Saturday, June 14, 2008
Order Valtrex Herpes Treatment : Valtrex
Formulary considerations for drugs used to prevent cytomegalovirus disease.
Four types of therapeutic strategies for managing cytomegalovirus (CMV) in solid organ transplant recipients, the mechanisms of action and efficacy of drugs used for prophylaxis, and the criteria for evaluating drugs for inclusion in a formulary are described. Universal and selective prophylaxis are simple to implement and effective for CMV prophylaxis, but they are costly and patient nonadherence and viral resistance can develop. Preemptive therapy may cause less resistance and cost less, but it is more complex and associated with a higher incidence of infection, which may have no effect on secondary effects from CMV infection, and higher recurrence of disease than prophylactic therapy. Treatment of active disease may be less costly for the drug than other approaches, but intravenous access is required and the rates of infection recurrence and mortality are higher compared with prophylaxis and preemptive therapy. Criteria for deciding which CMV prophylactic drugs to include in a formulary include efficacy, safety, convenience, and cost. CMV immune globulin i.v. is costly and exhibits reduced efficacy when used alone in patients at high risk for CMV disease. Intravenous ganciclovir is effective, but it is costly because of infusion costs. Intravenous drug therapies are inconvenient and associated with a risk of bacterial and fungal infection. Oral Acyclovir / Aciclovir is safe to use and inexpensive (since a genetic exists), but it has poor efficacy and is inconvenient because of the need for four large daily doses. Valacyclovir ( Valtrex ) is more convenient and with similar safety and probably better efficacy than Acyclovir / Aciclovir, but it is more costly. Oral ganciclovir and oral valganciclovir have similar safety and costs, with greater efficacy than Acyclovir / Aciclovir. The single daily dose and lack of resistance to valganciclovir are advantages over oral ganciclovir, which requires three daily doses and can result in the development of resistance.
Inhibition of sickling in vitro by three purine-based antiviral agents: an approach to the treatment of sickle cell disease.
As a result of an in vitro screening effort the antiviral agent Acyclovir / Aciclovir was found to inhibit aggregation of hemoglobin S and the sickling of erythrocytes from individuals with sickle cell disease. Sickling of the erythrocytes was significantly inhibited at 200 microg/ml under essentially anaerobic conditions, considerably more hypoxic than the conditions in which sickling occurs in sickle cell patients. The structurally related guanine-based antiviral agents ganciclovir, Valacyclovir ( Valtrex ), and Penciclovir ( Denavir ) were also tested. Valacyclovir ( Valtrex ) and ganciclovir showed comparable anti-sickling activity at concentrations similar to that of Acyclovir / Aciclovir. An examination of the shared structural characteristics of the four guanine derivatives linked anti-sickling activity to the presence of an oxygen atom alpha to the N9 of the guanine moiety. These findings suggest a new approach in the search for new agents for the treatment of patients with sickle cell disease.
Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients.
PURPOSE: In situ cytotoxic gene therapy can potentially trigger a systemic immune response, which could impact occult metastatic disease. We are currently conducting three clinical trials using in situ adenoviral vector mediated herpes simplex virus-thymidine kinase (HSV-tk) gene delivery followed by the HSV-tk prodrug ganciclovir (GCV) or Valacyclovir ( Valtrex ) (VCV). This study evaluates the systemic T-cell response after gene therapy in each trial. METHODS AND MATERIALS: The study protocol included three separate clinical trials in the Baylor Prostate Cancer SPORE Program: Trial A gene therapy in prostate cancer patients failing radiotherapy (36 patients), Trial B neoadjuvant gene therapy in pre-radical prostatectomy patients (22 patients), and Trial C gene therapy in combination with radiotherapy for prostate cancer (27 patients). Heparinized blood was collected at the time of vector injection and at selected intervals afterward. A complete blood count was performed, and peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting after labeling with dual color-labeled antibody pairs. RESULTS: The pretreatment mean percentage of activated CD8+ T cells (DR+CD8+ T cells) was 12.23%, 16.72%, and 14.09% (Trials A, B, and C, respectively). Two weeks posttreatment, this increased to 22.87%, 26.15%, and 39.04% (Trials A, B, and C, respectively), and these increases were statistically significant (p = 0.0188, p = 0.0010, p < 0.0001, respectively). The increase of DR+CD8+ T cells was significantly larger in Trial C than in Trial A (p = 0.0044) or Trial B (p = 0.0288). Total CD8+ T cells significantly increased at 2 weeks posttreatment in Trial B and C (p = 0.0013, p = 0.0004, respectively). Interestingly, only in Trial C were significant increases in activated CD4+ T cells seen at 2 weeks (p = 0.0035). CONCLUSIONS: This is the first report of systemic T-cell responses after HSV-tk+GCV/VCV gene therapy under three clinical trial conditions. There was an increase in activated CD8+ T cells in the peripheral blood after vector injection, suggesting the potential for activation of components of cell-mediated immune response in all trial conditions. The addition of radiotherapy to in situ gene therapy seems to further increase the total CD8+ T cells and activated CD4+ T cells.
Mechanism of corneal permeation of L-valyl ester of Acyclovir / Aciclovir: targeting the oligopeptide transporter on the rabbit cornea.
PURPOSE: To delineate mechanisms associated with the corneal transport of a L-valine prodrug of an antiviral agent, Acyclovir / Aciclovir. METHOD: The permeability and enzymatic hydrolysis of L-Val-ACV were evaluated using freshly excised rabbit cornea. Transport mechanism across rabbit cornea was investigated through a competitive inhibition study of L-Val-ACV with other substrates of human peptide transporter (hPepT1). RESULTS: L-Valyl ester of Acyclovir / Aciclovir (L-Val-ACV) was approximately threefold more permeable across the intact rabbit cornea than Acyclovir / Aciclovir (ACV). Dipeptides, beta-lactam antibiotics, and angiotensin converting enzyme (ACE) inhibitors, strongly inhibited the transport of L-Val-ACV indicating that a carrier mediated transport system specific for peptides is primarily responsible for the corneal permeation of L-Val-ACV. L-Val-ACV transport was found to be saturable (Km = 2.26 +/- 0.34 mM, Jmax = 1.087 +/- 0.05 nmoles cm(-2) min(-1)), energy and pH dependent. CONCLUSIONS Functional evidence of an oligopeptide transport system present on the rabbit cornea has been established. The peptide transporter on the corneal epithelium may be targeted to improve the ocular bioavailability of poorly absorbed drugs.
Advances in the treatment of Herpes virus infection: the role of Famciclovir ( Famvir ).
Shingles (herpes zoster) is the result of reactivation of varicella-zoster virus after years of latency. The acute phase is self-limiting but is often associated with moderate-to-severe pain; postherpetic neuralgia is the most frequent and debilitating complication of shingles, occurring in 3.4 per 1000 individuals per year. In the case of genital herpes, herpes simplex virus can reactivate to cause recurrent episodes as often as several times a year, sometimes for the remainder of a person's life. Antiviral agents such as Famciclovir ( Famvir ), Valacyclovir ( Valtrex ), and Acyclovir / Aciclovir can be used to shorten the course and decrease the severity of these diseases and may suppress the virus itself, thereby preventing future outbreaks of genital herpes. This article presents a brief synopsis of the etiology of herpes zoster and genital herpes and reviews 12 key studies that demonstrate the efficacy of Famciclovir ( Famvir ) in the management of these two conditions.
Susceptibilities of several clinical varicella-zoster virus (VZV) isolates and drug-resistant VZV strains to bicyclic furano pyrimidine nucleosides.
Varicella-zoster virus (VZV) is responsible for primary infections as well as reactivations after latency in the dorsal root ganglia. The treatment of such infections is mandatory for immunocompromised patients and highly recommended for elderly patients with herpes zoster infections (also called zona or shingles). The treatment of choice is presently based on four molecules, Acyclovir / Aciclovir (ACV), valAcyclovir / Aciclovir, Famciclovir ( Famvir ), and (in Europe) brivudine (BVDU). We present here our data on the antiviral activity of a new class of potent and selective anti-VZV compounds, bicylic pyrimidine nucleoside analogues (BCNAs), against a broad variety of clinical isolates and different drug-resistant virus strains. The results show that the BCNAs are far more potent inhibitors than ACV and BVDU against clinical VZV isolates as well as the VZV reference strains Oka and YS. The BCNAs were not active against ACV- and BVDU-resistant VZV strains bearing mutations in the viral thymidine kinase gene but kept their inhibitory potential against virus strains with mutations in the VZV DNA polymerase gene. Mutant virus strains selected in the presence of the BCNAs were solely cross-resistant to drugs, such as ACV and BVDU, that depend for their antiviral action on metabolic activation by the viral thymidine kinase.
Developments in the antiviral treatment of genital herpes.
There have been impressive advances made over the last decade in the management of sexually transmitted viral diseases, especially in the development of effective antiviral agents. Acyclovir / Aciclovir, first synthesized in 1974, has proved to be an effective and safe drug for the treatment of primary and frequently recurring genital herpes, according to the various medical publications over the last 10 years. This article reviews the use of Acyclovir / Aciclovir in the treatment of genital herpes and discusses the potential problem of Acyclovir / Aciclovir resistance. It also discusses two newer antiherpes drugs, Famciclovir ( Famvir ) and valAcyclovir / Aciclovir, and the preliminary results of studies on their efficacy in the treatment of genital herpes.
Valacyclovir ( Valtrex ) treatment ameliorates the persistently increased pentylenetetrazol-induced seizure susceptibility in mice with herpes simplex virus type 1 infection.
herpes simplex virus type 1 (HSV-1) is an important pathogen related to epilepsy. We have shown previously that corneal inoculation of mice with HSV-1 causes acute spontaneous behavioral and electrophysiological seizures and increases hippocampal excitability and kainite-induced seizure susceptibility. In this study, we aimed to determine whether early-life HSV-1 infection in mice might cause short- and long-term enhanced susceptibility to pentylenetetrazol (PTZ)-induced seizures and to evaluate whether early antiviral drug therapy was effectively ameliorating this deficit. Seizure threshold was calculated by the latency of onset of the myoclonic jerk, generalized clonus, and maximal tonic-clonic convulsion. We demonstrate that the localization of viral antigens was predominantly within the bilateral temporal areas (amygdala, piriform, and entorhinal cortex) of HSV-1-infected mice. We also present evidence that mice of all HSV-1-infected groups had a shorter latency and higher severity to PTZ-induced seizures than in age-matched, mock-infected controls. Treatment of HSV-1-infected mice with Valacyclovir ( Valtrex ), a potent inhibitor of HSV-1 replication, produced a dose-dependent decrease in the signs of neurological deficits, pathological damages, and PTZ-induced seizure severity. Our results are consistent with the hypothesis that early-life HSV-1 infection leads to persistent enhancement of neuronal excitability in limbic circuits, which could result in an overall increased propensity to induce seizures later in life. Additionally, prompt optimal antiviral therapy effectively decreases seizure susceptibility in HSV-1-infected mice by limiting the level of viral replication and inflammatory response induced by virus. The present study provides not only experimental evidence, but also a new therapeutic strategy in HSV-1-associated human epilepsy.
A randomized, placebo-controlled comparison of oral Valacyclovir ( Valtrex ) and Acyclovir / Aciclovir in immunocompetent patients with recurrent genital herpes infections. The ValAcyclovir / Aciclovir International Study Group.
OBJECTIVE: To compare Valacyclovir ( Valtrex ) hydrochloride with Acyclovir / Aciclovir in the treatment of recurrent genital herpes infection. DESIGN: A multicenter, double-blind, placebo-controlled, randomized, parallel-design study. SETTING: University clinics (dermatology, gynecology, and infectious diseases) and private practices. PATIENTS: One thousand two hundred patients with recurrent genital herpes simplex infections. INTERVENTIONS: Patients self-initiated oral therapy with 1000 mg of Valacyclovir ( Valtrex ) hydrochloride twice daily, 200 mg of Acyclovir / Aciclovir 5 times daily, or placebo for 5 days. MAIN OUTCOME MEASURES: Resolution of all signs and symptoms of recurrent genital herpes infection. RESULTS: Both drugs were significantly more effective than placebo in speeding resolution of herpetic episodes (median duration, 4.8, 4.8, and 5.9 days, respectively); the hazards ratios for Valacyclovir ( Valtrex ) and Acyclovir / Aciclovir vs placebo were 1.66 (95% confidence interval [CI], 1.38-2.01) and 1.71 (95% CI, 1.41-2.06) (both P < .001). Similarly, Valacyclovir ( Valtrex ) and Acyclovir / Aciclovir significantly hastened lesion healing (hazards ratios vs placebo were 1.88 [95% CI, 1.53-2.32] and 1.90 [95% CI, 1.55-2.34], respectively; P < .001). Pain duration was shorter in Valacyclovir ( Valtrex )- and Acyclovir / Aciclovir-treated patients (median, 2 vs 3 days). Viral shedding stopped 2.55 times faster in patients treated with Valacyclovir ( Valtrex ) and 2.24 times faster in patients treated with Acyclovir / Aciclovir than in patients treated with placebo. Aborted episodes, in which lesions did not progress beyond the macule or papule stage, tended to occur in more patients treated with Valacyclovir ( Valtrex ) (25.9%) or Acyclovir / Aciclovir (24.8%) than in patients treated with placebo (19.8%). Valacyclovir ( Valtrex ) and Acyclovir / Aciclovir did not differ significantly with regard to their respective effects on any of the above efficacy parameters. The nature, severity, and frequency of adverse events did not differ among the 3 treatment groups. CONCLUSIONS: Twice-daily Valacyclovir ( Valtrex ) was as effective and well tolerated in the treatment of recurrent genital herpes simplex virus infection as 5-times-daily Acyclovir / Aciclovir. Therefore, Valacyclovir ( Valtrex ) could prove a useful alternative to Acyclovir / Aciclovir when convenience of dosing or compliance issues are the prime considerations in treatment.
Differential effects of Famciclovir ( Famvir ) and valAcyclovir / Aciclovir on the pathogenesis of herpes simplex virus in a murine infection model including reactivation from latency.
The ability of Famciclovir ( Famvir ) and valAcyclovir / Aciclovir 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 ( Famvir )-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 ( Denavir ) and Acyclovir / Aciclovir, in infected neurons.
For the primary infection of genital herpes, antiviral therapy with Acyclovir / Aciclovir is the gold standard. For recurrences, there are two options: antiviral treatment of each outbreak as it arises, or suppression of outbreaks with daily oral therapy. Patients tend to prefer the latter because it can decrease the number and severity of outbreaks, but it increases asymptomatic viral shedding and, therefore, the risk of unwittingly transmitting herpes simplex virus to uninfected sexual partners.
Isolated foot ulcer complicating acute leukemia: an unusual manifestation of herpes simplex virus infection simulating pyoderma gangrenosum.
An isolated foot ulcer developed in a child with newly diagnosed acute mixed lineage leukemia during induction chemotherapy. Despite its clinical resemblance to pyoderma gangrenosum, herpes simplex virus infection was eventually diagnosed on histopathology. Treatment with oral Acyclovir / Aciclovir was ineffective, but the ulcer healed with intravenous Acyclovir / Aciclovir followed by oral valAcyclovir / Aciclovir. Viral infection remains an unusual but important cause of isolated extragenital cutaneous ulceration in the immunocompromised child
