Enhanced acyclovir delivery using w/o type microemulsion: preclinical assessment of antiviral activity using murine model of zosteriform cutaneous HSV-1 infection.

The present study was aimed to develop and evaluate a microemulsion-based dermal drug delivery of an antiviral agent, acyclovir. A water-in-oil microemulsion was prepared using isopropyl myristate, Tween 20, Span 20, water and dimethylsulphoxide. It was characterized for drug content, stability, globule size, pH, viscosity and ex vivo permeation through mice skin. In vivo antiviral efficacy of optimized formulation was assessed in female Balb/c mice against herpes simplex virus-I (HSV-I)-induced infection. It was observed that optimized formulation when applied 24-h post-infection could completely inhibit the development of cutaneous herpetic lesions vis-à-vis marketed cream.

Current management and recommendations for access to antiviral therapy of herpes labialis.

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 pharmacist-controlled 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.

Resistance of herpes simplex viruses to nucleoside analogues: mechanisms, prevalence, and management.

Herpes simplex viruses (HSV) type 1 and type 2 are responsible for recurrent orolabial and genital infections. The standard therapy for the management of HSV infections includes acyclovir (ACV) and penciclovir (PCV) with their respective prodrugs valacyclovir and famciclovir. These compounds are phosphorylated by the viral thymidine kinase (TK) and then by cellular kinases. The triphosphate forms selectively inhibit the viral DNA polymerase (DNA pol) activity. Drug-resistant HSV isolates are frequently recovered from immunocompromised patients but rarely found in immunocompetent subjects. The gold standard phenotypic method for evaluating the susceptibility of HSV isolates to antiviral drugs is the plaque reduction assay. Plaque autoradiography allows the associated phenotype to be distinguished (TK-wild-type, TK-negative, TK-low-producer, or TK-altered viruses or mixtures of wild-type and mutant viruses). Genotypic characterization of drug-resistant isolates can reveal mutations located in the viral TK and/or in the DNA pol genes. Recombinant HSV mutants can be generated to analyze the contribution of each specific mutation with regard to the drug resistance phenotype. Most ACV-resistant mutants exhibit some reduction in their capacity to establish latency and to reactivate, as well as in their degree of neurovirulence in animal models of HSV infection. For instance, TK-negative HSV mutants establish latency with a lower efficiency than wild-type strains and reactivate poorly. DNA pol HSV mutants exhibit different degrees of attenuation of neurovirulence. The management of ACV- or PCV-resistant HSV infections includes the use of the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir. There is a need to develop new antiherpetic compounds with different mechanisms of action.

Assessment of correlation between skin target site free drug concentration and the in vivo topical antiviral efficacy in hairless mice for (E)-5-(2-bromovinyl)-2'-deoxyuridine and acyclovir formulations.

Recently, we reported that the in vivo efficacy of acyclovir (ACV) formulations was a single valued function of skin target site free drug concentration (C) irrespective of the formulation compositions. A long-term objective of this research has been to generalize the C concept using model drugs which are similar to as well as different from ACV in their mechanism of actions. (Bromovinyl)deoxyuridine (BVDU) was selected as a model drug based on the reported similarity in its mechanism of action with ACV. The relationship between the C predictions and the in vivo efficacies for some topical formulations containing different concentrations (0.05-10%) of either ACV or BVDU in 95% DMSO as a vehicle with or without 5% Azone as skin permeation enhancer was examined. Hairless mice infected cutaneously with HSV-1 were used to quantitatively estimate the in vivo topical antiviral efficacy. A finite dose of the test antiviral formulation was applied twice a day for 4 days, starting the day after virus inoculation. On the fifth day, the lesions were scored and the efficacy values were calculated. For each formulation, in vitro flux experiments were performed in an in vivo-in vitro experimental design that closely approximated the in vivo study protocol. As was previously shown, with all ACV formulations, a good correlation was found between the C predictions and the in vivo topical efficacy. With the BVDU formulations, on the other hand, this was found not to be the case. BVDU formulations with 5% Azone were generally much more effective than those without Azone at comparable C values. This finding is believed to be the first of its kind showing that skin "permeation enhancers" may enhance efficacy by more than simply increasing skin permeation rates.

Assessment trials of the therapeutic efficacy of the drug "Zovirax" in some recurrent ocular and genital herpetic infections.

In this work are reported the results of the researches performed by the authors more than a decade ago, aimed at assessing the clinical benefit of the introduction of the drug "Zovirax" in the treatment of recurrent herpetic infections with genital or ocular location. The results of the treatment carried out on a restricted group of patients were positive both in cases of genital herpes and of herpetic keratitis. The clinical benefit consisted in the reduction of the mean duration of the disease, in the shortening of the period of the infective virus elimination from the lesion, as well as in the decrease of the intensity and duration of the clinical symptomatology as a whole. With respect to these clinical parameters, the observations of the authors performed on a low number of cases are consistent with the data obtained by other authors in the framework of more extensive studies. The renewed discussion of these clinical and laboratory observations carried out by the authors during the first years after the introduction in our country of this drug in the therapeutic arsenal of herpetic infections is aimed at establishing a landmark for the comparison with more recent results of similar studies, starting from the idea of the opportunity of assessing periodically the sensitivity of herpes simplex virus strains, circulating among the autochthonous population, to the inhibitory action of some antiviral drugs. In other words, the in vitro testing of the susceptibility of these strains to the chemotherapeutic agents in current use is predictive for the efficacy degree of these drugs in the treatment of some forms of herpetic infections. This evaluation represents at the same time, undoubtedly, a useful epidemiological surveillance means of the circulation of human herpes viruses among the population. We refer especially to the risk of appearance of pharmacoresistant mutants, a risk possible under the conditions of the increased access of patients to the antiviral chemotherapeutic medication, which implicitly augments the probability of a fortuitous administration of treatments insufficient as regards the dose or the duration. In this work there are also shown the results regarding some experimental aspects related to the immune control mechanisms of the herpetic infection, which may complement the chemotherapeutic action. Under the treatment with acycloguanosine the synthesis of herpetic antigens is kept at a level sufficient for the circulating antibody synthesis induction and the HSV infected cells treated with the drug are recognized and lysed by effectors of the cell-mediated immune response of the host. Hence, it may be asserted that, in some clinical cases of recurrent herpes with frequent episodes, it is useful to perform immunostimulating treatments, able to potentiate the cell-mediated immune mechanisms possibly involved in the limitation of the herpetic infection at the peripheral level and of its spreading in the central nervous system.

Serological assessment of acyclovir treatment of herpes genitalis.

Oral acyclovir was given to 60 patients with herpes genitalis--20 experiencing a first attack and 40 with recurrent attacks. All patients were followed up for 1 year. Serial serum samples from the patients as well as from 20 controls were studied to determine the effect of therapy on the immune response to herpes simplex virus (HSV). No toxicity was observed, and very few patients had rather insignificant side effects (e.g., diarrhea). The frequency of recurrence (number of recurrences per year) of genital herpes in acyclovir-treated patients was found significantly lower than in controls. More frequent recurrences were observed in those who had high antibody titer in their early convalescent phase sera than in those without or with a low titer of such antibodies. The antibody titers were reduced in those who received acyclovir as compared with controls. The mean time to seroconversion was longer in the acyclovir-treated group than in controls. Oral acyclovir is thus effective and well tolerated in patients with herpes genitalis. Treatment with acyclovir also diminishes the humoral antibody response to HSV, but it does not prevent recurrence. The effects of acyclovir on the immune response to HSV are discussed.

Preclinical assessment of topical treatments of herpes simplex virus infection: 5% (E)-5-(2-bromovinyl)-2'-deoxyuridine cream.

The potential efficacy of topical therapy with (E)-5-w-bromovinyl)-2'-deoxyuridine (BVDU) for cutaneous herpesvirus infection was evaluated in vitro and in guinea pigs. Drug sensitivity testing against herpes simplex virus type 1 strain E115 revealed an ID50 of 0.008 microgram/ml for BVDU and 0.19 microgram/ml for acyclovir (ACV). In vitro drug diffusion studies showed poor penetration of guinea pig skin by BVDU from the cream compared to BVDU from dimethylsulfoxide (DMSO) (0.04 vs. 1.5 microgram/cm2 per h). 5% BVDU cream, 5% BVDU/DMSO, and 5% ACV in polyethylene glycol (PEG) were then compared in the treatment of experimental dorsal cutaneous HSV-1 infection in guinea pigs. Lesion number, total lesion area and virus titer were reduced by all three formulations compared to control sites treated with the corresponding drug vehicles (P less than or equal to 0.01). BVDU cream effected a greater reduction in lesion number (20+ vs. 13%) and total lesion area (40% vs. 28%) than did ACV/PEG and a significantly greater decrease in virus titer (990% vs. 55%, P less than 0.002). BVDU/DMSO was clinically twice as effective as BVDU cream (P less than or equal to 0.01) and reduced lesion virus titers to a similar degree. The results of these studies show that BVDU is a more potent virus-inhibitory agent than ACV in vitro and is superior to topical ACV in vivo when formulated in a simple aqueous cream. The marked efficacy of BVDU/DMSO in the animal model demonstrates the potential of this antiviral if drug delivery is improved.