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At least 19 recordsLinked to original sources
PubMed1997

Valacyclovir.

OBJECTIVE: To discuss the clinical pharmacology, antiviral activity, clinical efficacy, and other therapeutic issues associated with valacyclovir use for the treatment of herpesvirus infections. DATA SOURCE: Literature searches using MEDLINE were prospectively designed to include relevant articles and abstracts between January 1982 and March 1996. The searches focused on valacyclovir pharmacology, clinical efficacy, and issues associated with herpesvirus infections. STUDY SELECTION: Selection of clinical and basic science studies were limited to those focusing on valacyclovir. All articles with pertinent information relevant to the scope of this article were reviewed. DATA SYNTHESIS: Valacyclovir is an amino acid ester prodrug of acyclovir. It is currently approved for the treatment of herpes zoster infections in immunocompetent adults (1 g p.o. tid for 7 d) and recurrent episodes of genital herpes in immunocompetent adults (500 mg bid for 5 d). Valacyclovir is rapidly and almost completely hydrolyzed to acyclovir prior to systemic exposure. The bioavailability of valacyclovir is 54% compared to approximately 20% for oral acyclovir. At higher dosages (2 g qid), the plasma AUC of acyclovir following oral valacyclovir administration approximates that seen after intravenous administration of 10 mg/kg every 8 hours. Clinical data indicate that valacyclovir is at least as effective as acyclovir in decreasing the duration of pain associated with postherpetic neuralgia, and in reducing time to genital lesion healing and the length of the episode. CONCLUSIONS: Valacyclovir has improved bioavailability over acyclovir and is at least as efficacious. The favorable safety profile of acyclovir and increased systemic exposure make it a particularly ideal candidate for further studies of herpes group viral infections in immunocompromised patients.

Acyclovir↗
PubMed1995

Valacyclovir: a review of its antiviral activity, pharmacokinetic properties, and clinical efficacy.

Oral administration of the prodrug valacyclovir results in enhanced bioavailability and significantly greater plasma concentrations of acyclovir than can be achieved with oral doses of acyclovir itself. The results of clinical trials with valacyclovir have demonstrated significant benefits in the resolution of pain associated with herpes zoster infection. Efficacy parameters were similar for valacyclovir and acyclovir in the treatment of herpes simplex; however the results were achieved with lower and less-frequent doses of valacyclovir. The cost of a course of therapy with valacyclovir is expected to be similar to that of other antivirals. The potential clinical benefits of valacyclovir will likely be apparent in the case of acyclovir-resistant herpesvirus infections, where high-dose intravenous treatment with acyclovir has been necessary. Most of these resistant viruses have been encountered in immunocompromised patients, and the resistance has been attributed to inadequate exposure to the drug. Because optimal levels of acyclovir are achieved with a simpler dosing regimen of valacyclovir, compliance may be improved in many patients, thus reducing the incidence of resistant virus.

Acyclovir↗
PubMedDate not supplied

Pharmacology of new antiherpes agents: famciclovir and valacyclovir.

Limitations of acyclovir in treating infections caused by herpes simplex virus include the development of resistant isolates and relatively poor oral bioavailability. Penciclovir and famciclovir may have added clinical utility in the treatment of herpes virus infections in humans. Intracellular pharmacokinetics differ for valacyclovir and famciclovir, but the importance of these differences is unknown. Animal studies suggest that famciclovir (but not valacyclovir) can affect subsequent latent infection with HSV-1; the relevance of these findings to humans requires further investigation. Famciclovir and valacyclovir appear to decrease time to resolution of pain compared with acyclovir in patients with herpes zoster infections.

2-Aminopurine↗
PubMed1996

Valacyclovir.

Explore the source record for details and available documents.

Acyclovir↗
PubMed1996

Varicella-zoster virus.

Varicella-zoster virus (VZV) is a ubiquitous human alphaherpesvirus that causes varicella (chicken pox) and herpes zoster (shingles). Varicella is a common childhood illness, characterized by fever, viremia, and scattered vesicular lesions of the skin. As is characteristic of the alphaherpesviruses, VZV establishes latency in cells of the dorsal root ganglia. Herpes zoster, caused by VZV reactivation, is a localized, painful, vesicular rash involving one or adjacent dermatomes. The incidence of herpes zoster increases with age or immunosuppression. The VZV virion consists of a nucleocapsid surrounding a core that contains the linear, double-stranded DNA genome; a protein tegument separates the capsid from the lipid envelope, which incorporates the major viral glycoproteins. VZV is found in a worldwide geographic distribution but is more prevalent in temperate climates. Primary VZV infection elicits immunoglobulin G (IgG), IgM, and IgA antibodies, which bind to many classes of viral proteins. Virus-specific cellular immunity is critical for controlling viral replication in healthy and immunocompromised patients with primary or recurrent VZV infections. Rapid laboratory confirmation of the diagnosis of varicella or herpes zoster, which can be accomplished by detecting viral proteins or DNA, is important to determine the need for antiviral therapy. Acyclovir is licensed for treatment of varicella and herpes zoster, and acyclovir, valacyclovir, and famciclovir are approved for herpes zoster. Passive antibody prophylaxis with varicella-zoster immune globulin is indicated for susceptible high-risk patients exposed to varicella. A live attenuated varicella vaccine (Oka/Merck strain) is now recommended for routine childhood immunization.

Acyclovir↗
PubMed1993

[Varicella: how and when to start antiviral treatment].

The Meeting "An Update on Chickenpox" (Florence, 19-3-1993) has contributed to verify, in the light of the most recent acquisitions, the new guidelines for a correct rationale in the diagnosis and therapy of chickenpox. The present availability of an effective specific antiviral therapy for chickenpox (acyclovir) leads to a careful selection of patients to be treated. The high incidence of chickenpox morbidity keeps long unaltered and, beyond the usually benign onset of the primary infection in the child, the severity of this pathology in particular subjects and situations at risk is to be certainly underlined. Treatment is suggested for cases of chickenpox contracted inside the family. Generally, boys are at higher risk. Adolescents and adults, usually with a lower incidence, report a much higher severity of the acute onset and complications. Another category to be certainly treated is the one--in constant increase--of immunocompromised subjects. In any case, acyclovir treatment improves the symptomatologic evolution (pruritus and fever) and duration of clinical course. Among the progenitors of acyclovir, Valacyclovir seems to have the best prospects of success for the immediate future of antiviral therapy.

Acyclovir↗
PubMedDate not supplied

Cost-consequence models for varicella-zoster virus infections.

Three cost-consequence models were developed for treatment of infections due to varicella-zoster virus (VZV) with acyclovir in immunocompetent patients--adult- and childhood-onset chickenpox, and herpes zoster (shingles) in adults. For chickenpox, separate models allow examination of differences in severity and impact of the disease for children and adults, as well as in the management of civilians and adults in military service. Each model includes direct medical costs, indirect costs and health-related productivity loss, symptom and quality of life impact, and model assumptions and conclusions. Alternatives of treatment and no treatment are addressed. Quality of life impact is conceptualized in terms of a quality-adjusted life-days decrement due to VZV symptoms of importance to the patient, such as pain, rash, and itching. As experience and data become available, alternative agents such as valacyclovir and famciclovir for the treatment of patients with herpes zoster should be included in the modeling process.

Acyclovir↗
PubMed1996

Efficacy of famciclovir in the treatment of herpes zoster.

Although vidarabine was the first systemic antiviral drug for the treatment of acute herpes zoster, the agent now used most frequently is acyclovir, a far safer drug that became available a decade ago. However, even with widespread use of acyclovir, postherpetic neuralgia (PHN) remains a principal cause of postinfectious morbidity. Newer antiviral agents, such as famciclovir and valacyclovir, have recently been introduced for the treatment of uncomplicated herpes zoster. In a double-blind, randomized study, 500 mg of famciclovir three times daily for 7 days was compared with placebo; in a second study, 500 mg of famciclovir three times daily for 7 days was compared with 800 mg of acyclovir five times daily for 7 days. Famciclovir significantly reduced duration of viral shedding (P = 0.0001) and accelerated lesion resolution compared with placebo. Famciclovir was comparable to acyclovir for these acute parameters. Most importantly, famciclovir recipients lost PHN two times faster than those receiving placebo (P = 0.02 all patients; P = 0.004 patients > or = 50 years) resulting in a reduction in the median duration of PHN (56 days all patients; 100 days patients > or = 50 years). This reduction translated to a 3.5-month reduction in the median duration of PHN for patients 50 years or older, those at greatest risk for developing the most common complication of herpes zoster. Famciclovir 500 mg administered three times a day for 7 days is an effective and well-tolerated treatment for acute herpes zoster, and is the only oral antiviral agent proven to reduce the duration of PHN when administered during acute zoster infection.

2-Aminopurine↗
PubMed1994

New antivirals with activity against varicella-zoster virus.

Herpes zoster is a serious medical problem, not only because of the discomfort associated with the acute rash, but also because of the potential for post-herpetic neuralgia. Acyclovir is currently the antiviral drug of choice for the treatment of herpes zoster. Efforts are underway to develop new drugs that have improved activity against varicella-zoster virus as well as more favorable pharmacokinetic properties. The goal of these efforts is to develop an orally administered antiviral drug that will accelerate the events of cutaneous healing as well as reduce the frequency and severity of post-herpetic neuralgia. Investigational drugs currently under evaluation include valaciclovir and famciclovir, the prodrugs of acyclovir and penciclovir, respectively. Two new uracil derivatives, sorivudine and BW882C87, with increased anti-varicella-zoster virus activity in vitro are also being studied.

2-Aminopurine↗
PubMed1993

Review of research leading to new anti-herpesvirus agents in clinical development: valaciclovir hydrochloride (256U, the L-valyl ester of acyclovir) and 882C, a specific agent for varicella zoster virus.

Research leading to the new anti-herpesvirus compounds discussed here has come from three approaches. The first approach was directed towards improving the bioavailability of acyclovir by examining the potential of a variety of prodrugs, leading to the new compound valaciclovir hydrochloride. The second approach was to examine a large number of 5-substituted pyrimidines for activity against those viruses which were not as potently inhibited by acyclovir as are herpes simplex viruses, i.e., varicella zoster virus (VZV) and human cytomegalovirus (HCMV). This research led to the new chemical entity 882C for VZV. A third approach has been to examine drug combinations with acyclovir. This research led to the compound 348U, an inhibitor of herpes simplex virus ribonucleotide reductase which acts synergistically in combination with acyclovir. This manuscript will focus on the first two approaches leading to new compounds valaciclovir hydrochloride and 882C since Dr. Safrin details such background for 348U/acyclovir. Attempts to improve the bioavailability of acyclovir began a decade ago. Early prodrugs were compounds with alterations in the 6-substituent of the purine ring of acyclovir. The 6-amino congener required the cellular enzyme adenosine deaminase for conversion to acyclovir and the 6-deoxycongener was dependent on cellular xanthine oxidase for conversion. Neither of these prodrugs had a chronic toxicity profile in laboratory animals as good as acyclovir. Efforts were directed towards simpler esters and 18 amino acid esters were made. The pharmacokinetic profile of each prodrug was determined in rats by measuring the recovery of acyclovir in urine after oral dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗
PubMed1993

Valaciclovir (BW256U87): the L-valyl ester of acyclovir.

Valaciclovir (BW256U87) is an L-valyl ester of acyclovir, which is extensively and almost completely converted to acyclovir. In healthy human volunteers, single valaciclovir doses of 100-1000 mg resulted in dose-proportional increases in acyclovir area under the curve (AUC). The 1,000 mg dose produced an acyclovir peak plasma concentration (Cmax) of 5-6 micrograms/ml, AUC6 of 19 hr. micrograms/ml, time to maximum plasma concentration (Tmax) of 1-2 hr, and half-life (T1/2) of 2.8 hr. Plasma valaciclovir peak levels were < 0.3 micrograms/ml, and the prodrug was undetectable after 3 hr. Multiple valaciclovir doses of 250-2,000 mg given four times daily for 10 days resulted in dose-proportional increases in acyclovir Cmax. There were less than proportional increases in the AUCs. No serious or unexpected adverse events or laboratory abnormalities were reported. In volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count < 150 cells/microliters), acyclovir and valaciclovir pharmacokinetic results were nearly identical to those in healthy volunteers. At the 2 g dose administered four times daily, steady-state acyclovir Cmax = 8.4 micrograms/ml, Tmax = 2.0 hr, AUC6 = 30.5 hr. micrograms/ml, and T1/2 = 3.3 hr. Nausea, vomiting, diarrhoea, and abdominal pain were commonly reported; however, only one adverse event (diarrhoea) was causally linked to valaciclovir exposure. There were no renal or neurologic adverse events. Valaciclovir is well absorbed and is rapidly converted to acyclovir, resulting in three- to fourfold higher acyclovir levels than can be achieved with oral acyclovir, even in patients with advanced HIV disease. The safety profile is generally favourable, with no evidence of nephrotoxicity or neurotoxicity.

Acyclovir↗
PubMed1996

Cytogenetic genotoxicity of antiherpes virostatics in Chinese hamster V79-E cells. I. Purine nucleoside analogues.

The antiherpes virostatics acyclovir (ACV), valaciclovir (VACV), penciclovir (PCV), famciclovir (FCV) and ganciclovir (GCV), which belong to the group of purine acyclic nucleoside analogues, were tested for clastogenic and sister chromatid exchange (SCE)-inducing activity in Chinese hamster V79-E cells upon chronic application with and without a recovery period. ACV induced borderline effects in both cytogenetic assays, a dose-dependent reduction of the mitotic index and an increasing cell cycle delay. With VACV and PCV only a decrease of the mitotic index and an increase of cell cycle delay were observed. FCV was negative with respect to the four parameters studied, presumably due to the incapacity of the target cells of metabolizing FCV to PCV. GCV was a very potent genotoxin in both assays. It induced a statistically significant SCE response even in the range of the cytomegalovirus IC50 of < 10 microM. By variation of the experimental protocol it was shown that SCEs are induced in the second cell cycle following exposure to GCV but not in the first one. It is assumed that the drugs under study are metabolized to their respective triphosphates and then inhibit DNA replication as detected by decreasing mitotic index and increasing cell cycle delay. In the case of GCV it is suggested that GCV-TP is incorporated into the target cell DNA and that chromosomal aberrations and SCEs are secondary lesions due to repair processes at the substituted template.

2-Aminopurine↗
PubMed1996

Scintillation proximity radioimmunoassay for the measurement of acyclovir.

A homogeneous, single-tube scintillation proximity radioimmunoassay (SPRIA) to quantitate acyclovir (Zovirax), ACV, (9-[(2[hydroxyethoxy)]methylguanine)] in human plasma is described. The reagents for the SPRIA are an anti-ACV monoclonal antibody (WACO4 MAb), tritiated ACV, and scintillation proximity reagent (goat anti-mouse immunoglobulin G (IgG) coupled to fluoromicrospheres). The ACV standard curve range in the SPRIA is from 0.7 ng ml-1 (3.0 nmol l-1) to 90.0 ng ml-1 (0.4 mumol l-1) with a 50% inhibitory concentration of 5.0 ng ml-1 (22.2 nmol l-1). However, the lower limit of quantification is 7 ng ml-1 at 1:10 dilution of plasma. Analytical recovery of ACV in spiked human plasma controls ranges between 90-110%. Intra- and inter-assay relative standard deviations were < 8%. This high throughput homogeneous assay is a rapid, convenient and simple alternative to the current radioimmunoassay that uses ammonium sulfate precipitation as the separation method. This technique is particularly attractive because it requires neither separation of bound from free drug nor use of scintillation fluid. The procedure was applied to quantitate ACV in samples from pre-clinical and clinical studies after the administration of valaciclovir, a prodrug of ACV (256U87, Valtrex, L-valyl ester of ACV). Automation of this assay will further improve efficiency in processing a larger number of samples.

Acyclovir↗
PubMed1996

Herpesvirus resistance to antiviral drugs: a review of the mechanisms, clinical importance and therapeutic options.

During the past decade, potent agents against herpes simplex virus (HSV) types 1 and 2, varicella zoster virus (VZV), and cytomegalovirus (CMV) have become available. The increasing clinical use of acyclovir, ganciclovir, and foscarnet has been associated with the emergence of drug-resistant herpesvirus strains. Resistance to acyclovir or ganciclovir most frequently results from deficient intracellular phosphorylation of these agents which is required for drug activation. Resistance to foscarnet is due to viral DNA polymerase mutants that permit viral replication despite the presence of the drug. In immunocompetent patients, herpesvirus resistance is rare and generally does not correlate with clinical outcome. In contrast, in immunocompromised hosts, resistance of HSV, VZV, and CMV is increasingly detected, and may be associated with disease refractory to antiviral therapy. Foscarnet treatment has been used with some clinical benefit in patients with acyclovir-resistant HSV or VZV, or ganciclovir-resistant CMV. For therapy of resistant mucocutaneous HSV disease, topical trifluorothymidine, and topical or intravenous cidofovir (HPMPC) have yielded encouraging results that warrant further investigation. Improved methods for detection of herpesvirus resistance, and validation of alternative therapy for patients with documented resistance are required to reduce the clinical impact of drug-resistant herpesviruses.

2-Aminopurine↗