无环鸟苷亲脂性前体药物脂质体的制备及体外抗病毒活性(英文)

本文通过将无环鸟苷(acyclovir,简称ACV)2’位羟基分别与月桂酰氯或棕榈酰氯进行酯化反应,制得亲脂性前体药物无环鸟苷月桂酸酯和无环鸟苷棕榈酸酯(分别简称为C₁₂-ACV和C₁₆-ACV),使脂质体包封率从ACV的29.9%提高到C₁₂-ACV的95.6%和C₁₆-ACV的97.1%;漏泄实验表明在4℃透析60h后,一半以上的ACV从脂质体中漏泄,而C₁₂-ACV和C₁₆-ACV的滞留率分别为70%和80%;体外抗疱疹病毒的试验中,在最低试验浓度0.044μmol/L时,ACV不显示抗病毒活性,而C₁₆-ACV脂质体抑制细胞病变率达75%,说明前体药物通过与脂质体脂膜的结合增加了药物的进入细胞能力,从而提高了ACV的抗病毒能力。     

无环鸟苷的体内动力学与临床应用

无环鸟苷(Acyclovir,ACV)是七十年代研制出来的一种核苷类抗病毒药物,对单纯及带状疱疹病毒有高度选择性活性。无环乌苷在美国是1982年上市的,目前已广泛应用于临床。近年来国内亦有研制报导,我校药学院新药设计研究室李正化教授改进了无环鸟苷合成     

无环鸟苷的临床应用进展

无环鸟苷(Acyclovir,ACV)为核苷类抗病毒药物,目前主要有口服(胶囊)、注射剂和外用三种。本文就近年来ACV 的临床应用进展情况作一介绍。一、ACV 的药理作用ACV 对单纯疱疹Ⅰ、Ⅱ型病毒(HSVⅠ、Ⅱ)的活性最大,对水痘—带状疱疹、巨细胞病毒(CMV)和Epstein-Barr(E-B)病毒也有抑制作用。近年来还报道ACV治疗乙型肝炎抗原阳性的慢性肝炎患者,显     

单纯疱疹病毒对常用抗病毒药物的耐药性

单纯疱疹病毒(HSV)与药物共同培养,传数代后,对单一抗病毒药物无环鸟苷(ACV)、环胞苷(CC)、丙氧鸟苷(DHPG)和膦羧基甲酸钠(PFA)均可产生耐药性。但耐药性产生的时间和程度各有不同。联合用药可延缓并减少病毒耐药株的发生,同时可降低用药浓度和剂量,从而减少毒性反应。不同耐药株的交叉药敏试验结果为临床合理用药提供了实验依据。     

金属钠-液氨法脱苄基

核苷类抗病毒药物是目前研究较为活跃的领域。1977年发现的无环鸟苷[ACV,9-(2-羟基乙氧基甲基)鸟嘌呤],于1982年被批准临摩使用于治疗包括病毒性肝炎在内的病毒性疾病。1982年,国外又合成出 DHPG[9-(1,3-二羟基-2-丙氧基甲基)鸟嘌呤],体外抗病毒实验证明其具有比 ACV 更强的抗病毒作用,溶解度大,毒副作用小,被认为是很有前途的抗病毒药物。     

抗病毒新药无环鸟苷脂质体混悬注射液的研究

新的安全高效的抗病毒药一直是临床所盼望的,近年来,在寻找这类药物时,发现无环鸟苷Acyclovir(ACV)与现有抗病毒药比较,具有较高的抗病毒活性与较低的细胞毒性,体外试验和动物实验研究表明,     

选择性抗疱疹剂

近年,我们已开发了多种选择性抗疱疹剂,它们很有希望用于人类疱疹病毒感染的治疗。这些新一代的抗病毒剂,包括无环鸟苷(Acyclovir,ACV)、溴乙烯基脱氧尿苷(BVDU)、氟碘阿糖胞苷(FIAC)和磷酰甲酸(PFA)(图1),可以认为是抗病毒化学治疗领域里选择性的标志。迄今,抗病毒药物只有数量有限的抗疱疹药物,即碘苷(IDU)、三氟胸苷(TFT)和阿糖腺苷(Ara-A);它们的抗病毒作用的专一性,即使有的话,也很少。有了 ACV、BVDU、FIAC 和 PFA,我们便开     

抗病毒新药:盐酸伐昔洛韦

伐昔洛韦(valaciclovir)是抗病毒药物阿昔洛韦的前体药物,生物利用度优于阿昔洛韦。美国药典通用名盐酸伐昔洛韦。我国已于1996年批准上市,现将其药理作用及临床应用简介如下: 1 药理作用 1.1 药效学 对疱疹性病毒I(HSV-Ⅰ)和疱疹性病毒Ⅱ(HSV-Ⅱ)的抑制作用强,对水痘疱疹病毒、非洲淋巴细胞瘤病毒以及巨细胞病毒抑制作用弱。本品毒性小,治疗指数高,药效优于阿昔洛韦(ACV)。对vero细胞毒性比ACV低46.9％。对HSV—1、HSV—Ⅱ的治疗指数ACV高42.9％和30.1％。本品体内抗病毒活性亦优于ACV。l 141例临床结果表明,本品1000mg,tid,连服7和14d与ACV 800mg每日5次,连服7d比较,对带状疱疹疼痛的缓解明显优于ACV。     

阿昔洛韦棕榈酸酯脂质体凝胶剂的局部透皮试验

对阿昔洛韦前体药物即阿昔洛韦棕榈酸酯所制得的脂质体胶剂的透皮效果进行初步研究。方法：采用体鼠皮的透皮实验方法,并以阿昔洛韦脂质体凝胶、阿昔洛韦凝胶、阿昔洛韦水溶要昔洛韦软膏剂作比较。结果阿昔洛韦前药脂质体凝胶在皮肤内的滞留多（７４．８２％,透皮率小（１５．６２％）结论：阿昔洛韦棕榈酸酯酯质体凝胶有肩民为高效、安全的新制剂。     

自体LAK细胞回输加无环鸟苷治疗慢性乙型肝炎疗效观察

近年来临床应用抗病毒药物和免疫疗法对慢性乙型肝炎治疗获得一定疗效。本文应用自体LAK细胞回输联合无环鸟苷(ACV)对慢性乙型肝炎进行治疗观察,临床结果显示,联合用药疗效优于各自单用,兹报告如下。 1 材料与方法 1.1 病例:按1990年(上海)全国病毒性肝炎学术会议修订的诊断标准,共选择慢性活动型肝炎(CAH)68例,病程均持续半年     

Increased acyclovir oral bioavailability via a bile acid conjugate

The objective of this work was to design an acyclovir prodrug that would utilize the human apical sodium-dependent bile acid transporter (hASBT) and enhance acyclovir oral bioavailability. Using each chenodeoxycholate, deoxycholate, cholate, and ursodeoxycholate, four bile acid prodrugs of acyclovir were synthesized, where acyclovir was conjugated to a bile acid via a valine linker. The affinity of the prodrug for hASBT was determined through inhibition of taurocholate uptake by COS-7 cells transfected with hASBT (hASBT-COS). The prodrug with the highest inhibitory affinity was further evaluated in vitro and in vivo. The prodrug acyclovir valylchenodeoxycholate yielded the highest affinity for hASBT (Ki = 35 microM), showing that chenodeoxycholate is the free bile acid with the greatest affinity for hASBT. Acyclovir valylchenodeoxycholate's affinity was similar to that of cholic acid (Ki = 25 microM). Further characterization showed that acyclovir was catalytically liberated from acyclovir valylchenode-oxycholate by esterase. Relative to cellular uptake studies of acyclovir alone, the cellular uptake from the prodrug resulted in a 16-fold greater acyclovir accumulation within hASBT-COS cells, indicating enhanced permeation properties of the prodrug. Enhanced permeability was due to hASBT-mediated uptake and increased passive permeability. The extent of acyclovir uptake in the presence of sodium was 1.4-fold greater than the extent of passive prodrug uptake in the absence of sodium (p = 0.02), indicating translocation of the prodrug by hASBT. The prodrug also exhibited an almost 12-fold enhanced passive permeability, relative to acyclovir's passive permeability. Oral administration of acyclovir valylchenodeoxycholate to rats resulted in a 2-fold increase in the bioavailability of acyclovir, compared to the bioavailability after administration of acyclovir alone. Results indicate that a bile acid prodrug strategy may be useful in improving the oral bioavailability of intestinal permeability-limited compounds.     

Increased efficacy of acyclovir-loaded microparticles against herpes simplex virus type 1 in cell culture.

Acyclovir is one of the most effective and selective agents against viruses of the herpes group. In order to increase its antiviral activity, acyclovir loaded microparticles, prepared by an O/W solvent evaporation method were developed. Their antiviral activity against herpes simplex virus type 1 (HSV-1) and toxicity were evaluated on Vero cells and then compared with those presented by a drug solution. The 50% inhibitory concentration (IC(50)) values for acyclovir loaded microspheres determined by plaque reduction assays at 48 and 96 h, were found to be 1.06 +/- 0.01 microM and 0.15 +/- 0.03 microM, respectively, while the equivalent values obtained for an acyclovir solution were 1.28 +/- 0.04 microM at 48 h and 0.27 +/- 0.02 microM at 96 h. These results indicate that acyclovir shows a higher antiviral activity, against herpes simplex virus type 1, when this drug was loaded in microparticles rather than as a drug solution, especially after 96 h of incubation. The toxicity of these microparticles was determined by the MTT test at 48 and 96 h. At 48 h only a small toxicity was found (cell viability ranged from 72 to 82%, with the higher concentration tested) and it could not be attributed to the microparticles, since the acyclovir control solution showed similar toxicity values. However, after 96 h a higher toxicity was observed with acyclovir microparticles as well as with the unloaded ones (cell viability located between 60 and 70%). In summary, acyclovir-loaded microparticles have shown to be promising carriers for the effective delivery of acyclovir in the treatment of HSV-1 infections in cells so they can have a potential use in vivo.     

Preliminary pharmacokinetic study of different preparations of acyclovir with beta-cyclodextrin

Acyclovir has absorption problems, because of its low solubility and/or its saturable absorption mechanism, that take place in the small intestine in a passive, variable, and incomplete manner. The oral bioavailability of acyclovir is thereby affected and reaches only 15-30%. The purpose of this study was to investigate the possibility of increasing the oral availability of acyclovir by forming inclusion complexes of acyclovir with beta-cyclodextrin. Acyclovir, its complex (1:1) with beta-cyclodextrin (acyclovir-beta-cyclodextrin complex), and a 50:50 mixture of acyclovir and the inclusion complex (acyclovir/complex mixture) as an aqueous suspension were administered intraintestinally to male Sprague-Dawley rats in doses equivalent to an acyclovir dose of 75 mg/kg. Sequential samples of plasma were taken by microdialysis. The samples were analyzed by high-performance liquid chromatography with ultraviolet detection. Plasma concentration versus time curves show that the complex and the mixture of acyclovir/complex have a higher bioavailability and a pharmacokinetic profile than that of the drug itself.     

Tolerance and pharmacokinetics of A515U,an acyclovir analogue,in healthy volunteers

Summary A515U (6-deoxyacyclovir) is an analogue of acyclovir devoid of antiviral activity in vitro but which is well absorbed and undergoes conversion to acyclovir after oral administration to rats. The tolerance and pharmacokinetics of various doses of A515U have been studied in 8 healthy volunteers. Single oral doses of 25, 50, 100, 200 and 400 mg A515U and 400 mg acyclovir for comparison were administered to the volunteers at weekly intervals. Concentrations of the parent drug and acyclovir were determined in plasma and urine. The prodrug was well tolerated and did not cause adverse reactions or changes in haematological or biochemical variables. It was well absorbed and conversion to acyclovir was rapid and extensive at all doses. Plasma concentrations of acyclovir achieved with 50 mg A515U orally were comparable to and less variable than those produced by 400 mg acyclovir. A515U was rapidly cleared with a short plasma elimination half life of approximately 0.5 h. The attainment of high plasma concentrations of acyclovir by oral administration of a prodrug may represent an important advance in antiviral chemotherapy.     

Iontophoresis Enhances the Transport of Acyclovir Through Nude Mouse Skin by Electrorepulsion and Electroosmosis

Purpose. Iontophoresis was employed for enhancing the transdermal delivery of acyclovir through nude mouse skin in vitro, with the aim of understanding the mechanisms responsible for drug transport, in order to properly set the conditions of therapeutical application. Methods. Experiments were done in horizontal diffusion cells, using as donor a saturated solution of acyclovir at two different pH values (3.0 and 7.4). Different electrical conditions (current density and polarity) were employed. Results. At pH 3.0, acyclovir anodal transport was due to electrorepulsion, since acyclovir was 20% in the protonated form. In acyclovir anodal iontophoresis at pH 7.4 the main mechanism involved was electroosmosis, since the drug was substantially unionized and the negative charge of the skin at this pH caused the electroosmotic flow to be from anode to cathode. In the case of cathodal iontophoresis at pH 3.0, acyclovir transport was enhanced approx. seven times, due to the presence of an electroosmotic contribution caused by the reversal of the charge of the skin. At pH 7.4 during cathodal iontophoresis acyclovir transport was not enhanced because the electroosmotic flow was in the opposite direction, compared to drug electric transport, i.e. anode to cathode. The increased skin permeability caused by current application was demonstrated to be less important than electrorepulsion and electroosmosis. Conclusions. Anodal iontophoresis shows potential applicability for enhancing acyclovir transport to the skin, considering that both electric transport and electroosmosis can be used by appropriately setting the pH of the donor.     

Enhanced oral bioavailability of acyclovir by inclusion complex using hydroxypropyl-β-cyclodextrin

Abstract

The therapeutic potential of acyclovir is limited by the low oral bioavailability owing to its limited aqueous solubility and low permeability. The present study was a systematic investigation on the development and evaluation of inclusion complex using hydroxypropyl-β-cyclodextrin for the enhancement of oral bioavailability of acyclovir. The inclusion complex of acyclovir was prepared by kneading method using drug: hydroxypropyl-β-cyclodextrin (1:1 mole). The prepared inclusion complex was characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, NMR spectroscopy and evaluated in vitro by dissolution studies. In vivo bioavailability of acyclovir was compared for inclusion complex and physical mixture in rat model. Phase solubility studies indicate the formation of acyclovir–hydroxypropyl-β-cyclodextrin complex with higher stability constant and linear enhancement in drug solubility with increase in hydroxypropyl-β-cyclodextrin concentration. Characterization of the prepared formulation confirms the formation of acyclovir–hydroxypropyl-β-cyclodextrin inclusion complex. Dissolution profile of inclusion complex demonstrated rapid and complete release of acyclovir in 30?min with greater dissolution efficiency (90.05?±?2.94%). In vivo pharmacokinetic data signify increased rate and extent of acyclovir absorption (relative bioavailability ～160%; p?<?0.0001) from inclusion complex, compared to physical mixture. Given the promising results in the in vivo studies, it can be concluded that the inclusion complex of acyclovir could be an effective and promising approach for successful oral therapy of acyclovir in the treatment of herpes viruses.     

Colloidal Dispersions for the Delivery of Acyclovir: A Comparative Study

This paper describes a comparative study on the performances of ethosomes and solid lipid nanoparticle as delivery systems for acyclovir. Ethosomes were spontaneously produced by dissolution of phosphatidylcholine and acyclovir in ethanol followed by addition of an aqueous buffer while solid lipid nanoparticle were produced by homogenization and ultrasonication. Both colloidal systems were morphologically characterized by cryo-transmission electron microscopy. The encapsulation efficiency was 94.2±2.8% for ethosomes and 53.2±0.2% for solid lipid nanoparticle. Concerning Z potential, both formulations are close to neutrality. The diffusion coefficients of the drug from ethosomes and solid lipid nanoparticle, determined by a Franz cell method, were 9.4 and 1.2-fold lower as compared to the free acyclovir in solution, thus evidencing the ability of both colloidal systems in enhancing the diffusion of the drug. The antiviral activity against HSV-1 of both systems was tested by plaque reduction assay in monolayer cultures of Vero cells. Data showed that no significant differences in the antiviral activity were observed by acyclovir in the free or loaded forms. Taken together these results, colloidal systems could be interesting to mediate the penetration of acyclovir within Vero cells.     

Oral chemotherapy of fatal B virus (herpesvirus simiae) infection

Acyclovir and ganciclovir, which were only about 10-fold less effective against B virus than herpes simplex virus type 1 in VERO cells, were tested in vivo in B virus-infected rabbits. Untreated control rabbits became paralysed from 8 days and died from 10 days. Oral acyclovir at a dose rate of 500 mg/kg/day for 21 days prevented death; acyclovir prevented disease at 700 mg/kg/day. In B virus-infected humans such a high dose of acyclovir could not be given by mouth. Nevertheless, high dose oral acyclovir is suggested for immediate prophylaxis when monkey handlers have been exposed to potentially fatal B virus infection. Should signs or symptoms of disease occur then high dose intravenous acyclovir has been recommended. Since ganciclovir was found to be more effective than acyclovir, intravenous ganciclovir might be preferred for the treatment of established infection.