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In herpes labialis, the duration of healing, pain and detectable virus is reduced by up to one day,[2] compared with the total duration of 2a€“3 weeks of disease presentation. The structure and mode of action of penciclovir are very similar to that of other nucleoside analogues, such as the more widely used aciclovir.
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Herpes simplex virus infection (HSV) is a common and ubiquitous infection of the skin which causes mucocutaneous lesions called cold sores (herpes labialis) or fever blisters.
After 24 h of cream application, excess cream was washed off and layers of stratum corneum were removed by successive tape stripping. Application of penciclovir 1% cream yielded higher concentration of drug in the deeper layers of the epidermis as well as a higher drug flux through the skin. Penciclovir 1% cream has the tendency to facilitate the diffusion of the drug through the stratum corneum into the deeper epidermis layers, in which it could reach the target basal cells at effective therapeutical concentration. BackgroundHerpes simplex virus infection (HSV) is a common and ubiquitous infection of the skin which causes mucocutaneous lesions called cold sores (herpes labialis) or fever blisters. As the permeability properties of the stratum corneum remain unchanged after removal from the body, a good correlation has been observed between in vivo and in vitro experiments with the same drug [9a€“11].
Comparison of drug concentration found in the tape stripping (A) and expressed as skin flux (B) or adjusted to the applied dose (C) after application of Penciclovir 1% cream and Acyclovir 5% cream on excised human skin after 24 h. In vitro human skin percutaneous absorption of penciclovir and acyclovir from creams as cumulative permeation and when adjusted to the applied dose. Display of the molecular surface properties of acyclovir and penciclovir as determined by the molecular modelling. DiscussionMeasurement of in vitro permeation across the split thickness of human skin enables the evaluation of the passive diffusion of the molecule into and across the skin to a solute reservoir, which simulates the capillaries of the dermis.
Keratin 5 in tape strips from excised human skin treated with penciclovir 1% cream was detected by Western blot analysis. These results give evidence that basal cells were removed during the tape stripping and were found mostly in the deeper epidermal layer. ConclusionIn this in vitro model the passive diffusion of two hydrophilic drugs from two comparable formulations were studied showing both creams delivered the drug in deeper epidermal skin layers where target basal cells were localized as determined by the expression of the specific keratin 5 protein.
Competing interestsThe authors declare that they have no competing interests.Authors' contributionsNHN contributed to the analysis, interpreted results and drafted manuscript. The live, attenuated shingles (herpes zoster) vaccine Zostavax® is approved in the EU for use in the prevention of herpes zoster and postherpetic neuralgia in adults aged ?50 years. JavaScript is currently disabled, this site works much better if you enable JavaScript in your browser.
Within a virally infected cell a viral thymidine kinase adds a phosphate group to the penciclovir molecule; this is the rate-limiting step in the activation of penciclovir. First, cellular thymidine kinases phosphorylate the parent form significantly less rapidly than does the viral thymidine kinase, so the active triphosphate is present at much higher concentrations in virally infected cells than in uninfected cells.
A difference between aciclovir and penciclovir is that the active triphosphate form of penciclovir persists within the cell for a much longer time than the activated form of aciclovir, so the concentration within the cell of penciclovir will be higher given equivalent cellular doses. It is estimated that approximately 80% of the population worldwide are carriers of the Herpes simplex virus, approximately 40% suffer from recurrent recurrent infections. Amounts of active ingredients having penetrated through the skin were measured, as well as the amounts in the washed-off cream, in skin strips and creams remaining in the skin.
The small difference in the surface properties between both molecules might also contribute to favour the passage of penciclovir through the epidermis into the deeper basal cells.
Thus, in vitro diffusion through non viable human skin is a convenient experimental tool to explore permeation characteristics of a drug from its topical formulation.The present study compared the in vitro skin distribution and permeation of two commercialized creams containing 1% penciclovir or 5% acyclovir, both containing approximately 40% propylene glycol.
These values represent the amount of unabsorbed drug.Cumulative amounts of each drug that had penetrated into the skin are presented in Figure 2A. This reveals parts of the molecule which participate to hydrophobic or electrostatic interactions, which might result in bioavailability difference. Several factors influence the skin permeation among which are the release of the drug from the formulation, its penetration into the stratum corneum layers (10a€“20 I?m) and its diffusion through the stratum corneum into the various epidermis layers (100 I?m) and the dermis (1200 I?m) to reach the circulation, as simulated by the fluid in the reservoir.When compared at an equivalent dose penciclovir from the cream has the trend to have a higher transcutaneous delivery than acyclovir. For the Strip 1 in lane 1, the Strip 2 in lane 2 and the last Strip in lane 5 the signal of the 60 kD band was faint when compared to the pooled strips in lane 3 and 4.
Molecular modelling enabled for the first time to reveal difference between acyclovir and penciclovir on the surface properties.
In adults aged ?60 years, zoster vaccine reduced the burden of illness associated with herpes zoster, with reductions in the incidence of postherpetic neuralgia and herpes zoster, according to the results of the Shingles Prevention Study. Because penciclovir is absorbed poorly when given orally (by mouth) it is used more as a topical treatment, and is the active ingredient in the cold sore medications Denavir (NDC 0135-0315-52), Vectavir and Fenivir.
Cellular (human) kinases then add two more phosphate groups, producing the active penciclovir triphosphate.
Second, the activated drug binds to viral DNA polymerase with a much higher affinity than to human DNA polymerases.
Presence of the basal cell marker keratin 5 was underscored in the deeper tape strips from the skin, giving evidence that both drugs can reach their target cells. It is estimated that approximately 80% of the population worldwide are carriers of the Herpes simplex virus, approximately 40% suffer from recurrent infections [1, 2]. In vitro skin permeation was assessed using human skin mounted in Franz-type diffusion cells [12]. Dark areas indicate hydrophilic areas and lighter areas are hydrophobic moieties, indicated by an arrow. These results indicate a more effective release of penciclovir from the cream and across the stratum corneum. This observation might support that penciclovir has the tendency to have a higher paracellular passage through the stratum corneum resulting in a tendency to reach higher concentration in deeper epidermal layers.As permeability properties of the stratum corneum remained unchanged in non viable human skin the findings of the present study might be extrapolated to in use condition.
MS and PM have made substantial contribution to drafting and revising the manuscript critically. Results of subsequent Short- and Long-Term Persistence Substudies indicate that the efficacy of zoster vaccine is maintained in the longer term, albeit with a gradual decline over time.
This activated form inhibits viral DNA polymerase, thus impairing the ability of the virus to replicate within the cell.

Western blot analysis enabled to determine whether the marker of basal cells keratin 5 could be detected in the various tape strips.
The skin was dermatomed to 500 I?m using a Wagner dermatome (model GB-231 Aesculap, Germany), which enabled us to obtain split thickness tissue constituted of the stratum corneum (10a€“20 I?m), the epidermis (100 I?m) and part of the dermis (1200 I?m) [14, 15].Test of skin integrityThe permeation of tritiated water was evaluated to determine the skin integrity as described by Bronaugh [16]. Both formulations contain approximately 40% of propylene glycol (Acyclovir, 5% Zovirax contains 40% and penciclovir 1% Pencivir contains 43%) which is widely use as a co-solvent and penetration enhancer [20]. As the excised skin was frozen before use this tissue might not be viable lacking metabolism and enzymatic activity [28]. By applying the cream at the prodormal stage, when skin appears undamaged it can be postulated the drug would be delivered at the level of basal cells where the HSV-1 virus could be found in case of cold sore infection.
In the Zostavax Efficacy and Safety Trial, zoster vaccine reduced the incidence of herpes zoster in adults aged 50–59 years. Kauffman, Division of Infectious Diseases, Veterans Affairs Ann Arbor Healthcare System, University of Michigan Medical School, Ann Arbor, MI, USA; M.
At the end of the experiment drug levels in the remaining skin were determined after removal of the stratum corneum by tape stripping. This fatty alcohol, which diffuses well through the stratum corneum [20] might alter the properties of this membrane leading to improved drug distribution especially for penciclovir, while further permeation into the receptor fluid might be impaired for acyclovir. Consequently, this excludes under experimental conditions of the present study that viral thymidine kinase could be active and could phosphorylate both drugs which would be retained in cells [25]. Findings of these studies are supported by the results of large, retrospective, cohort studies. These infections last for 4 to 10 days and can extend up to 30 days in immunocompromised patients where lesions may develop extensive necrosis [1]. Additionally, physico-chemical differences between the drugs were investigated by molecular modelling as this is a factor affecting dermal absorption [13].
This difference between these structurally related polar molecules might be explained by the formulation itself together with the presence of hydrophobic region in the acyclovir structure as determined by the molecular modelling.
In the future it could be of interest to perform the study with fresh and viable excised skin infected or not by HSV-1 to evaluate the contribution of the viral enzymatic activity on the drug bioavailability into the deeper epidermal layers where the target cells are present. Zoster vaccine was generally well tolerated, with injection-site adverse events being the most commonly reported adverse events. Levin, Division of Infectious Diseases, Children’s Hospital Colorado and University of Colorado, School of Medicine, Aurora, CO, USA; V. Topical treatment with antiviral drugs like acyclovir and penciclovir is effective in shortening lesion duration and in relieving pain, as has been shown in large randomized, double-blind, vehicle controlled multi-centre clinical trials [1a€“4].For best effect, antiviral drugs should be able to reach therapeutic concentrations in basal epidermal cells, which are the initial portal of entry to the virus spreading [5, 6]. The receptor phase (2 ml) was taken in order to measure the amount of tritiated water (%) which permeated across the skin, using a liquid scintillation counter. The total concentration of drug found in the pooled strips might include the entire epidermis in accordance with the finding that after 3 h of experiment duration the epidermis peels off with the stratum corneum [19].
Thus this chemical modelling software was used to compare acyclovir and penciclovir which are known as hydrophilic drugs.
This moiety may interact with hydrophobic structure in the stratum corneum preventing further penetration. In conclusion, zoster vaccine provides an important opportunity to reduce the burden of illness associated with herpes zoster by reducing the incidence of herpes zoster and postherpetic neuralgia. Consequently, skin absorption is one of the most critical factors for successful therapy with a topical formulation for the treatment of herpes labialis. As shown in Figure 3 the surface charge distribution is very similar but the hydrophobicity distribution showed two areas of higher hydrophobic moieties for acyclovir. It has been reported that increased lipophilicity is used to reduce systemic absorption, which was reported for the corticosteroids [21]. Morrison, Veterans Affairs Medical Center and University of Minnesota, Minneapolis, MN, USA; T. These are painful to touch and can cause a lot of discomfort.The Dr OZ - Best Proven Remedy For Cold SoresCold Sores Remedies Cold sores are fluid filled eruptions on the lips and around the mouth. The route of drug penetration across the stratum corneum, which is the main rate limiting barrier to skin absorption [7], depends on the properties of the respective drugs.
Less than 1% of the applied dose of tritiated water permeated through the skin.Skin permeationSkin permeation is the diffusion of the drug across the skin layer into the receptor phase which represents blood vessels. The hydrophilic feature of penciclovir as shown in Figure 3 might not react with hydrophobic structures, thus allowing penciclovir to be freely "drawn" by the solvent between the corneocytes of the stratum corneum within the hydrophilic region, constituting the paracellular pathway [13, 22].The stripping technique enables measurement of drug concentration in the stratum corneum by repeated application of adhesive tape to the skin sample generally between 10 to 15 times [14]. These are painful to touch and can cause a lot of discomfort.Genital Herpes Treatment - Breakthrough TreatmentGenital Herpes Treatment There are two subtypes of herpes simplex viruses. Penciclovir has an additional hydroxyl group when compared to acyclovir (Figure 1), which became available as a generic drug in the mid 1990s when its analogue penciclovir was launched [8].
After a 3 h duration of this experimental technique it has been reported that the stratum corneum peels readily from the dermis including all remaining epidermal layers [15, 19].
It was questionable whether under our experimental conditions, in which the tape stripping was done 24 h after the product application basal cells could be found in the tape strips.
Similar herpes zoster incidence across Europe: results from a systematic literature review. Knowing that keratin 5 is specifically expressed in the basal cell of the epidermis [23] a western blot analysis using a monoclonal antibody against this protein was performed.
As shown in Figure 4 this technique produced a narrow, unique 60 kDa band in samples of pooled tape strips (on lane 3 and 4) and only very faint bands of similar size from samples of tape strips 1, 2 and the last strip (on lane 5). The top layer of the stratum corneum was removed with adhesive tape (3 M Scotch nA° 550) and analyzed separately. A population-based study of the incidence and complication rates of herpes zoster before zoster vaccine introduction. Additional layers of the stratum corneum were removed by up to 12 consecutive adhesive tape strips.Following collection of all strips, the first and the second strips were put into separate vials containing 10 ml of water.
An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy. Generation and display of molecular surface properties enabled us to reveal those parts of the molecules which are involved in hydrophobic or hydrophilic interactions [18].Western blot analysisThe skin sample from one donor was washed off with soapy water and cotton-wool tips 24 h after the cream application. Following collection of all strips, the first and the second strips were put into separate vials.

Then pools of 3 to 4 strips were put in the same vial and the last strip was placed separately in another vial. Protein concentrations were measured by the BCA protein assay (Pierce).Ten I?l of protein samples corresponding to 3 I?g of protein from tape strips lysat were separated by 10% SDS-PAGE and transferred to polyvinylidene difluoride membranes (Immobilon-P, Millipore, Bedford, MA). A double-blind, randomized, controlled, multicenter safety and immunogenicity study of a refrigerator-stable formulation of Zostavax.
Zoster vaccine (Zostavax®): a review of its use in preventing herpes zoster and postherpetic neuralgia in older adults. Identified protein bands were detected using a video densitometer and ImageQuant software (Molecular Dynamics, Sunnyvale, CA).Statistical analysisUnpaired Student t-test were performed to define a P value between the pencyclovir cream and the acyclovir cream.
Varicella-zoster virus-specific immune responses in elderly recipients of a herpes zoster vaccine. Safety, tolerability, and immunogenicity of a booster dose of zoster vaccine (ZV) administered ?10 years after a first dose compared with a first dose of ZV [abstract]. Immune response and safety of herpes zoster vaccine in IBD patients on methotrexate or thiopurines [abstract no.
Zostavax is generally safe and immunogenic in HIV + adults virologically suppressed on ART: results of a phase 2, randomized, double-blind, placebo- controlled trial [abstract no.
Varicella-zoster virus-specific immune responses to herpes zoster in elderly participants in a trial of a clinically effective zoster vaccine. Varicella zoster virus-specific immune responses to a herpes zoster vaccine in elderly recipients with major depression and the impact of antidepressant medications. Safety, tolerability, and immunogenicity of zoster vaccine in subjects with a history of herpes zoster. Immunogenicity and safety of Zostavax® approaching expiry potency in individuals aged ?50 years. Safety and immunogenicity profile of the concomitant administration of Zostavax and inactivated influenza vaccine in adults aged 50 and older. Safety, tolerability, and immunogenicity after 1 and 2 doses of zoster vaccine in healthy adults ?60 years of age. Immunogenicity and safety of a live attenuated shingles (herpes zoster) vaccine (Zostavax®) in individuals aged ?70 years: a randomized study of a single dose versus two different two-dose schedules. Comparison of the levels of immunogenicity and safety of Zostavax in adults 50 to 59 years old and in adults 60 years old or older. Persistence of the efficacy of zoster vaccine in the Shingles Prevention Study and the Short-Term Persistence Substudy.
Herpes zoster vaccine effectiveness against incident herpes zoster and post-herpetic neuralgia in an older US population: a cohort study. Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population.
Evaluation of the incidence of herpes zoster after concomitant administration of zoster vaccine and polysaccharide pneumococcal vaccine.
The use, safety, and effectiveness of herpes zoster vaccination in individuals with inflammatory and autoimmune diseases: a longitudinal observational study. Association between vaccination for herpes zoster and risk of herpes zoster infection among older patients with selected immune-mediated diseases.
Effect of a zoster vaccine on herpes zoster-related interference with functional status and health-related quality-of-life measures in older adults. Zostavax® (zoster vaccine live) [refrigerator stable] suspension for subcutaneous injection: US prescribing information. Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study. Health economic evaluation of a vaccine for the prevention of herpes zoster (shingles) and post-herpetic neuralgia in adults in Belgium. Cost-effectiveness of vaccination against herpes zoster in adults aged over 60 years in Belgium. Estimating the cost-effectiveness of vaccination against herpes zoster in England and Wales. A health economic model for evaluating a vaccine for the prevention of herpes zoster and post-herpetic neuralgia in the UK. Assessing the potential effects and cost-effectiveness of programmatic herpes zoster vaccination of elderly in the Netherlands.
Economic evaluation of a vaccine for the prevention of herpes zoster and post-herpetic neuralgia in older adults in Switzerland.
Zoster vaccine recommendations: the importance of using a clinically valid correlate of protection.
Incremental 1-year medical resource utilization and costs for patients with herpes zoster from a set of US health plans.
The impact of herpes zoster and postherpetic neuralgia on health-related quality of life: a prospective study. Estimating the age-specific duration of herpes zoster vaccine protection: a matter of model choice? Studying physician knowledge, attitudes, and practices regarding the herpes zoster vaccine to address perceived barriers to vaccination. Herpes zoster vaccine awareness among people = 50 years of age and its implications on immunization. Discussing the zoster vaccine: an interview with Julie Gerberding, president of Merck vaccines.
UK first major European country to run Zostavax nationwide shingles vaccination programme [media release].

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