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.

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.

Viral infection parameters not nucleoside analogue itself correlates with host immunity in nucleoside analogue therapy for chronic hepatitis B

AIM: To determine the relationship between host immunity and the characteristics of viral infection or nucleoside analogues (NAs) themselves in patients with chronic hepatitis B (CHB) receiving NA therapy.

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.

Synthesis of novel ADPR analogues: substitution of pyrophosphate linkage by dipeptide

For investigating the biological function of ADPR, four novel analogues （compounds 2-5） in which the pyrophosphate linkage was replaced by the aspartic acid dipeptide were synthesized. 5＇-Amino adenosine or its analogues was used as the starting material, liquid phase peptide synthesis strategy was used to construct these ADPR analogues. The structures were characterized by 1H NMR and HRMS spectra. This study provides a versatile synthesis of peptide modified ADPR analogues and helps to understand the structure-activity relationship of ADPR.

Microwave-assisted Green and Efficient Synthesis of N^6-(2-Hydroxyethyl)adenosine and its Analogues

An efficient protocol for the synthesis of N^6-（2-Hydroxyethyl）adenosine and its analogues through nucleophilic substitution was developed. All the reactions were completed in 10 rain under microwave irradiation. Using water as solvent makes our method eco-friendly and easy to handle with.

Effect of somatostatin analogue octreotide injected into the third cerebral ventricle on pentagastrin-induced gastric acid secretion in rats

AIM： To investigate the effect of long-lasting somatostatin analogue octreotide （Oct） injected into the third cerebral ventricle （TCV） on gastric acid secretion in rats. METHODS： TCVs were cannulated in male Wistar rats anesthetized with sodium pentobarbital. One week later acute gastric lumen perfusion was carried out and gastric acid was continuously washed with 37℃ saline by a perfusion pump. Gastric perfusion samples were collected every 10 min and titrated by 0.01 moL/L NaOH to neutral. On the basis of subcutaneous （sc） injection of pentagastrin （G-5, 160 μg/kg）, Oct （0.025 μg, 0.05 μg, 0.1 μg, n=12 in each group） or vehicle （pyrogen-free physiological saline, n = 10） was injected into the TCV, Before and after the TCV injection, 1 h total acid output （TAO） was determined and experimental data were expressed in change rate （%） of TAO. RESULTS： Oct （0.025, 0.05 and 0.1 μg） injected into the TCV resulted in change rate of 1.56% （P〉0.05）, 20.21% （P〈 0.01） and 37.82% of TAO （P〈 0.001）, respectively. Moreover, comparison in change rate of TAO among these 3 doses showed P〈 0.05 between 0.025μg and 0.05 μg, P〈 0.01 between 0.025 μg and 0.ling, and P〈 0.05 between 0.05μg and 0.1 μg. However, sc injection of 0.05 μg Oct had no effect on G-5 stimulated gastric acid secretion. CONCLUSION： Octreotide injected into the third cerebral ventricle inhibits gastrin-induced gastric acid secretion in a dose-dependent manner.

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。

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。