Acyclovir

The antiviral drug acyclovir [9-(2-hydroxyethoxymethyl)guanine (ACV)], its 7-isomer (7-ACV) and its two derivatives: N2-acetyl ACV (ac-ACV) and N2,O-diacetyl ACV (diac-ACV) were examined for their potential in vitro lymphotoxicity and in vivo immunotoxicity in mice. In vitro lymphotoxicity of ACV and its acetylated derivatives was low, whereas the 7-ACV isomer enhanced the in vitro cell proliferation in PHA-stimulated cultures. Addition of 2'-deoxyguanosine (dGuo) did not exhibit any inhibitory potential of ACV. However, reduction in the absolute number of CD3+, CD8+, and CD25+ cells, but not Ig+ cells, was noted at high concentrations of ACV and its derivatives, suggesting a selective T cell cytotoxicity. Similarly, the in vivo exposure revealed selective T cell immunotoxicity of ACV and its derivatives since the reduced number of Thy 1.2+ and CD8+ cells was not accompanied with any marked changes in the Ig+ population. The CD4+/CD8+ ratio was affected both in vitro and in vivo by high concentrations of ACV.

Objective: To investigate how infants and children with suspected viral encephalitis are currently managed in a UK tertiary children's hospital. Methods: Case notes of all infants and children who received intravenous aciclovir for suspected encephalitis over a 6-month period were reviewed. Suspected viral encephalitis was defi ned as a child with fever or history of febrile illness and a reduced level of consciousness, irritability or a change in personality or behaviour or focal neurological signs. Results: Fifty one children were identifi ed. Two had proven herpes simplex encephalitis (HSV) and two had clinically diagnosed viral encephalitis with no cause identifi ed. Forty children had cerebrospinal fl uid (CSF) analysis, but basic results were incomplete in 13 cases. CSF was sent for the detection of HSV DNA by PCR in 27 cases. The initial dose of aciclovir was incorrect in 38 cases. The median (range) length of intravenous aciclovir treatment was 4 (1-21) days. Six children were given a full course of aciclovir (10 or more days). For 14 children, there appeared to be no real indication for starting aciclovir. Case note documentation was generally inadequate.

objective. To evaluate the correlation between self-report of a prior history of chickenpox and results of varicella-zoster virus (VZV) immunoglobulin (Ig) G serologic test results in an outbreak of VZV infection among Thai healthcare workers (HCWs) and to conduct a cost-benefit analysis of establishing routine VZV immunization as part of an occupational health program on the basis of the outbreak data.

Background Hydrophilic drugs are poorly absorbed when applied topically, due to low partitioning through the lipid matrix of the stratum corneum. Cutaneous blood flow rapidly clears the absorbed drug, which may result in low tissue levels. This is of importance for topically applied drugs whose site of action is within the epidermis or dermis. Dermal drug levels can be measured using cutaneous microdialysis, which is a means of continuously sampling substances from the dermal extracellular fluid. Objectives To measure the contribution of stratum corneum barrier and microvascular perfusion in determining dermal tissue levels of hydrophilic drugs (aciclovir and penciclovir) in vivo. Methods Studies were performed using microdialysis of the volar surface of the forearm of healthy volunteers (n ¼ 55) over a 5-h collection period. Stratum corneum was removed by tape stripping, and barrier disruption quantified by measurement of transepidermal water loss (TEWL); dermal microvascular perfusion was modulated by inclusion of noradrenaline in the microdialysis perfusate. Results With intact skin and normal cutaneous blood flow the concentration of penciclovir recovered was below assay threshold (0AE05 ng mL)1). With noradrenaline-induced local vasoconstriction, the area under the curve of drug absorbed through normal skin (± SEM) was 13AE3 ± 2AE9 ng mL)1 h (0)5) for penciclovir and 27AE6 ± 10AE6 ng mL)1 h (0)5) for aciclovir. Removal of the stratum corneum (to glistening) by tape stripping increased penciclovir absorption by 1300fold and aciclovir absorption by 440-fold, confirming the stratum corneum as the major barrier to hydrophilic drug absorption. Sequential barrier disruption by tape stripping gave a close correlation between penciclovir concentration absorbed per hour and barrier disruption measured by TEWL (r 2 ¼ 0AE9283). There was a 15AE6-fold difference in the recovery of penciclovir through barrierdeficient skin with and without cutaneous blood flow. There was no relationship between fibre depth and amount of drug dialysed, which suggests free movement of antiviral drug on reaching the aqueous environment of the dermis. Conclusions This study defines for the first time the relationship between the degree of mechanical barrier impairment and drug absorption at the same anatomical site in humans, and the role of blood flow in drug clearance in vivo.

Background: Acyclovir, a specific and selective inhibitor of
replication of herpesviridae family, has well documented efficacy
for speedy rash healing and decreasing pain of herpes zoster.
Limited oral bioavailability of acyclovir requires frequent dosing.
Valacyclovir is rapidly and almost completely converted to
acyclovir in vivo and gives three to fivefold increase in acyclovir
bioavailability. The aim of this study was to assess the clinical
efficacy, safety and tolerability of oral valacyclovir versus standard
oral acyclovir in the treatment of herpes zoster.
Methods: A blind randomized prospective study was performed
during May 2007 to August 2007 in Midnapore Medical College.
Immunocompetent patients, aged ≥40yrs presenting with herpes
zoster within 72 hours after onset of rash were enrolled and
randomized to receive one of the following treatments: 1000
mg of valacyclovir thrice daily for 7 days or acyclovir 800 mg 5
times daily for 7 days. A total of 60 patients were included and
randomized to receive either valacyclovir (n=30) or acyclovir
(n=30) and they were evaluated at 8 days, 15 days and 29 days,
respectively.
Results: A statistically significant reduction of skin lesion and
zoster associated pain were noticed in valacyclovir compared to
acyclovir group. However, presence of post herpetic neuralgia
on the 29th day was less in acyclovir compared to valacyclovir
group (70.0% vs. 83.3%, P>0.05). Only one patient on valacyclovir
and two patients on acyclovir complained of nausea and mild
abdominal pain.
Conclusion: We conclude that for the management of herpes
zoster, valacyclovir might be superior to acyclovir in respect to
reduction of skin lesions and pain.
Keywords: acyclovir, herpes zoster, treatment,

The lack of an effective anti-viral agent and the emergence of drug-resistant strains dictate a real need for discovery of novel therapies able to ameliorate viral infections. In this regards, medicinal plants and natural products offer safe and inexpensive platforms for discovery of efficient and novel anti-viral agents. We have investigated the potential anti-viral activities of Veronica persica Poir.  as a medicinal plant against herpes simplex viruses (HSVs). In vitro screening of the ethanol plant extract against HSV-1 and HSV-2 infected Vero cells revealed the extract to show a dose-dependent inhibitory activity against both virus strains. After fractionation of the extract by a stepwise methanol gradient and evaluation of each fraction, the 80% methanol fraction displayed a pronounced inhibitory activity against the herpes viruses. The highest antiviral activity was observed when the Vero cells were treated with the extract both during and after infection by viruses. Moreover...

We sought to evaluate whether U.S. Pharmacopeia (USP) apparatus 3 can be used as an alternative to USP apparatus 2 for dissolution testing of immediate-release (IR) dosage forms. Highly soluble drugs, metoprolol and ranitidine, and poorly soluble drugs, acyclovir and furosemide, were chosen as model drugs. The dissolution profiles of both innovator and generic IR products were determined using USP apparatus 2 at 50 rpm and apparatus 3 at 5, 15, and 25 dips per minute (dpm). The dissolution profiles from USP apparatus 3 were compared to those from USP apparatus 2 using the f 2 similarity test. The dissolution profile from USP apparatus 3 generally depends on the agitation rate, with a faster agitation rate producing a faster dissolution rate. It was found that USP apparatus 3 at the extreme low end of the possible agitation range, such as 5 dpm, gave hydrodynamic conditions equivalent to USP apparatus 2 at 50 rpm. With appropriate agitation rate, USP apparatus 3 can produce similar dissolution profiles to USP apparatus 2 or distinguish dissolution characteristics for the IR products of metoprolol, ranitidine, and acyclovir. Incomplete dissolution was observed for the furosemide tablets using USP apparatus 3. Although it is primarily designed for the release testing of extended-release products, USP apparatus 3 may be used for the dissolution testing of IR products of highly soluble drugs, such as metoprolol and ranitidine, and some IR products of poorly soluble drugs, such as acyclovir. USP apparatus 3 offers the advantages of avoiding cone formation and mimicking the changes in physiochemical conditions and mechanical forces experienced by products in the gastrointestinal tract.

Herpes labialis is a common skin infective condition, worldwide, which is primarily caused by HSV-1. Recurrent episodes of herpes labialis, also known as cold sores, can be frequent, painful, long-lasting and disfiguring for infected patients. At present, there are two types of antivirals for the treatment of herpes labialis, topical and oral, which are available over the counter or as prescription-only. The aim of antiviral therapy is to block viral replication to enable shortening the duration of symptoms and to accelerate healing of the lesions associated with herpes labialis. This review examines the evidence for the effectiveness of current topical and oral antivirals in the management of recurrent episodes of herpes labialis. In most countries, oral antivirals for herpes labialis are available as prescription-only. However, in early 2010, the oral antiviral famciclovir was reclassified from prescription-only medicine to pharmacistcontrolled status in New Zealand. The benefits and risks associated with moving an antiviral therapy for herpes labialis from prescription-only to pharmacist-controlled status are reviewed here, and the implications for patients, general physicians and pharmacists are considered.

Herpes simplex virus (HSV) infection is one of the most common viral sexually transmitted diseases worldwide. The first time infection of the mother may lead to severe illness in pregnancy and may be associated with virus transmission from mother to foetus/newborn. Since the incidence of this sexually transmitted infection continues to rise and because the greatest incidence of herpes simplex virus infections occur in women of reproductive age, the risk of maternal transmission of the virus to the foetus or neonate has become a major health concern. On these purposes the Authors of this review looked for the medical literature and pertinent publications to define the status of art regarding the epidemiology, the diagnosis, the therapy and the prevention of HSV in pregnant women and neonate. Special emphasis is placed upon the importance of genital herpes simplex virus infection in pregnancy and on the its prevention to avoid neonatal HSV infections.

The principles of percolation theory were applied to design controlled release matrix tablets containing acyclovir. This statistical theory studies disordered or chaotic systems where the components are randomly distributed in a lattice. The application of this theory to study the release and hydration rate of hydrophilic matrices allows to explain the changes in release and hydration kinetics of swellable matrix type controlled delivery systems. The objective of the present paper is to estimate the percolation threshold of HPMC K4M in matrices of acyclovir and to apply the obtained result to the design of hydrophilic matrices for the controlled delivery of this drug.

Proton-dependent oligopeptide transporter Peptide/histidine transporter 1 PHT1 Valacyclovir COS-7 Transient transfection a b s t r a c t Recently, the expression of the human peptide/histidine transporter (hPHT1, SLC15A4) mRNA was observed in the GI tract and in Caco-2 cells, suggesting that it may participate in the intestinal absorption of peptide-based agents. This study aims to elucidate the: (i) protein expression pattern of hPHT1 (SLC15A4) in human small intestine; (ii) cloning of the hPHT1 full-length sequence; (iii) functional characterization of hPHT1 in transiently transfected COS-7 cells. The expression of hPHT1 was measured using Western blot and immunohistochemical analysis. The hPHT1 full-sequence was amplified from BeWo cells, inserted into the pcDNA3.1-V5/His TOPO ® plasmid and transiently transfected into COS-7 cells to investigate the uptake kinetics of [ 3 H]histidine and [ 3 H]carnosine. Time, pH and sodiumdependent uptake studies were performed in mock (empty vector) and hPHT1-COS-7 cells.

A simple and sensitive fluorimetric method for determination of antiviral drugs: ribavirin, acyclovir, and amantadine hydrochloride has been developed. The method was based on the oxidation of these drugs by cerium(IV) in presence of perchloric acid and subsequent monitoring the fluorescence of the induced cerium(III) at k excitation 255 and k emission 355 nm. Different variables affecting the reaction conditions such as the concentrations of cerium(IV), type and concentration of acid medium, reaction time, temperature, and the diluting solvents were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9978-0.9996) were found between the relative fluorescence intensity and the concentrations of the investigated drugs in the range of 50-1400 ng ml -1 . The assay limits of detection and quantitation were 20-49, and 62-160 ng ml -1 , respectively. The precision of the method was satisfactory; the values of relative standard deviations did not exceed 1.58%. No interference could be observed from the excipients commonly present in dosage forms. The proposed method was successfully applied to the analysis of the investigated drugs in pure and pharmaceutical dosage forms with good accuracy and precision; the recovery percentages ranged from 99.2 to 101.2 ± 0.48-1.30%. The results obtained by the proposed fluorimetric method were comparable with those obtained by the official method stated in the United States Pharmacopoeia.

High-performance liquid chromatography with a hydrophilic-interaction liquid chromatographic (HILIC) column has been successfully used to retain and separate the polar phosphonic herbicides glyphosate and glufosinate. Online electrospray tandem ion-trap mass spectrometric and DAD detection were used. The effects on the separation of mobile phase acetonitrile content, buffer concentration, and flow rate, and of column temperature, were investigated. With UV-visible detection at 195 nm, LOQ were <850 mg kg −1 , showing the method is suitable for product quality control of these herbicides alone or in combination. Tandem mass spectrometric conditions were optimized for ion-trap detection. Quantification was by use of selected reaction monitoring transitions m/z 168 → 150 in negative-ion mode for glyphosate and m/z 182 → 136 in positive-ion mode for glufosinate. Limits of detection (LOD; S/N > 3) were 0.20 and 0.16 ng for glyphosate and glufosinate, respectively, and the respective limits of quantification (LOQ; S/N = 10) were 0.02 and 0.05 mg kg −1 . Sample derivatization was not necessary to achieve low detection limits in residue analysis in this study. Recovery from watermelon, spinach, potato, tomato, radish-root, and water fortified with the herbicides ranged from 63.6 to 107.3% and relative standard deviations were <15.3%.

Background Randomized clinical trials of valaciclovir in recurrent herpes labialis are lacking. Objectives To determine whether a single course of valaciclovir, i.e. 500, 1000 or 2000 mg, administered during the prodrome of herpes facialis, could be beneficial. Methods Three hundred and forty-five out-patients with herpes labialis were screened and randomized for a multicentre, double-blind clinical trial. Ninety-six patients had no recurrence after 6 months of follow-up; 249 patients were finally included in the intent-to-treat (ITT) population. The main outcome measure was the rate of aborted episodes at day 3. The three treatment groups were similar at baseline. Results There was no statistically significant difference between the groups in rates of aborted lesions at day 3 in the ITT population, in particular between the 500 mg and 2000 mg treatment groups.

Acyclovir, guanine, and impurity A have been baseline separated with isocratic conditions at pH = 3.0 and run time under 15 min by employing a SB-CN column from Agilent (150 mm × 4.6 mm and 3.5 m). Moreover, when run time was increased to 40 min six impurities (guanine, impurities A, F, G, Vir 3/4 and N 7 ) plus acyclovir were separated in the same conditions. The mobile phase consisted of buffer A/acetonitrile 96:4 (v/v), being buffer A:25 mM H 3 PO 4 (Milli-Q H 2 O) brought to pH 3.0 with KOH.

This study documents drug-excipient incompatibility studies of acyclovir in physical mixtures with lactose and in different tablet brands. Differential scanning calorimetry (DSC) was initially used to assess compatibility of mixtures. The Fourier-transform infrared (FTIR) spectrum was also compared with the spectra of pure drug and excipient. Although DSC results indicated incompatibility with lactose, FTIR spectra were mostly unmodified due to overlapping peaks. Samples of isothermally stressed physical mixture were stored at 95°C for 24 h. The residual drug was monitored using a validated high-performance liquid chromatography (HPLC) assay and data fitting to solid-state kinetic models was performed. The drug loss kinetics followed a diffusion model. The aqueous mixture of drug and excipient was heated in order to prepare an adduct mixture. HPLC analysis revealed one extra peak that was fractionated and subsequently injected into the liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/ MS) system. The MRM (Multiple Reaction Monitoring) chromatograms characterized the peak with molecular mass corresponding to an acyclovir-lactose Maillard reaction product. The presence of lactose in commercial tablets was checked using a new TLC method. Overall, the incompatibility of acyclovir with lactose was successfully evaluated using a combination of thermal methods and LC-MS/MS.

For the treatment of ocular keratitis acyclovir, as a highly specific inhibitor of herpes virus replication, is applied topically into the eye. The objective of this study was to design and evaluate freeze-dried, bioadhesive and biodegredable acyclovir ocular minitablets for prolonged local drug action. The sponge-like nature of the lyophilized ocular minitablets ensures rapid hydration and gelation of these tablets in the eye and thus would reduce the foreign body sensation. The polymers used were sodium carboxymethylcellulose (NaCMC), hydroxypropylmethylcellulose (HPMC), xanthan gum, chitosan and Carbopol 943P. The minitablets were evaluated for drug content, weight variation, bioadhesion, water uptake and in vitro drug release. In addition, the rheological characteristics of the polymers solutions were investigated. Rheological data revealed that all tested polymers exhibited pseudoplastic behaviour which is required to minimize interference with blinking. Drug release was found to be affected by the type and concentration of polymer. The order of sustainment was chitosan > xanthan > HPMC > Carbopol > NaCMC. Water uptake study, dissolution rate of the polymers and viscosity measurements could explain the different release profiles of the drug from the polymers. Chitosan minitablet was chosen for its significant sustained release and good bioadhesive property for in vivo study in rabbits. The tablet showed a good permeation into the cornea in comparison to the commercially available Zovirax ® eye ointment. In conclusion, chitosan ocular minitablets containing acyclovir could be considered as a promising sustained drug delivery system for ocular keratitis treatment.

In this prospective single-center study, we evaluated the efficacy and safety of valaciclovir (VACV) in the prevention of cytomegalovirus (CMV) infection after allogeneic bone marrow transplantation (BMT). The study population consisted of 12 patients who underwent allogeneic BMT from an unrelated donor. Patients received acyclovir (ACV) intravenously until they became able to take VACV orally. VACV was administered at a daily dose of 3000 mg and continued until day 100. CMV infection was monitored by CMV antigenemia assay and real-time polymerase chain reaction analysis of plasma. Thirty-five patients who did not receive any form of CMV chemoprophylaxis served as control subjects. CMV infection was detected in 4 (33.3%) of the 12 patients and in 24 (68.6%) of the 35 control subjects (P < .05). The onset of CMV infection was significantly delayed in the VACV group (median, day 43) compared with the control group (median, day 28.5; P < .01). Gastrointestinal symptoms as an adverse event due to VACV administration were observed in 2 patients. The plasma levels of ACV after VACV administration were measured in 8 patients and were similar to those in the healthy subjects. In conclusion, VACV shows normal absorption, even in the early posttransplantation period, and may prevent or delay CMV infection effectively and safely in allogeneic BMT recipients.

Despite aggressive therapies, median survival for malignant gliomas is less than 15 months. Patients with unmethylated O 6 -methylguanine-DNA methyltransferase (MGMT) fare worse, presumably because of temozolomide resistance. AdV-tk, an adenoviral vector containing the herpes simplex virus thymidine kinase gene, plus prodrug synergizes with surgery and chemoradiotherapy, kills tumor cells, has not shown MGMT dependency, and elicits an antitumor vaccine effect.

Acyclovir (ACV) given to HSV-2 positive women after 36 weeks reduces adverse outcomes but its benefit at lower gestation was undocumented. We determined the effect of oral acyclovir administered from 28 to 36 weeks on premature rupture of membranes (PROM) primarily and preterm delivery risk. This was a randomized, double-blind placebo-controlled trial among 200 HSV-2 positive pregnant women at 28 weeks of gestation at Mulago Hospital, Uganda. Participants were assigned randomly (1:1) to take either acyclovir 400 mg orally twice daily (intervention) or placebo (control) from 28 to 36 weeks. Both arms received acyclovir after 36 weeks until delivery. Development of Pre-PROM by 36 weeks and preterm delivery were outcomes. One hundred women were randomised to acyclovir and 100 to placebo arms between January 2014 and February 2015. There was tendency towards reduction of incidence of PROM at 36 weeks but this was not statistically significant (4.0% versus 10.0%; RR 0.35; 95% 0.11-1.10) ...

Alternative treatment for recurrent labial infection by herpes simplex virus (HSV) have been considered. The aim of this study was to evaluate the effectiveness of laser phototherapy in prevention and reduction of severity of labial manifestations of herpes labialis virus. Seventyone patients, divided into experimental (n=41) and control (n=30) groups were followed up for 16 months. Patients in the control group were treated topically with aciclovir and patients in the experimental group were subjected to laser phototherapy (one session per week, 10 weeks): 780 nm, 60 mW, 3.0 J/cm 2 or 4.5 J/cm 2 on healthy (no HSV-1 infection) and affected (with HSV-1 infection) tissues. Patients in the experimental group presented a significant decrease in dimension of herpes labialis lesions (P=0.013) and inflammatory edema (P=0.031). The reduction in pain level (P=0.051) and monthly recurrences (P=0.076) did not reach statistical significance. This study represents an in vivo indication that this treatment should be further considered as an effective alternative to therapeutic regimens for herpes labialis lesions.

The biochemical and functional properties of the thymidine kinase (TK) of the herpes simplex virus type 1 mutant R100, that is highly resistant to 9-(2-hydroxy-ethoxymethyl)guanine (acyclovir), are reported in comparison with the properties of its parental strain, wt. The ...

Background: Prior pilot studies support the use of antiviral medications with topical corticosteroids for herpes simplex labialis (HSL). ME-609 (Xerese, Xerclear) is a combination of 5% acyclovir and 1% hydrocortisone developed for the topical treatment of HSL.

We have treated I I 3 patients with zidovudine since its licensure, 80 with acquired immunodeficiency syndrome and 33 with acquired immunodeficiency syndromerelated complex. This paper reports on the efficacy and toxicity observed in these patients. Improved well-being, reduced frequency and severity of opportunist infections were notable in the first year of follow-up. More rapid improvement in pulmonary physiological tests during recovery from Pneumocystis carinii pneumonia was also observed in treated patients. Patients with lower initial platelet counts showed early increases in platelet counts. There was a consistent fall in human immunodeficiency virus (HIV) p24 antigen during treatment, although not always to undetectable levels. CD4 cell counts showed a rise in the first months of treatment but these were not sustained, despite continuing clinical benefit. Neuropsychological and clinical evidence of benefit in HIV encephalopathy are described. We have analysed the factors influencing marrow toxicity and have found that low CD4 count and the intercurrent use of ganciclovir and dapsone increase myelotoxicity. We describe the clinical and biochemical features of the myopathy associated with long-term use of zidovudine and summarise our findings on dose-reduction associated meningoencephalitis.

A 24-year-old black female (HIV-positive) was referred to our clinic with a 4-week history of an ulcerative lesion of the right upper and lower eyelids. She was on treatment for pulmonary tuberculosis and had been admitted to a secondary level hospital. She had no other ocular symptoms or signs. A tissue biopsy of the lesion revealed multinucleate squamous cells with ground glass viral nuclear inclusion bodies, indicative of herpes simplex virus (HSV) infection. The ulcer healed with oral and topical acyclovir therapy, confirming a herpetic origin. There is only one other reported case of this type of ulcerative eyelid lesion caused by HSV; the patient in this case was also immunocompromised.