Rapid quantification of the metabolite of valacyclovir hydrochloride in human plasma by liquid chromatography-tandem mass spectrometry

Objective To establish a rapid,sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of acyclovir (the metabolite of valacyclovir hydrochloride) in human plasma. Methods After addition of ganciclovir as internal standard (IS),plasma samples were prepared by one-step protein precipitation using acetonitrile as precipitant,followed by an isocratic elution with 0.1% formic acid solution-methanol (95∶5,v/v) on an Agilent ZORBAX SB-C18 (150mm×2.1mm i.d.,3.5μm) column. Detection was performed on a triple-quadrupole mass spectrometer utilizing electrospray ionization (ESI) interface operating in positive ion and selected reaction monitoring (SRM) mode with the precursor to product ion transitions m/z 226.2→152.1 for acyclovir and m/z 256.2→152.1 for the IS. Results The analytical results demonstrated a good linearity over the ranges from 0.005 to 4μg/mL (r=0.9999) for valacyclovir hydrochloride. The relative standard deviations (RSD) of intra-batch and inter-batch were less than 4.06% and 9.23%,respectively. The limit of detection and lower limit of quantification in human plasma were 2ng/mL and 5ng/mL,respectively. Conclusion The method was simple,sensitive,accurate and reproducible and has been successfully applied to a bioequivalence study of valacyclovir hydrochloride capsules in Chinese healthy male volunteers.

Oral acyclovir induced acute renal failure

BACKGROUND： The study aimed to investigate the clinical characteristics of acute renal failure（ARF） caused by oral acyclovir.METHODS： A 45-year-old Chinese male patient with acyclovir-induced ARF suffered fromabdominal pain for one day. The pain was extended to the epigastric area from the right lowerquadrant. Transient oliguria was seen in addition to microscopic hematuria and proteinuria. Theserum creatinine concentration was 304 !mol/L. Eight days before the occurrence of ARF, the patienttook oral acyclovir for facial neuritis.RESULTS： His renal function was restored completely following the discontinuation of acyclovir,with continuous renal replacement therapy for 54 hours and some symptomatic treatment.CONCLUSION： The presentation of acute renal failure caused by acyclovir can be diverse, butthe prognosis is good after active treatment.

Enzyme-catalyzed Transesterification of Unusual Substrate: Synthesis of Acyclovir and L-ascorbic Acid (Vitamin C) Vinyl Esters

The synthesis of acyclovir and L-ascorbic acid with divinyladipate was performed with alkaline protease from Bacillus subtilis and lipase from Lipozyme (immobilized from Mucor miehei) in different anhydrous organic solvents. Two corresponding derivatives were obtained.

Formulation and evaluation of acyclovir microcapsules using bakers yeast

Objective:To formulate and evaluate acyclovir microcapsules using bakers yeast.Methods: Acyclovir,pretreated yeast and deionised water were taken at a volumetric ratio of 1:2:4 respectively.This suspension was agitated in a magnetic stirrer at 25℃30℃.35℃,and 40℃for 4 hours.The suspension was then centrifuged for 10 minutes at 2 000 rpm.The supernatant solution was decanted and the cells were washed 5 times with deionised water.Then the suspended drug entrapped yeast cells were dried in a lyophillizer for 48 hours.The yield was noted.Results:The first four formulations were done with 200 mg of the drug,followed by 400 mg for the next four formulations and 800 mg the last four formulations.SEM showed that the surface of the microcapsules was intact,with no burst characteristics.FTIR showed no interaction between acyclovir and the cell wall.DSC showed that the peak was within the standard values. The mean particle size for all the samples was 8μm in diameter.The dissolution studies were done for all the twelve samples and showed a Fickian model of diffusion.Conclusions: From the results it is inferred that the samples prepared at 40℃(FY-4,FY- 8,FY-12) show better entrapment and release.So these samples are formulated in the form of a suspension and compared with marketed acyclovir suspension using HPLC technique.The formulated suspensions with FY-4,FY-8 and FY-12 shows drug content in accordance with the standards of the pharmacopoeial limits.

Design,synthesis and anti-HBV activity of novel bis(trifluoroethyl)phosphonomethyl ether derivatives of acyclovir

A series of novel bis（trifluoroethyl）phosphonomethyl ether derivatives of acyclovir was synthesized and their in vitro anti-HBV activity was evaluated in HepG2 2.2.15 cells. In contrast to acyclovir, most of the described phosphonates emerged as potent inhibitors of HBV replication. Especially, the most active compound 11 with IC50 value of 2.92 μmol/L was 33 times more potent than acyclovir with ICso value of 100 μmol/L.

HE TREATMENT OF HEPATIC CARCINOMA WITH HERPES SIMPLEX THYMIDINE KINASE GENE/ACYCLOVIR SYSTEM

A retroviral vector(LNHcTL)containing the herpes simplex virus type 1 thymldine kinase(HSVI-tk)gene was constructed and used for transduction of the gene into human hepatocellular carcinoma cells(SMMC-7721).Xenografted tumor on nude mice was produced with the injection of the transduced cells(SMMC- 7721/LN HcTL) inoculated subcutaneously and showed regression when treated with Acyclovir.The mean weight of the residual tumors was six times less than that of the controls'tumors. Patients with liver carcinoma were given an intratumoral injection of ampbotropic packing cells(PA317/LNHcTL)producing HSV1-tk recombinant retroviral particles,and then treated with Acyclovir intravenously, which showed a marked regression of the tumor.Our preliminary data suggest that HSV1-tk gene/Acyclovir system might be a useful therapeutic approach for the treatment of hepatic carcinoma in humans.

A newfangled study using risk silhouette and uncertainty approximation for quantification of acyclovir in diverse formulation

Risk assessment and uncertainty approximation are two major and important parameters that need to be adopted for the development of pharmaceutical process to ensure reliable results.Additionally,there is a need to switch from the traditional method validation checklist to provide a high level of assurance of method reliability to measure quality attribute of a drug product.In the present work,evaluation of risk profile,combined standard uncertainty and expanded uncertainty in the analysis of acyclovir were studied.Uncertainty was calculated using cause-effect approach,and to make it more accurately applicable a method was validated in our laboratory as per the ICH guidelines.While assessing the results of validation,the calibration model was justified by the lack of fit and Levene＇s test.Risk profile represents the future applications of this method.In uncertainty the major contribution is due to sample concentration and mass.This work demonstrates the application of theoretical concepts of calibration model tests,relative bias,risk profile and uncertainty in routine methods used for analysis in pharmaceutical field.

Evaluation of the effects of acyclovir and/or human amniotic membrane on herpes virus culture and quantitative virus inactivity by real-time polymerase chain reaction

·AIM: To investigate the permeability of amniotic membrane in herpes virus cell culture to acyclovir with real time polymerase chain reaction(RT-PCR).·METHODS: Madin-Darby Bovine Kidney(MDBK) cell culture and Bovine Herpes Virus(BHV1) type 1 were used in the study. Cell cultures were grouped into two on the basis of herpes virus inoculation. Each group was sub-grouped into three. Amniotic membrane(V-HAM),acyclovir(V-A), and amniotic membrane and acyclovir(V-HAM-A) were applied to these subgroup cultures,respectively. After the application of the membrane and the drug, the cultures were evaluated at 24 and 48 h for cytopathic effect positive(CPE +) with a tissue culture microscope. In the CPE(+) samples, the DNA was extracted for viral DNA analysis by RT-PCR.·RESULTS: In control cultures without herpes virus CPE was not detected. Besides, amniotic membrane and acyclovir did not have cytotoxic effect on cell cultures.CPE were detected in Bovine Herpesvirus type-1inoculated cell cultures after amniotic membrane and/or acyclovir application. DNA analysis with RT-PCR indicated that Cycle threshold(Ct) values were lower in the BHV1 and membrane applied group(amniotic membrane group 【 acyclovir group 【 membrane and acyclovir group). This showed that membrane did not have antiviral effect. The membrane and acyclovir cell culture groups with high Ct values indicated thatmembrane was permeable and had a low barrier effect to drug.·CONCLUSION: In our in-vitro study, we found that amniotic membrane, which can be used in the treatment of corneal diseases, did not have antiviral effect. Besides,we detected that amniotic membrane was permeable to acyclovir in BHV-1 inoculated MDBK cell culture.However, more studies are necessary to investigate the quantitative effects of amniotic membrane and acyclovir.

Effects of herpes simplex virus thymidine kinase/acyclovir system on growth of human pulmonary adenocarcinoma A549 cell line in vitro and in vivo

Objective: To observe the effect of anciclovir (ACV) treatment on tumors induced by inoculation of TK gene-transfected human pulmonary adenocarcinoma A549 cells in nude mice. Methods: A recombinant plasmid containing TK gene was constructed and transfected into A549 cells by electroporation. The sensitivity of the transgenic cells (A549-TK) to ACV was examined by MTT assay in vitro and for in vivo observation, inoculation of A549-TK and A-549 cells into nude mice was separately performed to induce tumor growth, the response of which to ACV treatment was observed, and the tumor tissues were pathologically examined. Results: A recombinant plasmid containing TK gene was successfully constructed and transfected into A549 cells. The sensitivity of A549-TK cells to ACV was 43 times higher than that of A549 cells. The tumors induced by A549-TK cells showed no significant increase in size after ACV treatment (P>0. 05) , and light microscopy revealed local tissue necrosis, karyoklasis, and nuclei disappearance. Conclusion: A549-TK cells acquires sensitivity to ACV both in vitro and in vivo, and ACV can inhibit the growth of tumors induced by A549-TK cell inoculation in nude mice.

An Evaluation of the Benefit of Cytomegalovirus Prophylaxis with Acyclovir on Post-Transplant Cytomegalovirus Infection Prevention in a Population of Renal Transplant Recipients in Nigeria

Background: Cytomegalovirus (CMV) is an important infection in renal transplant recipients and may significantly impact recipients’ long-term outcome and graft survival. Objective: This study aimed to evaluate the benefit of prophylaxis with acyclovir on post-transplant CMV infection prevention in a population of renal transplant recipients in Lagos, Nigeria. Subjects and Methods: The study was a cross-sectional design involving renal transplant recipients attending post-transplant follow-up clinics in Lagos, Nigeria between October 2004 and July 2005. Data on the use of CMV prophylaxis were obtained from the hospital case records of the study subjects. Enzyme-Linked Immunosorbent Assay (ELISA) was employed to detect CMV IgM antibodies for the diagnosis of post-transplant CMV infection and Microsoft Excel and EPI-Info 2002 statistical software were used for data entry and analysis. Results: Forty (40) renal transplant recipients were studied, 32 recipients were males and 8 were females with M:F ratio of 4:1. The mean age of the recipients was 39 ± 11.6 years old. The recipients’ post-transplant duration ranged from 2 to 80 months (Mean 17.6 ± 18.6 months). Fifteen (37.5%) of the transplant recipients received acyclovir prophylaxis for six months, one recipient (2.5%) received ganciclovir prophylaxis for three weeks while 24 recipients (60%) received no prophylactic therapy. There was no significant difference in the prevalence of seropositive CMV-IgM between transplant recipients who used CMV prophylaxis and those who did not (Fisher exact p = 0.45). Conclusion: Prophylaxis with acyclovir for six months showed no significant benefit on post-transplant CMV infection prevention in renal transplant recipients.

Evaluation of the Ability to Apply Near-Infrared Spectroscopy on Direct Assay of Acyclovir in Tablets

This paper aimed at developing a simple and fast approach using chemometrics processing for direct assay of acyclovir in tablets by NIR （near infrared） spectroscopy in diffuse reflectance mode. In making trials with 5 different tablet matrices, the experimental results showed that regardless the matrix variation, it was always possible to construct a quantitative model with suitable linear range, accuracy and precision for direct assay of acyclovir in tablet from NIR spectra. Therefore, the approach used in this study was suitable for on-site fast assay of APIs in tablets during manufacturing process or in post-marketing surveillance of drug quality.

Three-dimensional heterogeneous electro-Fenton system with reduced graphene oxide based particle electrode for Acyclovir removal

New pollutant pharmaceutical and personal care products(PPCPs),especially antiviral drugs,have received increasing attention not only due to their increase in usage after the outbreak of COVID-19 epidemics but also due to their adverse impacts on water ecological environment.Electro-Fenton technology is an effective method to remove PPCPs from water.Novel particle electrodes(MMT/rGO/Fe_(3)O_(4))were synthesized by depositing Fe3O4 nanoparticles on reduced graphene oxide modified montmorillonite and acted as catalysts to promote oxidation performance in a three-dimensional electro-Fenton(3D-EF)system.The electrodes combined the catalytic property of Fe3O4,hydrophilicity of montmorillonite and electrical conductivity of graphene oxides,and applied for the degradation of Acyclovir(ACV)with high efficiency and ease of operation.At optimal condition,the degradation rate of ACV reached 100%within 120 min,and the applicable pH range could be 3 to 11 in the 3D-EF system.The stability and reusability of MMT/rGO/Fe_(3)O_(4)particle electrodes were also studied,the removal rate of ACV remained at 92%after 10 cycles,which was just slightly lower than that of the first cycle.Potential degradation mechanisms were also proposed by methanol quenching tests and FT-ICR-MS.

Acyclovir-Loaded Solid Lipid Nanoparticles: A Permeation and Penetrability Study

Herpes simplex virus type I is a cutaneous infection treated with acyclovir. The topical treatment has therapeutic challenges due to the deficient delivery of the drug through epithelial barriers. This results in an inadequate drug-virus interaction in the basal epidermis (virus replication site). For this reason, it is essential to generate drug carrier systems that overcome these limitations. In this study, we evaluated the permeation (through in vitro test Franz cells) and penetration (by ex vivo test Tape Stripping) of a topical formulation of acyclovir loaded in solid lipid nanoparticles and a conventional formulation (Aciclor®). The acyclovir solid lipid nanoparticles were prepared using hot homogenization and sonication methods. The results yielded a particle size of 85 ± 2 nm, a polydispersity index of 0.24 ± 0.01, a zeta potential of −16 ± 2 mV, and 94% ± 3% of encapsulated drug. The in vitro test revealed that the permeability of acyclovir solid lipid nanoparticles formulation was superior compared to reference formulation, with values of 1473.74 ± 30.14 µg/cm2 for the solid lipid nanoparticles and 893.36 ± 38.09 µg/cm2 for the reference formulation. The ex vivo test demonstrated that acyclovir solid lipid nanoparticles exhibited superior penetrability through the stratum corneum compared to the reference formulation, with total amounts of 3767 µg for the solid lipid nanoparticles and 2162 µg for the reference formulation. These findings seem promising in advancing new effective therapies against herpes generated by herpes simplex virus type I.

Herpes simplex keratitis:A brief clinical overview

The aim of our minireview is to provide a brief overview of the diagnosis,clinical aspects,treatment options,management,and current literature available regarding herpes simplex keratitis(HSK).This type of corneal viral infection is caused by the herpes simplex virus(HSV),which can affect several tissues,including the cornea.One significant aspect of HSK is its potential to cause recurrent episodes of inflammation and damage to the cornea.After the initial infection,the HSV can establish a latent infection in the trigeminal ganglion,a nerve cluster near the eye.The virus may remain dormant for extended periods.Periodic reactivation of the virus can occur,leading to recurrent episodes of HSK.Factors triggering reactivation include stress,illness,immunosuppression,or trauma.Recurrent episodes can manifest in different clinical patterns,ranging from mild epithelial involvement to more severe stromal or endothelial disease.The severity and frequency of recurrences vary among individuals.Severe cases of HSK,especially those involving the stroma and leading to scarring,can result in vision impairment or even blindness in extreme cases.The cornea's clarity is crucial for good vision,and scarring can compromise this,potentially leading to visual impairment.The management of HSK involves not only treating acute episodes but also implementing long-term strategies to prevent recurrences and attempt repairs of corneal nerve endings via neurotization.Antiviral medications,such as oral Acyclovir or topical Ganciclovir,may be prescribed for prophylaxis.The immune response to the virus can contribute to corneal damage.Inflammation,caused by the body's attempt to control the infection,may inadvertently harm the corneal tissues.Clinicians should be informed about triggers and advised on measures to minimize the risk of reactivation.In summary,the recurrent nature of HSK underscores the importance of both acute and long-term management strategies to preserve corneal health and maintain optimal visual function.

阿昔洛韦联合人免疫球蛋白静注治疗病毒性脑炎的效果分析

目的分析阿昔洛韦联合人免疫球蛋白病毒性脑炎患儿的治疗效果。方法单纯随机选取2022年6月—2023年6月泉州市第一医院儿科收治的90例病毒性脑炎患儿作为研究对象,按照随机数表法分为两组,各45例,对照组应用阿昔洛韦干预,观察组应用阿昔洛韦联合人免疫球蛋白干预,对比两组各项指标的恢复情况、炎性因子的水平和临床效果、治疗有效率、不良反应发生率。结果观察组患儿症状恢复时间短于对照组,差异有统计学意义(P<0.05)。治疗前两组血清炎症因子、脑脊液炎症因子比较,差异无统计学意义(P均>0.05);治疗后观察组血清炎症因子、脑脊液炎症因子优于对照组,差异有统计学意义(P均<0.05)。观察组不良反应发生率为2.22%,低于对照组的13.33%,差异有统计学意义(χ^(2)=3.873,P<0.05)。观察组治疗总有效率为97.78%,高于对照组的86.67%,差异有统计学意义(χ^(2)=3.873,P<0.05)。结论对病毒性脑炎的患儿应用阿昔洛韦联合人免疫球蛋白静注治疗有利于促进患儿的康复,减轻患儿的炎症反应,控制病情,修复神经,降低并发症发生率,促进病情转归。

阿昔洛韦的光解影响因素研究

以350 W氙灯为光源,研究了阿昔洛韦(ACV)在模拟太阳光照射下的光降解行为,探讨了初始浓度、pH值以及水体中常见共存物质HCO_(3)^(-)和腐殖酸对ACV光解产生的影响。结果表明,ACV在模拟太阳光照射下的直接光解很难发生,故初始浓度对光解影响不大;而pH值的变化,显著影响了ACV的光解速率,pH值越大,ACV的降解速率越快。HCO_(3)^(-)对ACV的间接光解具有促进作用,腐殖酸对ACV的光解有抑制作用。

人免疫球蛋白联合阿昔洛韦治疗病毒性脑膜炎的临床效果分析

目的:探讨人免疫球蛋白联合阿昔洛韦治疗病毒性脑膜炎的临床效果。方法:选取2020年3月—2023年2月无锡市第八人民医院收治的80例病毒性脑膜炎患者作为研究对象,采用随机数字表法分为对照组与研究组,各40例。对照组采用阿昔洛韦治疗,研究组在对照组基础上采用人免疫球蛋白治疗。比较两组临床疗效、症状恢复时间、不良反应发生情况。结果:研究组治疗总有效率高于对照组,差异有统计学意义(P=0.048)。研究组头痛、意识障碍、高热恢复时间短于对照组,差异有统计学意义(P<0.001)。两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:人免疫球蛋白联合阿昔洛韦治疗病毒性脑膜炎的临床效果较好,能够促进患者症状恢复,且不会增加不良反应,安全性较高。

人免疫球蛋白联合阿昔洛韦治疗病毒性脑炎患儿的效果

目的:观察人免疫球蛋白联合阿昔洛韦治疗病毒性脑炎患儿的效果。方法:选取2020年3月至2023年3月该院收治的76例病毒性脑炎患儿进行前瞻性研究,按照随机数字表法将其分为对照组和观察组各38例。对照组给予阿昔洛韦治疗,观察组在对照组基础上联合人免疫球蛋白治疗。比较两组临床疗效,临床症状改善时间,治疗前后炎性因子[降钙素原(PCT)、γ干扰素(INF-γ)、白细胞介素-6(IL-6)]水平、免疫功能指标[免疫球蛋白M(IgM)、免疫球蛋白G(IgG)]水平,以及不良反应发生率。结果:观察组治疗总有效率为92.11%(35/38),高于对照组的73.68%(28/38),差异有统计学意义(P<0.05);观察组发热消失时间、惊厥消失时间、意识恢复时间和头晕、呕吐消失时间均短于对照组,差异有统计学意义(P<0.05);治疗后,两组PCT、INF-γ、IL-6水平均低于治疗前,且观察组低于对照组,差异有统计学意义(P<0.05);两组IgG水平均高于治疗前,且观察组高于对照组,差异有统计学意义(P<0.05);两组IgM水平和不良反应发生率比较,差异均无统计学意义(P>0.05)。结论:人免疫球蛋白联合阿昔洛韦治疗病毒性脑炎患儿可提高临床疗效,促进临床症状恢复,减轻机体炎症反应,提高免疫功能,效果优于单纯阿昔洛韦治疗。

RANDOMIZED CASE-CONTROLLED TRIAL OF ORAL LOW-DOSE ACYCLOVIR FOR PREVENTION OF VIRUS INFECTIONS IN RECIPIENTS OF RENAL ALLOGRAFTS

A randomized case-controlled trial of oral low-dose acyclovir (600-800 mg per day) has been conducted for the prevention of virus infections in 66 recipients of renal allografts since 1990. In comparison with the untreated controls, acyclovir could prevent herpes virus simplex (HSV), reduce morbidity of pneumonia from 10 cases (30%) to 3 cases (9%) (P<0.05) and lower CMV-IgM positive rate from 30% to 12%. Serum Cr and BUN in acyclovir group were lower than those in control group. These results strongly suggested that oral administration low-dose acyclovir could prevent virus infections after renal transplantation.

小儿热速清颗粒联合干扰素及阿昔洛韦对疱疹性咽峡炎患儿的影响

目的:探讨小儿热速清颗粒联合干扰素及阿昔洛韦治疗疱疹性咽峡炎患儿的效果。方法:选取2021年1月—2022年4月于咸宁市咸安区妇幼保健院治疗的78例疱疹性咽峡炎患儿作为研究对象,采用掷硬币法将患儿分为观察组和对照组,各39例。两组均给予常规治疗,对照组采用阿昔洛韦及干扰素喷雾治疗,观察组在对照组基础上给予小儿热速清颗粒治疗。比较两组临床疗效、炎症因子水平、免疫功能、临床症状改善时间和不良反应。结果:观察组临床总有效率高于对照组,差异有统计学意义(P<0.05);治疗后,两组超敏C反应蛋白(hs-CRP)、肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)水平较治疗前降低,且观察组低于对照组,差异有统计学意义(P<0.05);治疗后,两组免疫球蛋白M(IgM)、免疫球蛋白A(IgA)、免疫球蛋白G(IgG)水平较治疗前提高,且观察组高于对照组,差异有统计学意义(P<0.05);观察组临床症状改善时间早于对照组,差异有统计学意义(P<0.05);观察组不良反应发生率略高于对照组,差异无统计学意义(P>0.05)。结论:小儿热速清颗粒联合干扰素及阿昔洛韦用于疱疹性咽峡炎患儿的治疗中,能促进临床症状消退,缓解炎症反应,调节免疫功能,提高临床疗效,且不会增加不良反应。