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PubMed2001

Infection due to acyclovir resistant herpes simplex virus in patients undergoing allogeneic hematopoietic stem cell transplantation.

Over an eight-month period from October 1997 to May 1998, four patients who had received bone marrow transplant (BMT) from unrelated donor presented with severe mucosal cutaneous infections involving acyclovir resistant herpes simplex virus 1 (HSV-1). The four isolates were acyclovir (ACV) resistant, three of which were also foscarnet resistant as determined by the dye uptake method. The sequencing of the thymidine kinase (TK) gene did not permit to establish a relation between mutations and resistance to ACV. Three patients were considered as clinically cured of their HSV infection by replacement of ACV or foscarnet with either valacyclovir (one case) or cidofovir (two cases) but eventually two of them died of graft vs host disease. One patient died of extensive HSV infection despite administration of cidofovir. This study emphasizes the importance of monitoring the herpes virus resistance to antiviral drugs in bone marrow transplant recipients and the usefulness of the evaluation of novel antiviral drug for treatment of infections due to strains of HSV resistant to ACV and foscarnet that occur in about 5% of immunocompromised patients.

Acute Disease↗
PubMed1998

Synthesis and evaluation of 2-amino-6-fluoro-9-(2-hydroxyethoxymethyl)purine esters as potential prodrugs of acyclovir.

2-Amino-6-fluoro-9-(2-hydroxyethoxymethyl)purine (2) and its ester derivatives 4a-d were synthesized as potential prodrugs of acyclovir, and were evaluated for their oral acyclovir bioavailability in rats and in vivo antiviral efficacy in HSV-1-infected mice. Treatment of 2-amino-6-chloro-9-(2-hydroxyethoxymethyl)purine (3) with trimethylamine in THF/DMF (4:1) followed by a reaction of the resulting trimethylammonium chloride salt 5 with KF in DMF gave 2 in 78% yield. Esterification of 2 with an appropriate acid anhydride (Ac2O, (EtCO)2O, (n-PrCO)2O, or (i-PrCO)2O) in DMF in the presence of a catalytic amount of DMAP at room temperature produced the esters 4a-d in 90-98% yields. Of the prodrugs tested in rats, the isobutyrate 4d achieved the highest mean urinary recovery of acyclovir (51%) that is 5.7-fold higher than that of acyclovir (9%) and comparable to that of valacyclovir (50%). The prodrug 4d protected dose-dependently the mortality of HSV-1-infected mice, and the group treated with 4d at a dose of 400 mg/kg showed the longest mean survival day (14.6+/-3.1 days) (mean+/-S.D.).

Acyclovir↗
PubMed2002

Anti-viral prophylaxis reduces the incidence of lymphoproliferative disease in lung transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is a serious, often fatal complication after solid organ transplantation. Primary Epstein-Barr virus (EBV) infection is the major risk factor for PTLD after lung transplantation, with 30% to 50% of EBV-naive patients who seroconvert and are diagnosed with PTLD. METHOD: In this study, we analyzed the incidence of PTLD in lung and heart-lung transplant recipients before 1996 (historic group) and then compared the impact of long-term anti-viral prophylaxis on the development of PTLD in EBV-seronegative recipients from January 1996 to December 2000 (post-1996 group). Routine induction therapy was not given after 1995. Patients not surviving 30 days, 25 of 341 (7.3%), were excluded. RESULTS: Historic group: PTLD developed in 7 of 167 (4.2%) patients, at a mean of 394 +/- 278 (95-885) days. The mortality was 87.5% at a mean follow-up of 186 +/- 207 (17-520) days after diagnosis. Post-1996 group: Eighteen of 149 (12.3%) patients were EBV seronegative at the time of transplantation, and of these 15 (83%) began receiving continuous anti-viral prophylaxis: acyclovir or valacyclovir or ganciclovir from January 1996. None of the EBV-seronegative recipients receiving continuous anti-viral prophylaxis were diagnosed with PTLD; however, 1 of 3 (33%) of the EBV-seronegative recipients who did not receive anti-viral prophylaxis were diagnosed with PTLD. In the EBV-seronegative recipients, no deaths had been caused by PTLD at a mean follow-up of 806 +/- 534 (39-1,084) days. In the post-1996 group, PTLD developed in 1 of 131 (0.76%) EBV-seropositive recipients. CONCLUSION: Continuous, specific anti-viral prophylaxis in high-risk EBV-seronegative recipients significantly reduces the incidence of PTLD after lung transplantation in the absence of induction therapy.

Acyclovir↗
PubMed2004

[The mild encephalitis-hypothesis--new findings and studies].

Causes and pathogenesis of psychiatric disorders is poorly understood. Infections by viruses or other agents may disturb neurotransmitters and elicit behavioral abnormalities, and induce long lasting immune reactions, referred to as mild encephalitis (ME). New findings (pathology, biochemistry, imaging) in schizophrenia and bipolar psychoses are compatible with ME hypothesis. In Chorea Sydenham and PANDAS syndrome autoimmune ME seems to explain anxiety-compulsive-hyperactivity symptoms. Add-on-therapy with Cox-II-blockers or valacyclovir improved acute schizophrenia, CSF filtration some cases of therapy resistant psychoses.

Acyclovir↗
PubMed2002

Cytomegalovirus (CMV) polymerase chain reaction profiles in individuals with advanced human immunodeficiency virus infection: relationship to CMV disease.

Cytomegalovirus (CMV) disease is a common complication of patients with advanced human immunodeficiency virus infection. The aim of the present study, based on a case-cohort design, was to determine the predictive value of follow-up and baseline qualitative plasma CMV polymerase chain reaction (PCR) values for CMV end-organ disease in 378 patients (158 who progressed to CMV end-organ disease and 220 who did not develop CMV disease). These patients are part of the full AIDS Clinical Trials Group 204 multinational study (1227 patients), a randomized, controlled trial that compared the effects of valacyclovir with those of acyclovir for CMV disease prevention. Baseline PCR positivity was a significant risk factor for CMV disease progression (relative risk [RR], 1.81; 95% confidence interval [CI], 1.09-3.00). In multivariate analyses, time-updated PCR positivity was strongly associated with progression to CMV end-organ disease (RR, 4.42; 95% CI, 2.87-6.81). Change in cumulative PCR status was informative for the risk of subsequent CMV disease.

AIDS-Related Opportunistic Infections↗
PubMed2002

Challenges in genital herpes simplex virus management.

Development of serologic assays to detect antibodies to herpes simplex virus (HSV) glycoproteins (g)G1 and (g)G2 has allowed accurate definition of the seroprevalence of HSV-2 worldwide. Studies from all continents indicate epidemic proportions of HSV-2 infection. In the United States, 1 in 5 sexually active adults is infected. In Africa and the Caribbean, HSV prevalence is higher. Since the development of the acyclic nucleoside derivatives acyclovir, famciclovir, and valacyclovir, treatment of mucocutaneous HSV is a practice of everyday medical care. Yet, despite effective drugs, there is widespread discontent by clients and providers about care of patients with genital herpes. Much of this relates to transmission complexities and the varied natural history of the infection. However, over time, most patients adjust to their disease and the medical and psychosocial complications. Recent studies show condoms reduce transmission, providing an important tool for counseling the patient with newly diagnosed genital herpes.

2-Aminopurine↗
PubMed2006

Recurrent benign lymphocytic meningitis.

Recurrent benign lymphocytic meningitis is a recurring, typically innocuous, painful form of aseptic meningitis. This syndrome is associated with transient neurological symptoms in one-half of afflicted patients. The causative agent is usually herpes simplex virus type 2, which can be confirmed by detection of viral DNA in the cerebrospinal fluid using polymerase chain reaction. Clinical disease resolves spontaneously; however, acyclovir, valacyclovir, and famciclovir have been administered to some patients for both episodic therapy and suppression of recurrences. This therapy is thought to be beneficial, although there is no controlled trial data to support efficacy and safety.

2-Aminopurine↗
PubMed2007

Recommendations for the management of herpes zoster.

The objective of this article is to provide evidence-based recommendations for the management of patients with herpes zoster (HZ) that take into account clinical efficacy, adverse effects, impact on quality of life, and costs of treatment. Systematic literature reviews, published randomized clinical trials, existing guidelines, and the authors' clinical and research experience relevant to the management of patients with HZ were reviewed at a consensus meeting. The results of controlled trials and the clinical experience of the authors support the use of acyclovir, brivudin (where available), famciclovir, and valacyclovir as first-line antiviral therapy for the treatment of patients with HZ. Specific recommendations for the use of these medications are provided. In addition, suggestions are made for treatments that, when used in combination with antiviral therapy, may further reduce pain and other complications of HZ.

2-Aminopurine↗
PubMed1998

Chronic vulvar ulceration in an immunocompetent woman due to acyclovir-resistant, thymidine kinase-deficient herpes simplex virus.

A 34-year-old healthy woman presented with a 15-month history of persistent, nonhealing vulvar ulcerations due to herpes simplex virus (HSV) type 2. Extensive dermatologic workup and serial skin biopsies failed to reveal an underlying vulvar dermatosis or autoimmune bullous disorder. Virologic studies revealed resistance to acyclovir in vitro due to deficiency in thymidine kinase activity. Serum antibody to human immunodeficiency virus was negative on two occasions, separated by 1 year. Immunologic evaluation showed normal HSV-specific proliferative and CD8 cytotoxic T lymphocyte responses as well as normal NK cell function. Vulvar lesions failed to heal in association with trials of topical trifluorothymidine and oral valacyclovir but resolved completely with the application of 1% foscarnet cream. No recurrence of HSV has been observed in 24 months of follow-up to date.

Acyclovir↗
PubMed2005

Varicella-zoster-virus folliculitis promoted clonal cutaneous lymphoid hyperplasia.

Post herpes zoster (HZ) reactions have been associated with panoply of neoplastic, inflammatory, and fibro-inflammatory cutaneous disorders. Varicella zoster virus (VZV) DNA has not been identified in most of these reports. After an episode of HZ, a healthy, active 90-year-old female developed ulcerative nodules in the affected trigeminal V1 dermatome and the contra-lateral trigeminal region over a 1-year period. Excision and/or biopsy of all these lesions showed similar pathologic changes that consisted of herpetic folliculitis, adjacent dense mixed nodular lymphocytic infiltrates with germinal centers (cutaneous lymphoid hyperplasia (CLH)), and in the deeper excision specimens, an obliterative vasculitis of a vessel with smooth muscle in its wall. Immunophenotype analysis revealed a mixed, predominate T- and B-cell population without loss of pan-T cell antigens or aberrant expression by B cells of T-cell antigens. Polymerase chain reaction for herpetic DNA was positive for VZV DNA. Lymphocyte gene rearrangement analysis revealed 2 distinct, anatomically and chronologically, monoclonal B-cell populations and a monoclonal T-cell population in one nodule. Treatment with valacyclovir has lead to almost complete resolution of her cutaneous nodules after 6 months of therapy. In this case, it can be surmised that persistence of VZV infection and lack of effective cell-mediated immunity lead to development of both immunopathology (vasculitis) and excessive lymphoid cell proliferation (CLH).

Acyclovir↗
PubMed2006

Progress report on phase I/II clinical trial of Ad-OC-TK plus VAL therapy for metastatic or locally recurrent prostate cancer: Initial experience at Kobe University.

There is no effective therapy for hormone-refractory prostate cancer and a novel therapeutic modality, such as a gene therapy, should be actively pursued. Previously, Gardner and Chung conducted a phase I clinical trial of Ad-OC-TK (recombinant adenoviral vector containing osteocalcin promoter-driven herpes simplex virus thymidine kinase gene) plus VAL (valacyclovir) for the treatment of hormone-refractory prostate cancer at the University of Virginia. We report on our ongoing phase I/II clinical trial of Ad-OC-TK plus VAL for the treatment of advanced prostate cancer at the Kobe University Hospital, Japan.

Acyclovir↗
PubMed2006

Anti-cytomegalovirus prophylaxis in solid-organ transplant recipients.

Ganciclovir and its prodrug, valganciclovir, are more effective than acyclovir in preventing cytomegalovirus (CMV) infection and disease in solid-organ transplant recipients. However, the indirect effects of prophylactic use of ganciclovir and acyclovir are comparable, and the greater effectiveness of ganciclovir may be compensated for by less drug-related toxicity with acyclovir or valacyclovir. No conclusive data exist concerning the best technique and duration of surveillance for CMV infection in patients for whom active surveillance for late-onset CMV should be performed, i.e., those reaching the end of prophylaxis. Only large randomised controlled trials, with long follow-up periods, will provide definitive conclusions regarding the comparative prophylactic roles of the major antiviral agents in this population, and how their use fits with a strategy of active surveillance and pre-emptive therapy.

Acyclovir↗
PubMed2005

Successful renal transplantation during pregnancy.

Little is known about the implications of performing a renal transplant on a patient who is already pregnant. This case study reports a successful outcome of pregnancy, diagnosed coincidentally following renal transplantation at 13 weeks gestation. The recipient was a 23-year-old woman with chronic kidney disease who received a live-related renal transplant from her father. Pregnancy was discovered at routine ultrasound scanning of the renal allograft at 5 days posttransplant and estimated at 13 weeks gestation. She received ciclosporin monotherapy as immunosuppression throughout the pregnancy, and was given valacyclovir as prophylaxis against cytomegalovirus (CMV) infection. Renal function remained stable throughout the pregnancy, which progressed normally, resulting in the vaginal delivery of a healthy, liveborn male infant at 37 weeks gestation. This case study demonstrates that transplantation during pregnancy can have a successful outcome.

Acyclovir↗
PubMed2004

Pharmacokinetics of novel dipeptide ester prodrugs of acyclovir after oral administration: intestinal absorption and liver metabolism.

The amino acid prodrug of acyclovir (ACV), valacyclovir (VACV), is an effective antiherpetic drug. Systemic availability of ACV in humans is 3 to 5 times higher after oral administration of VACV. Enhanced bioavailability of VACV has been attributed to its carrier-mediated intestinal absorption via hPEPT1 peptide transporter followed by rapid and complete conversion to ACV. An earlier report suggested that the dipeptide ester prodrugs of ACV possess high affinity toward the intestinal oligopeptide transporter hPEPT1 and therefore seem to be promising candidates in the treatment of oral herpes virus infections. In the present study, we have examined the bioavailability of a series of dipeptide prodrugs of ACV after oral administration in Sprague-Dawley rats with cannulated jugular and portal veins. The area under plasma-concentration time curves expressed as minutes microgram milliliter(-1) for total concentration of VACV (208.4 +/- 41.2), and the dipeptide prodrugs Gly-Val-ACV (GVACV) (416.1 +/- 140.9), Val-Val-ACV (VVACV) (147.7 +/- 89.3), and Val-Tyr-ACV (VYACV) (180.7 +/- 81.2) were significantly higher than that of ACV (21.2 +/- 5.2) upon intestinal absorption. Interestingly, the bioavailability of ACV after administration of GVACV was approximately 2-fold higher than VACV. There was significant metabolism by hepatic first pass effect of the dipeptide prodrugs as evident by the higher levels of ACV obtained after systemic absorption compared with intestinal absorption of GVACV and VVACV. The dipeptide prodrugs of ACV exhibited higher systemic availability of regenerated ACV upon oral administration and thus seem to be promising drug candidates in treatment of genital herpes infections.

Acyclovir↗
PubMed2005

Delineation of human peptide transporter 1 (hPepT1)-mediated uptake and transport of substrates with varying transporter affinities utilizing stably transfected hPepT1/Madin-Darby canine kidney clones and Caco-2 cells.

In the present investigation, the uptake and transport kinetics of valacyclovir (VACV), 5-aminolevulinic acid (5-ALA), and benzylpenicillin (BENZ) were studied in stably transfected Madin-Darby canine kidney (MDCK)/human peptide transporter 1 (hPepT1)-V5&His clonal cell lines expressing varying levels of epitope-tagged hPepT1 protein (low, medium, and high expression) and in Caco-2 cells to delineate hPepT1-mediated transport kinetics. These compounds were selected due to the fact that they are known PepT1 substrates, yet also have affinity for other transporters. Caco-2 cells, traditionally used for studying peptide-based drug transport, were included for comparison purposes. The time, pH, sodium, and concentration dependence of cellular uptake and permeability were measured using mock, clonal hPepT1-MDCK, and Caco-2 cells. A pH-dependent effect was observed in the hPepT1-expressing clones and Caco-2 cells, with an increase of 1.96-, 1.84-, and 2.05-fold for VACV, 5-ALA, and BENZ uptake, respectively, at pH 6 versus 7.4 in the high-expressing hPepT1 cells. BENZ uptake was significantly decreased in Caco-2 and MDCK cells in Na(+)-depleted buffer, whereas VACV uptake only decreased in Caco-2 cells. Concentration-dependent uptake studies in the mock-corrected hPepT1-MDCK and Caco-2 cells demonstrated hPepT1 affinity ranking of VACV > 5-ALA > BENZ. The apical-to-basal apparent permeability coefficient (P(app)) values of VACV, 5-ALA, and BENZ in mock-corrected hPepT1-MDCK cells showed solely hPepT1-mediated transport in contrast to Caco-2 cells. Lower K(m) values and higher P(app) in Caco-2 cells compared with hPepT1-MDCK cells suggested the involvement of multiple transporters in Caco-2 cells. Thus, hPepT1-MDCK cells corrected for endogenous transporter expression may be a more appropriate model for screening compounds for their affinity to hPepT1.

Acyclovir↗
PubMed2002

Noninvasive bioluminescence imaging of herpes simplex virus type 1 infection and therapy in living mice.

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.

Acyclovir↗
PubMed2001

Drug inhibition of Gly-Sar uptake and hPepT1 localization using hPepT1-GFP fusion protein.

An hPepT1-GFP fusion construct was made to study drug inhibition of dipeptide uptake and apical, basolateral, or subcellular hPepT1 localization. The hPepT1 stop codon was mutated by polymerase chain reaction and was subsequently cloned into the pEGFP-N1 vector. The hPepT1-GFP fusion construct was then transfected into Caco-2 and HeLa cells, and drug inhibition was studied by inhibiting 3H-Gly-Sar uptake. Western blot analysis was used to determine hPepT1-GFP expression levels and confocal microscopy was used to examine the localization. Both anti-hPepT1 antibody and anti-GFP antibody recognized a 120-kd hPepT1-GFP fusion protein in the transfected cells. The 3H-Gly-Sar uptake in transfected HeLa cells was enhanced more than 20 times compared with the control. Valacyclovir (5 mmol/L) was able to completely inhibit 3H-Gly-Sar uptake in these transfected cells. Confocal microscopy showed that the hPepT1-GFP mainly localized in the Caco-2 cell apical membrane, but was present throughout the entire HeLa cell membranes. The hPepT1-GFP fusion protein was not found in either early endosome or lysosome of Caco-2 cells under normal conditions; however, it was detected in some subsets of lysosomes and early endosomes in phorbol 12-myristate 13-acetate (PMA)-treated Caco-2 cells.

Acyclovir↗
PubMed2004

Oral antivirals for the acute treatment of recurrent herpes labialis.

OBJECTIVE: To evaluate the use and benefit of oral antivirals in the acute treatment of episodic, recurrent herpes labialis. DATA SOURCES: A literature search was performed in MEDLINE (1966-August 2003) using acyclovir, famciclovir, valacyclovir, cold sores, herpes labialis, and HSV-1 as search terms. DATA SYNTHESIS: We reviewed 5 placebo-controlled and 2 comparative studies evaluating oral antivirals for acute treatment of recurrent herpes labialis. No studies directly compared different antivirals. Studies discussing the efficacy of antivirals for chronic suppression of herpes simplex virus-1 infection were not included. CONCLUSIONS: Treatment with oral antivirals decreases the duration of lesion episodes and pain by approximately one day; however, the antivirals do not abort lesions from developing. Clinical implications of these results appear relatively modest.

2-Aminopurine↗