~1HIV/AIDS药恩曲他滨(emtricitabine)

1 商品名 Emtriva2 开发与上市厂商 美国Gilead Sciences公司研制,2003年7月首次在美国上市。

抗HIV-1药 恩曲他滨(emtricitabine)

1商品名 Emtriva2上市与开发厂商 美国Gilead Sciences公司研制开发,2003年7月,首次在美国获准并上市。3作用特点 恩曲他滨为一种新型核苷类逆转录酶抑制剂,对HIV-1、HlV-2及HBV均有抗病毒活性。 本品口服后被磷酸化为具有细胞活性的5’-三磷酸盐,5’-三磷酸盐通过进入病毒DNA主链,与主链结合,导致链终止,从而抑制HIV-1逆转录酶及HBV DNA聚合酶活性。

Influence of Solvent Polarity on the Physio-Chemical Properties and Quantitative Determinations of Tenofovir Disoproxil and Emtricitabine with Chloranilic Acid as Complexing Agent

Purpose: Tenofovir disoproxil fumarate (TEN) and emtricitabine (EMT) are both second generation ant-retroviral drugs used in the “treatment” of HIV/AIDS. The aim of this study is to establish the physic-chemical properties of their reaction with chloranilic acid in different solvent systems and to justify the chemical basis for simultaneous quantitative determination of these drugs in their combined formulation. Method: TEN and EMT were individually isolated from their single formulations and purified by chromatography to obtain secondary standard. Purity of the isolates were tested for by comparison with literature values. Stock solution of chloranilic acid (CA) [3.0 × 10﹣3 M] was prepared in the following solvents of different polarities: ethanol, acetonitrile, ethylacetate, chloroform and hexane. Equal volumes of CA and TEN [3.0 × 10﹣2 M] and EMT [3.0 × 10﹣2 M] dissolved in different solvents were mixed whereby colored products were observed. Absorption maxima were determined. Calibration curves were generated and validated. Quantitative simultaneous determination of TEN and EMT was determined by standard protocol. Stoichiometric relationships between the drugs and CA were established. Equilibrium constants were determined at different temperatures from which the Gibb’s free energies were calculated. Arrhenius equation was used to calculate the enthalpy, entropy was similarly calculated. Results: Absorption maxima of CA in different solvents are as follows: Ethanol 310 nm;Acetonitrile 330 nm;Ethyl acetate 340 nm;Chloroform 350 nm and hexane 310 nm. The complex of CA and TEN in the different solvents are: Alcohol 525 nm, Acetonitrile 500 nm;Ethyl acetate 505 nm;Chloroform 510 nm and hexane 515 nm. For EMT complex absorption maxima are: Alcohol 510 nm;Acetonitrile 515 nm’ Ethyl acetate 520 nm’ Chloroform 505 nm and hexane 530 nm. Simultaneous quantitative recovery values for TEN are: Ethanol;97.89% ± 1.21;Acetonitrile 101.17 V 1.51%;Ethyl acetate 96.55% ± 0.71%;Chloroform 99.11% ± 0.34% and hexane 98.03% ± 0.15%. For EMT the values are also: Ethanol: 98.92% ± 1.45%;Acetonitrile 100.471 ± 13;Ethyl acetate 97.06% ± 0.87%;Chloroform 99.31% ± 0.94% and Hexane 99.97% ± 1.63%. Stoichiometry of complexation showed a 1:1 ratio for both drugs. Equilibrium constants for TEN were highest in acetonitrile and least for Ethanol while for EMT, equilibrium constant was least for acetonitrile and highest in chloroform. Gibb’s free energy for TEN was least in ethanol and highest in acetonitrile. Gibb’s free energy for EMT was least in acetonitrile and highest in chloroform. Enthalpy for TEN was least in chloroform and highest in hexane. Similarly, the enthalpy for EMT was highest in chloroform and lowest in hexane. Conclusion: These results shows that solvent polarity influence charge transfer complexes in a non consistent fashion. The structure of the donor might have contributed to thermodynamics of complexation since orbital overlap may vary from solvent to solvent. For quantitative analysis hexane appears to be the most suitable solvent because it has the highest molar absorptivity and higher enthalpy of interactions. Molecules that can donate electrons and their stereochemistry could contribute to intensity of absorption maxima of the electronic transitions.

Stability Indicating RP-UPLC Method for Assay of Emtricitabine and Tenofovir Disoproxil Fumarate in Bulk and Dosage Forms

A simple, sensitive and rapid stability indicating reverse phase ultra performance liquid chromatography (RP-UPLC) method was developed and validated for the determination of Emtricitabine (EMT) and Tenofovir disoproxil fumarate (TDF) in pure and tablet dosage forms. The chromatographic separation was achieved by using Waters (Alliance) UPLC system equipped with auto-sampler and photo diode array detector. A volume of 5 μL of standard or test was injected into the column and the components were separated by using the mixture of 0.68% potassium dihydrogen orthophosphate buffer of pH = 6 and methanol in the ratio 45:55 v/v as mobile phase at a flow rate of 1.2 mL/min through BEH C18 (100 mm × 2.1, 1.8 μm) at ambient temperature and were detected at a wavelength of 261 nm. System suitable parameters such as plate count and tailing factor for EMT and TDF were found to be 2427 & 3685, 1.16 & 1.23 respectively, and resolution between EMT and TDF peaks was found to be 3.12. The chromatographic parameters like retention time, peak area and peak height of EMT and TDF were found to be 0.684 & 0.930, 694,200 & 8,778,000 and 272,881 & 3685 respectively. Percent of assay of EMT and TDF in bulk and dosage forms was determined and found to be 101.48 and 103.22 respectively. Study of degradation was examined and found that the drugs were stable under degradation conditions. The present method was developed keeping the principles of green chemistry by using eco-friendly solvent methanol in mobile phase. The developed method was found to be simple, rapid and applied for the analysis of Truvada;therefore the proposed method is recommended for the analysis of EMT and TDF in pure and tablet dosage forms in any quality control laboratories.

An open-label evaluation of safety and tolerability of coformulated bictegravir/emtricitabine/tenofovir alafenamide for post-exposure prophylaxis following potential exposure to human immunodeficiency virus-1

Background: Single-tablet regimen (STR) provides a convenient once-daily regimen for the prevention of human immunodeficiency virus (HIV) infection. Here, we investigated the safety and tolerability of coformulated bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) as a three-drug, STR for post-exposure prophylaxis (PEP) in Chinese individuals.Methods: This was a prospective, open-label, single-arm trial conducted in a sexually transmitted diseases and acquired immunodeficiency syndrome clinic of a tertiary hospital in Beijing, China. Adults requiring PEP were prescribed BIC/FTC/TAF one pill once a day for 28 days. Clinical and laboratory data were collected and analyzed at baseline, weeks 2, 4, 8, 12, and 24.Results: Of 112 participants enrolled in the study, 109 (97.3%) were male and the mean age was 30 ± 8 years. PEP completion was 96.4% (95% confidence interval: 91.1-99.0%). Two participants stopped PEP after 2 days because the source partner was identified as HIV uninfected. One participant was excluded due to hepatitis B virus infection according to the exclusion criteria. One discontinued due to the participant’s decision. No participant acquired HIV through week 24. Adherence was 98.9% (standard deviation [SD]: 3.3%) by self-reporting and 98.5% (SD: 3.5%) by pill count. Only five participants experienced mild clinical adverse events attributed to the study drug (including headache, diarrhea, and nausea) and four participants had elevated serum creatinine (grade 1).Conclusions: A once daily, STR of BIC/FTC/TAF used as PEP was safe and well-tolerated with a high rate of completion and adherence in Chinese. BIC/FTC/TAF may be a good option for PEP.

Current therapy with nucleoside/nucleotide analogs for patients with chronic hepatitis B

BACKGROUND: Currently, more and more nucleos(t)ide analogs are appearing as therapeutic options in the treatment of chronic hepatitis B (CHB). Their efficacy and safety profile in hepatitis B virus (HBV) infection have already been studied in detail worldwide. This review summarizes the efficacy of lamivudine, adefovir, entecavir and newer antiviral agents such as emtricitabine, telbivudine and clevudine in the treatment of hepatitis B in different clinical situations. DATA SOURCES: An English-language literature search using OVID and MEDLINE was performed and a total of 40 articles on the treatment of chronic hepatitis with nucleos(t)ide analogues were selected. RESULTS: Nucleos(t)ide analogs such as lamivudine, adefovir and entecavir are well tolerated and induce a decrease in serum HBV-DNA levels associated with normalization of serum alanine aminotransferase (ALT) levels. But their sustained response with HBeAg to anti-HBe seroconversion is rarely obtained and HBsAg loss is exceptional. The response is maintained during therapy which needs to be continued indefinitely in the majority of patients since withdrawal of treatment is generally followed by a rapid reactivation of hepatitis B. However, drug resistant mutations can be induced in long-term treatment. Other newer antiviral agents such as emtricitabine, telbivudine and clevudine in the treatment of hepatitis B are still under phaseⅡorⅢclinical trials. CONCLUSIONS: Nucleos(t)ide analogs play an important role in the therapy of hepatitis B now and in the future. Lamivudine is limited by the frequent emergence of drugresistant (HBV) mutants (YMDD). Adefovir and entecavir appear to be effective against both YMDD mutation and wild type. Therapeutic options against hepatitis B virus remain a major clinical challenge.

美国FDA批准第2种1型HIV感染暴露前预防用药Descovy

美国FDA于2019年10月3日批准吉列德科学公司(Gilead Sciences Inc.)的二联复方药物Descovy作为1型HIV感染暴露前预防用药(pre-exposure prophylaxis,PrEP)用于高危成人及体重在35 kg以上的青少年预防由于性行为引起的1型HIV感染,但接入式阴道性交(receptive vaginal sex)除外,因为Descovy对预防此类性行为引起HIV感染的有效性尚未经研究证实。Descovy有效成分包括恩曲他滨(emtricitabine)200 mg和替诺福韦艾拉酚胺(tenofovir alafenamide)25 mg。

美国FDA批准抗HIV药Odefsey固定剂量复方片剂上市

美国FDA于2016年3月1日批准吉利德（Gilead）公司的Emtricitabine,Rilpivirine,and Tenofovir Alafenamide（参考译名：恩曲他滨-利匹韦林-替诺福韦艾拉酚胺,商品名：Odefsey）片剂上市,作为完整用药方案,用于未接受过抗逆转录病毒治疗.

Changes in blood lipid levels and influencing factors among treatment-naïve adult male HlV/AlDS patients following BlC/FTC/TAF vs.3TC+EFV+TDF

Background:Antiretroviral therapy(ART)was often associated with dyslipidemia among human immunodeficiency virus(HIV)/acquired immunodeficiency syndrome(AIDS)patients.This study aimed to assess treatment-naïve adult male patients with HIV/AIDS who initiated ART with either co-formulated bictegravir,emtricitabine,and tenofovir alafenamide(BIC/FTC/TAF)or lamivudine,efavirenz,and tenofovir disoproxil fumarate(3TC+EFV+TDF),monitoring at weeks 4,12,24,and 48.Methods:A case-control retrospective study was conducted.The newly diagnosed HIV-infected individuals attending the sexual transmission disease(STD)/AIDS clinic of Beijing Youan Hospital,Capital Medical University,from January to December 2021.The patients were divided into BIC/FTC/TAF group or 3TC+EFV+TDF group.High-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),triglyceride(TG),and total cholesterol(TC)at different time points over 48 weeks between two groups were compared.A multivariate Cox regression model was used to identify relevant influencing factors for the population at high risk of increased LDL-C.Results:A total of 870 participants,with 510 in BIC/FTC/TAF group and 360 in 3TC+EFV+TDF group.There were no statistically significant differences in median age,baseline CD4/CD8 ratio,median body mass index(BMI)between the two groups.In both two groups,levels of TG,TC,and LDL-C were higher at 4 weeks,12 weeks,and 24 weeks of treatment(all P<0.05),and there were no statistically significant differences at 48 weeks compared to those at baseline(all P>0.05).In addition,the differences in average changes of the level of TG,TC,HDL-C,and LDL-C from weeks 4,12,24,and 48 to baseline between two groups were not statistically significant(all P>0.05).Multivariate Cox proportional risk model analysis showed that initiating ART with HIV RNA≥10^(5)copies/mL(compared with<10^(5)copies/mL)was associated with an increased risk of elevated LDL-C(hazard ratio=1.26,95%confidence interval:1.07-1.48,P=0.005).Conclusions:Transient elevations in blood lipid levels(TC,TG,HDL-C,and LDL-C)were observed in treatment-naïve adult male HIV/AIDS patients with BIC/FTC/TAF at 4 weeks,12 weeks,and 24 weeks of treatment.However,these levels did not differ significantly from baseline after 48 weeks of treatment,regardless of whether patients were in the BIC/FTC/TAF or 3TC+EFV+TDF group.

恩曲他滨抗HBV治疗临床应用专家共识

恩曲他滨（emtricitabine，FTC）为胞嘧啶核苷类似物，自2006年始，已先后于欧洲和亚洲完成多中心、随机、双盲、对照研究证实其在慢性乙型肝炎（chronic hepatitis B，CHB）患者中的抗病毒作用。FTC多种国产制剂已完成生物等效性试验，被批准用于中国CHB患者的抗病毒治疗。为规范FTC的临床应用，《中华实验和临床感染病杂志（电子版）》、《中国肝脏病杂志（电子版）》与《Infection International（Electronic Edition）》编辑部邀请国内相关专家，对FTC相关数据进行汇总讨论，形成《恩曲他滨抗HBV治疗临床应用专家共识》，以供临床医生参考。

Gilead Sciences公司提交了Truvada／TMC-278固定剂量复方用于治疗HIV感染的上市授权申请（MAA）

Gilead Sciences公司向EMA提交了由Truvada （emtricitabine＆tenofovir disoproxil fumarate）和Tibotec Pharmaceuticals研发的非核苷逆转录酶抑制剂TMC-278（rilpivirine hydrochloridc），tenofovir disoproxil fumarate／emtricitabine／rilpivirjne hydrochloridc，组成的固定剂量复方的上市授权申请（marketing authorization application，MAA），用于治疗成人HIV感染。

美国FDA的抗病毒药物咨询委员会就批准Quad给药方案进行投票表决

美国FDA的抗病毒药物咨询委员会以13票赞成、1票反对的投票结果通过了支持批准Quad治疗方案的新药申请。Quad治疗方案是Gilead Sciences公司的每日1次单片剂复方药,每片药物中包括Elvitegravir 150 mg,Cobicistat 150 mg,emtricitabine 200 mg和tenofovir disoproxil fumarate 300 mg,旨在治疗从未接受过治疗的感染HIV-1的成人。