Emerging and Established Methods for Acyclovir Quantification: A Detailed Review

Background: Because neonatal herpes simplex virus (NHSV) infection is difficult to diagnose, there has been a move towards using more empiric acyclovir (ACV). Objective: The purpose of this study was to review the use of ACV to optimize future management of NHSV. Methods: Charts were reviewed for infants started on intravenous ACV up to day 43 of life – January 2001 through February 2007 – at five hospitals in Edmonton and Calgary. Results: ACV was started for possible (N = 115) or proven (N = 3) herpes simplex virus (HSV) infection. Six of the infants with possible HSV infection later had proven HSV infection. Seizures (34%), hemodynamic instability (29%) and skin lesions (24%) were the most common indications for ACV. Among the 118 infants, 106 (90%) had cerebrospinal fluid obtained and 82 (69%) had at least one surface swab for HSV but 4 (3%) had no specimens submitted for HSV detection. ACV was continued for 3.9 ± 3.5 days in the infants with no proven HSV disease. Possible nephrotoxicity from ACV was recorded in 3 of these 109 infants and in none of the infants with proven HSV disease. Conclusions: Clinicians in Alberta primarily consider the diagnosis of NHSV infection when confronted with a neonate with seizures, hemodynamic instability or suspicious skin lesions, but need to consider the diagnosis more often if all cases are to be treated at first presentation. They often perform incomplete investigations to rule out NHSV infection. Adverse events from ACV appear to be uncommon when the drug is used for suspected NHSV disease.

Genotypic analysis of herpes simplex virus (HSV) DNA extracted from clinical specimens from a case of fatal disseminated neonatal HSV demonstrated that an infant developed an acyclovir-resistant HSV containing a mutation in the HSV thymidine kinase gene during the first seven days of acyclovir therapy.

Herpes simplex virus 1 (HSV-1) is double-stranded DNA virus that belongs to the Orthoherpesviridae family. It causes serious neurological diseases of the central nervous system, such as encephalitis. The current U.S. Food and Drug Administration (FDA)-approved drugs for preventing HSV-1 infection include acyclovir (ACV) and valacyclovir; however, their long-term use causes severe side effects and often results in the emergence of drug-resistant strains. Therefore, it is important to discover new antiviral agents that are safe and effective against HSV-1 infection. Korean chestnut honey (KCH) has various pharmacological activities, such as antioxidant, antibacterial, and anti-inflammation effects; however, antiviral effects against HSV-1 have not yet been reported. Therefore, we determined the antiviral activity and mechanism of action of KCH after HSV-1 infection on the cellular level. KCH inhibited the HSV-1 infection of host cells through binding and virucidal steps. KCH decreased the production of reactive oxygen species (ROS) and calcium (Ca2+) following HSV-1 infection and suppressed the production of inflammatory cytokines by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-кB) activity. Furthermore, we found that KCH inhibited the expression of the nod-like receptor protein 3 (NLRP3) inflammasome during HSV-1 infection. Taken together, the antiviral effects of KCH occur through multiple targets, including the inhibition of viral replication and the ROS-mediated NLRP3 inflammasome pathway. Our findings suggest that KCH has potential for the treatment of HSV-1 infection and related diseases.

Could Antivirals be used to Treat Alzheimer‘s Disease?

Genital herpes simplex virus (HSV) infections of mice: A model for evaluating cross susceptibility of drug resistant mutants

Challenges of aciclovir-resistant HSV infection in allogeneic bone marrow transplant recipients

It has recently been demonstrated that the anti-herpetic drug acyclovir (ACV) also displays antiviral activity against the human immunodeficiency virus type 1 (HIV-1). The triphosphate form of ACV is accepted by HIV-1 reverse transcriptase (RT), and subsequent incorporation leads to classical chain termination. Like all approved nucleoside analogue RT inhibitors (NRTIs), the selective pressure of ACV is associated with the emergence of resistance. The V75I mutation in HIV-1 RT appears to be dominant in this regard. By itself, this mutation is usually not associated with resistance to currently approved NRTIs. Here we studied the underlying biochemical mechanism. We demonstrate that V75I is also selected under the selective pressure of a monophosphorylated prodrug that was designed to bypass the bottleneck in drug activation to the triphosphate form (ACV-TP). Pre-steady-state kinetics reveal that V75I discriminates against the inhibitor at the level of catalysis, whereas binding of the inhibitor remains largely unaffected. The incorporated ACV-monophosphate (ACV-MP) is vulnerable to excision in the presence of the pyrophosphate donor ATP. V75I compromises binding of the next nucleotide that can otherwise provide a certain degree of protection from excision. Collectively, the results of this study suggest that ACV is sensitive to two different resistance pathways, which warrants further investigation regarding the detailed resistance profile of ACV. Such studies will be crucial in assessing the potential clinical utility of ACV and its derivatives in combination with established NRTIs.

New strategy for determination of anti-viral drugs based on highly conductive layered composite of MnO2/graphene/ionic liquid crystal/carbon nanotubes

Herpes simplex virus (HSV) infection induces enzymes involved in DNA precursor metabolism and DNA synthesis. The level of the DNA precursors dCTP, dTTP and dGTP increases after HSV infection, while the dATP level decreases. Inhibition of viral DNA synthesis by acyclovir (ACV) increases all four deoxyribonucleoside triphosphate levels, in particular that of dTTP. In the present work the dynamics of metabolism of pyrimidine deoxyribonucleotides and changes in the dTTP and dCTP pools in HSV-1-infected HL cells and in infected cells where viral DNA synthesis was inhibited by ACV were studied. In the absence of the drug the major part of the dCDP synthesized was incorporated into DNA. ACV treatment inhibited DNA synthesis completely but increased de novo dTMP synthesis. A continued ribonucleotide reductase activity in ACV-treated HSV-1-infected cells contributes to the increasing dTTP pool. The allosteric regulation of dCMP deaminase activity in HSV-1-infected cells was investigated. The great increase of de novo dTMP synthesis was shown to be due to stimulation of dCMP deaminase activity by an increasing dCTP pool. The high dTTP pool is suggested to be of secondary importance to the dCTP pool in the regulation of dCMP deaminase activity in HSV-1-infected cells.

This study investigated the use of pure polymer chitosan (CS), xanthan gum (XG), monomer 2-acrylamido-2-methylpropane sulfonic acid (AMPS) and initiator potassium persulfate (KPS) as drug carrier system crosslinked through N′ N′-methylene bis-acrylamide (MBA) for controlled drug delivery of acyclovir (ACV). ACV is highly effective and selective antiviral drugs used for prophylaxis and treatment against herpes simplex viruses (HSV) infections. Present oral marketed formulations are associated with number of side effects and shortcomings which hampered its clinical effectiveness. Hydrogels (FCX1-FCX9) composed of CS, XG, AMPS, MBA, and KPS were prepared by free radical polymerization technique and characterized through FTIR, PXRD, thermal analysis and SEM. Swelling dynamics and drug release behavior was also investigated. FTIR studies confirmed that ACV was successfully encapsulated into hydrogel polymeric network. SEM revealed porous structure whereas thermal analysis showed enhanced thermal stability of polymeric network. PXRD indicated amorphous dispersion of ACV during preparation process. Swelling dynamics and ACV release behavior from developed hydrogels was dependent on pH of the medium and concentration of pure reactants used. Korsmeyer-Peppas model was best fit to regression coefficient. The present work demonstrated a potential for developing a pH sensitive hydrogel for an antiviral drug ACV by using pure polymers CS, XG, and monomer AMPS.

Virus infections are one of the major complications after BMT. Herpes simplex (HSV) and varicella zoster (VZV) infections occur in up to 80% of pts. (Harkness 1980). ACV a new specific antiviral agent has shown high activity in the treatment of VZV- and HSVinfections (Mitchell 1981).

Identification and characterization of acyclovir-resistant clinical HSV-1 isolates from children

To investigate the efficacy of a combination treatment composed of the cationic, membrane-penetrating peptide G2, and acyclovir (ACV) in both in vitro and ex vivo models of herpes simplex virus 1 (HSV-1) ocular infection. The antiviral activity of a combined G2 peptide and ACV therapy (G2-ACV) was assessed in various treatment models. Viral entry, spread, and plaque assays were performed in vitro to assess the prophylactic efficacy of G2, G2-ACV, and ACV treatments. In the ex vivo model of HSV-1 infection, the level of viral inhibition was also compared among the three treatment groups via Western blot analysis and immunohistochemistry. The potential change in expression of the target receptor for G2 was also assessed using immunohistochemistry and RT-PCR. Statistically significant effects against HSV-1 infection were seen in all treatment groups in the viral entry, spread, and plaque assays. The greatest effects against HSV-1 infection in vitro were seen in the G2-ACV group. In the ex vivo model, statistically significant anti-HSV-1 effects were also noted in all control groups. At 24 hours, the greatest inhibitory effect against HSV-1 infection was seen in the ACV group. At 48 hours, however, the G2-ACV-treated group demonstrated the greatest antiviral activity. Syndecan-1, a target of G2, was found to be upregulated at 12-hours postinfection. This study shows that G2-ACV may be an effective antiviral against HSV-1 (KOS) strain when applied as single prophylactic applications with or without continuous doses postinfection.

Herpes simplex virus resistance to antiviral drugs.

Eczema herpeticum in children with atopic dermatitis.