Virtual screening, ADME/T, and binding free energy analysis of anti-viral, anti-protease, and anti-infectious compounds against NSP10/NSP16 methyltransferase and main protease of SARS CoV-2.

Recently, a pathogen has been identified as a novel coronavirus (SARS-CoV-2) and found to trigger novel pneumonia (COVID-19) in human beings and some other mammals. The uncontrolled release of cytokines is seen from the primary stages of symptoms to last acute respiratory distress syndrome (ARDS). Thus, it is necessary to find out safe and effective drugs against this deadly coronavirus as soon as possible. Here, we downloaded the three-dimensional model of NSP10/NSP16 methyltransferase (PDB-ID: 6w6l) and main protease (PDB-ID: 6lu7) of COVID-19. Using these molecular models, we performed virtual screening with our anti-viral, inti-infectious, and anti-protease compounds, which are attractive therapeutics to prevent infection of the COVID-19. We found that top screened compound binds with protein molecules with good dock score with the help of hydrophobic interactions and hydrogen bonding. We observed that protease complexed with Cyclocytidine hydrochloride (anti-viral and anti-cancer), Trifluridine (anti-viral), Adonitol, and Meropenem (anti-bacterial), and Penciclovir (anti-viral) bound with a good docking score ranging from -6.8 to -5.1 (Kcal/mol). Further, NSP10/NSP16 methyltransferase complexed with Telbivudine, Oxytetracycline dihydrate (anti-viral), Methylgallate (anti-malarial), 2-deoxyglucose and Daphnetin (anti-cancer) from the docking score of -7.0 to -5.7 (Kcal/mol). In conclusion, the selected compounds may be used as a novel therapeutic agent to combat this deadly pandemic disease, SARS-CoV-2 infection, but needs further experimental research.HighlightsNSP10/NSP16 methyltransferase and main protease complex of SARS CoV-2 bind with selected drugs.NSP10/NSP16 methyltransferase and protease interacted with drugs by hydrophobic interactions.Compounds show good DG binging free energy with protein complexes.Ligands were found to follow the Lipinski rule of five.

Antiviral effect of Chinese herbal prescription JieZe-1 on adhesion and penetration of VK2/E6E7 with herpes simplex viruses type 2.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese Herbal Prescription JieZe-1(JZ-1), added and subtracted from Yihuang Decoction, a famous formula in the 12th year of Kangxi in Qing Dynasty, has a clear effect on Genital Herpes (GH) and no obvious adverse reactions occur clinically. JZ-1 also has preventive and therapeutic effects on Trichomonas vaginitis, Candida albicans vaginitis and GH in vitro and in vivo experiments. AIM OF STUDY: The effect and mechanism of JZ-1 on anti-herpes simplex virus type 2(HSV-2) in vitro focusing on adhesion and penetration stages were investigated. MATERIALS AND METHODS: A model of HSV-2 infection of VK2/E6E7 was developed. In order to explore JZ-1's anti-HSV-2 effect in vitro, cell morphology, ultrastructural pathology, cell viability and expression of viral glycoprotein D (gD) were assessed at 6 h, 12 h, 18 h, and 24 h of JZ-1 treatment. Then we measured the exact time required for adhesion and penetration of HSV-2 into VK2/E6E7 among a series of times at room temperature and under temperature control techniques. We treated VK2/E6E7 with JZ-1, penciclovir, or berberine and explored the mechanism of JZ-1 in blocking HSV-2 adhesion and penetration of host cells by assessing the cell ultrastructural pathology, viability, viral proteins gB, gD, VP16, ICP5, and ICP4 and host cell proteins HVEM, Nectin-1, and Nectin-2. RESULTS: HSV-2 can fully adhere and penetrate into VK/E6E7 within 5 mins at room temperature while it takes 60mins under temperature control techniques. JZ-1 and penciclovir showed significant anti-HSV-2 effects, with improved host cell morphologies and increased host cell viabilities observed after treatment for 24 h. The anti-HSV-2 effect of JZ-1 can be detected after treatment for 6 h while that of penciclovir was not obvious until treatment for 12 h. JZ-1 showed distinct effect on HSV-2 adhesion and penetration stages by significantly reducing the expression of viral proteins gB, gD, VP16, ICP5, and ICP4, improving cell morphology and increasing cell viability. However, these effects were not exerted via downregulated expression of membrane fusion-related proteins such as HVEM, Nectin-1, or Nectin-2. The specific anti-HSV-2 mechanism of JZ-1 need to be further explored. CONCLUSION: The anti-HSV-2 effect of JZ-1 was superior to that of penciclovir and berberine in vitro, and was mainly mediated by enhancing host cell defense and blocking adhesion and penetration of HSV-2.

Evaluation of the antiviral activities of Bacharis dracunculifolia and quercetin on Equid herpesvirus 1 in a murine model.

Equid herpesvirus 1 (EHV-1) is a pathogen of high economic importance in equine breeding operations around the world. EHV-1 infection causes respiratory, neurologic and reproductive disease. The absence of an efficient therapy has caught the attention of the scientific community and the therapeutic activities of natural products with its antivirals effects might be effective for the disease's treatment. Herein it was evaluated the prophylactic and therapeutic potential of quercetin and ethanolic extracts of Bacharis dracunculifolia formulations compared to Penciclovir® in an in vivo EHV-1 infection model. Six to seven-week-old female C57BL/6 mice were randomly organized into fifteen groups with six animals each. Ex-1 represents the treatment post-challenge groups to assess morbidity, mortality and weight variation. Ex-2 represents the animals that received treatment for 5 days post-challenge for lesion evaluation. In Ex-3 animals were treated prior to viral challenge to assess morbidity, mortality and weight variation. All mice in the treatment groups were challenged by intranasal inoculation of 3.0 × 105 TCID50 EHV-1. The quercetin and B. dracunculifolia treatment decreased morbimortality in post-challenge treatment (Ex-1) and EHV-1 related lesions (Ex-2). Treatment prior to viral challenge (Ex-3) did not show any significant results. Based on the results of the present study, both tested formulations are promising antiviral agents for the treatment of EHV-1 infection.

[Topical ozone therapy: An innovative solution to patients with herpes zoster].

OBJECTIVE: To observe the clinical efficacy and safety of topical ozone therapy for patients with herpes zoster by reflectance confocal microscopy (RCM).
 Methods: A total of 60 patients with herpes zoster were divided into a control group and an ozone treatment group (n=30). In the control group, patients took oral valacyclovir tablets or granules (0.3 g per day, three times a day) and they were subjected to local weak laser irradiation treatment plus topical 2% mupirocin ointment twice a day. In the ozone group, the treatment is same as the control group except mupirocin ointment was replaced with topical ozone treatment (hydrotherapy every day plus ozonated oil twice a day). The clinical symptoms, discoid cell and adverse reactions were observed and taken records at day 0, 3, 7 and 14. Statistical analysis was performed to compare the clinical efficacy between the 2 groups. 
 Results: On the seventh day of treatment, the discoid cells of the ozone group disappeared, and the difference between the control group and the ozone group was statistically significant (P<0.05). The difference of decreased percentage of pain scores at each time point between the 2 groups was statistically significant (P<0.05). The clinical efficacy was 100% in the ozone group and 86.7% in the control group, with significant difference between the 2 groups (P<0.05).
 Conclusion: Topical ozone therapy in patients with herpes zoster is helpful in relieving pain, shortening the course as well as improving the clinical efficacy without obvious adverse reactions. It is worth to be popularized.

Anti HSV-2 activity of Peganum harmala (L.) and isolation of the active compound.

Genital herpes is a sexually transmitted disease caused by herpes simplex virus type 2 (HSV-2). Nucleoside analogues such as acyclovir (ACV) are the usual therapy for treating HSV infection. However, the overuse of this drug has led to the emergence of resistant strains. Therefore, the search for new alternative or complementary molecules to overcome this obstacle is needed. In this objective, Peganum harmala was investigated for its HSV-2 activity. The organic extracts of the different plant organs were evaluated for their cytotoxicity on Vero cells by the MTT test and anti HSV-2 activity by plaque reduction assay. Only the methanol seeds extract was active with a 50% inhibitory concentration (IC50) and a selectivity index (SI) of 161 and 13.2 µg/mL, respectively. In addition, the study of the antiviral mode of action revealed that this extract exerts a virucidal action both during the entry of viruses and the release of the newly formed virions, whereas no cell protection effect was observed. The active compound was isolated by bio-guided purification using thin layer chromatography (TLC) and identified by GC-MS and HPLC-DAD-ESI-MSn as harmine. The combination of harmine standard compound with ACV showed a combination index (CI) of 0.5 indicating that these two compounds have a synergic effect. This data suggests that harmine could be associated to ACV to improve the treatment of genital herpes essentially for the immunocompromised patients.

Acupuncture and Kinesio Taping for the acute management of Bell's palsy: A case report.

BACKGROUND: Bell's palsy is an idiopathic, acute peripheral palsy of the facial nerve that supplies the muscles of facial expression. Despite an expected 70% full recovery rate, up to 30% of patients are left with potentially disfiguring facial weakness, involuntary movements, or persistent lacrimation. The most frequently used treatment options are corticosteroids and antiviral drugs. However, accompanying clinical conditions, such as uncontrolled diabetes, hypertension, gastrointestinal disturbances, polypharmacy of geriatric patients, and significant sequelae ratios, indicate the need for safe and effective complementary therapies that would enhance the success of the conventional interventions. CASE SUMMARY: A 26-year-old female presented with numbness and earache on the left side of the face; these symptoms had been ongoing for 8-10h. Physical examination revealed peripheral facial paralysis of House-Brackmann grade III and corticosteroid-valacyclovir treatment was initiated. On the same day, Kinesio Taping was applied to the affected nerve and muscle area with the aim of primarily neurofacilitation and edema-pain relief. On the fifth day, acupuncture treatment was started and was continued for 3 consecutive days. A physical therapy program was administered for the subsequent 10days. At the 3-week follow-up examination, Bell's palsy was determined as grade I, and the treatment was stopped. CONCLUSION: Acupuncture and Kinesio Taping, in conjunction with physical therapy modalities, are safe and promising complementary therapies for the acute management of Bell's palsy. However, further large scale and randomized controlled studies are necessary to assess whether these complementary interventions have significant additive or synergistic effect for complete recovery of patients with Bell's palsy.

A general practice approach to Bell's palsy.

BACKGROUND: Bell's palsy is characterised by an acute onset of unilateral, lower motor neuron weakness of the facial nerve in the absence of an identifiable cause. Establishing the correct diagnosis is imperative and choosing the correct treatment options can optimise the likelihood of recovery. OBJECTIVE: This article summarises our understanding of Bell's palsy and the evidence-based management options available for adult patients. DISCUSSION: The basic assessment should include a thorough history and physical examination as the diagnosis of Bell's palsy is based on exclusion. For confirmed cases of Bell's palsy, corticosteroids are the mainstay of treatment and should be initiated within 72 hours of symptom onset. Antiviral therapy in combination with corticosteroid therapy may confer a small benefit and may be offered on the basis of shared decision making. Currently, no recommendations can be made for acupuncture, physical therapy, electrotherapy or surgical decompression because well-designed studies are lacking and available data are of low quality.

Herpes Simplex Virus Suppressive Therapy in Herpes Simplex Virus-2/Human Immunodeficiency Virus-1 Coinfected Women Is Associated With Reduced Systemic CXCL10 But Not Genital Cytokines.

BACKGROUND: Herpes simplex virus type-2 (HSV-2) may heighten immune activation and increase human immunodeficiency virus 1 (HIV-1) replication, resulting in greater infectivity and faster HIV-1 disease progression. An 18-week randomized, placebo-controlled crossover trial of 500 mg valacyclovir twice daily in 20 antiretroviral-naive women coinfected with HSV-2 and HIV-1 was conducted and HSV-2 suppression was found to significantly reduce both HSV-2 and HIV-1 viral loads both systemically and the endocervical compartment. METHODS: To determine the effect of HSV-2 suppression on systemic and genital mucosal inflammation, plasma specimens, and endocervical swabs were collected weekly from volunteers in the trial and cryopreserved. Plasma was assessed for concentrations of 31 cytokines and chemokines; endocervical fluid was eluted from swabs and assayed for 14 cytokines and chemokines. RESULTS: Valacyclovir significantly reduced plasma CXCL10 but did not significantly alter other cytokine concentrations in either compartment. CONCLUSIONS: These data suggest genital tract inflammation in women persists despite HSV-2 suppression, supporting the lack of effect on transmission seen in large scale efficacy trials. Alternative therapies are needed to reduce persistent mucosal inflammation that may enhance transmission of HSV-2 and HIV-1.

Clinical study in genital herpes: natural Gene-Eden-VIR/Novirin versus acyclovir, valacyclovir, and famciclovir.

BACKGROUND: This paper reports the results of a clinical study that tested the effect of suppressive treatment with the botanical product Gene-Eden-VIR/Novirin on the number of genital herpes outbreaks. The results in this study were compared to those published in clinical studies of acyclovir, valacyclovir, and famciclovir. METHODS: The framework was a retrospective chart review. The population included 139 participants. The treatment was one to four capsules of Gene-Eden-VIR/Novirin per day. The duration of treatment was 2-48 months. The study included three controls recommended by the US Food and Drug Administration (FDA): baseline, no treatment, and dose response. RESULTS: The treatment decreased the number of outbreaks per year in 90.8% of the participants. The treatment also decreased the mean number of outbreaks per year from 7.27 and 5.5 in the control groups to 2.39 (P<0.0001 and P<0.001, respectively). The treated participants reported no adverse experiences. Out of the 15 tests that compared Gene-Eden-VIR/Novirin to the three drugs, Gene-Eden-VIR/Novirin had superior efficacy in eight tests, inferior efficacy in three tests, and comparable efficacy in four tests. Gene-Eden-VIR/Novirin also had superior safety. CONCLUSION: The clinical study showed that the natural Gene-Eden-VIR/Novirin decreases the number of genital herpes outbreaks without any side effects. The study also showed that the clinical effects reported in this study are mostly better than those reported in the reviewed studies of acyclovir, valacyclovir, and famciclovir.

Valacyclovir treatment of chronic fatigue in adolescents.

Chronic fatigue syndrome (CFS) presents with fatigue, low motivation, diminished mood, and reduced activity, all symptoms having extensive diagnostic overlaps with depression. Studies have linked chronic viral infections with CFS, and antiviral therapy has effectively treated CFS in adult patients. In a retrospective case series, 15 adolescents and preteens referred to the author for treatment-resistant depression or mood disorder were evaluated and found to have met the Fukuda diagnostic criteria for CFS. While a subset (4/15) had been diagnosed in the past with CFS, the majority had a current diagnosis of depression or a mood disorder. The Diagnostic and Statistical Manual-IV Text Revision (DSM-IV TR) criteria for depression were not met in all patients, although 3 cases of mood disorder not otherwise specified (MD-NOS) and 1 case of Tourette syndrome (TS) plus MD-NOS were diagnosed. Baseline scores on the Children's Depression Inventory (CDI) were below the cutoff for depression in all but 1 patient. Baseline self-assessment scales for CFS or fatigue were obtained and sleep was evaluated with sleep logs. All patients were treated subsequently with valacyclovir, with 93% having a positive response. At the end of treatment, scores on fatigue self-assessment scales improved significantly (P < .001). Vigor subscale scores also improved significantly (P < .001). Some patients experienced complete resolution of symptoms. Although not every patient was tested, available laboratory testing revealed increased counts of natural killer (NK) cells and decreased human herpesvirus 6 (HHV-6) antibody titers in all patients who responded to valacyclovir. This article discusses the significance of infectious agents in the pathogenesis of psychiatric symptoms. The study's data support an intriguing hypothesis that a portion of treatment-resistant depression in fact may be undiagnosed CFS or other chronic viral infection.

The combination of valacyclovir with an anti-TNF alpha antibody increases survival rate compared to antiviral therapy alone in a murine model of herpes simplex virus encephalitis.

The added benefit of combining valacyclovir (VACV), an antiviral agent, with etanercept (ETA), an anti-tumor necrosis factor alpha (TNF-α) antibody, for the treatment of herpes simplex virus type 1 (HSV-1) encephalitis (HSE) was evaluated in a mouse model. BALB/c mice were infected intranasally with 1.85 × 104 plaque forming units of HSV-1. Groups of mice received a single intraperitoneal injection of vehicle or ETA (400 µg/mouse) on day 3 post-infection combined or not with VACV (1 mg/ml of drinking water) from days 3 to 21 post-infection. On day 5 post-infection, groups of mice were sacrificed for determination of viral DNA load, detection of ETA in brain homogenates and for in situ hybridization. The survival rate of mice was significantly increased when VACV was administered in combination with ETA (38.5% for VACV vs 78.6% for combined treatment; P = 0.04) although VACV or ETA alone had no significant effect compared to the vehicle. The benefit of combined therapy was still present when treatment was delayed until day 4 post-infection. The viral DNA load was significantly reduced in mice treated with VACV alone (P < 0.01) or combined with ETA (P < 0.05) compared to the uninfected group whereas ETA alone had no effect. These results reinforce the notion that both virus-induced and immune-related mechanisms participate in the pathogenesis of HSE and suggest that potent antiviral agent could be combined with immune-based therapy, such as a TNF-α inhibitor, to improve prognosis of HSE.

Varicella zoster virus vasculopathy: a treatable form of rapidly progressive multi-infarct dementia after 2 years' duration.

We describe an extraordinarily protracted case of varicella zoster virus (VZV) multifocal vasculopathy in a man who presented initially with ischemic optic neuropathy and then suffered 4 episodes of stroke manifesting as multi-infarct dementia over a 2-year period. Brain magnetic resonance imaging (MRI) and angiography (MRA) revealed cortical and subcortical infarctions as well as vasculitic occlusion and stenosis. The patient was treated with corticosteroids and later with cyclophosphamide. More than 2 years after the onset of neurological disease, two cerebrospinal fluid (CSF) examinations revealed the presence of anti-VZV IgG antibody with reduced serum-to-CSF ratios of anti-VZV IgG compared with ratios for total IgG and albumin, indicative of intrathecal synthesis of anti-VZV IgG. After definitive diagnosis, immunosuppressive drugs were discontinued and he was treated with intravenous acyclovir; both mental status and gait improved and no further episodes of neurological dysfunction ensued. The favorable outcome in this patient indicates that VZV vasculopathy can be treated successfully even after 26 months. VZV must be considered as a possible cause of neurological disease in any patient with idiopathic multifocal vasculopathy.

Effect of ASP2151, a herpesvirus helicase-primase inhibitor, in a guinea pig model of genital herpes.

ASP2151 is a herpesvirus helicase-primase inhibitor with antiviral activity against varicella zoster virus and herpes simplex virus types 1 (HSV-1) and 2 (HSV-2). Here, we examined the potency and efficacy of ASP2151 against HSV in vitro and in vivo. We found that ASP2151 was more potent in inhibiting the replication of HSV-1 and HSV-2 in Vero cells in the plaque reduction assay and had greater anti-HSV activity in a guinea pig model of genital herpes than did acyclovir and valacyclovir (VACV), respectively. Oral ASP2151 given from the day of infection reduced peak and overall disease scores in a dose-dependent manner, resulting in complete prevention of symptoms at the dose of 30 mg/kg. The 50% effective dose (ED(50)) values for ASP2151 and VACV were 0.37 and 68 mg/kg, respectively, indicating that ASP2151 was 184-fold more potent than VACV. When ASP2151 was administered after the onset of symptoms, the disease course of genital herpes was suppressed more effectively than by VACV, with a significant reduction in disease score observed one day after starting ASP2151 at 30 mg/kg, whereas the therapeutic effect of VACV was only evident three days after treatment at the highest dose tested (300 mg/kg). This indicated that ASP2151 possesses a faster onset of action and wider therapeutic time window than VACV. Further, virus shedding from the genital mucosa was significantly reduced with ASP2151 at 10 and 30 mg/kg but not with VACV, even at 300 mg/kg. Taken together, our present findings demonstrated the superior potency and efficacy of ASP2151 against HSV.

Inhibitory effect of caffeic acid on human organic anion transporters hOAT1 and hOAT3: a novel candidate for food-drug interaction.

Several kinds of food have been shown to influence the absorption and metabolism of drugs, although there is little information about their effect on the renal excretion of drugs. In this study, we performed uptake experiments using Xenopus laevis oocytes to assess the inhibitory effects of chlorogenic acid, caffeic acid and quinic acid, which are contained in coffee, fruits and vegetables, on human organic anion transporters hOAT1 and hOAT3; these transporters mediate renal tubular uptake of anionic drugs from blood. Injection of hOAT1 and hOAT3 cRNA into oocytes stimulated uptake of typical substrates of hOAT1 and hOAT3 (p-aminohippurate and estrone sulfate, respectively); among the three compounds tested, caffeic acid most strongly inhibited these transporters. The apparent 50% inhibitory concentrations of caffeic acid were estimated to be 16.6 µM for hOAT1 and 5.4 µM for hOAT3. Eadie-Hofstee plot analysis showed that caffeic acid inhibited both transporters in a competitive manner. In addition to the transport of p-aminohippurate and estrone sulfate, that of antifolates and antivirals was inhibited by caffeic acid. These findings show that caffeic acid has inhibitory potential against hOAT1 and hOAT3, suggesting that renal excretion of their substrates could be affected in patients consuming a diet including caffeic acid.

A new topical treatment protocol for oral hairy leukoplakia.

OBJECTIVE: The aim of this study was to present a new topical treatment protocol for oral hairy leukoplakia (OHL), consisting of a 25% podophyllin resin with a 1% penciclovir cream (PP), and to compare this topical treatment protocol's efficacy with that of 2 other topical treatment protocols: a 25% podophyllin resin (P) and a 25% podophyllin resin with a 5% acyclovir cream (PA). STUDY DESIGN: Forty-two human immunodeficiency virus-positive patients with 69 OHL lesions were randomly treated using P, PA, or PP (14 patients in each topical treatment protocol). Clinical healing was determined when the white plaque could no longer be seen in the primary location of the lesion. Topical treatment performance was evaluated by clinical healing within each week of topical treatment protocol as well as by the recurrence of the lesion. Statistical survival analysis was performed using a Cox proportional hazards model. RESULTS: Approximately 55% of the patients presented with clinical healing of OHL within 7-8 weeks of each topical treatment protocol. After the sixth week, the PA treatment protocol presented a faster clinical healing rate of OHL. Recurrence was observed in 3 and 7 OHL lesions treated with P and PP treatment protocols, respectively. CONCLUSIONS: The PP treatment protocol proved to be effective; however, the PA treatment protocol was more effective in the clinical healing rate for OHL than P and PP after the sixth week of treatment, and no recurrent OHL was observed in the PA treatment group.

[Observation on the therapeutic effect of electroacupuncture of Jiaji (EX-B 2) plus regional encircled needling for herpes zoster].

OBJECTIVE: To observe the clinical therapeutic effect of electroacupuncture (EA) of Jiaji (EX-B 2) plus focus-encircled needling for promoting the crust formation of herpes zoster and analgesia. METHODS: Eighty cases of herpes zoster patients were equally randomized into EA group [treated with EA of Ashi-point, Jiaji (EX-B 2), Zhigou (SJ 6) and Houxi (SI 3), once daily for 10 times] and medication group (treated with valaciclovir hydrochloride 300 mg/time, b. i. d. and vitamin B1 10 mg/time, t.i.d., 10 days). The pain severity was evaluated by using visual analogous scale (VAS) method. The time when the cutaneous scabbing area was equal or over 50% was recorded. RESULTS: After the treatment, of the two 40 cases in EA and medication groups, 30 (75.0%) and 15 (37.5%) were cured, 7 (17.5%) and 12 (30.0%) improved, 3 (7.5%) and 13 (32.5%) failed, with the total effective rates being 92.5% and 67.5%, respectively. The therapeutic effect of EA was significantly superior to that of medication (P < 0.01). VAS scores of both groups reduced significantly (P < 0.01). Both the VAS score and the crust formation time of EA group were significantly lower than those of medication group (P < 0.01). CONCLUSION: EA of Jiaji (EX-B 2) in combination with focus-encircled needling is effective in facilitating the crust formation and pain relief in the treatment of herpes zoster, and the effect of acupuncture is superior to that of medication.

Development and evaluation of penciclovir-loaded solid lipid nanoparticles for topical delivery.

The objective of this investigation was to develop solid lipid nanoparticles (SLNs) of penciclovir and evaluate the potential of SLNs as the carrier of penciclovir for topical delivery. Penciclovir-loaded SLNs were prepared by a double (W/O/W) emulsion technique. The SLNs presented spherical with the mean diameter of 254.9 nm. The entrapment efficiency, drug loading and zeta potential were 92.40%, 4.62% and -25.0 mV, respectively. DSC study showed that penciclovir encapsulated in SLNs was in the amorphous form. The cumulative amount of penciclovir penetrated through excised rat skin from SLNs was more than 2-fold that of the commercial cream as a control at 12h after administration. There was no significant difference of penciclovir content deposited in epidermis between the cream and SLNs administrated for 2, 6 and 12h, while SLNs increased the cumulative uptake of penciclovir in dermis significantly at the same intervals. Microscopic pictures showed that the interaction between SLNs and the skin surface changed the apparent morphology of stratum corneum and broke the close conjugation of corneocyte layers, which was the possible reason that SLNs increased the permeation of penciclovir into skin dermis. It can be concluded from our study that SLNs provide a good skin targeting effect and may be a promising carrier for topical delivery of penciclovir.

Evaluation of the in vitro skin permeation of antiviral drugs from penciclovir 1% cream and acyclovir 5% cream used to treat herpes simplex virus infection.

BACKGROUND: 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. It is estimated that approximately 80% of the population worldwide are carriers of the Herpes simplex virus, approximately 40% suffer from recurrent recurrent infections. This study evaluates the in vitro skin permeation and penetration of penciclovir and acyclovir from commercialized creams for the treatment of herpes labialis (cold sores), using non viable excised human abdominal skin samples, which were exposed to 5 mg/cm2 of acyclovir 5% cream or penciclovir 1% cream. METHODS: After 24 h of cream application, excess cream was washed off and layers of stratum corneum were removed by successive tape stripping. 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. Molecular modelling was used to evaluate physico-chemical differences between the drugs. Western blot analysis enabled to determine whether the marker of basal cells keratin 5 could be detected in the various tape strips. RESULTS: 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. Molecular modelling showed two higher hydrophobic moieties for acyclovir. 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. CONCLUSION: 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. 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.

Structure-activity relationships for dipeptide prodrugs of acyclovir: implications for prodrug design.

A series of water-soluble dipeptide ester prodrugs of the antiviral acyclovir (ACV) were evaluated for their chemical stability, cytotoxicity, and antiviral activity against several strains of Herpes Simplex-1 and -2, vaccinia, vesicular stomatitis, cytomegalovirus and varicella zoster viruses. ACV dipeptide esters were very active against herpetic viruses, independently of the rate at which they liberate the parent drug. Their minimum cytotoxic concentrations were above 100 microM and the resulting MCC/EC(50) values were lower than those of ACV. When comparing the reactivity of Phe-Gly esters and amides (ACV, zidovudine, paracetamol, captopril and primaquine) in pH 7.4 buffer it was found that the rate of drug release increases with drug's leaving group ability. Release of the parent drug from Phe-Gly in human plasma is markedly faster than in pH 7.4 buffer, thus suggesting that the dipeptide-based prodrug approach can be successfully applied to bioactive agents containing thiol, phenol and amine functional groups.