C(PKC)and mitogen activating protein kinase kinase(MAPKK),and the NTPase activity on nuclear envelope was assayed using ATP and GTP as substrate,respectively.Results.Nuclear NTPase activity of rat hepatocytes was potently stimulated by incubation of hepato-cytes with LPA in concentration?and time ?dependent manners.In hepatocytes incubated with LPA,nu-clear NTPase activity was significantly higher than that of the control(P<0.01).In hepatocytes preincu-bated with PKC inhibitor H-7or MAPKK inhibitor PD98059,LPA-stimulated activation of nuclear NT-Pase was obviously attenuated.In addition,direct incubation of isolated hepatic nuclei with LPA had no effect on nuclear NTPase activity.Conclusion.LPA is involved in modulating nuclear NTPase activity in hepatocytes.The stimulating effect of LPA on the nuclear NTPase is mediated at least partly by PKC and MAPK-dependent pathway.

STUDY ON THE SYNTHESIS OF TETRACYCLIC DITERPENOID 7 Preparation of the Key Intermediate 5 for the Synthesis of Grandiflorenic Acid and its Analogues

The key intermediate 5 for synthesis of the contragestationally active diterpenoid grandiflorenic acid(1)and its analogues 2 and 3 was prepared and an acetyl transposition reaction occurred in the SeO_2 oxida- tion of 8.

Effect of different nucleoside analogues on liver fibrosis and peripheral blood dendritic cell function of patients with chronic hepatitis B

Objective: To study the effect of different nucleoside analogues on liver fibrosis and peripheral blood dendritic cell function of patients with chronic hepatitis B. Methods: Patients with chronic hepatitis B who received antiviral therapy in Infectious Diseases Hospital of Shanghai Huangpu District between April 2014 and October 2016 were selected as the research subjects and divided into 3 groups, group A received entecavir therapy, group B received adefovir dipivoxil therapy and group C received lamivudine therapy. 24 weeks and 48 weeks after treatment, the levels of liver fibrosis indexes in serum as well the levels of DC and the expression of surface markers in peripheral blood of the three groups were measured respectively. Results: After treatment, serum hyaluronic acid (HA), procollagen III (PC-III), laminin (LN) and collagen type IV (C-IV) levels of all groups were significantly lower than those before treatment, and the number of myeloid DC (mDC) and plasmacytoid DC (pDC) in peripheral blood as well as the expression levels of DC surface molecules CD80, CD86, CD1αand HLA-DR in peripheral blood were significantly higher than those before treatment. After treatment, the serum levels of HA, PC-III, LN and C-IV in group A were significantly lower than those in group B and C, and the number of mDC and pDC in peripheral blood as well as the expression of DC surface molecules CD80, CD86, CD1α and HLA-DR in peripheral blood were significantly higher than those in group B and C. Conclusion: Antiviral therapy by nucleoside analogues can effectively inhibit liver fibrosis and improve peripheral blood DC function in patients with chronic hepatitis B, and Entecavir function is better than that of adefovir dipivoxil and lamivudine.

基于代谢组学的‘海尔特兹’红树莓果实中核苷、核苷酸和类似物含量的变化规律研究

本研究基于代谢组学,采用液相色谱-质谱联用法,针对‘海尔特兹’红树莓4个不同时期果实中17种核苷、核苷酸和类似物含量及变化规律进行研究。结果表明:在海尔特兹’红树莓果实发育过程中,脱氧胞苷酸、5-甲基脱氧胞苷、玉米素核苷、N-[(5-羟基-2-吡啶基)甲基]腺苷、反式玉米素-O-葡萄糖苷核糖苷、1-甲基腺苷、鸟苷、2-苯基氨基腺苷、1,7-二甲基鸟苷和胞苷2’,3’-环磷酸的含量在青果时期最高;UDP-4-脱氢-6-脱氧-D-葡萄糖和dTDP-D-葡萄糖的含量在黄果时期最高;尿苷二磷酸葡萄糖、8-羟基鸟苷、胞苷的含量在红果时期最高;1-甲基肌苷和脂酰腺苷酸的含量在深红果时期最高。本研究阐明了17种核苷、核苷酸和类似物在‘海尔特兹’红树莓在果实发育中的含量变化规律,为后期相关研究及应用提供了参考。

核苷类似物治疗乙型肝炎肝硬化并发食管静脉曲张临床价值研究

目的:探讨核苷类似物治疗乙型肝炎肝硬化并发食管静脉曲张临床价值。方法:选取乙型肝炎肝硬化并发食管静脉曲张患者88例,根据是否抗病毒治疗分为对照组(33例)和治疗组(55例)。比较两组患者治疗前后肝功能指标[白蛋白(ALB)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、总胆红素(TBIL)]、Child-Pugh评分和凝血功能指标[凝血酶原时间(PT)、凝血酶原活动度(PTA)]以及治疗后乙型肝炎病毒DNA(HBV-DNA)阴转率、食管静脉曲张程度和消化道出血情况。结果:抗病毒治疗后,治疗组患者TBIL、ALT、AST较治疗前降低,ALB较治疗前升高(均P<0.05)。抗病毒治疗后,治疗组患者PT较治疗前降低,且治疗组低于对照组;治疗组PTA较治疗前升高,且治疗组高于对照组(均P<0.05)。治疗组抗病毒治疗后Child-Pugh评分较治疗前降低,且治疗组Child-Pugh评分低于对照组(均P<0.05)。与对照组比较,治疗组在抗病毒治疗后HBV-DNA阴转率升高(P<0.05)。在未行EVL治疗患者中,治疗组食管静脉曲张减轻程度高于对照组(P<0.05)。在接受及未接受EVL治疗的患者中,治疗组消化道出血率低于对照组(均P<0.05)。结论:核苷类似物能够抑制乙型肝炎肝硬化并发食管静脉曲张患者HBV病毒复制,改善肝功能和凝血功能,减轻食管静脉曲张程度,降低消化道出血风险。

慢性乙型肝炎患者接受核(苷)酸类似物抗病毒治疗后血清HBV-DNA的表达及临床意义

目的探讨慢性乙型肝炎(CHB)患者接受核(苷)酸类似物(NAs)抗病毒治疗后血清乙型肝炎病毒脱氧核糖核酸(HBV-DNA)的表达及临床意义。方法回顾性分析2021年1月至2022年10月河南省人民医院83例采用NAs抗病毒治疗的CHB患者临床资料,根据血清学应答标准将其分为应答组(46例)和未应答组(37例)。比较两组基线资料、治疗前及治疗3、6、12个月时血清HBV-DNA水平;绘制受试者工作特征(ROC)曲线,以曲线下面积(AUC)检验血清HBV-DNA对CHB患者NAs抗病毒治疗未应答的预测价值。结果治疗前,应答组和未应答组HBV-DNA比较,差异无统计学意义(P>0.05);两组治疗前至治疗12个月的HBV-DNA呈下降趋势,组间、时点、交互效应有统计学意义(P<0.05)。绘制ROC曲线显示,治疗3个月时HBV-DNA对CHB患者NAs抗病毒治疗未应答的预测价值较低(AUC=0.694,P=0.002),治疗6个月时HBV-DNA对CHB患者NAs抗病毒治疗未应答具有一定预测价值(AUC=0.751,P<0.001)。结论血清HBV-DNA表达在CHB患者NAs抗病毒治疗前后变化明显,且治疗6个月时血清HBV-DNA可作为抗病毒治疗未应答的预测指标。

恩替卡韦、富马酸替诺福韦二吡呋酯及富马酸丙酚替诺福韦治疗慢性乙型肝炎的疗效及安全性分析

目的观察恩替卡韦(entecavir,ETV)、富马酸替诺福韦二吡呋酯(tenofovir disoproxil fumarate,TDF)及富马酸丙酚替诺福韦(tenofovir alafenamide fumarate,TAF)抗病毒治疗慢性乙型病毒性肝炎(慢乙肝)的临床疗效及安全性。方法选择2021年3月—2023年6月我院收治的181例慢乙肝患者,依据抗病毒治疗用药不同分为3组,ETV组(n=66)、TDF组(n=64)及TAF组(n=51)。比较3组患者的血脂、肝功能、HBsAg、HBV DNA、血肌酐及估算的肾小球滤过率(estimated glomerular filtration rate,eGFR)等指标在治疗前后及组间的差异。结果ETV组有效率为86.36%(57/66),TDF组有效率为90.63%(58/64),TAF组有效率为90.20%(46/51),3组比较差异无统计学意义(P>0.05)。治疗后,3组的HBsAg水平、HBV DNA载量均低于治疗前(P均<0.05),且3组间HBsAg水平、HBV DNA载量的变化幅度比较,差异具有统计学意义(P<0.05)。治疗后,3组的ALT、AST水平均低于治疗前(P均<0.05),且3组间ALT、AST水平的变化幅度比较,差异有统计学意义(P<0.05)。治疗后,ETV组的HDL-C、LDL-C均高于治疗前(P均<0.05),TC、TG较治疗前差异均无统计学意义(P均>0.05);TDF组的TC、HDL-C均低于治疗前(P均<0.05),TG、LDL-C较治疗前差异均无统计学意义(P均>0.05);TAF组的TC、TG、HDL-C、LDL-C较治疗前差异均无统计学意义(P均>0.05),但3组间TC、TG、HDL-C、LDL-C的变化幅度比较,差异均有统计学意义(P均<0.05)。治疗后,3组的血肌酐、eGFR较治疗前差异均无统计学意义(P均>0.05),但3组间血肌酐、eGFR的变化幅度比较,差异均有统计学意义(P均<0.05)。结论ETV、TDF、TAF治疗慢乙肝的临床疗效相近,服用TAF不会对血脂造成影响,但服用ETV会引起HDL-C、LDL-C水平升高,服用TDF可降低TC、HDL-C水平,并且均有较好的肾脏安全性。

新型冠状病毒RNA依赖性RNA聚合酶抑制剂研究进展

由严重急性呼吸综合征冠状病毒2型导致的新型冠状病毒感染席卷全球,寻找广谱抗病毒特效药一直是一项重大任务。RNA病毒的RNA依赖性RNA聚合酶是一类不同病毒间在结构和功能上高度保守的关键非结构蛋白,针对该聚合酶为靶点开发新的小分子抑制剂至关重要。本文作者从新型冠状病毒RNA依赖性RNA聚合酶的结构为出发点,详细阐述了该病毒RNA依赖性RNA聚合酶的作用机制以及不同种类抑制剂的特点。着重从药物化学的角度介绍了核苷类似物和非核苷类似物的作用特点和作用机制,综述了多种小分子聚合酶抑制剂化学结构与生物活性之间的关系。

Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors:A case report and literature analysis

Hepatitis B virus(HBV)reactivation(HBVr)represents a severe and potentially life-threatening condition,and preventive measures are available through blood test screening or prophylactic therapy administration.The assessment of HBVr traditionally considers factors such as HBV profile,including hepatitis B surface antigen(HBsAg)and antibody to hepatitis B core antigen,along with type of medication(chemotherapy;immunomodulants).Nevertheless,consideration of possible patient’s underlying tumor and the specific malignancy type(solid or hematologic)plays a crucial role and needs to be assessed for decision-making process.

传统泡菜中高效降解核苷乳酸菌的筛选及其特性研究

高尿酸血症是一种因尿酸代谢障碍而引发的一种代谢性疾病。乳酸菌作为一类重要的益生菌可通过多种方式改善高尿酸血症。该研究旨在从泡菜中筛选能够高效降解核苷的乳酸菌并分析其特性。利用高效液相色谱法分析所筛选菌株的核苷降解能力,检测菌株对黄嘌呤氧化酶抑制作用、体外环境耐受性及抗生素敏感性。结果表明,短乳杆菌(Levilactobacillus brevis)SLlac-18对肌苷和鸟苷的降解率分别可达97.81%和97.89%;且对黄嘌呤氧化酶的活力具有一定抑制作用。此外,在pH 2.0的环境下,SLlac-18的存活率可达96%;在3 g/L胆盐环境下处理5 h条件下,SLlac-18的存活率可达96.33%;而在胃肠液环境中,SLlac-18同样表现较高的耐受性,存活率均在90%以上,且菌株对红霉素、氨苄西林等4种常见抗生素具有敏感性。短乳杆菌SLlac-18具有潜在降尿酸功能,且具有良好的益生特性,可以应用于高尿酸血症预防和辅助治疗中,具有一定应用价值。