acyclovir and Disease-Models--Animal

To review recent advancements in the management of herpes simplex virus (HSV) epithelial keratitis.. Trifluridine eye drop, acyclovir (ACV) ointment, ganciclovir gel, and oral ACV are still the main therapeutic agents. Cryopreserved amniotic membrane has been recently used as an adjuvant treatment. Resistance to ACV has become a concerning issue. The animal models of HSV vaccine are able to reduce HSV keratitis. New antivirals are under development.. Current cases of HSV epithelial keratitis are manageable with available medications, but new advancements are required to decrease disease burden in the future. HSV vaccine can be revolutionary.

Topics: Acyclovir; Administration, Oral; Animals; Antiviral Agents; Disease Models, Animal; Epithelial Cells; Epithelium, Corneal; Eye Infections, Viral; Ganciclovir; Humans; Keratitis, Herpetic; Ointments; Ophthalmic Solutions; Trifluridine

Peripheral injury of the facial nerve is a frequent disorder. It is a stressful situation for the patient and it is functionally hazardous for the cornea. Facial palsy is due to a lesion involving the facial pontine nucleus or the nerve trunk in its route from the pontocerebellar angle to the parotid. The idiopathic facial paralysis or Bell's palsy (BP) is the most common cause but acute facial palsy can also be due to tumors. A rigorous clinical history and examination must be performed to guide the additional biological, radiological and cochleovestibular investigations in order to reach the diagnosis. The pathophysiology of BP remains unclear, but seems to be due to the reactivation of Herpes simplex virus type 1 within the intrapetrous pathway of facial nerve. The treatment remains controversial but, for most of the authors, consists of early administration of corticosteroids with or without antiviral agents. Ninety percent of the patients recover normal facial function with this treatment. The severe BP resulting in hemifacial spasm must be quickly identified by electrophysiological testing. They need appropriate rehabilitation and for some authors facial nerve surgical decompression in emergency.

Topics: Acyclovir; Administration, Oral; Adrenal Cortex Hormones; Animals; Anti-Inflammatory Agents; Antiviral Agents; Audiometry; Bell Palsy; Disease Models, Animal; Electromyography; Glucocorticoids; Herpes Simplex; Herpesvirus 1, Human; Humans; Magnetic Resonance Imaging; Mice; Multicenter Studies as Topic; Prednisone; Prognosis; Prospective Studies; Randomized Controlled Trials as Topic; Time Factors

Topics: Acyclovir; Animals; Antiviral Agents; Carcinogens; Didanosine; Disease Models, Animal; Evidence-Based Medicine; Humans; Intestinal Absorption; Neoplasms; Risk Factors; Tissue Distribution; Zalcitabine; Zidovudine

Novel antiherpetic 3-quinolinecarboxamides were discovered as part of a drug discovery program at Sterling Winthrop Inc. A major goal of this research was to identify novel non-nucleoside agents possessing activity against acyclovir resistant herpes simplex virus. From screening compound libraries in an HSV-2 plaque reduction assay, 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (1) emerged as an attractive lead structure. By modifying the quinoline ring at the 1-, 2-, 3-, 4-, and 7-positions, analogues were identified that have up to 5-fold increased in vitro potency relative to acyclovir. In a single dose mouse model of infection the 1-(4-FC6H4) analogue 17, one of the most potent derivatives in vitro, displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple dose regimen, however, it was 2-fold less potent. Mechanism of action studies indicate that these new compounds interact with a different, as yet undefined, molecular target than acyclovir.

Topics: Acyclovir; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Herpesvirus 2, Human; Humans; Mice; Quinolines; Simplexvirus; Structure-Activity Relationship; Vero Cells; Viral Plaque Assay

Our laboratory has developed two cellular models of human prostate cancer progression. The LNCaP prostate cancer progression model is based upon the well-known cellular interaction between human prostate or bone stromal cells and LNCaP cells in vivo. The marginally tumorigenic LNCaP cells acquired tumorigenic and metastatic potential upon cellular interaction with either prostate or bone fibroblasts. A subline termed C4-2 was observed to grow readily in castrated animals and acquired metastatic potential spreading from the primary tumor site to the lymph node, the seminal vesicles, and the axial skeleton, resulting in an intense osteoblastic reaction. The second model is ARCaP, where prostate cancer cells derived from the ascites fluid of a man with metastatic disease exhibited an Androgen- and estrogen-Repressed Prostate Cancer cell growth and tumor formation in either a hormone-deficient or a castrated environment. However, the growth of either the tumor cells in vitro or the tumors in vivo was suppressed by both estrogen and androgen. While the tumor cells expressed low levels of androgen receptor and prostate-specific antigen (PSA), they were highly metastatic when inoculated orthotopically. Distant metastases to a number of organs were detected, including the liver, lung, kidney, and bone. We have employed a human prostate cancer progression model as a system to study the efficacy of gene therapy. Results of the study show that whereas universal promoters, such as Cytomegalovirus (CMV) and Rous Sarcoma Virus (RSV) promoter-driven tumor suppressors (e.g. p53, p21, and p16), were effective in inhibiting prostate tumor growth, the advantages of driving the expression of therapeutic toxic genes using a tissue-specific promoter prostate-specific antigen (PSA) and a tumor--but not tissue-specific promoter, osteocalcin (OC), are preferred. In the case of the PSA promoter, we can achieve cell-kill in PSA-producing human prostate cancer cells. To circumvent the supporting role of bone stroma for prostate cancer epithelial growth, we have recently developed a novel concept where the expression of therapeutic toxic genes is driven by a tumor--but not a tissue-specific OC promoter. Osteocalcin-thymidine kinase (OC-TK) was found to efficiently eradicate the growth of osteosarcoma, prostate, and brain tumors both in vitro and in vivo. We observed that androgen-independent human prostate cancer cells lines expressed OC-TK at higher levels than androgen-dependent hu

Topics: Acyclovir; Androgens; Disease Models, Animal; Disease Progression; Genetic Therapy; Humans; Male; Osteocalcin; Prodrugs; Promoter Regions, Genetic; Prostate-Specific Antigen; Prostatic Neoplasms; Thymidine Kinase; Tumor Cells, Cultured

Topics: Acyclovir; Animals; Antiviral Agents; Cell Division; Cell Survival; Cells, Cultured; Cidofovir; Cytomegalovirus; Cytomegalovirus Infections; Cytosine; Disease Models, Animal; Fibroblasts; Ganciclovir; Humans; Mice; Organophosphonates; Organophosphorus Compounds; Virus Replication

Animal and human models of ultraviolet radiation-induced herpes simplex virus disease provide opportunities to study the mechanism of virus latency and reactivation. These models can also be used to study the efficacy of antiviral agents. Prophylactic oral acyclovir altered the development of ultraviolet radiation-induced herpes labialis under both natural and experimental conditions.

Topics: Acyclovir; Animals; Disease Models, Animal; Herpes Simplex; Humans; Simplexvirus; Ultraviolet Rays; Virus Activation

Acyclovir and suramin were examined for their efficacy alone and in combination, against duck hepatitis B virus (DHBV) in persistently infected Pekin ducks. The pharmacokinetics of acyclovir in ducks showed that the peak plasma concentration was reached 30 min after oral administration. Oral acyclovir and suramin administered intravenously suppressed the replication and production of infectious virions as measured by marked reduction of DNA polymerase activity during treatment. However, rebound of enzyme activity was observed soon after cessation of drug therapy. In contrast, sustained reduction of polymerase activity was attained by combined therapy of acyclovir followed by suramin, demonstrating a significant enhancement of anti-DHBV activity which requires confirmation in a larger experimental study. This report reviews the work with the duck model, demonstrating that it is ideal for screening antiviral compounds for treatment of infection with hepadna viruses.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Ducks; Enterovirus Infections; Hepatitis B virus; Suramin

Herpes is a well-known contagious infection equally affecting both sexes. Among many antiviral drugs employed for its treatment, acyclovir (ACY) is the drug of choice. The currently available therapies of ACY suffer from limitations like poor oral bioavailability (10-15%) and high-dose requirement. The present scientific study aims to explore pluronic lecithin organogel (PLO) as a novel drug delivery platform for ACY to bring an improvement in its delivery through topical route. The properties of organogel like biocompatibility and amphiphilic nature which facilitates dissolution of various drugs of different solubility characteristics along with enhancing the permeation potential of active molecules make it a favorable drug delivery platform for the management of topical diseases. The developed PLO formulations were characterized for micromeritic characteristics, viz., zeta potential, percentage drug content, organogel morphology, skin permeation, retention, and stability studies. The selected topical formulation was further compared with the marketed one for its therapeutic efficacy by inducing cutaneous Herpes simplex virus type 1 infection followed by confirmation of viral load by immunofluorescence and PCR analyses. The developed formulation showed significant improvement over the marketed product as reflected in lesion scoring index and PCR analysis. Further, it proved better to the marketed formulation in t.i.d. treatment regimen in comparison to control. The improvement in overall performance leading to enhanced bioavailability and safety is attributed to the synergism between excipient properties and formulation characteristics. The drug ACY in this micro environment not only finds an improved delivery vehicle but it also offers enhanced drug-target interactions.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Female; Gels; Herpesvirus 1, Human; Lecithins; Male; Mice; Poloxamer

Although the seroprevalence of Herpes simplex virus type 1 (HSV-1) currently amounts to ∼ 67% worldwide, the annual incidence of a severe disease progression, particularly herpes encephalitis, is approximately 2-4 cases per 1,000,000 infections. Nucleoside analogues, such as acyclovir (ACV), valacyclovir (VACV) or famciclovir, are still the therapeutic treatment of choice for HSV infections. However, nucleoside drugs have limited efficacy against severe HSV disease and for treatment of nucleoside-resistant viral strains, alternative therapies such as helicase-primase inhibitors (HPIs) which are highly potent by inhibiting viral replication are under development. In preclinical studies we analyzed the antiviral efficacy of drug candidates of a novel compound class of HPIs for the treatment of HSV to identify the most active eutomer structure in an intranasal infection mouse lethal challenge model. HSV-1 infected BALB/c mice treated with vehicle control developed fatal disease according to humane endpoints after 5-7 days. In contrast, the animals dosed orally once daily with the HPI compounds at 10 or 4 mg/kg/day showed a significantly increased survival (70% and 100% for 10 mg/kg/day; 90% and 100% for 4 mg/kg/day, respectively) compared to the vehicle treatment (0-10%), when therapy was initiated 6 h post HSV-1 inoculation. We observed a significantly improved outcome in clinical parameters and survival over 21 days in the group receiving novel HPI candidates using even the lowest dose of 4 mg/kg/day. With VACV treatment of 75 mg/kg daily survival was also significantly increased (80%-90% for 75 mg/kg/day) but to lesser extent. Initial IM-250 therapy at 10 mg/kg/day could be delayed up to 72 h resulting in significantly increased survival compared to the vehicle control. Furthermore, we detected significantly fewer viral genome copies in the lungs and brains of HPI treated animals compared to vehicle (440-fold reduction for 4 mg/kg/day IM-250 in the brain) or VACV controls by quantitative PCR. In conclusion the preclinical studies of the novel HPI compounds showed superior efficacy in comparison to the current standard HSV treatment represented by VACV with respect to the survival according humane endpoints, the clinical score and virus load in lungs and brains. Thus, candidates of this new drug class are promising antivirals of HSV infections and further translation into clinical trials is warranted.

Topics: Acyclovir; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; DNA Helicases; DNA Primase; Female; Herpes Simplex; Herpesvirus 1, Human; Mice; Mice, Inbred BALB C; Survival Rate; Valacyclovir; Vero Cells; Viral Load

Nucleobase and nucleoside analogs (NNA) are widely used as anti-viral and anti-cancer agents, and NNA phosphorylation is essential for the activity of this class of drugs. Recently, diphosphatase NUDT15 was linked to thiopurine metabolism with NUDT15 polymorphism associated with drug toxicity in patients. Profiling NNA drugs, we identify acyclovir (ACV) and ganciclovir (GCV) as two new NNAs metabolized by NUDT15. NUDT15 hydrolyzes ACV and GCV triphosphate metabolites, reducing their effects against cytomegalovirus (CMV) in vitro. Loss of NUDT15 potentiates cytotoxicity of ACV and GCV in host cells. In hematopoietic stem cell transplant patients, the risk of CMV viremia following ACV prophylaxis is associated with NUDT15 genotype (P = 0.015). Donor NUDT15 deficiency is linked to graft failure in patients receiving CMV-seropositive stem cells (P = 0.047). In conclusion, NUDT15 is an important metabolizing enzyme for ACV and GCV, and NUDT15 variation contributes to inter-patient variability in their therapeutic effects.

Topics: Acyclovir; Adolescent; Adult; Aged; Animals; Antibiotic Prophylaxis; Antiviral Agents; Biological Variation, Population; Cell Line; Child; Child, Preschool; Crystallography, X-Ray; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; DNA, Viral; Drug Resistance, Viral; Female; Ganciclovir; Hematopoietic Stem Cell Transplantation; Host Microbial Interactions; Humans; Infant; Infant, Newborn; Male; Middle Aged; Muromegalovirus; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Pyrophosphatases; Treatment Outcome; Young Adult

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

There is a major clinical need for new therapies for the treatment of chronic itch. Many of the molecular components involved in itch neurotransmission are known, including the neuropeptide NPPB, a transmitter required for normal itch responses to multiple pruritogens in mice. Here, we investigated the potential for a novel strategy for the treatment of itch that involves the inhibition of the NPPB receptor NPR1 (natriuretic peptide receptor 1). Because there are no available effective human NPR1 (hNPR1) antagonists, we performed a high-throughput cell-based screen and identified 15 small-molecule hNPR1 inhibitors. Using in vitro assays, we demonstrated that these compounds specifically inhibit hNPR1 and murine NPR1 (mNPR1). In vivo, NPR1 antagonism attenuated behavioral responses to both acute itch- and chronic itch-challenged mice. Together, our results suggest that inhibiting NPR1 might be an effective strategy for treating acute and chronic itch.

Topics: Animals; Behavior, Animal; Cell-Free System; Dermatitis, Contact; Disease Models, Animal; Ganglia, Spinal; Humans; Mice, Inbred C57BL; Mice, Knockout; Neurons; Pruritus; Receptors, Atrial Natriuretic Factor; Reproducibility of Results; Signal Transduction; Small Molecule Libraries

Current drug-delivery systems are designed primarily for parenteral applications and are either lipid or polymer drug conjugates. In our quest to inhibit herpes simplex virus infection via the compounds found in commonly used cosmetic products, we found that activated carbon particles inhibit infection and, in addition, substantially improve topical delivery and, hence, the efficacy of a common antiviral drug, acyclovir (ACV). Our in vitro studies demonstrate that highly porous carbon structures trapped virions, blocked infection and substantially improved efficacy when ACV was loaded onto them. Also, using murine models of corneal and genital herpes infections, we show that the topical use of drug-encapsulated carbon (DECON) reduced dosing frequency, shortened treatment duration, and exhibited higher therapeutic efficacy than currently approved topical or systemic antivirals alone. DECON is a nontoxic, cost-effective and nonimmunogenic alternative to current topical drug-delivery systems that is uniquely triggered for drug release by virus trapping.

Topics: Acyclovir; Animals; Antiviral Agents; Carbon; Cell Line, Tumor; Charcoal; Chlorocebus aethiops; CHO Cells; Corneal Diseases; Cricetulus; Disease Models, Animal; Drug Carriers; Female; HeLa Cells; Herpes Genitalis; Herpesvirus 1, Human; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Vero Cells

Acyclovir use is limited by a high frequency of administration of five times a day and low bioavailability. This leads to poor patient compliance.. To overcome the problem of frequent dosing, we used nanotechnology platform to evaluate the proof of concept of substituting multiple daily doses of acyclovir with a single dose.. Acyclovir was formulated as solid lipid nanoparticles (SLN). The nanoparticles were characterized for particle size, surface charge and morphology and in vitro drug release. The pharmacokinetic and pharmacodynamic of SLN acyclovir were compared with conventional acyclovir in a mouse model.. SLN showed drug loading of 90.22% with 67.44% encapsulation efficiency. Particle size was found to be of 131 ± 41.41 nm. In vitro drug release showed 100% release in SIF in 7 days. AUC0-∞ (119.43 ± 28.74 μg/ml h), AUMC0-∞ (14469 ± 4261.16 μg/ml h) and MRT (120.10 ± 9.21 h) were significantly higher for ACV SLN as compared to ACV AUC0-∞ (12.22 ± 2.47 μg/ml h), AUMC0-∞ (28.78 ± 30.16 μg/ml h) and MRT (2.07 ± 1.77 h), respectively (p<0.05). In mouse model, a single dose of ACV SLN was found to be equivalent to ACV administered as 400mg TID for 5 days in respect to lesion score and time of healing.. The proof of concept of sustained-release acyclovir enabling administration as a single dose was thus demonstrated.

Topics: Acyclovir; Animals; Antiviral Agents; Biological Availability; Cell Survival; Disease Models, Animal; Drug Liberation; Female; Haplorhini; Herpes Simplex; Humans; Lecithins; Male; Mice; Mice, Inbred BALB C; Phospholipids; Polysorbates

To develop an endogenous rodent model of postinfectious anti-NMDA receptor (NMDAR) encephalitis.. Six mice were inoculated intranasally with herpes simplex virus (HSV) 1 and subsequently treated with acyclovir for 2 weeks. Serum was collected at 3, 6, and 8 weeks postinoculation and tested for NMDAR antibodies through a cell-based assay. Eight weeks postinoculation, mice were killed and their brains were sectioned and immunostained with antibodies to postsynaptic density (PSD)-95 and NMDARs. Colocalization of hippocampal PSD-95 and NMDAR clusters, representing postsynaptic membrane NMDARs, was quantified via confocal imaging. Hippocampi were additionally analyzed for NMDAR and PSD-95 protein using Western blot analysis.. Four of 6 mice (67%) developed serum antibodies to NMDARs: 1 at 3 weeks, 1 at 6 weeks, and 2 at 8 weeks postinoculation. As compared to inoculated mice that did not develop NMDAR antibodies, immunofluorescence staining revealed decreased hippocampal postsynaptic membrane NMDARs in mice with serum antibodies at 8 weeks postinoculation. Western blot analysis showed that mice that had NMDAR antibodies at 8 weeks had decreased total NMDAR but not PSD-95 protein in hippocampal extracts (. Mice inoculated intranasally with HSV-1 developed serum NMDAR antibodies. These antibodies were associated with reduced hippocampal NMDARs, as has been shown in previous models where antibodies from patients with anti-NMDAR encephalitis were infused into mice, paving the way for future studies into the pathophysiology of autoimmune encephalitides.

Topics: Acyclovir; Animals; Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Antibodies; Disease Models, Animal; Disks Large Homolog 4 Protein; Encephalitis, Herpes Simplex; Female; Herpesvirus 1, Human; Hippocampus; Mice, Inbred BALB C; Receptors, N-Methyl-D-Aspartate

The gut commensal Bacteroides fragilis or its capsular polysaccharide A (PSA) can prevent various peripheral and CNS sterile inflammatory disorders. Fatal herpes simplex encephalitis (HSE) results from immune pathology caused by uncontrolled invasion of the brainstem by inflammatory monocytes and neutrophils. Here we assess the immunomodulatory potential of PSA in HSE by infecting PSA or PBS treated 129S6 mice with HSV1, followed by delayed Acyclovir (ACV) treatment as often occurs in the clinical setting. Only PSA-treated mice survived, with dramatically reduced brainstem inflammation and altered cytokine and chemokine profiles. Importantly, PSA binding by B cells is essential for induction of regulatory CD4

Topics: Acyclovir; Animals; Antiviral Agents; B-Lymphocytes; Bacteroides fragilis; Chlorocebus aethiops; Disease Models, Animal; Encephalitis, Herpes Simplex; Female; Gastrointestinal Microbiome; Herpesvirus 1, Human; Host Microbial Interactions; Humans; Interleukin-10; Male; Mice; Mice, Knockout; Polysaccharides, Bacterial; Symbiosis; T-Lymphocytes; Vero Cells

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.

Topics: Acyclovir; Animals; Disease Models, Animal; Drug Carriers; Drug Compounding; Emulsions; Female; Herpes Simplex; Herpesvirus 1, Human; Mice; Mice, Inbred BALB C; Oils; Permeability; Skin; Solubility; Thermodynamics; Water

Topics: Acyclovir; Animals; Antiviral Agents; Circadian Clocks; Disease Models, Animal; DNA-Binding Proteins; Dose-Response Relationship, Drug; Female; Herpes Simplex; Herpesvirus 2, Human; Host Microbial Interactions; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Nectins; Severity of Illness Index; Skin; Survival Rate; Treatment Outcome

Pritelivir, a helicase-primase inhibitor, has excellent in vitro and in vivo activity against human herpes simplex virus (HSV). Mice lethally infected with HSV type 1 or 2, including acyclovir-resistant strains, were treated 72 h after infection for 7 days with pritelivir or acyclovir. Both drugs were administered orally twice daily either alone or in combination. Dosages of pritelivir from 0.3 to 30 mg/kg reduced mortality (P < 0.001) against HSV-1, E-377. With an acyclovir resistant HSV-1, 11360, pritelivir at 1 and 3 mg/kg increased survival (P < 0.005). With HSV-2, MS infected mice, all dosages higher than the 0.3 mg/kg dose of pritelivir were effective (P < 0.005). For acyclovir resistant HSV-2, strain 12247, pritelivir dosages of 1-3 mg/kg significantly improved survival (P < 0.0001). Combination therapies of pritelivir at 0.1 or 0.3 mg/kg/dose with acyclovir (10 mg/kg/dose) were protective (P < 0.0001) when compared to the vehicle treated group against HSV-2, strain MS (in line with previous data using HSV-1). An increased mean days to death (P < 0.05) was also observed and was indicative of a potential synergy. Pharmacokinetic studies were performed to determine pritelivir concentrations and a dose dependent relationship was found in both plasma and brain samples regardless of infection status or time of initiation of dosing. In summary, pritelivir was shown to be active when treatment was delayed to 72 h post viral inoculation and appeared to synergistically inhibit mortality in this model in combination with acyclovir. We conclude pritelivir has potent and resistance-breaking antiviral efficacy with potential for the treatment of potentially life-threatening HSV type 1 and 2 infections, including herpes simplex encephalitis.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Drug Therapy, Combination; Encephalitis, Herpes Simplex; Female; Humans; Mice; Pyridines; Sulfonamides; Thiazoles; Tissue Distribution; Treatment Outcome

Several cases of herpes simplex encephalitis (HSE) caused by acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) have been reported. Amino acid substitutions of R41H, Q125H, and A156V in the viral thymidine kinase (vTK) gene have been reported to confer ACV resistance. Recombinant HSV-1 clones, containing each amino acid substitution in the vTK gene, were generated using the bacterial artificial chromosome system. A recombinant HSV-1 with the Q125H substitution showed ACV resistance while the R41H or A156V substitutions were ACV-sensitive. Furthermore, the Q125H recombinant HSV-1 was less virulent than the repaired virus, but it maintained neurovirulence in mice at relatively high levels. Substitution of Q125H, which was detected in the neonatal HSE patient, conferred ACV resistance, but the substitutions of R41H and A156V, which were detected in immunocompetent adult HSE patients, did not. This suggests that HSE caused by ACV-resistant HSV-1 might be a very rare event to occur during the course of ACV treatment in immunocompetent patients. Showing resistance to ACV treatment does not always indicate emergence of ACV-resistant HSV-1 in HSE patients.

Topics: Acyclovir; Adult; Aged; Amino Acid Substitution; Animals; Antiviral Agents; Cell Line; Chromosomes, Artificial, Bacterial; Disease Models, Animal; Drug Resistance, Viral; Encephalitis, Herpes Simplex; Female; Herpesvirus 1, Human; Humans; Infant, Newborn; Male; Mice, Inbred ICR; Microbial Sensitivity Tests; Middle Aged; Mutant Proteins; Reverse Genetics; Thymidine Kinase; Virulence; Virulence Factors

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 × 10

Topics: Acyclovir; Administration, Intranasal; Animals; Antiviral Agents; Asteraceae; Disease Models, Animal; Female; Guanine; Herpesviridae Infections; Herpesvirus 1, Equid; Horses; Mice; Mice, Inbred C57BL; Phytotherapy; Plant Extracts; Quercetin; Random Allocation

Acyclovir (ACV)-resistant (ACVr) herpes simplex virus type 1 (HSV-1) infections are concern in immunocompromised patients. Most clinical ACVr HSV-1 isolates have mutations in the viral thymidine kinase (vTK) genes. The vTK-associated ACVr HSV-1 shows reduced virulence, but the association between the level of resistance and the virulence of the vTK-associated ACVr HSV-1 is still unclear.. The virulence in mice of 5 vTK-associated ACVr HSV-1 clones with a variety of ACV sensitivities, when inoculated through intracerebral and corneal routes, was evaluated in comparison with ACV-sensitive (ACVs) parent HSV-1 TAS.. Although all the 5 ACVr HSV-1 clones and ACVs HSV-1 TAS showed a similar single-step growth capacity in vitro, the virulence of ACVr HSV-1 clones significantly decreased. A 50% lethal dose (LD. A statistically significant correlation between the virulence and susceptibility to ACV among ACVr HSV-1 clones was demonstrated.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Drug Resistance, Viral; Female; Herpes Simplex; Herpesvirus 1, Human; Mice, Inbred BALB C; Mutant Proteins; Thymidine Kinase; Virulence

The present investigation focuses on the development and evaluation of acyclovir-loaded flexible membrane vesicles (ACY-FMVs) and evaluates their targeting potential to localize the drug into skin layers. The drug-loaded FMVs were prepared by thin-film hydration method and characterized for various attributes including micromeritics, entrapment efficiency, vesicle shape, size, and degree of deformability. The values of particle size and zeta potential of the developed carrier system were found to be 453.7 nm and - 11.62 mV, respectively. The system was further incorporated into a hydrogel and evaluated for skin permeability and retention characteristics in comparison to marketed formulation. The developed formulation demonstrated enhanced retention of drug deep inside the skin layers which can probably decrease the frequency of application of the drug, thereby reducing its adverse effects. Skin irritancy studies performed on Laca mice skin proved the safety and non-irritant nature of ACY-FMVs. The pharmacodynamic studies on murine model for HSV-1 infection demonstrated immense potential and safety of topically applied ACY-FMVs. However, more intensive studies need to be pursued to explore and exploit the potential of lipid-based systems in anti-viral therapeutics. These preclinical findings provide a hope for corroborating the efficacy in clinical situations.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Chemistry, Pharmaceutical; Chlorocebus aethiops; Disease Models, Animal; Drug Carriers; Herpes Simplex; Liposomes; Mice; Particle Size; Skin Absorption; Vero Cells

Bell's palsy is caused by the reactivation of herpes simplex virus type 1 (HSV-1). Using Balb/c mice inoculated with the KOS strain of HSV-1, we previously developed an animal disease model that simulated mild Bell's palsy. The current study developed an animal disease model of more severe facial palsy than that seen in the mouse model.. Three-week-old female Wister rats weighing 60-80g were inoculated on the auricle with HSV-1 and acyclovir was administered intraperitoneally to deactivate the infected HSV-1. Instead of HSV-1, phosphate-buffered saline was used for inoculation as a negative control. Quantitative polymerase chain reaction (PCR), behavior testing (blink reflex), electroneuronography, histopathology of the peripheral nerve, and immunohistochemistry of the facial nerve nucleus were evaluated.. Facial palsy occurred 3-5 days after virus inoculation, and the severity of the facial palsy progressed for up to 7 days. Quantitative PCR showed an increase in HSV-1 DNA copies in the facial nerve from 24 to 72h, suggesting that HSV-1 infection occurred in the nerve. Electroneuronography values were 33.0±15.3% and 110.0±18.0% in HSV-1-inoculated and control rats, respectively. The histopathology of the peripheral nerve showed demyelination and loss of the facial nerve, and the facial nerve nucleus showed degeneration.. Facial palsy developed in Wister rats following inoculation of the KOS strain of HSV-1 onto the auricles. The behavioral, histopathological, and electroneuronography data suggested that the severity of facial palsy was greater in our rats than in animals in the previous mouse disease model.

Topics: Acyclovir; Animals; Antiviral Agents; Bell Palsy; Blinking; Disease Models, Animal; DNA, Viral; Ear; Facial Nerve; Facial Paralysis; Female; Herpes Simplex; Herpesvirus 1, Human; Immunohistochemistry; Mice, Inbred BALB C; Polymerase Chain Reaction; Rats; Rats, Wistar

Aciclovir (ACV), valaciclovir (VACV) and famciclovir (FCV) are used for systemic infections caused by herpes virus. In Japan, only topical ACV is permitted for use against herpetic keratitis. We investigated the effectiveness of topical ACV, oral VACV and oral FCV on mouse epithelial herpetic keratitis.. C57/BL76 mice were inoculated with HSV-1 McKrae strain in the cornea. Once infection was confirmed 4 days after inoculation, topical ACV, oral VACV and FCV were started and administered for 5 days. Control groups were given either topical or oral saline. On days 2, 4, 6 and 10 after medication started, tears, eyeballs, and trigeminal ganglia were examined using viral culture and real-time PCR.. Viral culture of tears detected no HSV in the topical ACV group on day 4 after administration start; with similar results for the oral VACV group on day 4; and the oral FCV group on day 6. Real-time PCR of the eyeballs showed significant decrease of HSV DNA copy number in the topical ACV group on days 4 and 6 compared to the topical saline group. Real-time PCR of the trigeminal ganglia showed significant decrease of HSV DNA copy number in the oral VACV group on days 4 and 6, and in the oral FCV group on day 6 compared to the oral saline group.. We suggest that 5-day administration of topical ACV, oral VACV and oral FCV are effective for mouse epithelial herpetic keratitis and sufficiently decrease HSV amounts in the ocular surface and eyeballs.

Topics: 2-Aminopurine; Acyclovir; Administration, Oral; Administration, Topical; Animals; Antiviral Agents; Disease Models, Animal; DNA Copy Number Variations; DNA, Viral; Epithelium, Corneal; Eye Infections, Viral; Famciclovir; Female; Herpesvirus 1, Human; Keratitis, Herpetic; Mice; Mice, Inbred C57BL; Real-Time Polymerase Chain Reaction; Tears; Trigeminal Nerve; Valacyclovir; Valine

Despite antiviral therapy, the mortality rate of herpes simplex virus encephalitis (HSE) remains high and many surviving patients harbor neurological sequelae. Although viral replication is responsible for substantial neurological damages, an exaggerated inflammatory response could also contribute to this process. Artesunate (ART) and rapamycin (RAPA) have shown some benefits in the treatment of herpes simplex virus infections. Herein, we evaluated the benefit of combining ART or RAPA with valacyclovir (VACV) in a murine model of HSE. Infected mice were treated with VACV (1mg/mL in drinking water) from day 3 post-infection (p.i.) combined or not with daily intraperitoneal administration of ART (30mg/kg) or RAPA (20mg/kg) from days 4 to 13 p.i. Viral load, infectious titers, cytokine and chemokine levels were measured in brain homogenates on days 5, 7 and 9. The survival rates of mice treated with VACV and ART or RAPA were higher than with VACV alone (71.9% versus 43.2% for ART and 66.7% versus 43.2% for RAPA; both P⩽0.05) but no significant difference was seen in the brain viral loads. Levels of IL-1β, IL-2 (both P⩽0.05), IL-6, IFN-γ (both P⩽0.01), CCL2 (P⩽0.01), CCL3 and CCL4 (both P⩽0.05) were reduced in mice treated with VACV combined with ART versus VACV alone. Levels of IL-6, IL-1β and IFN-γ slightly increased on day 7 in mice treated with VACV combined with RAPA compared to VACV alone and then decreased on day 9. Our results suggest that immunomodulatory compounds such as ART or RAPA could benefit antiviral therapy in HSE.

Topics: Acyclovir; Administration, Oral; Animals; Antiviral Agents; Artemisinins; Artesunate; Brain; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Encephalitis, Herpes Simplex; Female; Immunologic Factors; Injections, Intraperitoneal; Mice, Inbred BALB C; Sirolimus; Survival Analysis; Treatment Outcome; Valacyclovir; Valine; Viral Load

An experimental model of the primary genital herpes (herpes simplex type 2, HSV-2) in the female guinea pigs was suggested to study the infectious process activity of polyprenyl phosphates (PPP) and PPP+acyclovir (AC) complex treatment. The morphofunctional features of the guinea pig ovaries were studied in the control and experimental groups (the latter were inoculated with PPP and/or AC as a primary infection treatment) at the stage of the recurrent genital herpes aggravation. It was shown that in the case of combined PPP +AC use significant changes in the disease symptoms were observed, as well as a decrease in the infectious process activity and duration, and positive remote effect on the ovarian morphophysiology.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Female; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Humans; Polyisoprenyl Phosphates

Herpes keratitis (HK) remains the leading cause of cornea-derived blindness in the developed world, despite the availability of effective antiviral drugs. Treatment toxicity and the emergence of drug resistance highlight the need for additional therapeutic approaches. This study examined ataxia telangiectasia mutated (ATM), an apical kinase in the host DNA damage response, as a potential new target for the treatment of HK.. Small molecule inhibitor of ATM (KU-55933) was used to treat herpes simplex virus type 1 (HSV-1) infection in three experimental models: (1) in vitro--cultured human corneal epithelial cells, hTCEpi, (2) ex vivo--organotypically explanted human and rabbit corneas, and (3) in vivo--corneal infection in young C57BL/6J mice. Infection productivity was assayed by plaque assay, real-time PCR, Western blot, and disease scoring.. Robust ATM activation was detected in HSV-1-infected human corneal epithelial cells. Inhibition of ATM greatly suppressed viral replication in cultured cells and in explanted human and rabbit corneas, and reduced the severity of stromal keratitis in mice. The antiviral effect of KU-55933 in combination with acyclovir was additive, and KU-55933 suppressed replication of a drug-resistant HSV-1 strain. KU-55933 caused minimal toxicity, as monitored by clonogenic survival assay and fluorescein staining.. This study identifies ATM as a potential target for the treatment of HK. ATM inhibition by KU-55933 reduces epithelial infection and stromal disease severity without producing appreciable toxicity. These findings warrant further investigations into the DNA damage response as an area for therapeutic intervention in herpetic ocular diseases.

Topics: Acyclovir; Animals; Antiviral Agents; Ataxia Telangiectasia Mutated Proteins; Blotting, Western; Cells, Cultured; Disease Models, Animal; Drug Combinations; Enzyme Inhibitors; Epithelium, Corneal; Female; Herpesvirus 1, Human; Humans; Immunohistochemistry; Keratitis, Herpetic; Mice; Mice, Inbred C57BL; Morpholines; Organ Culture Techniques; Pyrones; Rabbits; Real-Time Polymerase Chain Reaction; Viral Plaque Assay; Virus Replication

A wide range of antiviral drugs is currently available; however, drug-resistant viruses have begun to emerge and represent a potential public health risk. Here, we explored the use of compounds that inhibit or interfere with the action of essential host factors to prevent virus replication. In particular, we focused on the cyclin-dependent kinase 9 (CDK9) inhibitor, FIT-039, which suppressed replication of a broad spectrum of DNA viruses through inhibition of mRNA transcription. Specifically, FIT-039 inhibited replication of herpes simplex virus 1 (HSV-1), HSV-2, human adenovirus, and human cytomegalovirus in cultured cells, and topical application of FIT-039 ointment suppressed skin legion formation in a murine HSV-1 infection model. FIT-039 did not affect cell cycle progression or cellular proliferation in host cells. Compared with the general CDK inhibitor flavopiridol, transcriptome analyses of FIT-039-treated cells revealed that FIT-039 specifically inhibited CDK9. Given at concentrations above the inhibitory concentration, FIT-039 did not have a cytotoxic effect on mammalian cells. Importantly, administration of FIT-039 ameliorated the severity of skin lesion formation in mice infected with an acyclovir-resistant HSV-1, without noticeable adverse effects. Together, these data indicate that FIT-039 has potential as an antiviral agent for clinical therapeutics.

Topics: Acyclovir; Adenoviruses, Human; Animals; Antiviral Agents; Cyclin-Dependent Kinase 9; Cytomegalovirus; Disease Models, Animal; DNA Viruses; Drug Resistance, Viral; Flavonoids; HEK293 Cells; HeLa Cells; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Host-Pathogen Interactions; Humans; Mice; Mice, Inbred ICR; Piperidines; Protein Kinase Inhibitors; Pyridines; Rats; Rats, Wistar; Transcription, Genetic; Transcriptome; Virus Replication

Acyclovir (ACV) is an effective and widely used antiviral agent. However, its clinical application is limited by severe nephrotoxicity. We assessed ACV-induced nephrotoxicity and identified the differentially expressed proteins using mass spectrometry-based proteomic analysis. In total, 30 ICR mice were intraperitoneally administrated ACV (150 or 600 mg/kg per day) for 9 days. After administration of ACV, levels of serum creatinine and urea nitrogen increased significantly. In addition, mouse kidneys exhibited histopathological changes and reduced expression levels of vascular endothelial growth factor (VEGF) and its receptor VEGFR2. In the proteomic analysis, more than 1,000 proteins were separated by two-dimensional polyacrylamide gel electrophoresis, and a total of 20 proteins were up- or down-regulated in the ACV group compared with the saline group. Among these, six proteins (MHC class II antigen, glyoxalase 1, peroxiredoxin 1, αB-crystallin, fibroblast growth factor receptor 1-IIIb, and cytochrome c oxidase subunit Vb) were identified in association with ACV-induced nephrotoxicity. These findings were confirmed by Western blotting analysis. The differential expression levels of α-BC, Prx1, Glo I and CcO Vb suggest that oxidative damage and mitochondrial injury may be involved in ACV-induced nephrotoxicity. Furthermore, VEGF and FGF may play a role in tissue repair and the restoration process following ACV nephrotoxicity.

Topics: Acyclovir; Animals; Antiviral Agents; Creatinine; Disease Models, Animal; Kidney; Kidney Diseases; Kidney Function Tests; Mice; Mice, Inbred ICR; Proteome; Proteomics; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

Over-the-counter access to an inexpensive, effective topical microbicide could reduce the transmission of HIV and would increase women's control over their health and eliminate the need to obtain their partners' consent for prophylaxis. Chronic infection with herpes simplex virus 2 (HSV-2), also known as human herpes virus 2, has been shown to facilitate HIV infection and speed the progression to immunodeficiency disease. Our objective is to develop a drug formulation that protects against both HSV-2 and HIV infection and adheres to the vaginal surface with extended residence time.. We developed a formulation using two approved antiviral active pharmaceutical ingredients, aciclovir and tenofovir, in a novel bioadhesive vaginal delivery platform (designated SR-2P) composed of two polymers, poloxamer 407 NF (Pluronic(®) F-127) and polycarbophil USP (Noveon(®) AA-1). The efficacy of the formulation to protect from HSV-2 infection was tested in vitro and in vivo. In addition to its efficacy, it is essential for a successful microbicide to be non-irritating to the vaginal mucosa. We therefore tested our SR-2P platform gel in the FDA gold-standard microbicide safety model in rabbits and also in a rat vaginal irritation model.. Our studies indicated that SR-2P containing 1% aciclovir and 5% tenofovir protects (i) Vero cells from HSV-2 infection in vitro and (ii) mice from HSV-2 infection in vivo. Our results further demonstrated that SR-2P was not irritating in either vaginal irritation model.. We conclude that SR-2P containing aciclovir and tenofovir may be a suitable candidate microbicide to protect humans from vaginal HSV-2 infection.

Topics: Acrylic Resins; Acyclovir; Adenine; Animals; Anti-Infective Agents; Chlorocebus aethiops; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions; Female; Herpes Genitalis; Herpesvirus 2, Human; Mice, Inbred BALB C; Organophosphonates; Poloxamer; Rabbits; Rats, Sprague-Dawley; Tenofovir; Treatment Outcome; Vaginal Creams, Foams, and Jellies; Vero Cells

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.

Topics: Acyclovir; Animals; Anti-Infective Agents; Antimicrobial Cationic Peptides; Antiviral Agents; Blotting, Western; Cell Line; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Herpesvirus 1, Human; Immunohistochemistry; Keratitis, Herpetic; Vero Cells

Acyclovir (ACV)-resistant (ACV(r)) mutants were generated from plaque-purified ACV-sensitive herpes simplex virus type 1 (HSV-1) by culturing the virus in Vero cells in the presence of 2-amino-7-(1,3-dihydroxy-2-propoxymethyl) purine (S2242). Three DNA polymerase (DNApol)-associated ACV(r) HSV-1 generated under ACV selection in a previous study (Suzutani, T., Ishioka, K., De Clercq, E., et al., Antimicrob. Agents Chemother., 47, 1707-1713, 2003) were also included. The sensitivity of the mutants to other antivirals and their neurovirulence were determined. The treatment efficacy of ACV and ganciclovir (GCV) against ACV(r) HSV-1 infections was evaluated in mice. Amino acid substitutions were demonstrated in conserved regions II and III in DNApol in 5 of the 6 mutants, while the other substitution was located in non-conserved regions. DNApol-associated ACV(r) clones showed cross-resistance to foscarnet, penciclovir, and vidarabine but were sensitive or hypersensitive to GCV, brivudin, sorivudine, and spongothymidine. The ACV(r) clone with an N815S mutation in DNApol showed similar neurovirulence to that of the parent virus; however, those with other mutations showed attenuation. GCV was effective in the treatment of the ACV(r) clone with similar virulence to that of parent HSV-1, while ACV was less effective in mice. These results indicate the importance of the characterization of HSV-1 isolates for the proper treatment of HSV-1 infections exhibiting ACV-resistance.

Topics: Acyclovir; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Encephalitis, Herpes Simplex; Herpesvirus 1, Human; Mice; Mice, Inbred BALB C; Mutation; Selection, Genetic; Serial Passage; Treatment Outcome; Vero Cells; Viral Plaque Assay; Virulence

To determine the efficacy of a new helicase-primase inhibitor, ASP2151, for treating herpetic keratitis.. Murine corneas were infected with herpes simplex virus type 1 (HSV-1). ASP2151 was administered orally or topically, and the severity of epithelial dendritic keratitis was determined. The effectiveness of ASP2151 was compared with that of acyclovir and valacyclovir. The reduction of the amount of HSV in tears, enucleated eyes and trigeminal ganglia was determined by real-time PCR or plaque assay.. Orally administered ASP2151 reduced the epithelial keratitis score significantly more than that of the vehicle-treated group (p<0.01). It also lowered the HSV-DNA levels in the tears significantly more than that by valacyclovir (p<0.01). ASP2151 ointment resulted in the same reduction of the keratitis score as acyclovir ointment, and lowered the HSV DNA in tears more than acyclovir ointment. Topical instillation of ASP2151 improved the herpetic dendritic keratitis score significantly and reduced the titre of HSV DNA in the tears in a dose-responsive way.. ASP2151 had significantly better anti-HSV activity against herpes simplex keratitis than valacyclovir and acyclovir after systemic or topical use. These findings indicate that ASP2151 should be considered as an alternative treatment for herpes simplex keratitis.

Topics: Acyclovir; Administration, Oral; Administration, Topical; Animals; Disease Models, Animal; DNA Helicases; DNA Primase; DNA, Viral; Herpesvirus 1, Human; Keratitis, Herpetic; Mice; Mice, Inbred BALB C; Oxadiazoles; Real-Time Polymerase Chain Reaction; Tears; Treatment Outcome; Valacyclovir; Valine; Viral Proteins

Mucoepidermoid carcinoma (MEC) is the most common malignant tumor originating in major and minor salivary glands (SGs). Although the precise multifactorial etiology of human SG-MEC is largely unknown, we have recently shown that cytomegalovirus (CMV) is an important component of MEC tumorigenesis. Despite the well-documented overexpression of the EGFR → ERK signaling pathway in SG-MEC, there has been limited to no clinical success with inhibition of this pathway. Using our previously characterized mouse model of CMV-induced SG dysplasia/neoplasia, we report that inhibitors of the EGFR → ERK pathway do not ameliorate or rescue well-established pathology, either singly or in combination, but they do inhibit the evolution of progressive pathogenesis ("disease tolerance") in the face of mounting CMV burden. Failure to rescue SG pathology, suggested a possible increase in the ligand levels of alternative pathways that share cell proliferation and survival effectors (e.g. ERK and PI3K). Here we present evidence of a highly significant upregulation of ligands for the EGFR, FGFR, IL-6R, and TNFR signaling pathways, all of which converge upon the Raf/MEK/ERK amplifier module. This explains our finding that even in the presence of the highest nontoxic dose of an ERK phosphorylation inhibitor, pERK is undiminished. Given the considerable pathway crosstalk, a deep understanding of subversion and dysregulation of the SG interactome by CMV is a priori quite daunting. Circumventing this dilemma, we present evidence that concurrent inhibition of ERK phosphorylation (U0126) and CMV replication (acyclovir) obviates progressive pathogenesis and results in complete SG rescue (tumor regression). These findings provide a mechanistic foundation for potential clinical trials that utilize similar concurrent treatment with extant FDA-approved drugs.

Topics: Acyclovir; Amphiregulin; Animals; Carcinoma, Mucoepidermoid; Cytopathogenic Effect, Viral; Disease Models, Animal; EGF Family of Proteins; ErbB Receptors; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblast Growth Factor 8; Glycoproteins; Herpesviridae Infections; Intercellular Signaling Peptides and Proteins; Interleukin-6; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Muromegalovirus; Organ Culture Techniques; Phosphorylation; Submandibular Gland; Submandibular Gland Neoplasms; Tumor Necrosis Factor-alpha; Up-Regulation

Vaginal microbicides may play an important role in protecting women from HIV infection. A strong synergy between HSV and HIV has been observed, and epidemiological studies demonstrate that HSV infection increases the risk of HIV acquisition. Incorporation of the antiretroviral tenofovir (TFV) along with the antiherpetic acyclovir (ACV) into combination intravaginal rings (IVRs) for sustained mucosal delivery of both compounds could lead to increased microbicide product adherence and efficacy compared with conventional vaginal formulations. A novel, dual-protection "pod IVR" platform developed in-house and delivering ACV and TFV was evaluated in rabbit and sheep models. The devices were safe and exhibited sustained release of both drugs independently and at controlled rates over the 28-day studies. Daily release rates were estimated based on residual drug content of the used devices: rabbits, 343 ± 335 μg day(-1) (ACV) and 321 ± 207 μg day(-1) (TFV); sheep, 174 ± 14 μg day(-1) (ACV) and 185 ± 34 μg day(-1) (TFV). Mean drug levels in sheep vaginal samples were as follows: secretions, 5.25 ± 7.31 μg ml(-1) (ACV) and 20.6 ± 16.2 μg ml(-1) (TFV); cervicovaginal lavage fluid, 118 ± 113 ng ml(-1) (ACV) and 191 ± 125 ng ml(-1) (TFV); tissue, 173 ng g(-1) (ACV) and 93 ng g(-1) (TFV). An in vitro-in vivo correlation was established for both drugs and will allow the development of future formulations delivering target levels for prophylaxis and therapy. These data suggest that the IVR based on the pod design has potential in the prevention of transmission of HIV-1 and other sexually transmitted pathogens.

Topics: Acyclovir; Adenine; Administration, Intravaginal; Animals; Anti-HIV Agents; Antiviral Agents; Delayed-Action Preparations; Disease Models, Animal; Drug Combinations; Drug Delivery Systems; Equipment Design; Female; Herpes Genitalis; Herpesvirus 2, Human; HIV Infections; HIV-1; Humans; Organophosphonates; Rabbits; Sexually Transmitted Diseases, Viral; Tenofovir; Treatment Outcome

Acute retinal necrosis is a rapidly progressive and devastating viral retinitis caused by the herpesvirus family. Systemic acyclovir is the treatment of choice; however, the progression of retinal lesions ceases approximately 2 days after treatment initiation. An intravitreal injection of acyclovir may be used an adjuvant therapy during the first 2 days of treatment when systemically administered acyclovir has not reached therapeutic levels in the retina. The aims of this study were to determine the pharmacokinetic profile of acyclovir in the rabbit vitreous after intravitreal injection and the functional effects of acyclovir in the rabbit retina.. Acyclovir (Acyclovir; Bedford Laboratories, Bedford, OH, USA) 1 mg in 0.1 mL was injected into the right eye vitreous of 32 New Zealand white rabbits, and 0.1 mL sterile saline solution was injected into the left eye as a control. The animals were sacrificed after 2, 9, 14, or 28 days. The eyes were enucleated, and the vitreous was removed. The half-life of acyclovir was determined using high-performance liquid chromatography. Electroretinograms were recorded on days 2, 9, 14, and 28 in the eight animals that were sacrificed 28 days after injection according to a modified protocol of the International Society for Clinical Electrophysiology of Vision.. Acyclovir rapidly decayed in the vitreous within the first two days after treatment and remained at low levels from day 9 onward. The eyes that were injected with acyclovir did not present any electroretinographic changes compared with the control eyes.. The vitreous half-life of acyclovir is short, and the electrophysiological findings suggest that the intravitreal delivery of 1 mg acyclovir is safe and well tolerated by the rabbit retina.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Electroretinography; Half-Life; Intravitreal Injections; Rabbits; Retina; Time Factors; Vitreous Body

The outcome of neonatal herpes simplex (HSV) infection, even after therapy with high dose acyclovir (ACV), is not optimum. We therefore evaluated N-Methanocarbathymidine ((N)-MCT) using the guinea pig model of neonatal herpes. Treatment with ACV (60 mg/kg/day) was compared to doses of 1, 5, and 25 mg/kg/day of (N)-MCT initiated 1, 2, or 3 days postinoculation (dpi). Both ACV and (N)-MCT significantly improved survival, but only (N)-MCT significantly reduced the number of animals with symptoms when begun at 1 dpi. When therapy was begun at 2 dpi, only (N)-MCT (1, 5, or 25 mg/kg/day) significantly increased survival. In fact, (N)-MCT improved survival up to 3 dpi, the last time point evaluated. (N)-MCT was highly effective and superior to high dose ACV therapy for the treatment of neonatal herpes in the guinea pig model.

Topics: Acyclovir; Animals; Animals, Newborn; Antiviral Agents; Disease Models, Animal; Guinea Pigs; Herpes Simplex; Humans; Infant, Newborn; Pregnancy Complications, Infectious; Survival Analysis; Thymidine; Treatment Outcome

Using pharmacokinetics to explore the mechanism of honey to enhance the efficacy of acyclovir (ACV) treatment of herpes simplex keratitis (HSK), providing the basis for combination of the prescription of two drugs and dosage regimen designed.. Single dosages of 5% honey and 0% honey Meyasu eye ointment are injected into rabbit eyes. The aqueous humor of rabbit eye is measured at different times, specifically the content of ACV in aqueous humor by HPLC. Mathematical models are established, from which pharmacokinetic parameters are extracted and compared by mathematics and statistics methods.. Both the 5% and 0% honey Meyasu eye ointment in rabbit eyes are belong to a two-compartment model. The absorption half-life of the 5% Meyasu eye ointment in aqueous humor is as 2.30 times longer, the distribution half-life is 2.12 times longer, the peak concentration is 1.17 times longer, the peak time is 1.36 times longer, AUC is 1.41 times longer when compared to the 0% Meyasu eye ointment.. Honey can significantly increase the ACV concentration and bioavailability in the eye, extend the action time of ACV in target cells and increase the retention capacity of ACV in the target tissue; thereby improving treatment success.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Eye; Female; Honey; Humans; Keratitis, Herpetic; Male; Rabbits

The study aimed to predict effective human jejunal permeability (P(eff)) using a biophysical model based on parametrized paracellular, aqueous boundary layer, and transcellular permeabilities, and the villus-fold surface area expansion factor (k(VF)). Published human jejunal data (119 P(eff), 53 compounds) were analyzed by a regression procedure incorporating a dual-pore size paracellular model. Transcellular permeability, scaled by k(VF), was equated to that of Caco-2 at pH 6.5. The biophysical model predicted human jejunal permeability data within the experimental uncertainty. This investigation revealed several surprising predictions: (i) many molecules permeate predominantly (but not exclusively) by the paracellular route, (ii) the aqueous boundary layer thickness in the intestinal perfusion experiments is larger than expected, (iii) the mucosal surface area in awake humans is apparently nearly entirely accessible to drug absorption, and (iv) the relative "leakiness" of the human jejunum is not so different from that observed in a number of published Caco-2 studies.

Topics: Animals; Disease Models, Animal; Dogs; Humans; Jejunal Diseases; Kidney Diseases; Models, Biological; Permeability; Porosity; Regression Analysis

A mouse model of recurrent herpes simplex type 2 (HSV-2) would improve our understanding of the immunobiology of recurrent disease and provide a useful model for evaluating antiviral treatments. We developed a model to evaluate recurrent vaginal HSV-2 shedding using high-dose acyclovir (ACV) therapy beginning at 3 days post infection (dpi). Treatment with 150mg/kg of ACV for 10 days increased survival to 80% following vaginal challenge with HSV-2 strain 186 and to 100% after challenge with strain MS. We then evaluated recurrent vaginal HSV-2 shedding in surviving mice. Although infectious virus was not detected in vaginal samples after 21dpi, viral DNA was detectable by PCR in 80% of mice (47/59) on at least 1 day, while no animal was positive for virus on every day. ACV therapy administered from day 21 to 31 significantly reduced recurrent virus shedding during this period from 7.3% (8/109 swabs) to 0.8% (1/126 swabs) (p=0.013). Lastly, ACV-rescued HSV-2-infected mice treated with cyclophosphamide at 35 and 38dpi rapidly succumbed, indicating that this model can be used to study immune control of the persistent infection. Thus, this model provides an inexpensive model for evaluating therapeutic strategies and immune control of persistent HSV.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; DNA, Viral; Female; Herpes Genitalis; Herpesvirus 2, Human; Humans; Male; Mice; Polymerase Chain Reaction; Recurrence; Survival Analysis; Vagina; Virus Shedding

Genital herpes, caused by herpes simplex virus type-2 (HSV-2), is a recurrent, lifelong disease affecting tens of millions of people in the USA alone. HSV-2 can be treated therapeutically with acyclovir (ACV) and its derivatives; however, no treatment can prevent HSV reactivation. Novel topical anti-HSV microbicides are much needed to reduce HSV-2 transmission and to treat primary or reactivated infections, especially for ACV-resistant strains. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are single-stranded DNA analogues that enter cells readily and can reduce target gene expression through steric blockage of complementary messenger RNA (mRNA).. We investigated the antiviral activities of PPMOs targeted to the translation start-site regions of the mRNA for two HSV-2 immediate early genes, immediate early protein (ICP)0 and ICP27, and two early genes, unique long gene (UL)30 and UL39.. In cell cultures, PPMOs targeting ICP0 or ICP27 mRNA were found to be highly effective against two strains of HSV-2, one of which was ACV-resistant. In vivo, daily topical applications of up to 1 mM ICP27 PPMO caused no gross or microscopic damage to the genital tract of uninfected BALB/c mice or cotton rats. Cotton rats receiving topical application of ICP27 PPMO 24 h after HSV-2 inoculation showed a reduction in genital lesions and a 37.5% reduction in mortality at 14 days post-infection. Mice receiving topical application of 100 μM of an ICP27 and ICP0 PPMO combination before HSV-2 inoculation had no detectable viral replication in the genital tract at 3-5 days post-infection.. These results demonstrate that topically applied PPMOs hold promise as candidate antiviral microbicides against HSV-2 genital infection.

Topics: Acyclovir; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; Drug Resistance, Viral; Female; Herpes Genitalis; Herpesvirus 2, Human; Immediate-Early Proteins; Mice; Mice, Inbred BALB C; Morpholines; Morpholinos; Peptides; Secondary Prevention; Sigmodontinae; Vero Cells; Viral Proteins; Virus Activation; Virus Replication

Herpes simplex virus type 2 (HSV-2) infections produce a recurrent disease state associated with susceptibility to other pathogens, including human immunodeficiency virus (HIV), and cannot be cured by current therapeutic treatments. The HSV-2 epidemic must therefore be addressed by therapeutic strategies that reduce recurrent lesions and ideally lack the possibility for development of drug resistance. To this end, the therapeutic potential of SCV-07 (gamma-D-glutamyl-L-tryptophan), a synthetic dipeptide with potent immunomodulatory and antimicrobial activity, was studied in the guinea pig model of recurrent genital HSV-2. Initial evaluations showed that when delivered orally, but not subcutaneously, SCV-07 significantly reduced recurrent lesions. Oral dose ranging studies indicated that, of the tested amounts, 5microg/kg was optimal when delivered after an overnight fast. Interestingly, fasting induced a significant increase in recurrent lesions in vehicle-treated guinea pigs relative to non-fasted animals. Despite this increase, SCV-07 significantly reduced lesion formation in treated animals but showed no durability following cessation of treatment. In fact, this regimen of SCV-07 treatment produced statistically indistinguishable outcomes compared with those provided by topical aciclovir. These data illustrate that SCV-07 may provide an easily administered alternative or supplemental treatment option for genital HSV-2 recurrent disease.

Topics: Acyclovir; Animals; Antiviral Agents; Dipeptides; Disease Models, Animal; Drug Therapy, Combination; Female; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Humans; Secondary Prevention; Treatment Outcome

The zebrafish (Danio rerio) is rapidly gaining ground as a disease model. However, until now, the use of this species with human pathogens has been restricted to just three bacteria; no studies involving viruses that infect humans are recorded. In this study, the zebrafish was used as a model of herpes simplex virus type 1 (HSV-1) infection of the nervous system. Fish infected using viral culture supernatants showed detectable HSV-1 DNA concentrations 1-4 days after inoculation, indicating that this virus can experimentally infect and persist in this host. The kinetics of infection was dose dependent, especially in the head. Histological immunodetection of HSV-1 glycoproteins confirmed the presence of HSV-1 in the organs studied; infection led to histopathological changes. Moreover, the suppression of the immune system by cyclophosphamide and the antiviral effect of acyclovir were demonstrated. The infection of the encephalon was studied in detail, and the time course of viral colonization recorded. Immunofluorescence studies provided immunoreactive evidence of viral antigens in the encephalon and spinal cord. Viruses cleared from infected brains showed the ability to infect human neuroblastoma cells. This study is the first to demonstrate HSV-1 infection in the zebrafish and manifests the potential use of this species in herpesvirus studies.

Topics: Acyclovir; Animals; Antiviral Agents; Cyclophosphamide; Disease Models, Animal; Female; Herpes Simplex; Herpesvirus 1, Human; Immunosuppressive Agents; Male; Time Factors; Zebrafish

In vitro and in vivo studies demonstrated the antiviral efficacy of nerve growth factor (NGF) and its cyto-protective effect in herpes simplex virus (HSV)-infected cells. The aims of this study were to evaluate the role of endogenous NGF in HSV corneal infection, and the effects of topical NGF treatment on herpetic keratitis.. Herpetic keratitis was induced in 40 rabbits with the HSV-1 McKrae strain. Animals were divided into four groups, and treated with topical neutralizing anti-NGF antibodies, NGF, acyclovir or balanced salt solution (BSS) respectively. The clinical course of HSV keratitis was evaluated and scored by slit-lamp examination. In addition, biochemical (immunohistochemistry for glycoprotein D) and molecular (nested PCR for glycoprotein D) analyses were carried out to estimate viral replication.. Treatment with anti-NGF antibodies induced a more severe keratitis associated with increased biochemical and molecular markers of active viral replication. Two animals in this group developed lethal HSV encephalitis. Conversely, topical treatment with NGF induced a significant amelioration of clinical and laboratory parameters when compared to the BSS treated group (control). No significant differences were observed between NGF- and acyclovir-treated groups.. This study demonstrated the crucial role of endogenous NGF in herpetic keratitis. The comparable effects of NGF and acyclovir confirm the antiviral activity of NGF, and indicate a potential use of topical NGF in herpetic keratitis.

Topics: Acyclovir; Administration, Topical; Animals; Antibodies, Blocking; Antiviral Agents; Cytoprotection; Disease Models, Animal; Female; Herpesvirus 1, Human; Immunoenzyme Techniques; Keratitis, Herpetic; Nerve Growth Factor; Polymerase Chain Reaction; Prospective Studies; Rabbits; Viral Envelope Proteins; Virus Replication

Cytomegalovirus (CMV) is one of the most common causes of major birth defects in humans. Of the approximately 8400 children born each year in the U.S. with CMV-induced birth defects, more than 1/3 of these children exhibit hypoplasia and hypocalcification of tooth enamel. Our objective was to initiate the investigation of the pathogenesis of CMV-induced tooth defects.. Mouse Cap stage mandibular first molars were infected with mouse CMV (mCMV) in vitro in a chemically-defined organ culture system and analysed utilising histological and immunolocalisation methodologies. The antiviral, acyclovir, was used to inhibit mCMV replication and comparisons made between mCMV-infected and acyclovir-treated, mCMV-infected teeth.. Active infection of Cap stage molars for up to 15 days in vitro results in smaller, developmentally-delayed and dysmorphic molars characterised by shallow, broad and misshapen cusps, infected and affected dental papilla mesenchyme, poorly differentiated odontoblasts and ameloblasts, and no dentin matrix. Initial protein localisation studies suggest that the pathogenesis is mediated through NF-kappaB signaling and that there appears to be an unusual interaction between abnormal mesenchymal cells and surrounding matrix. Rescue with acyclovir indicates that mCMV replication is necessary to initiate and sustain progressive tooth dysmorphogenesis.. Our results indicate that mCMV-induced changes in signaling pathways severely delays, but does not completely interrupt, tooth morphogenesis. Importantly, our results demonstrate that this well-defined embryonic mouse organ culture system can be utilised to delineate the molecular mechanism underlying the CMV-induced tooth defects that characterise the amelogenesis imperfecta phenocopy seen in many CMV-infected children.

Topics: Acyclovir; Ameloblasts; Amelogenesis Imperfecta; Animals; Antiviral Agents; Cell Proliferation; Disease Models, Animal; Epithelial Cells; Herpesviridae Infections; Humans; Mice; Muromegalovirus; NF-kappa B; Odontoblasts; Odontogenesis; Tooth; Tooth Germ

To determine the efficacy of A-5021, a new analogue of acyclovir, on murine herpetic keratitis.. Herpes simplex virus type 1 (strain CHR3) was inoculated onto bilateral scarified BALB/c corneas. Clinical scores on the corneas treated with A-5021 eyedrops were compared with those obtained from the treatment with 3% acyclovir eye ointment by slit lamp microscopy. Virus titers of the trigeminal ganglia and eyeballs were quantitated on Vero cell monolayers. Mice treated with saline or a white petroleum jelly were used as controls.. A-5021 eyedrops significantly suppressed both corneal epithelial and stromal lesions at all concentrations used. Clinical scores on the epithelium and stroma treated with 0.1% A-5021 were equivalent to those with 3% acyclovir treatment. When compared with the non-drug-treated control mice, virus titers in the eyeballs and trigeminal ganglia in A-5021- and acyclovir-treated mice were significantly less than those in controls.. A-5021 eyedrops, which are easily applied onto the affected cornea, ameliorated clinical scores and suppressed virus growth. It is a promising alternative treatment of herpetic keratitis.

Topics: Acyclovir; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; Female; Guanine; Herpesvirus 1, Human; Keratitis, Herpetic; Mice; Mice, Inbred BALB C; Ophthalmic Solutions; Trigeminal Ganglion; Vero Cells

To evaluate in vivo corneal absorption of the amino acid prodrugs of acyclovir (ACV) using a topical well model and microdialysis in rabbits.. Stability of L-alanine-ACV (AACV), L-serine-ACV (SACV), L-isoleucine-ACV (IACV), gamma-glutamate-ACV (EACV) and L-valine-ACV (VACV) prodrugs was evaluated in various ocular tissues. Dose-dependent toxicity of these prodrugs was also examined in rabbit primary corneal epithelial cell culture (rPCEC) using 96-well based cell proliferation assay. In vivo ocular bioavailability of these compounds was also evaluated with a combination of topical well infusion and aqueous humor microdialysis techniques.. Among the amino acid ester prodrugs, SACV was most stable in aqueous humor. Enzymatic degradation of EACV was the least compared to all other prodrugs. Cellular toxicity of all the prodrugs was significantly less compared to trifluorothymidine (TFT) at 5mM. Absorption rate constants of all the compounds were found to be lower than the elimination rate constants. All the prodrugs showed similar terminal elimination rate constants (lambda(z)). SACV and VACV exhibited approximately two-fold increase in area under the curve (AUC) relative to ACV (p<0.05). Clast (concentration at the last time point) of SACV was observed to be 8+/-2.6microM in aqueous humor which is two and three times higher than VACV and ACV, respectively.. Amino acid ester prodrugs of ACV were absorbed through the cornea at varying rates (ka) thereby leading to varying extents (AUC). The amino acid ester prodrug, SACV owing to its enhanced stability, comparable AUC and high concentration at last time point (Clast) seems to be a promising candidate for the treatment of ocular HSV infections.

Topics: Acyclovir; Animals; Anterior Chamber; Antiviral Agents; Aqueous Humor; Area Under Curve; Biological Availability; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Stability; Epithelium, Corneal; Keratitis, Herpetic; Male; Ophthalmic Solutions; Prodrugs; Rabbits; Toxicity Tests

Acyclovir-resistant herpes simplex viruses (HSV) are commonly recovered from immunocompromised individuals who exhibit chronic and/or disseminated herpetic lesions.. The virulence and response to topical acyclovir therapy were evaluated in a mouse model of zosteriform cutaneous HSV infection using two HSV-1 isolates from the same immunocompromised patient (one susceptible and one resistant to acyclovir).. The acyclovir-resistant virus, with a Thr63Ile change in the ATP-binding site of the thymidine kinase gene, produced almost as many skin lesions as the wild-type susceptible virus. As expected from in vitro susceptibility data, the herpetic lesions of the mice infected with the drug-resistant virus did not respond to topical acyclovir therapy.. Some thymidine kinase HSV mutants associated with drug resistance may retain their pathogenicity at least in the mouse model described in this study.

Topics: Acyclovir; Administration, Topical; Amino Acid Substitution; Animals; Antiviral Agents; Disease Models, Animal; Drug Resistance, Viral; Female; Herpes Simplex; Herpesvirus 1, Human; Humans; Mice; Mice, Hairless; Mutation, Missense; Thymidine Kinase; Virulence

The aim of this study was to obtain a prolonged release of Vitamin A palmitate (RAP) and aciclovir from biodegradable microspheres for intraocular administration with an antiviral action and to be capable of preventing the inherent risks of intravitreal administration. The RAP effect on the microsphere characteristics was also studied. Poly(D,L-lactic-co-glycolic) acid microspheres were prepared by the solvent evaporation method. Different quantities of aciclovir (40-80 mg) and RAP (10-80 mg) were added to the internal phase of the emulsion. Microspheres were analysed by scanning electron microscopy, which revealed a spherical surface and a porous structure, and granulometric analysis that showed an adequate particle size for intraocular administration. The aciclovir loading efficiency increased when Vitamin A palmitate was added. Differential scanning calorimetry detected no differences in the polymer glass transition temperature and the aciclovir melting endotherm in all formulations. The release of aciclovir during the first days of the in vitro assay was improved with respect to microspheres without RAP. The microspheres showed a constant release of aciclovir and RAP for 49 days. Best results were obtained for microspheres prepared with 40 mg aciclovir, 80 mg RAP and 400mg polymer. A dose of 4.74 mg of microspheres would be therapeutic for the herpes simplex and Epstein-Barr viruses' treatment in an animal model and would reduce the intravitreal adverse effects. The injectability of a suspension of microspheres in isotonic saline solution resulted appropriate for its injection through a 27 G needle.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Biocompatible Materials; Calorimetry, Differential Scanning; Delayed-Action Preparations; Disease Models, Animal; Diterpenes; Drug Administration Routes; Eye; Lactic Acid; Microscopy, Electron, Scanning; Microspheres; Pharmaceutical Preparations; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polymers; Retinyl Esters; Vitamin A

To examine the efficacy of valaciclovir (VACV) oral formulation as an alternative to topical treatments in a case of herpetic keratitis.. The patient was a 61-year-old man who presented with dendritic keratitis in his left eye. After recognizing his difficulty in using eye ointment, we prescribed oral VACV 500 mg tablets twice daily for 7 days. We also describe our experiments with orally administered VACV in a mouse model of this disease. In this study, 143 Balb/c mice were inoculated with herpes simplex virus type 1 (HSV)-1 in each eye and treated with oral VACV 50 or 100 mg/kg twice daily, oral acyclovir (ACV) 50 mg/kg 5 times/d, 3% ACV eye ointment (ACV-O) 5 times/d, 3% ACV eye drops 5 times/d, or control for 5 days.. After 7 days, the patient's lesion was observed healed. Corrected left visual acuity was also improved, and HSV DNA was below detectable level. In the mouse study, slit-lamp examination on days 3, 4, 5, and 7 revealed that all 5 ACV and VACV treatment groups were significantly more effective in improving symptoms of herpetic epithelial keratitis versus control (P < 0.05). Moreover, VACV 100 mg/kg was superior to other treatments. Viral titers in mouse eyeball and trigeminal ganglia were lowest in the VACV 100 mg/kg group versus other treatment groups.. Our case example suggests that when frequent application, blurred vision, and foreign body sensation after ACV-O application cause difficulty for patients to follow treatment, oral VACV might be an effective and safe option for patients with herpetic keratitis.

Topics: Acyclovir; Administration, Oral; Animals; Antiviral Agents; Cornea; Disease Models, Animal; DNA, Viral; Gene Dosage; Herpesvirus 1, Human; Humans; Keratitis, Dendritic; Keratitis, Herpetic; Male; Mice; Mice, Inbred BALB C; Middle Aged; Polymerase Chain Reaction; Prodrugs; Valacyclovir; Valine

Mortality and morbidity rates remain high among patients with herpes simplex virus encephalitis (HSVE). Chemokine-mediated recruitment and activation of leukocytes to focal areas of viral CNS infection are crucial steps in antiviral response and clearance. However, the inflammatory reaction and cellular antiviral response may enhance collateral damage to neurons and account for chronic progressive brain damage. We identified a specific mRNA expression of the interferon-gamma-inducible chemokines (CXCL9, CXCL10 and CXCL11), and RANTES (CCL5) in the acute course and long-term of experimental HSVE. This pattern was substantially altered by anti-viral and anti-inflammatory treatment. Our findings indicate a pivotal role of these chemokines in the immunopathogenesis of HSVE.

Topics: Acyclovir; Animals; Anti-Inflammatory Agents; Antiviral Agents; Chemokines; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Encephalitis, Herpes Simplex; Female; Gene Expression Regulation; Methylprednisolone; Mice; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Time Factors; Viral Load

An adult mouse model for studies of latency and recurrence after vaginal HSV-2 infection is not available at present, largely because the infection kills most mice within 14 days. We describe here an antiviral therapy that rescues most vaginally infected mice from death. Vaginally infected mice were nearly all rescued by combined treatment with one dose of monoclonal anti-HSV glycoprotein D 3 days after infection plus valacyclovir in the drinking water on days 3, 4, 5, 7, 9, 11, 13, and 15 after infection. At 60 days after infection, PCR measurements revealed that most rescued mice had viral DNA in their lumbosacral dorsal root ganglia, lumbosacral spinal cords, and paracervical autonomic ganglia, consistent with the possibility that latent infections were established. At this time, immunolabeling revealed CD45+ lymphoid cells in these neural tissues in rescued mice but not in normal control mice. In vivo depletion of T lymphocytes with monoclonal antibodies caused a recurrence of herpes illness symptoms earlier and in a larger proportion of rescued mice than was observed in non-depleted rescued mice. Interestingly, many rescued mice (46/114) spontaneously developed a syndrome of typical herpes illness symptoms that began with ruffled fur on a mouse that previously had sleek fur and progressed to arched backs, feeble gait, hindlimb paralysis, and death or euthanasia, or in some cases to recovery to health. This high incidence of apparent spontaneous recurrence of HSV-2 infection in rescued mice suggests that it may be possible, with some refinement of the procedure, to obtain an effective adult mouse model for studies of therapeutic vaccination to inhibit or prevent HSV-2 recurrence after genital tract infection.

Topics: Acyclovir; Administration, Oral; Animals; Antibodies, Monoclonal; Antibodies, Viral; Antiviral Agents; Disease Models, Animal; Drug Therapy, Combination; Female; Herpes Genitalis; Herpesvirus 2, Human; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Secondary Prevention; Valacyclovir; Valine; Viral Envelope Proteins; Virus Latency

To induce experimental peripheral facial paralysis by inoculation of HSV1 and to compare the effects of steroid, acyclovir, lipoprostoglandin E2 and steroid + acyclovir treatments in terms of clinical recovery, electrophysiologically and histopathologically.. A total of 132 adult female rats were used in this study. HSV type 1 strain was inoculated at the back of the left ear by using 27 gauge needle. Of all animals, 70 (53%) rats which developed facial paralysis were divided into five groups (n = 14 for each group) as control, steroid + acyclovir, lipoprostaglandin E1, steroid only and acyclovir only. At the end of the 21 days period, the rats were clinically examined and electrophysiological tests were performed, then decapitated and the nerve specimens were obtained.. A modified electroneurography (ENoG) test was performed and the latencies and the amplitudes were compared. The findings of the intact side were better, but with no significant difference. Histopathologicaly edema was significantly smaller in all groups compared to the controls (p < 0.05). Similarly, no difference was seen in terms of vacuolar degeneration and Schwann cell hyperchromatisation among the groups and no significant difference in recovery period and rate of facial paralysis when all groups were compared.. Facial paralysis induced by HSV1 recovered spontaneously within a week. In the treatment of facial paralysis, steroid alone, acyclovir alone, steroid + acyclovir, or lipoprostaglandin E1 all reduced edema in the infected facial nerve but there was no statistical difference in of the rate or degree of recovery.

Topics: Acyclovir; Alprostadil; Analysis of Variance; Animals; Anti-Inflammatory Agents; Bell Palsy; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Electrophysiology; Facial Nerve; Facial Paralysis; Female; Herpesvirus 1, Human; Incidence; Injections, Intramuscular; Injections, Intraperitoneal; Methylprednisolone Hemisuccinate; Prognosis; Rats; Treatment Outcome; Vasodilator Agents

The antiviral activities of extracts from 5 species of marine algae collected at Haeundae (Pusan, Korea), were examined using plaque reduction assays. Although the activity of a methanol (MeOH) extract of Sargassum ringoldianum (Sargassaceae) was the most potent against several types of viruses, it was also cytotoxic. A MeOH extract of Symphyocladia latiuscula (Rhodomelaceae) and its fractions exhibited antiviral activities against acyclovir (ACV) and phosphonoacetic acid (PAA)-resistant (AP(r)) herpes simplex type 1 (HSV-1), thymidine kinase (TK(-)) deficient HSV-1 and wild type HSV-1 in vitro without cytotoxicity. The major component, 2,3,6-tribromo-4,5-dihydroxybenzyl methyl ether (TDB) of a CH(2)Cl(2)-soluble fraction was active against wild type HSV-1, as well as AP(r) HSV-1 and TK(-) HSV-1 (IC(50) values of 5.48, 4.81 and 23.3 microg/ml, respectively). The therapeutic effectiveness of the MeOH extract and TDB from S. latiuscula was further examined in BALB/c mice that were cutaneously infected with HSV-1 strain 7401H. Three daily oral administrations of the MeOH extract and TDB significantly delayed the appearance of score 2 skin lesions (local vesicles) and limited the development of further score 6 (mild zosteriform) lesions in infected mice without toxicity compared with controls. In addition, TDB suppressed virus yields in the brain and skin. Therefore TDB should be a promising anti HSV agent.

Topics: Acyclovir; Administration, Oral; Animals; Antiviral Agents; Brain; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Resistance, Viral; Ethers; Female; Herpes Simplex; Herpesvirus 1, Human; Mice; Mice, Inbred BALB C; Phosphonoacetic Acid; Rhodophyta; Skin; Thymidine Kinase; Vero Cells; Viral Plaque Assay

Bell's palsy has recently been claimed to be caused by herpes simplex virus type 1 (HSV-1) infection. The anti-viral agent acyclovir is a specific inhibitor of herpesvirus replication, and the most effective agent for the treatment herpesvirus infection. The purpose of this experiment was to assess the effect of acyclovir on the facial nerve paralysis included by HSV-1 infection.. We succeeded in producing an animal model of acute and transient facial nerve paralysis induced with HSV-1 neuritis simulating human Bell's palsy. In this study, acyclovir administration was performed before and after facial nerve paralysis, and continued for 5 days. Controls were given phosphate-buffer saline (PBS) instead of acyclovir, and the incidence and duration of facial nerve paralysis was compared in the acyclovir groups and controls.. The incidence of facial nerve paralysis was significantly lower in the group given acyclovir before the paralysis than in the controls, and the duration of facial nerve paralysis was shorter.. Administration of acyclovir before the paralysis reduced the incidence and duration of facial nerve paralysis. Administration of acyclovir after the paralysis improved the duration of facial nerve paralysis.

Topics: Acyclovir; Animals; Antiviral Agents; Bell Palsy; Data Interpretation, Statistical; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Herpes Simplex; Mice; Mice, Inbred BALB C; Time Factors

The aim of this study was to develop models that allow serial, noninvasive imaging of human prostate cancer cells in immunodeficient mice using a dedicated small animal positron emission tomography scanner (microPET).. LNCaP tumor cells were stably transduced ex-vivo with the mutant herpes simplex virus type 1 thymidine kinase (HSV-sr39tk) PET reporter gene and green fluorescent protein (GFP). The stably transduced LNCaP cells were then enriched via fluorescent cell sorting and implanted into SCID mice. Beginning 2 weeks after tumor cell inoculation, mice were repeatedly scanned by microPET performed 1 hr after tail-vein injection of approximately 200 muCi Fluorine-18 labeled penciclovir ((18)F-FHBG). PET-images were correlated to tumor size, % injected dose (ID)/g tumor tissue, PSA levels, autoradiography, and histology.. Monitoring LNCaP xenografts using microPET and our reporter gene approaches is feasible. MicroPET was capable of detecting subcutaneous tumors as small as 3 mm in diameter (approximately 0.2% ID/g). The magnitude of (18)F-FHBG-uptake in PET-images correlated with the tumor volumes and the serum PSA levels. Other non-HSV1-TK-specific tracers were also studied. While (18)F-flurodeoxyglucose ((18)F-FDG) gave poor imaging results in LNCaP cells, (11)C-acetate gave satisfactory images.. We demonstrated the feasibility of monitoring prostate cancer xenografts in a mouse model using microPET and the HSV1-sr39tk PET reporter gene/(18)F-FHBG reporter probe system. Extension of this approach may allow repetitive imaging of tumor metastases.

Topics: Acyclovir; Animals; Disease Models, Animal; Flow Cytometry; Fluorine Radioisotopes; Genetic Vectors; Green Fluorescent Proteins; Guanine; Herpesvirus 1, Human; Humans; Luminescent Proteins; Male; Mice; Mice, SCID; Neoplasm Transplantation; Prostatic Neoplasms; Thymidine Kinase; Tomography, Emission-Computed; Transduction, Genetic; Transfection; Transplantation, Heterologous; Tumor Cells, Cultured

A dipeptide prodrug of the antiviral nucleoside acyclovir (ACV), val-val-ACV (VVACV), was evaluated in vivo as a potential drug candidate for improving antiviral efficacy against herpetic epithelial and stromal keratitis.. The effect of 1% VVACV on epithelial keratitis induced by inoculation of HSV-1 strain McKrae (25 microL of 10(5) plaque-forming units [PFU]) in the scarified rabbit cornea and stromal keratitis induced by intrastromal injection of HSV-1 strain RE (10 microL of 10(5) PFU) was compared with that of 1% trifluorothymidine (TFT) and balanced salt solution as the vehicle control. Both eyes of 10 rabbits were used in each treatment group. Lesions were evaluated by slit lamp examinations over a 2-week period after infection. Aqueous humor samples and corneas were analyzed for drug concentrations at the end of each experiment. Cytotoxicity of VVACV in comparison with val-acyclovir (VACV), ACV, and TFT was evaluated in cellular proliferation assays.. The dipeptide prodrug VVACV demonstrated excellent activity against HSV-1 in the rabbit epithelial and stromal keratitis models: 1% VVACV was as effective as 1% TFT. The prodrug was also less cytotoxic than TFT, which is the only effective drug currently licensed and routinely used for topical treatment of ocular herpes infections in the United States.. The less cytotoxic and highly water-soluble prodrug VVACV, which showed excellent in vivo activity against HSV-1 in rabbit epithelial and stromal keratitis, is a promising drug candidate for treatment of ocular HSV infections.

Topics: Acyclovir; Animals; Antiviral Agents; Aqueous Humor; Biological Availability; Chlorocebus aethiops; Cornea; Corneal Stroma; Disease Models, Animal; Drug Evaluation, Preclinical; Epithelium, Corneal; Herpesvirus 1, Human; Keratitis, Herpetic; Prodrugs; Rabbits; Trifluridine; Valacyclovir; Valine

Studies in conventional murine models of HSV infection use immunologically naive animals. These models thus mimic primary infections rather than recurrent infections in humans. We have, therefore, used a newly developed mouse model that more closely mimics recurrent HSV infection in humans. In this model, the mice are infected, and zosteriform HSV-1 infection develops in the presence of a primed immune response using adoptive transfer of immunity (ATI) as we have described previously. Using the ATI mouse model, it has been shown that a more beneficial therapy for recurrent mucocutaneous HSV infection could be achieved by controlling both the viral replication and the inflammatory response to the virus. Topical treatment was initiated in this model at the time of first occurrence of symptoms and was given three times daily for 4 days. Topical treatment with ME-609 (which contains 5% acyclovir and 1% hydrocortisone) in the ATI mouse model was substantially more efficacious than 5% Zovirax cream, 1% hydrocortisone or no treatment, respectively. The beneficial properties of ME-609 were also found to be superior to those of Zovirax cream when tested in the standard guinea pig model, representing a primary HSV infection. ME-609 represents a novel treatment principle of recurrent HSV infections and the present paper summarizes the preclinical and early clinical experience of ME-609.

Topics: Acyclovir; Administration, Cutaneous; Adoptive Transfer; Animals; Antiviral Agents; Cell Line; Chlorocebus aethiops; Disease Models, Animal; Ear; Guinea Pigs; Herpes Simplex; Herpesvirus 1, Human; Hydrocortisone; Mice; Virus Replication

Synthetic oligonucleotides containing CpG motifs in specific sequence contexts have been shown to induce potent immune responses. We have evaluated mucosal administration of two immunostimulatory sequence (ISS)-containing phosphorothioate-stabilized oligonucleotides for antiherpetic efficacy in animal models. The ISS oligonucleotides, suspended in phosphate-buffered saline, were tested in mouse and guinea pig vaginal models of herpes simplex virus type 2 (HSV-2) infection. For comparison, groups of untreated, non-ISS oligonucleotide-treated, and acyclovir-treated animals also were monitored. The results indicated that vaginal epithelial application of ISS (up to 6 h after viral inoculation) with mice lethally challenged with HSV-2 delayed disease onset and reduced the number of animals that developed signs of disease (P = 0.003). ISS application significantly increased survival rates over those of controls (P = 0.0014). The ISS also impacted an established infection in the guinea pig model of HSV-2 disease. A single administration of ISS (21 days after viral inoculation) significantly reduced the frequency and severity of HSV-2 lesions compared to results with non-ISS oligonucleotide-treated and untreated guinea pigs (P < 0.01). HSV-2 is shed from the vaginal cavity of the guinea pig in the absence of lesions, similar to the case with humans. As an additional indication of ISS efficacy, the magnitude of viral shedding also was significantly reduced in ISS-treated animals (P < 0.001). These effects appeared to be immunologically mediated, since ISS had no direct effect on HSV-2 replication in vitro using standard plaque assays. These data suggest that ISS may be useful in the treatment and control of genital herpes in humans.

Topics: Acyclovir; Adjuvants, Immunologic; Administration, Intravaginal; Animals; Antiviral Agents; Base Sequence; Chlorocebus aethiops; Disease Models, Animal; Female; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Humans; Mice; Microbial Sensitivity Tests; Oligonucleotides; Treatment Outcome; Vero Cells; Virus Shedding

Mouse models of herpes simplex virus type 1 (HSV-1) infection provide significant insights into viral and host genes that regulate disease pathogenesis, but conventional methods to determine the full extent of viral spread and replication typically require the sacrifice of infected animals. To develop a noninvasive method for detecting HSV-1 in living mice, we used a strain KOS HSV-1 recombinant that expresses firefly (Photinus pyralis) and Renilla (Renilla reniformis) luciferase reporter proteins and monitored infection with a cooled charge-coupled device camera. Viral infection in mouse footpads, peritoneal cavity, brain, and eyes could be detected by bioluminescence imaging of firefly luciferase. The activity of Renilla luciferase could be imaged after direct administration of substrate to infected eyes but not following the systemic delivery of substrate. The magnitude of bioluminescence from firefly luciferase measured in vivo correlated directly with input titers of recombinant virus used for infection. Treatment of infected mice with valacyclovir, a potent inhibitor of HSV-1 replication, produced dose-dependent decreases in firefly luciferase activity that correlated with changes in viral titers. These data demonstrate that bioluminescence imaging can be used for noninvasive, real-time monitoring of HSV-1 infection and therapy in living mice.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Female; Genes, Reporter; Herpes Simplex; Herpesvirus 1, Human; Keratitis, Herpetic; Luciferases; Luminescent Measurements; Mice; Organ Specificity; Time Factors; Valacyclovir; Valine

Levels of bystander death occurring in herpes simplex virus type 1 (HSV-1)-infected mouse brain stems were studied, as well as the extent to which bystander death is influenced by guanosine nucleoside analogue treatment. Consecutive sections from brain stems of HSV-1-infected mice were stained alternately for (i) viral infection and (ii) cell death (TUNEL assay). Virus antigen was detectable in brain stems on day 3 of infection, while TUNEL staining was comparatively lower. An increase in the extent of TUNEL staining was observed on day 4 of infection. Despite this increase, however, the ratio of TUNEL-stained to infection marker-stained tissue still indicated that the amount of TUNEL staining remained lower than infection staining at this time point. On days 5 and 6 of infection, TUNEL staining continued to increase and the TUNEL/infection marker ratio switched on day 6 in favour of excess TUNEL staining, which was observed in and around the foci of infection, suggesting bystander death. The excess TUNEL staining on day 6 of infection was further increased on treatment with antivirals. The significance and implications of these results are discussed with respect to the nature and mechanism of action of the TUNEL assay, dynamics of primary HSV-1 infection, immunological influences and potential effects of antiviral treatment. The potential problems of the TUNEL assay are considered in the context of viral infection and the TUNEL assay, in combination with infection marker staining, may potentially provide a model system for quantitative analysis of true bystander death during HSV infection in vivo.

Topics: 2-Aminopurine; Acyclovir; Animals; Antiviral Agents; Apoptosis; Brain Stem; Disease Models, Animal; DNA Fragmentation; Famciclovir; Female; Ganciclovir; Guanine; Herpes Simplex; Herpesvirus 1, Human; Humans; In Situ Nick-End Labeling; Mice; Mice, Inbred BALB C; Valacyclovir; Valine

Recurrent herpes simplex labialis represents a disease still difficult to treat, despite the availability of many established antiviral drugs used in clinical research since 30 years ago. Although differences between the human disease and that obtained in experimental animal suggest caution in predicting an effective clinical response from the experimental results, some of the animal models seem to be useful in optimising the topical formulation of single antiviral drugs. In the present work the dorsal cutaneous guinea pig model was used to compare 5 different topical antiviral formulations with clinical promise (active molecule: 5% w/w micronized aciclovir, CAS 59277-89-3), using both roll-on and lipstick application systems. The aim being to evaluate which vehicle (water, oil, low melting and high melting fatty base) and application system (roll-on, lipstick) enhances the skin penetration and the antiviral activity of the drug, after an experimental intradermal infection with Herpes simplex virus type 1 (HSV-1). As reference, a commercial formulation (5% aciclovir ointment) was used. The cumulative results of this study showed that the formulation A, containing 5% aciclovir in an aqueous base in a roll-on application system, has the better antiviral efficacy in reducing the severity of cutaneous lesions and the viral titer; among the lipsticks preparations, the formulation D, containing 5% aciclovir in a low melting fatty base, demonstrates a very strong antiviral activity, though slightly less than formulation A. This experimental work confirms the validity of the dorsal cutaneous guinea pig model as a rapid and efficient method to compare the antiviral efficacy of new formulations, with clinical promise, to optimise the topical formulation of the active antiviral drugs.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Disease Models, Animal; Guinea Pigs; Herpes Simplex; Herpesvirus 1, Human; Male; Recurrence; Skin

There are 3 new topical treatments for herpes labialis that have either been approved by the US Food and Drug Administration (penciclovir cream [Denavir] and n-docosanol cream [Abreva]) or recently undergone extensive clinical evaluation (acyclovir cream). The relative efficacy of these products is unknown.. To compare the efficacy of penciclovir cream, acyclovir cream, n-docosanol cream, and acyclovir ointment in an experimental animal model of cutaneous herpes simplex virus type 1 (HSV-1) disease.. The backs of guinea pigs were infected with HSV-1 using a vaccination instrument. Active treatments and corresponding vehicle controls were applied for 3 to 5 days beginning 24 hours after inoculation.. After completion of treatment, the animals were killed and the severity of the infection assessed from the number of lesions, the total lesion area, and the lesion virus titer.. Penciclovir cream effected modest reductions in lesion number (19%), area (38%), and virus titer (88%) compared with its vehicle control, and each of these differences was significantly greater (P<.05) than the reductions effected by acyclovir ointment (0%, 21%, and 75%, respectively). The acyclovir cream effect (reductions of 4%, 28%, and 77%, respectively) was less than that of penciclovir cream, and this difference was confirmed by 2 additional head-to-head experiments. Two experiments with n-docosanol cream failed to show statistically significant differences by any parameter between n-docasonol cream and vehicle control-treated sites or between n-docosanol and untreated infection sites.. In this model, the efficacy of penciclovir cream was greater than acyclovir cream, acyclovir cream was greater than or equal to acyclovir ointment, and acyclovir ointment was greater than n-docosanol cream. Since our model was designed to evaluate compounds that function primarily through antiviral activity, the negative findings with n-docosanol in these studies do not exclude that it might work clinically through other mechanisms.

Topics: Acyclovir; Administration, Topical; Animals; Disease Models, Animal; Fatty Alcohols; Female; Guanine; Guinea Pigs; Herpes Labialis; Herpesvirus 1, Human; Humans; Treatment Outcome

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Disease Models, Animal; Fatty Alcohols; Guanine; Guinea Pigs; Herpes Labialis; Humans; Ointments; Treatment Outcome

Acyclovir (ACV) resistant herpes simplex virus (HSV) isolates can be readily selected in animal infection models receiving suboptimal ACV treatment, however no comparative studies of the emergence of resistance following suboptimal treatment with valacyclovir (VCV) or famciclovir (FCV), the prodrugs of acyclovir and penciclovir, respectively, have been reported.. Mice (n = 30) were infected with HSV type 1 or 2 in the ear pinnae and administered oral prodrugs at one fifth a dose previously shown to be effective. To select and amplify drug-resistant HSV, a total of seven consecutive in vivo passages with suboptimal treatment were performed for each virus sample and progeny virus from each passage was characterized by the plaque reduction (PRA) and plating efficiency assays (PEA).. No drug-resistant HSV-2 and only a single drug-resistant HSV-1 variant were identified. Virus recovered from the first three sequential passages of this HSV-1 sample was susceptible by PRA, although the proportion of resistant virus recovered gradually increased upon passage. The resistant HSV-1 phenotype was confirmed by PRA after four sequential passages in mice. Unexpectedly, this in vivo-selected drug-resistant HSV-1 failed to yield an infection completely refractory to treatment in subsequent passages.. Sub-optimal therapy of immunocompetent mice with either VCV or FCV did not readily select for HSV-mutants resistant to either ACV or PCV, suggesting that selection of resistance with either prodrug remains difficult using this system. Futhermore, this study suggests that the PEA may represent a useful adjunct to the PRA for monitoring alterations in the proportion of drug-resistant virus even when no change in IC50 is apparent.

Topics: Acyclovir; Administration, Oral; Animals; Antiviral Agents; Disease Models, Animal; Drug Resistance, Viral; Female; Guanine; Herpes Simplex; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Prodrugs; Simplexvirus; Viral Load

Topics: 2-Aminopurine; Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Famciclovir; Herpes Simplex; Herpesvirus 1, Human; Mice; Recurrence; Valacyclovir; Valine; Virus Latency

Recent studies have implicated bile duct epithelial cells (BDEC) as a reservoir of hepatitis B virus (HBV) infection that may be particularly important in the development of post-liver transplant recurrence of hepatitis B. The aim of this study was to compare the effects of antiviral therapy on duck HBV (DHBV) expression in hepatocytes and BDEC and to determine if this was affected by biliary hyperplasia.. Ducklings congenitally infected with DHBV received penciclovir (10 mg/kg per day) treatment from 9 days of age. In order to mimic the biliary hyperplasia that often accompanies severe post-liver transplant HBV recurrence, half the animals underwent bile duct ligation. Duck HBV-DNA in serum was measured at day 1, and serum and liver DHBV-DNA were determined when the animals were killed on day 17. Intrahepatic expression of viral preS1 antigen and DHBV-DNA was measured by immunohistochemistry and in situ hybridization, respectively.. Viraemia became undetectable in the penciclovir-treated animals at day 17, following 8 days of therapy. Examination of liver tissue revealed that all hepatocytes and the majority of BDEC contained DHBV preS1 antigen and DHBV-DNA. Penciclovir greatly reduced the intrahepatic viral burden, but there was no antiviral effect on viral markers within BDEC. Despite the increased number of BDEC after bile duct ligation, the same proportion of BDEC was seen to be infected, and this was unaffected by antiviral therapy.. In the duck model with and without biliary hyperplasia, penciclovir controls DHBV replication and reduces viral burden in hepatocytes, but not in BDEC. The BDEC appear to be an important reservoir of virus that is relatively unaffected by antiviral treatment, and may play an important role in disease persistence and relapse following cessation of therapy.

Topics: Acyclovir; Animals; Antiviral Agents; Bile Ducts; Cell Division; Disease Models, Animal; DNA, Viral; Ducks; Epithelial Cells; Guanine; Hepadnaviridae Infections; Hepatitis B Surface Antigens; Hepatitis B Virus, Duck; Hyperplasia; In Situ Hybridization; Liver; Protein Precursors; Reverse Transcriptase Inhibitors; Treatment Outcome; Viral Envelope Proteins; Virus Replication

Neurological damage in Herpes simplex type 1 encephalitis results from neuronal cell death secondary to viral invasion, and from inflammatory changes and cerebral oedema secondary to the immune response to the virus. Corticosteroids could have an important role in the management of Herpes simplex encephalitis because their anti-inflammatory action reduces cerebral oedema. However their use has been limited by concerns that their immunosuppressive actions could increase viral replication and spread. The present study examined this issue in a rat model in which injection of HSV-1 into the cervical vagus nerve produced a well-defined focal encephalitis, characterised by an orderly progression of the virus through central neural pathways connected with vagal afferent termination sites in the medulla oblongata. After injection of HSV-1, rats were treated twice a day, either with vehicle (saline, 400 microl i.p.), with acyclovir (30 mg/kg i.p.), with dexamethasone (5 mg/kg i.p.), or with both acyclovir and dexamethasone. Animals were sacrificed after 72 h, and viral load in different brain regions was quantified by computer-assisted measurement of the area occupied by immunohistochemical reaction product. Treatment with acyclovir reduced viral load to 17 +/- 5% of the saline value (P < 0.01). After dexamethasone treatment, the viral load (63 +/- 13% of the saline value) was also reduced (P < 0.05). Treatment with both acyclovir and dexamethasone reduced viral load to 26 +/- 8% of the saline value (P < 0.01 compared with saline, and P > 0.05 compared to acyclovir alone). Our results confirm the effectiveness of acyclovir in a new model of HSV-1 infection, and provide evidence that corticosteroids do not inhibit the antiviral action of acyclovir. In addition corticosteroids may decrease the extent of infection in their own right. The acute time course studied in our model parallels the time course of acute Herpes simplex encephalitis in humans. Our data suggests that corticosteroids are not detrimental when combined with acyclovir in the management of this condition.

Topics: Acyclovir; Amygdala; Animals; Antigens, Viral; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Encephalitis, Herpes Simplex; Female; Focal Infection; Herpesvirus 1, Human; Immunohistochemistry; Medulla Oblongata; Rats; Rats, Inbred F344; Vagus Nerve; Viral Load; Virus Replication

Acyclovir triphosphate is a potent inhibitor of hepatitis B virus DNA polymerase, but acyclovir treatment provides no benefit in patients with hepatitis B virus infection. This is due in part to the fact that hepatitis B virus, unlike herpes simplex virus, does not code for a viral thymidine kinase which catalyzes the initial phosphorylation of acyclovir. We synthesized 1-O-octadecyl-sn-glycero-3-phospho (3-P)-acyclovir and found that it was highly active in reducing hepatitis B virus replication in 2.2. 15 cells, while acyclovir was inactive. The greater antiviral activity of 1-O-octadecyl-sn-glycero-3-P-acyclovir appeared to be due to liver cell metabolism of the compound to acyclovir monophosphate (K. Y. Hostetler et al., Biochem. Pharmacol. 53:1815-1822, 1997). However, a closely related compound without a hydroxyl group at the sn-2 position of glycerol, 1-O-hexadecylpropanediol-3-P-acyclovir, was more active and selective in 2.2.15 cells in vitro. In this study, we treated woodchucks chronically infected with woodchuck hepatitis virus with increasing oral doses of 1-O-hexadecylpropanediol-3-P-acyclovir and assessed the response to therapy versus acyclovir or a placebo. At a dosage of 10 mg/kg of body weight twice a day, the test compound significantly inhibited viral replication in vivo, as indicated by a 95% reduction in serum woodchuck hepatitis virus DNA levels and by a 54% reduction in levels of woodchuck hepatitis virus replicative intermediates in the liver. Higher doses were somewhat less effective. In contrast, 20 mg of acyclovir/kg twice daily, a 5. 3-fold-higher molar dosage, had no demonstrable activity against woodchuck hepatitis virus. Oral 1-O-hexadecylpropanediol-3-P-acyclovir appeared to be safe and effective in chronic woodchuck hepatitis virus infection.

Topics: Acyclovir; Administration, Oral; Animals; Antiviral Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Hepatitis B; Hepatitis B Virus, Woodchuck; Male; Marmota; Treatment Outcome

Our understanding of the pathogenesis of acyclovir (ACV)-resistant herpes simplex virus (HSV) is limited, especially with regard to reactivation and recurrent disease. To further explore the pathogenesis of ACV-resistant HSV-2 viruses, we used the guinea pig model of genital HSV-2 infection to evaluate several ACV-resistant isolates of both thymidine kinase (Tk)-altered and Tk-deficient phenotypes obtained from HIV-infected patients. Two plaque-purified workpools from each isolate were initially evaluated. Each produced acute disease and at least one clinical recurrence. The two strains that produced the most severe primary disease and most recurrences, one Tk-deficient virus and one Tk-altered virus, were further evaluated and shown to produce acute and recurrent genital disease similar to that seen with wild-type viruses. Furthermore, the reactivated virus producing recurrent lesions could be a pure population with minimal Tk activity. Finally, we showed that topical foscarnet treatment could alter disease and vaginal virus replication following vaginal inoculation with these two ACV-resistant strains. Using the guinea pig model of genital HSV-2 infection, we found that recurrent disease following infection with markedly Tk-deficient viruses was more common than expected, especially in select isolates. Furthermore, this model should be useful in evaluating potential new therapies for ACV-resistant HSV strains.

Topics: Acyclovir; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; Drug Resistance, Microbial; Female; Foscarnet; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Humans; Mice; Rabbits; Reverse Transcriptase Inhibitors; Vero Cells; Virus Activation

Eugenol (4-allyl-1-hydroxy-2-methoxybenzene) was tested for antiviral activity against HSV-1 and HSV-2 viruses. In vitro, it was found that the replication of these viruses was inhibited in the presence of this compound. Inhibitory concentration 50% values for the anti-HSV effects of eugenol were 25.6 microg/mL and 16.2 microg/mL for HSV-1 and HSV-2 respectively, 250 microg/mL being the maximum dose at which cytotoxicity was tested. Eugenol was virucidal and showed no cytotoxicity at the concentrations tested. Eugenol-acyclovir combinations synergistically inhibited herpesvirus replication in vitro. Topical application of eugenol delayed the development of herpesvirus induced keratitis in the mouse model.

Topics: Acyclovir; Animals; Antiviral Agents; Chlorocebus aethiops; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Combinations; Eugenol; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Vero Cells

To study the treatment efficacy of antiviral antibiotic 17997 against HSVl infected guinea pig skin infection.. Guinea pig skin was infected by HSV1. 24hrs or 48hrs of post infection local treatment of 0.3% 17997 cream was started, tid for five days. In the mean time, acyclovir treatment, cream treatment and virus control were included.. Local treatment of 0.3% 17997 cream showed therapeutic effects, it reduced the average scores of skin lesion, accelerated crusting-time and healing-time.. 0.3% 17997 cream showed significant treatment efficacy when compared with cream and virus controls by reducing skin lesion scores and healing-time. The treatment efficacy of 3.0% acyclovir cream was a little bit better than 0.3% 17997 cream.

Topics: Acyclovir; Administration, Topical; Animals; Anti-Bacterial Agents; Antiviral Agents; Disease Models, Animal; Female; Guinea Pigs; Herpes Simplex; Herpesvirus 1, Human; Male; Treatment Outcome

The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guani ne (A-5021) was evaluated in murine cells and in several murine models of herpes simplex virus (HSV) infection. Against HSV type 1 (HSV-1), A-5021 was 15-30- and 30-60-fold more active, and against HSV type 2 (HSV-2), it was 2- and 8-fold more active than acyclovir and penciclovir in Balb/3T3 cells, respectively. When antiviral compounds were administered orally (once daily) to mice infected intraperitoneally with HSV-1 (Tomioka), A-5021 was more active than acyclovir or famciclovir in spite of its relatively low oral bioavailability. A-5021 was as active as penciclovir when the antiviral compounds were given intravenously (three times daily) to mice infected intraperitoneally with HSV-2 (186). In mice with a cutaneous HSV-1 (KOS) infection, three times daily oral therapy with A-5021 at 25 mg/kg per day produced more significant reduction in severity of skin lesions than equivalent treatment with acyclovir or famciclovir. In mice infected intracerebrally with HSV-1 (Tomioka), complete survival was observed in the group treated intravenously with A-5021 at 25 mg/kg per day (three times daily), while more than 50% of mice died in the groups treated intravenously with acyclovir of up to 100 mg/kg per day (three times daily). Moreover, A-5021 was more effective than acyclovir in clearing infectious virus from the brain. These findings demonstrate that A-5021 has potent anti-HSV activity in several murine models.

Topics: 3T3 Cells; Acyclovir; Administration, Oral; Animals; Antiviral Agents; Area Under Curve; Disease Models, Animal; Drug Evaluation; Encephalitis; Guanine; Herpes Simplex; Injections, Intravenous; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Peritoneum; Simplexvirus; Skin; Survival Rate

The efficacy of recombinant human interferon alpha B/D in experimental HSV-1 encephalitis was investigated in the murine system. Recombinant Hu-IFN-alpha B/D significantly reduced the mortality in a mouse encephalitis model (about 30%, P = 0.021), whereas natural mouse interferon was inactive. Combination of acyclovir with Hu-IFN-alpha B/D had an additive effect.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Drug Therapy, Combination; Encephalitis, Herpes Simplex; Herpesvirus 1, Human; Humans; Interferon Type I; Mice; Recombinant Proteins

To compare trifluridine eyedrops, cidofovir eyedrops, and penciclovir ophthalmic ointment for the treatment of herpes simplex virus type 1 keratitis.. New Zealand white rabbits were infected with the McKrae strain of herpes simplex virus type 1. Three days after viral inoculation, the rabbits were randomly assigned to treatment with 1% trifluridine, 0.2% cidofovir, 3% penciclovir ointment, or phosphate-buffered saline (for control) on various schedules. The severity of keratitis was graded in a masked manner.. Treatment with any of the antiviral drugs resulted in significantly less severe keratitis than treatment with phosphate-buffered saline. There was no statistically significant difference between eyes given trifluridine 2, 4, or 7 times a day and eyes given cidofovir 2 times a day (P=.06, P=.43, and P=.19, respectively, using the F test of the analysis of variance). Cidofovir given twice a day was significantly more effective than penciclovir given either 2 or 4 times a day (P<.001 and P=.002, respectively). Even with once-a-day dosage, all 3 drugs were significantly more effective than phosphate-buffered saline (P<.001 for all). There was no significant difference between once-a-day trifluridine and cidofovir treatments (P=.17). Trifluridine administered 5 times a day was as effective as 1% cidofovir. A similar degree of punctate keratitis was seen after 4 to 5 days in eyes treated with trifluridine at the highest frequency, 1% cidofovir, or penciclovir ointment.. Trifluridine treatment was highly effective in this rabbit model, even when given only once a day. Treatment with cidofovir was as effective as that with trifluridine.. Cidofovir and penciclovir treatments may prove to be effective against epithelial keratitis. Clinical trials of trifluridine, cidofovir, and penciclovir with lower treatment frequencies appear to be warranted.

Topics: Acyclovir; Animals; Antiviral Agents; Cidofovir; Cornea; Cytosine; Disease Models, Animal; Female; Guanine; Herpesvirus 1, Human; Keratitis, Herpetic; Male; Ointments; Ophthalmic Solutions; Organophosphonates; Organophosphorus Compounds; Rabbits; Trifluridine

The purpose of this study was to define the relationship between herpes simplex virus (HSV) latency and in vivo ganglionic reactivation. Groups of mice with numbers of latently infected neurons ranging from 1.9 to 24% were generated by varying the input titer of wild-type HSV type 1 strain 17syn+. Reactivation of the virus in mice from each group was induced by hyperthermic stress. The number of animals that exhibited virus reactivation was positively correlated with the number of latently infected neurons in the ganglia over the entire range examined (r = 0.9852, P < 0. 0001 [Pearson correlation]).

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Herpes Simplex; Herpesvirus 1, Human; Humans; Male; Mice; Neurons; Trigeminal Ganglion; Virus Activation; Virus Latency

We demonstrate that the novel immunosuppressive agent mycophenolate mofetil (MMF), that has been approved for use in kidney transplant recipients, strongly potentiates the antiviral activity of acyclovir in murine models for herpesvirus infections. Hairless mice that were infected intracutaneously with herpes simplex virus type 1 were treated systemically with ACV (20 mg/kg per day) and topically with 5% MMF. Combined use of both drugs resulted in an almost complete protection, whereas single use of either compound had virtually no effect. When athymic-nude mice were infected with an ACV-resistant (ACVr)-thymidine kinase-deficient (TK-) HSV-2 strain, combined use of systemically administered ACV (100 mg/kg per day) and topically applied MMF (5%) protected 60% of the animals against the infection, whereas all mice treated with either drug alone succumbed. Since transplant recipients under MMF therapy may develop opportunistic herpesvirus infections, requiring treatment with acyclovir (or valaciclovir), our findings have important implications for the treatment of these herpesvirus infections.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Drug Synergism; Herpes Genitalis; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Mice; Mice, Nude; Mycophenolic Acid

Acyclovir diphosphate dimyristoylglycerol is a lipid prodrug of acyclovir that forms liposomes and provides substantial activity against herpes simplex virus, acyclovir-resistant strains of herpes simplex virus, and human cytomegalovirus. We therefore tested this promising new drug in a rabbit model of herpes simplex retinitis.. A total of 22 pigmented rabbits were pretreated with either acyclovir diphosphate dimyristoylglycerol, ganciclovir, acyclovir, or buffer. Retinae then were inoculated with herpes simplex virus-1 or buffer 1 week after the injection of drug. In another experiment we compared the effects of acyclovir diphosphate dimyristoylglycerol and acyclovir diphosphate dioleoylglycerol on the optical clarity of vitreous.. Animals injected intravitreally with acyclovir diphosphate dimyristoylglycerol showed retinitis that was less severe than that in animals injected with ganciclovir, acyclovir, and buffer; differences in grading scores of the retinitis between animals injected with acyclovir diphosphate dimyristoylglycerol and those injected with buffer were statistically significant (P = 0.0015). Vitreous and optical media became clear 4 days after acyclovir diphosphate dioleoylglycerol injection compared with 10 days after with acyclovir diphosphate dimyristoylglycerol injections.. Acyclovir diphosphate dimyristoylglycerol had prolonged antiviral activity against herpes simplex virus-1 retinitis in a rabbit model. This drug delivery system, modified to improve optical clarity, may allow long-acting intravitreal treatment of cytomegalovirus retinitis and other retinal diseases.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Ganciclovir; Herpes Simplex; Liposomes; Phosphatidylglycerols; Prodrugs; Rabbits; Retinitis; Simplexvirus; Virus Replication

The animal model of necrotic hepatitis caused by HSV-1 infection in juvenile mice was used to compare the efficacies of the oral antiherpes agents famciclovir (FCV), valaciclovir (VACV) and brivudin (BVDU). The experimental infection allows the measurement of viral replication in the liver by macroscopic lesions and the evaluation of mortality from encephalitis. Mice intravenously inoculated with a highly virulent clinical HSV-1 isolate were orally treated by gavage over a period of 3 days starting on day 2 post infection. The reference drug acyclovir (ACV) was administered subcutaneously. Necrotic hepatitis was significantly (p < 0.01) reduced by treatment with FCV, VACV and ACV at a dose of 50 mg/kg per day divided into 3 doses. No significant effect was achieved with BVDU at 200 mg/kg per day. Treatment with FCV at 50 mg/kg per day, ACV at 100 mg/kg per day, and VACV at 200 mg/kg per day significantly (p < 0.001) decreased mortality in mice. BVDU treatment at 200 mg/kg per day did not reduce mortality but significantly prolonged (p < 0.05) the survival time.

Topics: 2-Aminopurine; Acyclovir; Animals; Antiviral Agents; Bromodeoxyuridine; Cell Line; Disease Models, Animal; Famciclovir; Hepatitis, Animal; Herpes Zoster; Herpesvirus 1, Human; Liver; Mice; Mice, Inbred BALB C; Valacyclovir; Valine; Viral Plaque Assay; Virus Replication

Neonatal herpes simplex virus (HSV) infection produces severe disease with unacceptable morbidity and mortality with current antiviral therapies. The effect of therapy with passive anti-HSV antibody and acyclovir was evaluated using a guinea pig model of neonatal HSV. Newborn animals were inoculated intranasally and treated with acyclovir (60 mg/kg/day) or antibody (or both), beginning on days 0, 2, or 3 after HSV-2 inoculation. Acyclovir alone was effective only when begun on day 0, and antibody alone was effective when begun on or before day 2. Only combination therapy was effective on day 3, reducing mortality from 82% (14/17) in controls to 44% (7/16; P < .05). Combined therapy also significantly reduced the duration of skin, eye, and mouth disease and respiratory symptoms but not recurrent disease. These data suggest that addition of antibody therapy to acyclovir may improve the outcome of neonatal HSV disease.

Topics: Acyclovir; Animals; Animals, Newborn; Antibodies, Viral; Antibody-Dependent Cell Cytotoxicity; Antiviral Agents; Chemotherapy, Adjuvant; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Guinea Pigs; Herpes Genitalis; Herpes Simplex; Herpesvirus 2, Human; Immunization, Passive; Pregnancy; Rabbits; Random Allocation; Recurrence

The ability of famciclovir and valaciclovir to affect the establishment and maintenance of latency in mice with a cutaneous herpes simplex type 1 (HSV-1) infection was examined. Mice were treated via drinking water starting at various times between days 1 and 5 and terminating on day 10 after inoculation. Clinical signs and viral replication in the target tissues were monitored. Three to four months later, trigeminal and dorsal root ganglia were explanted from groups of 16 mice and examined for latent virus by cocultivation. The two compounds differed in their effects on the acute neural infection, and ganglia explanted from famciclovir-treated mice were markedly reduced in their ability to reactivate virus, although neither drug affected latency if treatment was delayed for several months. The difference between the compounds is likely to reflect differences in the metabolism of their respective products, penciclovir and acyclovir, in infected neurons.

Topics: 2-Aminopurine; Acute Disease; Acyclovir; Animals; Antiviral Agents; Brain Stem; Disease Models, Animal; Ear, External; Famciclovir; Female; Ganglia, Spinal; Herpes Simplex; Herpesvirus 1, Human; Mice; Mice, Inbred BALB C; Prodrugs; Trigeminal Ganglion; Valacyclovir; Valine; Virus Activation; Virus Latency; Virus Replication

The purpose of this study was to carry out an extensive examination of the C* concept for prediction of the topical antiviral efficacies of acyclovir (ACV) formulations in a hairless mouse model for the treatment of cutaneous herpes simplex virus type-1 (HSV-1) infections. This method is based on estimation of the free drug concentration at the target site (C*), which is presumed to be the basal cell layer of the epidermis. Five different formulations (containing 5% ACV) were examined in a finite dose multiple dosing regimen (twice a day application) to simulate the clinical situation. For determination of C*, in vitro ACV fluxes across the hairless mouse skin were measured in an in vivo-in vitro experimental design that approximated the in vivo antiviral treatment protocol. Then, the in vivo antiviral efficacies were measured using a 1-day delayed (after HSV-1 virus inoculation) 4-day treatment protocol. 10 microL/cm2 dose of ACV formulation was applied every 12 h for 4 days after which the lesions were scored and efficacies were calculated. Our results indicate that, over a wide range of efficacies, the predictions based on C* (estimated from the experimental fluxes) are in good agreement with the in vivo antiviral efficacies. These studies, therefore, support the validity of the C* concept for various ACV formulations and suggest that the C* approach has potential for future practical situations.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Herpes Simplex; Herpesvirus 1, Human; Humans; Mice; Mice, Hairless

A novel ocular microdialysis-perfusion technique was developed that allowed for the continuous sampling of the vitreous humor for drug. The technique produced accurate and rapid vitreous drug concentration time profiles with a resolution of 20 minutes on the time axis. The vitreous elimination of ganciclovir (GCV) and acyclovir (ACV) was extremely rapid, having vitreous half lives of 2.62 and 2.98 hours, respectively, and a transretinal mechanism of clearance was established for these compounds. Further, it was shown that the compounds do not exhibit saturation kinetics over the dosage ranges used in the clinical setting. Ocular pigmentation had a dramatic effect on the vitreous pharmacokinetics of GCV and ACV. The rate of elimination of GCV and ACV from the vitreous of the pigmented rabbit was much slower than the elimination from the albino rabbit (t 1/2 = 5.59 vs. 2.62 for GCV and 8.63 vs. 2.98 for ACV). The mean residence time of GCV was 2 times greater in the pigmented rabbit than in the albino rabbit and 3 times greater for ACV. Further, the volumes of distribution increased by 3.5 fold for GCV and 6.2 fold for ACV, respectively.

Topics: Acyclovir; Animals; Antiviral Agents; Cytomegalovirus Retinitis; Disease Models, Animal; Drug Delivery Systems; Ganciclovir; In Vitro Techniques; Male; Melanins; Microdialysis; Rabbits; Vitreous Body

We treated two patients with dendritic keratitis that did not respond to acyclovir (ACV) ointment therapy. Their systemic immune status was normal: however, one patient had a long history of atopic disease and the other had previously undergone topical corticosteroid treatment. HSV-1 was isolated from the patients and inoculated into animals to investigate its viral pathogenicity and latent infection.. HSV-1 isolates from the patients were tested for drug sensitivity to acyclovir, ganciclovir, idoxuridine, trifluridine, foscarnet and interferon-beta in vitro. In in vivo studies, bilateral corneas of two New Zealand white rabbits and 10 BALB/c mice in each of four groups were infected by the respective viral isolates. The extent of corneal epithelial and/or stromal lesions produced by the viruses was evaluated. The trigeminal ganglial tissues of the mice were examined for viral latent infection by co-culture with Vero cells.. Herpetic keratitis in both patients was characterized by prolonged clinical course, succeeded by various types of corneal lesions and ocular complications. In in vitro studies, the two HSV-1 isolates demonstrated cross-resistance to ACV, ganciclovir and/or idoxuridine. Both strains demonstrated weakly virulent corneal epithelial and/or stromal lesions in rabbits and mice. One isolate displayed delayed advent but prolonged course of epithelial lesions in rabbits. The latent infection incidences of the isolates in mice trigeminal ganglia were 6.25% (1/16) and 0% (0/18) respectively.. Topical immune depression may induce ACV-resistant HSV-1 infection in the cornea, with a prolonged course in association with ocular complications. The prolonged infectious course of the viral isolates in the animal study partially supported the clinical demonstrations in the patient. The existence of latent infection by one ACV-resistant HSV-1 in its animals may indicate the possibility of its recurrence. Trifluridine may be an alternative choice for treating corneal epithelial lesions caused by ACV-resistant HSV-1.

Topics: Acyclovir; Administration, Topical; Adult; Animals; Antiviral Agents; Cornea; Culture Techniques; Disease Models, Animal; Drug Resistance, Microbial; Fluorescent Antibody Technique, Indirect; Herpesvirus 1, Human; Humans; Idoxuridine; Keratitis, Dendritic; Male; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Ointments; Rabbits; Trigeminal Ganglion

Supported by the antiherpetic properties of 3-quinolinecarboxamides and the importance of the planar intramolecular H-bonded beta-keto amide pharmacophore, a series of novel conformationally rigid analogues that contain a heterocyclic bridge between the 3- and 4-positions of the quinoline ring have been evaluated. Two isoxazolo-fused derivatives 17 and 23 displayed good in vitro antiherpetic potency that was similar to that of 1, the 3-quinolinecarboxamide that served as the comparison structure for this study. The pyrazolo, pyrrolo, and pyrimido derivatives showed considerably less or no activity. In vitro activity did not translate to in vivo efficacy. For 17, the lack of in vivo activity is likely a consequence of insufficient plasma drug levels (both Cmax and duration) in mice relative to the MIC versus HSV-2.

Topics: Animals; Antiviral Agents; Disease Models, Animal; Herpes Genitalis; Herpesvirus 2, Human; Magnetic Resonance Spectroscopy; Mice; Quinolines; Viral Plaque Assay

Various anti-viral agents, e.g., interferon, have recently been used for the treatment of viral hepatitis. In the present study, duck hepatitis B virus (DHBV) was cultured in vitro and the anti-DHBV effects of acyclovir (ACV) and vidarabin 5'-monophosphate (VMP) were studied. The portal perfusion method was applied to the livers of 7-day-old white ducks weighing 100 g, bred in Japan, and hepatocytes were infected with DHBV in vitro. Duck hepatocytes infected with DHBV were cultured in medium containing ACV or VMP, and the anti-DHBV effects of these drugs were assessed by determining DHBV-DNA and duck hepatitis B surface antigen in the medium. Both ACV and VMP had anti-DHBV effects when used immediately after infection; however, both drugs were ineffective in hepatocytes obtained from a DHBV carrier duck. In conclusion, the anti-DHBV effects of these drugs were very limited. However, this culture system appears to be useful for studies of hepatitis virus and anti-viral drugs.

Topics: Acyclovir; Animals; Antibodies, Monoclonal; Antigens, Viral; Blotting, Southern; Cells, Cultured; Disease Models, Animal; DNA, Viral; Drug Therapy, Combination; Ducks; Hepatitis B; Hepatitis B virus; Perfusion; Vidarabine Phosphate

The ribonucleotide reductase inhibitor MDL 101,731 was examined for antiviral activity against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) in vitro and in combination with acyclovir in the murine zosteriform model of HSV-1 infection. The in vitro antiviral activity (IC50) for both serotypes of HSV was similar and in the range 23-98 nM for Vero cells. Comparable activities were obtained against acyclovir-resistant viruses. In the zosteriform model, topical combination therapy of MDL 101,731 with acyclovir (5%:5% w/w) applied 48 h after infection was more effective than acyclovir alone and even appeared to promote lesion resolution.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Deoxycytidine; Disease Models, Animal; Enzyme Inhibitors; Female; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Mice; Mice, Inbred BALB C; Molecular Structure; Ribonucleotide Reductases

Acyclovir phosphonate [9-(3-phosphono-propyloxymethyl)guanine; SR3722] and the S enantiomer (SR3772), R enantiomer (SR3773), and R,S enantiomeric mixture (SR3745A) of ganciclovir phosphonate (9-[((+/-)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine) were evaluated for their antiviral activities against murine cytomegalovirus. In severe combined immunodeficient mice infected with murine cytomegalovirus, SR3773 and SR3745A (12.5, 25, and 50 mg/kg of body weight per day) were superior to ganciclovir in extending the mean time to death, whereas SR3722 and SR3772 was less potent than ganciclovir. In normal BALB/c mice, SR3773 and ganciclovir were approximately equally active in preventing death. SR3773 caused renal tubular damage when administered at 50 mg/kg/day for 15 days. These results suggest that SR3773 may have potential for use in the treatment of human cytomegalovirus infections, but it may also exhibit renal toxicity.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Female; Ganciclovir; Herpesviridae Infections; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Microbial Sensitivity Tests; Muromegalovirus; Nucleotides; Stereoisomerism

The use of controlled transdermal delivery of acyclovir (ACV) in the treatment of cutaneous herpes simplex virus type 1 infections in hairless mice was investigated. Using an in vivo animal model (A. Gonsho, et al. Int. J. Pharm. 65:183-194 (1990)) made it possible to quantify both, the topical and the systemic antiviral efficacy of ACV transdermal patches as a function of the drug delivery rate of the patches. Drug delivery rates required to attain systemic efficacy were found to be higher than the rates required to attain the same magnitude of topical efficacy. The ACV concentrations in the basal cell layer of the epidermis for 50% topical efficacy and 50% systemic efficacy were estimated. The basal epidermis layer was considered to be the site of antiviral drug activity (skin target site). Systemic plasma levels were obtained from pharmacokinetic studies and were used to estimate the ACV concentration achieved systemically in the basal epidermis layer. A computational model for drug permeation across skin was employed to estimate the ACV concentration achieved topically in the basal epidermis layer. Equal topical and systemic efficacies were found to correspond to equal drug concentrations at the site of antiviral activity. The length of the effective diffusion pathway of drug molecules in the dermis prior to entering the blood circulation was assumed to be approximately equal to 1/20 of the anatomical dermis thickness because of dermis vascularization.

Topics: Acyclovir; Administration, Cutaneous; Animals; Disease Models, Animal; Female; Herpes Simplex; Herpesvirus 1, Human; Mice; Mice, Hairless; Skin; Skin Absorption; Skin Diseases

Detection of hepadnaviral DNA in extrahepatic tissues of human and animal models of hepatitis B virus (HBV) has raised the question of whether virus replication in organs other than the liver could be targeted for the treatment of chronic hepatitis B. Since duck hepatitis B virus (DHBV) replication is dynamic in the liver, kidney, pancreas, and spleen of newly hatched ducklings infected in ovo, we used the duck model and the new antiherpesvirus agent, famciclovir (FCV), to determine whether antiviral effect of nucleoside analogues on DHBV replication is pluripotential. Day-old ducklings hatched from eggs laid by a DHBV-carrier duck were bled and administered FCV (25 mg/kg/bd) orally for periods of 1, 2, 3, 6, 9, and 12 days. Seventeen (17) hours after the last dose of each regimen the duckling(s) was bled and postmortem samples of liver, kidney, pancreas, and spleen were snap-frozen and stored at -70 degrees C. Analysis of plasma samples of ducklings treated for 2 days and longer by dot-blot hybridisation showed that levels of DHBV DNA were reduced significantly compared to levels in samples collected before treatment begun. Southern blot hybridisation of tissue DNA corroborated these results and showed that DHBV DNA replicative intermediates in all the tissues examined were reduced to levels that reflected the amount of virus released into the blood of each treated duckling. It is concluded from these results that if antiviral agents could be transformed to active metabolites in any infected tissues including the liver, replication of hepadnaviruses would be inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 2-Aminopurine; Acyclovir; Administration, Oral; Animals; Animals, Newborn; Antiviral Agents; Biotransformation; Disease Models, Animal; DNA, Viral; Ducks; Eggs; Famciclovir; Guanine; Hepadnaviridae Infections; Hepatitis B Virus, Duck; Kidney; Liver; Organ Specificity; Pancreas; Poultry Diseases; Prodrugs; Spleen; Viremia; Virus Replication; Xanthine Oxidase

The creatine kinase/creatine phosphate (CK/CrP) system plays an important role in cellular energy homeostasis. CK isoenzymes, which reversibly generate ATP from CrP, are compartmentalized at cellular sites where energy is produced or utilized. It has been noted that the expression of CK is induced in cells infected by several DNA viruses, implicating a role for cellular energy modulation as an important step for efficient viral replication. A CK substrate analog, 1-carboxymethyl-2-iminoimidazolidine (cyclocreatine; CCr), was tested in vitro for antiviral activity against a variety of herpes viruses and RNA viruses. Several members of the human herpes virus family were found to be sensitive to CCr, including herpes simplex types 1 and 2 (HSV-1 and HSV-2). varicella-zoster virus, and cytomegalovirus. When administered to mice infected vaginally with HSV-2, CCr significantly reduced mortality, reduced vaginal lesion scores, and lowered the titers of recoverable virus. This treatment combined with acyclovir appeared to enhance the antiviral effects of acyclovir. In a second model, mice infected intraperitoneally with HSV-2 and treated with CCr showed a significant increase in survival compared to placebo. We conclude that CCr is the first example of a new class of antiviral compounds that target the CK/CrP system.

Topics: Acyclovir; Animals; Creatinine; Disease Models, Animal; Drug Resistance, Microbial; Drug Therapy, Combination; Encephalitis; Female; Guanosine Triphosphate; Herpes Genitalis; Herpesviridae; Herpesviridae Infections; Humans; Mice; Microbial Sensitivity Tests; RNA Viruses; Survival Rate; Virus Replication

Previous studies demonstrated that the adjuvant-free form of a fusion protein consisting of a truncated herpes simplex virus type 1 (HSV-1) glycoprotein D and human interleukin-2 (tgD-IL-2) elicited superior protective immunity in mice. In this study, the immunotherapeutic efficacy of tgD-IL-2 against vaginal HSV-2 infection was investigated using a guinea pig model. Footpad injections of tgD-IL-2 (12.5 micrograms/dose) after the onset of primary lesions strongly suppressed recurrence in the chronic phase of infection; consequently, the number of days with lesions was reduced 65%. Continuous medication with 100 mg/kg/day acyclovir for 5 days failed to suppress recurrent infection. In a UV radiation-induced recurrence model, prophylactic tgD-IL-2 significantly suppressed both duration and severity of disease. A single injection of tgD-IL-2 plus acyclovir produced an additive effect on the suppression of the disease in the acute phase. These results suggest that tgD-IL-2 is a promising immunotherapeutic agent against HSV-2 genital infections.

Topics: Acute Disease; Acyclovir; Animals; Chemotherapy, Adjuvant; Disease Models, Animal; Female; Guinea Pigs; Herpes Genitalis; Herpesvirus 2, Human; Immunotherapy; Interleukin-2; Recombinant Fusion Proteins; Recurrence; Ultraviolet Rays; Vagina; Viral Envelope Proteins; Virus Replication; Virus Shedding

Intranasal inoculation of newborn guinea pigs with herpes simplex virus (HSV) resulted in local skin-eye-mouth (SEM), central nervous system (CNS), and disseminated infections with high but not universal mortality. Cutaneous HSV inoculation produced self-limited SEM infection without evidence of CNS or disseminated disease. HSV infection of the upper respiratory tract of the newborn guinea pig resulted in early spread to the CNS and frequent viral dissemination. The outcome of infection was favorably affected by treatment with acyclovir. Spontaneous cutaneous recurrences occurred in most survivors. The newborn guinea pig should provide a useful model to explore both the pathophysiology and control of neonatal HSV infection.

Topics: Acyclovir; Animals; Animals, Newborn; Cell Line; Disease Models, Animal; Female; Guinea Pigs; Herpes Genitalis; Herpes Simplex; Herpesvirus 2, Human; Humans; Nasal Mucosa; Pregnancy; Rabbits; Scalp

In vitro permeability studies were conducted on isolated rabbit corneal membranes using aliphatic acyl esters of acyclovir to determine the effect of lipophilicity on the transcorneal diffusion. Corneal membrane permeability coefficients increased with increasing lipophilicity of the straight chain aliphatic esters. The branch chain ester, acyclovir isobutyrate, displayed an anomalously low corneal permeability when compared to acyclovir esters having similar molecular size and 1-octanol/water partition coefficient. In vivo corneal penetration studies were conducted on unanesthetized rabbits. The aqueous humor concentrations of acyclovir and the ester prodrugs were measured at twenty five minutes after the topical instillation of an aqueous solution of the appropriate compound. The concentration of acyclovir in the aqueous humor increased with increasing 1-octanol/water partition coefficient. The lipophilic modification was shown to have a greater effect on increasing productive corneal absorption than the precorneal loss pathways. The effectiveness of acyclovir butyrate as a treatment for primary herpetic keratitis was evaluated in the McKrae strain infected rabbit model. The compound did not lose activity due to the esterification of the 2' hydroxyl group.

Topics: Absorption; Acyclovir; Acylation; Animals; Aqueous Humor; Biological Transport; Cell Membrane Permeability; Cornea; Disease Models, Animal; Drug Evaluation; Esters; Herpesvirus 1, Human; Keratitis, Herpetic; Male; Prodrugs; Rabbits

To determine the potential efficacy and anatomic sites of action of prophylactic oral acyclovir using a murine model of ultraviolet-B-induced reactivation of herpes simplex 1 keratitis.. Latent infection with herpes simplex 1 (McKrae) was established in 80 National Institutes of Health inbred strain of mice. Forty of the mice were given acyclovir orally and the other 40 latently infected mice served as controls. Mice were exposed to 250 mJ/cm2 of ultraviolet-B radiation and killed on days 1, 2, 3, and 4 after ultraviolet-B radiation. Trigeminal ganglia and eyes from these mice were homogenized and incubated on Vero cell monolayers for recovery of reactivated virus.. Based on the recovery of infectious virus after ultraviolet-B in treated versus control groups, acyclovir effectively reduced detectable viral reactivation at both the ocular level (P = 0.003) and the ganglionic level (P = 0.025). The numbers of viral culture-positive eye and trigeminal ganglia homogenates in the control group were 11 and 6 out of 40, respectively, compared to 1 and 0 out of 40 culture-positive eye and trigeminal ganglia homogenates in the acyclovir treated mice. Therapeutic serum levels of acyclovir were confirmed by high performance liquid chromatography. In the acyclovir-tested group, the single case of viral break-through at the ocular surface was not an acyclovir-resistant mutant.. Prophylactic acyclovir effectively reduces the incidence of herpes simplex virus-1 reactivation after ultraviolet-B-induced reactivation in National Institutes of Health inbred strain of mice.

Topics: Acyclovir; Administration, Oral; Animals; Cornea; Disease Models, Animal; Female; Herpesvirus 1, Human; Keratitis, Herpetic; Mice; Mice, Inbred Strains; Premedication; Ultraviolet Rays; Vero Cells; Virus Activation

The nucleoside analogue (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) inhibited the replication of herpes simplex virus (HSV) types 1 and 2 in tissue culture cells at about 1.0 micrograms/ml, whereas Acyclovir (ACV) had an EC50 of about 0.10-0.50 micrograms/ml. The purpose of these studies was to evaluate the efficacy of topically applied HPMPC in animal models of primary and recurrent genital HSV-2 infections. Mice treated with 5%, 1% or 0.5% HPMPC three times daily, beginning 6 or 24 h after virus inoculation had reduced vaginal viral replication regardless of time of initiation of therapy. ACV at 5% also reduced vaginal viral replication, but not as effectively as HPMPC. In primary infection of guinea pigs, therapy with 5% or 1% HPMPC beginning at 24 h but not 72 h significantly altered lesion development. However, 5% HPMPC was highly toxic to guinea pigs. Vaginal viral replication was reduced significantly with either 1% or 0.3% HPMPC initiated at 24 h. In these studies, HPMPC was also more efficacious than 5% ACV. Topical treatment with 1% HPMPC did not reduce the incidence or severity of spontaneous or UV-induced recurrent genital lesions. These results indicate that topical therapy with 1%, 0.5% or 0.3% HPMPC was more effective than 5% ACV in the treatment of primary genital HSV-2 infections of guinea pigs and mice and suggest that HPMPC should be considered for topical use in humans.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Cidofovir; Cytosine; Disease Models, Animal; Female; Guinea Pigs; Herpes Genitalis; Mice; Organophosphonates; Organophosphorus Compounds; Simplexvirus; Ultraviolet Rays; Vagina; Vaginal Diseases; Virus Replication

The nucleoside analog 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5- ethyluracil (FEAU) was tested in a rabbit model of acute herpetic keratitis and its effectiveness compared with that of acyclovir (ACV). FEAU or ACV was applied topically 3 times daily, beginning 3 days post-HSV-1 inoculation and continued for a period of 7 days. FEAU at a concentration of 1% (w/v) or 3% ACV resulted in significant lessening of the severity of corneal lesions, conjunctivitis, iritis, and corneal clouding at 24 to 48 h after beginning chemotherapy. No toxic reaction was observed in any rabbit eyes treated with either FEAU or ACV. The duration of virus shedding into tear film and colonization of the trigeminal ganglia, however, were not reduced by either FEAU or ACV treatment begun 3 days post-inoculation. Fifty percent effective dose (ED50) of FEAU determinations performed on isolates from tear film and on the virus inoculum in secondary rabbit kidney cultures yielded a range of 4.6-7 microM, with two in vitro resistant isolates having ED50S of greater than or equal to 1500 microM of FEAU. Fifty percent cell growth inhibition for FEAU was 3000 microM at 72 h.

Topics: Acyclovir; Animals; Antiviral Agents; Arabinofuranosyluracil; Cells, Cultured; Cornea; Disease Models, Animal; Drug Evaluation, Preclinical; Keratitis, Herpetic; Male; Ophthalmic Solutions; Rabbits; Simplexvirus

This report describes the study of a novel animal model for the topical treatment of cutaneous herpes virus infections, with a focus upon the relationship between the dermal flux of the antiviral agent and the effectiveness of the topical therapy. A recently developed (trans)dermal delivery system (TDS) for controlling acyclovir (ACV) fluxes was employed in the treatment of cutaneous herpes simplex virus type 1 (HSV-1) infections in hairless mice. The TDS's were fabricated with rate-controlling membranes to provide nearly constant fluxes of ACV for up to 3 to 4 days. At the end of each experiment an extraction procedure was used to determine the residual ACV, validating the drug delivery performance of the TDS. Virus was inoculated into the skin of the mice at a site distant from the TDS area, and the induced lesion development was evaluated to distinguish between topical and systemic effectiveness of the therapy. In the main protocol, ACV therapy was initiated 0, 1, 2, and 3 days after virus inoculation and the lesion development "scored" on Day 5. The topical efficacies of 1- and 2-day-delayed treatments were essentially the same as that of a 0-day-delayed treatment, while the topical efficacy of a 3-day-delayed treatment was much poorer. Also, in the cases of 0-, 1-, and 2-day-delayed treatments, topical efficacy increased with increasing flux in the range of 10 to 100 micrograms/cm2-day. When the ACV flux was 100 micrograms/cm2-day or greater, a maximum 100% topical efficacy was obtained. The results for systemic efficacy were shifted to higher fluxes: approximately 10-fold greater ACV fluxes were necessary to provide efficacy equal to the topical efficacy results. The animals treated with a high ACV flux (350-500 micrograms/cm2-day) lived significantly longer than those treated with a low ACV flux (10-125 micrograms/cm2-day) and those of untreated (placebo) animals. Further, their mean survival time decreased with an increase in the time delay for ACV treatment. In contrast, the mean survival time for the animals which received a low ACV flux was similar to that of the control animals and remained unaltered with an increase in the time delay for ACV treatment. The approach developed in this study should be valuable in (a) the screening of new antiviral agents for the topical treatment of cutaneous herpes virus infections and (b) in the optimization of drug delivery systems (i.e., topical formulations).

Topics: Acyclovir; Administration, Cutaneous; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Herpes Simplex; Mice; Mice, Hairless; Simplexvirus

The effect of oral BV-araU was tested in cutaneous model infections of shaved Balb/c mice with herpes simplex virus type 1 (HSV-1). Progression of cutaneous symptoms associated with cutaneous infection with HSV-1 F strain was inhibited by BV-araU at doses of 20 and 50 mg/kg twice daily, beginning one day post-infection, resulting in significant increase in the survival rate. Onset of disease was suppressed in most animals receiving 100 mg of BV-araU per kg. BV-araU (20 mg/kg or more) also significantly increased the survival rate of mice infected with HSV-1 WT-51 strain. The efficacy of BV-araU was not affected by gender or age (6-9 weeks) of the mice. BV-araU was effective even when the treatment was started 2.5 days post-infection. The efficacy of BV-araU against F strain infection was comparable to that of acyclovir, but acyclovir showed therapeutic effects at lower doses compared with BV-araU against WT-51 strain infection. Against infection of cyclophosphamide-treated immunosuppressed mice with HSV-1 KOS(S) strain, BV-araU decreased the morbidity rate and severity of symptoms at doses of 200 and 100 mg/kg, respectively, and all mice given 50 mg of BV-araU or more per kg survived, suggesting oral efficacy can be achieved against HSV-1 infections in immunosuppressed individuals.

Topics: Acyclovir; Administration, Oral; Animals; Antiviral Agents; Arabinofuranosyluracil; Disease Models, Animal; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Herpes Simplex; Immune Tolerance; Male; Mice; Mice, Inbred BALB C

Discs 1.6 mm in diameter trephined from corneal collagen shields were used to deliver acyclovir (ACV) to the cornea of mice inoculated with herpes simplex virus type 1 (HSV-1). In the first minute after application to the cornea, there was a 23% decrease of ACV in the discs. After the first minute, ACV clearance from the discs appeared to be exponential with a half-life of 21 minutes. Treatment given 3 times a day reduced HSV-1 titer in tear film, corneal tissue, and trigeminal ganglia. This animal model should be useful to conserve novel potential anti-viral drugs undergoing initial screening.

Topics: Acyclovir; Animals; Biological Dressings; Collagen; Cornea; Disease Models, Animal; Drug Carriers; Drug Evaluation, Preclinical; Keratitis, Dendritic; Mice; Mice, Inbred BALB C; Simplexvirus

Inoculation of congenitally hairless guinea pigs with varicella-zoster virus (VZV) (Oka strain) results in a self-limited exanthematous infection analogous to varicella in children. Administration of acyclovir or 6-methoxypurine arabinoside modified the course of infection. This model should facilitate pre-clinical testing of putative anti-VZV agents.

Topics: Acyclovir; Animals; Antiviral Agents; Cells, Cultured; Child, Preschool; Disease Models, Animal; Drug Evaluation, Preclinical; Exanthema; Guinea Pigs; Herpes Zoster; Herpesvirus 3, Human; Humans

The acyclic nucleoside derivative HOE 602 (2-amino-9-[1,3-bis(isopropoxy)-2-propoxymethyl]purine) was evaluated for its antiviral activity in cell culture and for its therapeutic efficacy in mice infected with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) or with murine cytomegalovirus (MCMV). HOE 602 was inactive in vitro against a variety of DNA- and RNA-viruses. However it prevented symptoms and mortality in mice systemically infected with HSV-1, HSV-2 or MCMV when administered intraperitoneally or orally at a dosage of 100 mumol/kg twice per day. Pharmacokinetic studies in mice and macaques revealed that HOE 602 was converted via three metabolic steps to ganciclovir, which seemed to be the antivirally active compound. The bioavailability of ganciclovir after oral administration of HOE 602 or ganciclovir was similar in mice, while in rhesus monkeys much higher serum levels of ganciclovir were reached with HOE 602. After intraperitoneal or intravenous administration higher drug levels were obtained with ganciclovir. The excellent therapeutic efficacy in animal models, the high enteral absorption in monkeys, and the favourable physical properties will hopefully lead to an orally active drug against cytomegalovirus and severe herpes infections in man.

Topics: Acyclovir; Animals; Antiviral Agents; Biological Availability; Cytomegalovirus Infections; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Ganciclovir; HeLa Cells; Herpes Simplex; Macaca mulatta; Mice; Mice, Inbred BALB C; Molecular Structure; Purines; Vero Cells

1-beta-D-Arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) and acyclovir were compared for their antiviral effects against herpes simplex virus type 1 (HSV-1) model infections in mice. Both drugs were not toxic to mice when they were administered orally by the same schedule used for therapeutic experiments. Brovavir was less toxic than acyclovir when injected by the intraperitoneal (i.p.) route. Marked efficacies of brovavir by either oral or i.p. administration were demonstrated in both experimental encephalitis and i.p. infection with HSV-1 WT-51 strain. Treatment with brovavir at a dose of 15 or 25 mg/kg twice daily resulted in increasing both survival rate and mean survival time of the infected mice. On the contrary, acyclovir showed only marginal effect against the experimental encephalitis. Survival rates of mice treated with brovavir were higher than those treated with acyclovir at corresponding doses with statistical significance. The superiority of brovavir was also found in the intracerebral infection with strain VR-3, a highly virulent strain for mice. Brovavir, but not acyclovir, at a dose of 200 mg/kg reduced the mortality. Acyclovir, however, were significantly effective in reducing mortality of systemically infected mice by both oral and i.p. administrations. The effective dose of acyclovir was lower than that of brovavir against i.p. infection with strain WT-51. Differences in mortality of strain VR-3-infected mice were statistically significant between acyclovir- and brovavir-treated groups.

Topics: Acyclovir; Animals; Antiviral Agents; Arabinofuranosyluracil; Disease Models, Animal; Drug Administration Routes; Encephalitis; Herpes Simplex; Humans; Male; Mice; Simplexvirus; Survival Rate

Topics: Abortion, Threatened; Acute Disease; Acyclovir; Animals; Animals, Newborn; Disease Models, Animal; Female; Fetal Death; Herpes Simplex; Litter Size; Mice; Pregnancy; Pregnancy Complications, Infectious

The cell-specific expression of herpes simplex virus 1 thymidine kinase (HSV-1-tk) has provided a simple and highly efficient technique to achieve conditional ablation of targeted cell types in transgenic mice. The ablation is induced by treating transgenic animals expressing HSV-1-tk with the antiherpetic drug ganciclovir. In lymphoid tissues of mice expressing HSV-1-tk from an immunoglobulin promoter, administration of ganciclovir leads to massive destruction of B- and T-cell lineages. Tissues not expressing HSV-1-tk are insensitive to drug treatment. After depletion of greater than 99% of total thymocytes, a number of progenitor cells remain that are able to repopulate all T-cell lineages within 7 days. The ability to control and direct ablation allows for creation of conditional mutant phenotypes at precise periods of development. This technique also provides a potential means to enrich stem cell populations as well as permitting the creation of animal models for particular pathological conditions.

Topics: Acyclovir; Animals; Antigens, Differentiation, T-Lymphocyte; Cell Survival; Disease Models, Animal; Enhancer Elements, Genetic; Ganciclovir; Immunologic Deficiency Syndromes; Lymphoid Tissue; Mice; Mice, Transgenic; Simplexvirus; Thymidine Kinase; Time Factors; Tissue Distribution

Topics: Acyclovir; Adenine; Animals; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Ganciclovir; Guanine; Herpes Simplex; Male; Mice; Mice, Inbred ICR; Prodrugs

Cytomegalovirus (CMV) pneumonia causes significant morbidity and mortality in bone marrow transplant recipients and in patients with AIDS. 9-(1,3-Dihydroxy-2-propoxymethyl) guanine (ganciclovir) and phosphonoformic acid (PFA) demonstrate activity against CMV in human infections, although recurrent CMV and systemic drug toxicity frequently develop. We examined the efficacy of aerosol administration of antiviral agents against murine CMV (MCMV) infection. Animals were inoculated with MCMV intranasally and were treated with oral ganciclovir; with aerosolized ganciclovir, PFA, or ribavirin; or with buffer. MCMV in lung and salivary gland homogenates was quantified by plaque assay. Oral ganciclovir (200 mg/kg per day) reduced titers of MCMV in both tissues by greater than 95%. Aerosolized ganciclovir, 100 and 200 mg/kg per day, reduced lung titers of MCMV by 93% and 97%, respectively. Aerosolized PFA, 20 and 200 mg/kg per day, reduced lung titers of MCMV by 60% and 68%, respectively. Aerosolized ganciclovir and PFA inhibited replication of MCMV in salivary glands substantially less than did oral administration of either agent. Our results suggest that aerosol administration of antiviral agents can potently and selectively inhibit replication of MCMV in the lung.

Topics: Acyclovir; Administration, Oral; Aerosols; Animals; Antiviral Agents; Cytomegalovirus Infections; Disease Models, Animal; Female; Foscarnet; Ganciclovir; Mice; Mice, Inbred BALB C; Phosphonoacetic Acid; Pneumonia, Viral; Pregnancy; Pregnancy Complications, Infectious; Ribavirin

The herpesvirus DNA polymerase inhibitor foscarnet, applied topically, and the anti-herpesvirus guanosine analogue buciclovir, given orally, decreased virus replication and disease development in primary skin infections of mice caused by herpes simplex virus type 1 (HSV-1). If the same tissues were infected via sensory nerves, following zosteriform spread of the virus the same treatments showed strongly decreased efficacy, or were inefficacious, when started before development of clinical signs in the infected tissues. These results were obtained in murine models of zosteriform spread of HSV-1 to the ear (following inoculation of the ventral side of the neck) or to the lower flank (following inoculation of the upper flank). In these models the immune system played a dominant role in virus clearance. The topically applied foscarnet could not prevent disease development in these models of recrudescent disease even when applied before the virus was detected in the skin, but a decrease in virus titre was obtained. Orally administered buciclovir lost efficacy when administered at the time of virus entry into the skin, i.e. 1 or 2 days before development of clinical signs. In the flank model, measuring lesion development, orally administered acyclovir also had a strongly decreased efficacy, when compared with its effect during infections in which lesion development did not involve translocation of virus through nerves. In the presence of developing immunity the inhibitors could not accelerate the clearance of virus from infected tissues. Furthermore, all treatments (topical foscarnet and oral buciclovir or acyclovir) were without effect on disease development when treatment was initiated on appearance of the first clinical signs of disease. As disease development following zosteriform spread of HSV resembles that in recurrent herpes in humans, and as the limited efficacy of the inhibitors observed resembles the poor results obtained with inhibitors of herpesvirus DNA synthesis in clinical studies on the treatment of symptomatic recurrent herpes, we suggest the use of animal models of zosteriform spread for pre-clinical evaluation of new antiherpes drugs.

Topics: Acyclovir; Administration, Oral; Administration, Topical; Animals; Antiviral Agents; Disease Models, Animal; DNA Replication; DNA, Viral; Foscarnet; Herpes Simplex; Male; Mice; Nervous System Diseases; Organophosphorus Compounds; Phosphonoacetic Acid; Recurrence; Simplexvirus; Skin; Skin Diseases, Infectious; Virus Replication

Topics: Acyclovir; Animals; Bone Marrow Transplantation; Culture Techniques; Cytomegalovirus; Cytomegalovirus Infections; Disease Models, Animal; Female; Ganciclovir; Graft vs Host Reaction; Lung; Mice; Organ Size; Pulmonary Fibrosis; Spleen; Virus Replication

Of a series of newly synthesized derivatives of the pyrrolo[2,3-d]pyrimidine nucleosides tubercidin, toyocamycin, and sangivamycin, the xylosyl analog of tubercidin, xylotubercidin, exhibited the greatest potency and selectivity against herpes simplex virus type 2 (HSV-2) in vitro. At dosage regimens that were not toxic for the host, xylotubercidin proved efficacious in various HSV-2 animal model infections. When applied topically at 0.25, 0.5, or 1% in dimethyl sulfoxide or when administered systemically (intraperitoneally) at 12.5 or 25 mg/kg per day, xylotubercidin suppressed the development of herpetic skin lesions and the paralysis and mortality associated therewith in hairless mice inoculated intracutaneously with HSV-2. In this model, acyclovir was effective only if administered topically at 5 or 10% in dimethyl sulfoxide. When administered intraperitoneally over a dosage range of 10 to 50 mg/kg per day, xylotubercidin achieved a significant reduction in the mortality rate of mice infected intraperitoneally with HSV-2. Under the same conditions, acyclovir did not offer any protection even when administered at doses up to 250 mg/kg per day. Xylotubercidin thus appears to have considerable potential for both topical and systemic treatment of HSV-2 infections.

Topics: Acyclovir; Animals; Antiviral Agents; Disease Models, Animal; Herpes Simplex; Mice; Mice, Inbred Strains; Ribonucleosides; Tubercidin

The antiherpes virus activities of acyclovir and its close analogue 3-[(2-hydroxy-1-hydroxymethylethoxy)methyl]guanine (BWB759U) were compared in vitro and in vivo. The activities of both compounds against herpes simplex virus and varicella-zoster virus were similar in the majority of cell lines. However, in mouse-derived and HeLa cells, BSB759U was more effective than acyclovir against herpes simplex virus. Mutants of herpes simplex virus deficient in thymidine kinase and resistant to acyclovir were found to vary in their sensitivity to BWB759U. In two mouse models of herpes simplex virus infection BWB759U was more effective than acyclovir.

Topics: Acyclovir; Animals; Cell Line; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Ganciclovir; HeLa Cells; Herpes Simplex; Herpesvirus 3, Human; Humans; Mice; Mice, Inbred BALB C; Simplexvirus; Time Factors; Viral Plaque Assay

Three percent 5-ethyl-2'-deoxyuridine (EdU) in an aqueous cream base was compared with 5% acyclovir (ACV) in polyethylene glycol ointment and 3% EdU in 95% dimethyl sulfoxide (DMSO) for efficacy in the topical treatment of an experimental dorsal cutaneous herpes simplex virus type 1 infection in guinea pigs. Topical ACV treatment reduced the mean lesion number by 15%, the lesion area by 32%, and the lesion virus titer by 60% when compared with measurements at contralateral sites treated with the vehicle alone. Application of 3% EdU cream was more beneficial, effecting reductions of 29, 44, and 68% in the same measurements. EdU in DMSO was even more effective, reducing the lesion measurements by 39, 60, and 90%, respectively. The penetration of EdU and ACV through guinea pig skin was compared in single-chamber diffusion cells. In the aqueous cream, EdU readily penetrated excised skin and exhibited rates of flux 10-fold greater than those shown by ACV in ointment formulation (0.56 versus 0.05 microgram/cm2 per h; P = 0.05). The flux of EdU in DMSO was 3.39 micrograms/cm2 per h, six times higher than the flux in the cream vehicle. EdU was more effective than ACV in this experimental animal model, most likely due to better percutaneous drug delivery of EdU from the cream and DMSO vehicles.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Deoxyuridine; Disease Models, Animal; Emulsions; Female; Guinea Pigs; Herpes Simplex; Ointments; Skin Absorption; Skin Diseases, Infectious

Adult Hartley guinea pigs infected with guinea pig cytomegalovirus (CMV) develop a mononucleosis syndrome with a brief viremia, splenomegaly, lymphadenopathy, and peripheral lymphocytosis with circulating atypical lymphocytes. The present study used this experimental model to evaluate in vivo the therapeutic efficacy of acyclovir (ACV) and phosphonoformate (PFA) during CMV infection. Guinea pigs were treated with ACV or PFA from day 3 to day 7 postinoculation. The course of the mononucleosis syndrome and the spread of virus in various tissues were similar in drug- and sham-treated infected guinea pigs. Infected animals treated with ACV or PFA developed disseminated CMV disease with severe interstitial pneumonia, whereas sham-treated infected and drug-treated noninfected animals did not. In addition, mortality rates in infected animals treated with ACV were significantly higher than those in sham-treated animals. Furthermore, the normal lymphoproliferative response to CMV infection appeared to be reduced in ACV-treated as compared to sham-treated animals, with fewer peripheral lymphocytes, less lymphoid tissue in the spleen and lymph nodes, and less mononuclear inflammation around the inclusion-containing cells of the liver and salivary gland. These results show that ACV and PFA are not useful in the treatment of CMV infection in guinea pigs but instead may have harmful effects.

Topics: Acyclovir; Animals; Antiviral Agents; Cytomegalovirus Infections; Disease Models, Animal; Foscarnet; Guinea Pigs; Infectious Mononucleosis; Liver; Lung; Organophosphorus Compounds; Phosphonoacetic Acid; Spleen

Carbocyclic arabinofuranosyladenine (cyclaradine), a novel nucleoside analog with such desired features as hydrolytic and enzymatic stability, adenosine deaminase resistance, and low systemic toxicity, inhibited the replication of herpes simplex virus types 1 and 2. The 5'-methoxyacetate prodrug form exhibited significant efficacy in the topical treatment of genital infections by herpes simplex virus type 2.

Topics: Acyclovir; Animals; Disease Models, Animal; Female; Guinea Pigs; Herpes Genitalis; Male; Structure-Activity Relationship; Vidarabine

Antiherpetic activity of a new antiviral agent, Acyclovir (ACV), was compared with that of Idoxuridine (IDU) in the treatment of keratitis induced in rabbits by type I herpes simplex virus (HSV). After topical application for 5 days, both compounds were well tolerated, but ACV was significantly more effective than IDU. Virological tests demonstrated that virus multiplication continued for a shorter period in eyes treated with ACV than in those of controls, or of animals treated with IDU, but early viral regrowth was possible. Using two HSV markers, seroneutralization and thermal sensitivity of cell culture development, variations were observed in a rabbit treated with IDU and in a control animal also. Epithetial regeneration after treatment was assessed by optical microscopy and by scanning and transmission electron microscopy. Epithelial scarring was observed to be almost complete in rabbits treated with IDU. The correlation between therapeutic, virological, and histological results in positive evidence for the use of ACV in HSV-induced ocular lesions.

Topics: Acyclovir; Animals; Antiviral Agents; Cornea; Disease Models, Animal; Female; Guanine; Idoxuridine; Keratitis, Dendritic; Rabbits

Acyclovir, a new potent antiviral drug, was used to treat herpes simplex virus (HSV) infection in the rabbit ocular model. Acyclovir (3% ointment) used topically one to five times a day on acute ocular HSV infection gave beneficial results as measured by a reduction in corneal involvement, conjunctivitis, iritis, and corneal clouding. Topical treatment did not prevent the establishment of latent HSV infection. Intravenous acyclovir used two times a day (50 mg/kg) on rabbits with latent HSV infection appeared to suppress HSV in the nervous system but did not eradicate established latent HSV infection.

Topics: Acyclovir; Administration, Topical; Animals; Antiviral Agents; Disease Models, Animal; Guanine; Injections, Intravenous; Keratitis, Dendritic; Male; Rabbits