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PubMed1998

[Valacyclovir].

The paper concerns the new antiviral compound Valaciclovir--prodrug of Aciclovir, which is now in clinical studies. Antiviral activity, pharmacokinetic properties observed in animal studies, as well in immunocompetent and immunosuppressed patients are presented. Its clinical efficacy in herpes virus infection is also discussed.

Acyclovir↗
PubMed1996

Valacyclovir.

Explore the source record for details and available documents.

Acyclovir↗
PubMed2001

[Neurologic toxicity caused by zelitrex (valaciclovir) in 3 patients with renal failure. Is overdose associated with improvement of product bioavailability improvement?].

INTRODUCTION: We report three cases of neurotoxicity in patients with renal failure, treated with Zelitrex (valacyclovir). EXEGESIS: The patients are two women and a man, aged 76 +/- 4.6 years, who presented acute mental confusion during a treatment with valacyclovir. In two cases, the patients previously had altered renal function and were under peritoneal dialysis. In the last case, the patient had simultaneous neurotoxicity and acute renal failure. After the discontinuation of the drug, the outcome was favourable in all cases. CONCLUSION: Our cases focus attention on the possible neurotoxicity of valacyclovir, which is an amino acid ester prodrug of acyclovir, rapidly and almost completely hydrolysed to acyclovir prior to systemic exposure. The bioavailability of valacyclovir is 54% compared to approximately 20% for oral acyclovir and may account for unexpected overdoses, which may lead to serious neurological toxicity.

Acyclovir↗
PubMed1999

Recognition of L-amino acid ester compounds by rat peptide transporters PEPT1 and PEPT2.

Peptide transporters (PEPT1 and PEPT2) in epithelia play an important role in the absorption of small peptides and peptide-like drugs. Recently, it was demonstrated that various nonpeptidic compounds can be transported by these transporters. In the present study, we focused on the L-amino acid ester compounds and examined the mechanisms of their interaction with rat PEPTs (rPEPTs) using stable transfectants. Valacyclovir, the L-valyl ester prodrug of the antiherpetic agent acyclovir, competitively inhibited [(14)C]glycylsarcosine uptake in the rPEPT1- or rPEPT2-expressing cells. Dixon plot analyses showed that the inhibition constant (K(i)) values of valacyclovir were 2.7 and 0.22 mM for rPEPT1 and rPEPT2, respectively, suggesting that rPEPT2 had higher affinity for this agent. Various L-valine alkyl esters significantly inhibited [(14)C]glycylsarcosine uptake. L-Valine methyl ester (Val-OMe) competitively inhibited [(14)C]glycylsarcosine uptake with K(i) values of 3.6 and 0.83 mM for rPEPT1 and rPEPT2, respectively, indicating that Val-OMe is also a high-affinity substrate for rPEPT2. Val-OMe had a trans-stimulation effect on [(14)C]glycylsarcosine efflux from both transfectants, suggesting the translocation of L-valine methyl ester via rPEPTs. Val-OMe showed the most potent inhibitory effect among the several L-amino acid methyl esters examined. We conclude that Val-OMe, as well as valacyclovir, could be recognized and transported by rPEPT1 and rPEPT2 and that these L-valyl esters showed higher affinity for rPEPT2 as do most substrates of these transporters. Our results suggest that L-valine is a desirable L-amino acid for the esterification of poorly permeable drugs to enhance their oral bioavailability targeting intestinal PEPT1.

Acyclovir↗
PubMed1999

Prevention of perinatal herpes: prophylactic antiviral therapy?

So what is the take-home message from these studies? The first question, about fetal and neonatal safety, appears to be answered positively. With more than 1,812 infants reported to have been exposed to varying amounts and duration of maternal acyclovir suppression, there has not been any apparent, short-term adverse fetal or neonatal effect. Use of acyclovir in infants, even in those that are premature, is very well tolerated, with a wide margin of safety. In addition, the pharmacokinetics studies by Frenkel et al and Kimberlin et al, as well as the animal studies, suggest that maternal use of acyclovir may actually provide a prophylactic and therapeutic benefit to an infant who is exposed to HSV. The second question, as to whether acyclovir suppression would simply change symptomatic outbreaks into asymptomatic ones, also appears to have some answers. The information provided by Wald et al indicated that acyclovir suppression actually decreases asymptomatic shedding, along with decreasing clinical recurrences. Because asymptomatic shedding seems to be similar in pregnant and nonpregnant patients, it would be reasonable to assume that asymptomatic shedding also would be decreased at delivery in pregnant women with HSV infection. This supposition is supported by the data from the randomized trials and cohort studies that demonstrated a lower than expected asymptomatic shedding rate. As yet, however, there has been no randomized trial in pregnant women that has had an adequate sample size to confirm this on a statistically significant basis. The third question, whether acyclovir suppression would lower the frequency of symptomatic recurrences at parturition, reducing the need for cesarean in these patients, has answers as well, although they may not be as clear cut as one would like. Women who experience their first genital herpes outbreak while they are pregnant seem to benefit from acyclovir suppression, with both a decrease in the risk of clinical recurrences at delivery and a decreased need for cesarean delivery. This is well documented by a randomized trial and other cohort studies. Acyclovir's efficacy in patients who have a history of genital herpes infections antedating their pregnancy is less clear. The data appear to indicate a clinically important decrease in the likelihood of symptomatic reactivations at the time of delivery, although the sample sizes in the randomized studies have been too small to draw a statistically significant conclusion one way or the other. Unfortunately, a definitive trial for this group of women may never be done. Assuming a 13% recurrence risk at the time of delivery and a 50% decrease in recurrences with the use of acyclovir, 652 women would have to complete the study to achieve a power of 80%. Conducting the study at the largest, single institution, prenatal center in the United States, Scott et al were only able to enroll 222 women during a period of 6 years. Likewise, Brocklehurst et al terminated their trial early because of recruitment difficulties. They enrolled only 63 women during a period of 4 years using two different sites in the United Kingdom. Unless a multicenter trial is conducted or a meta-analysis performed on the available data, we will probably have to be content with the data as it now stands. With valacyclovir and famciclovir now available, it is unlikely that any further work will be done with acyclovir. Information from the valacyclovir trials, however, may reach statistical significance because of changes in the study design that will allow smaller sample sizes to reach adequate power. Famciclovir treatment holds promise because of its longer intracellular half-life, but until concerns about potential mutagenicity are resolved and more information on its efficacy for suppressive therapy becomes available, it should not be considered for maternal suppressive therapy. Acyclovir appears to be effective, at least in some cohorts, and is probably safe for the fetus. (AB

Acyclovir↗
PubMed2000

Treatment of common cutaneous herpes simplex virus infections.

Herpes simplex virus infection is increasingly common in the United States. New antiviral medications have expanded treatment options for the two most common cutaneous manifestations, orolabial and genital herpes. Acyclovir therapy remains an effective and often less expensive option. Famciclovir and valacyclovir offer improved oral bioavailability and convenient oral dosing schedules but are more expensive than acyclovir. Patients who have six or more recurrences of genital herpes per year can be treated with one of the following regimens: acyclovir, 400 mg twice daily; valacyclovir, 1 g daily; or famciclovir, 250 mg twice daily. These regimens are effective in suppressing 70 to 80 percent of symptomatic recurrences. Episodic treatment of recurrent genital herpes is of questionable benefit, but it may be helpful in appropriately selected patients. There is little evidence indicating benefit from treatment of recurrent orolabial herpes, which tends to be mild and infrequent.

2-Aminopurine↗
PubMed2001

Recognition and transport characteristics of nonpeptidic compounds by basolateral peptide transporter in Caco-2 cells.

Recent studies have revealed that diverse compounds lacking peptide bonds, such as valacyclovir and delta-aminolevulinic acid (delta-ALA), can be recognized by H+-coupled peptide transporters (PEPT1 and PEPT2). In the present study, recognition and transport characteristics of nonpeptidic compounds by the basolateral peptide transporter, which is distinct from PEPTs, were compared with those by PEPT1 using the human intestinal Caco-2 cells. [14C]Glycylsarcosine uptake via PEPT1 was inhibited by all nonpeptidic compounds tested. Similarly, most nonpeptidic compounds showed an inhibitory effect on [14C]glycylsarcosine uptake by the basolateral peptide transporter, although some kinds of nonpeptidic compounds, such as valine methyl ester, did not. Direct measurements of valacyclovir and delta-ALA transport revealed that both compounds were able to be transported by the basolateral peptide transporter. Because delta-ALA has been used recently in vitro and in clinical studies as an endogenous photosensitizer for photodynamic therapy, the intestinal transport characteristics of delta-ALA were further examined. Inhibition studies and Eadie-Hofstee plot analysis suggested that delta-ALA transport across the brush-border and basolateral membranes of the intestine was mainly mediated by peptide transporters. In addition, the apical-to-basolateral transport of delta-ALA was greater than that of the opposite direction. These findings provide the first evidence that the intestinal basolateral peptide transporter can recognize and transport nonpeptidic compounds, and play a definitive role in the absorption of delta-ALA.

ATP-Binding Cassette Transporters↗
PubMed1997

Management of herpes simplex and varicella-zoster virus infections.

Herpes simplex virus and varicella-zoster virus are common infections and are seen frequently in clinical practice. Infection with these viruses results in cutaneous lesions that may be diagnosed clinically, but widely available laboratory testing is useful for confirmation. Asymptomatic herpes simplex virus shedding, or "subclinical reactivation," likely occurs in all persons infected with herpes simplex virus and results in the transmission of virus despite the absence of signs or symptoms that suggest active infection. Oral and intravenous acyclovir are effective in treating initial and recurrent herpes simplex and varicella-zoster virus infections. The daily administration of oral acyclovir as suppressive therapy is effective in patients with frequently recurring genital infection with herpes simplex virus by reducing the number of symptomatic recurrences and the frequency of asymptomatic virus shedding. Two new antiviral agents, famciclovir and valacyclovir hydrochloride, have been approved for the short-term treatment of recurrent genital herpes simplex virus and recurrent zoster in nonimmunocompromised hosts. Famciclovir and valacyclovir demonstrate superior pharmacokinetics compared with acyclovir and allow for less frequent daily dosing with higher achievable serum drug concentrations. The attenuated live varicella virus vaccine is now available in the United States and prevents primary varicella-zoster virus infection in susceptible children and adults.

2-Aminopurine↗
PubMed2001

Shingles (Herpes Zoster) and Post-herpetic Neuralgia.

During childhood chickenpox, varicella-zoster virus becomes latent in neurons of the dorsal root or trigeminal ganglia. Shingles results years to decades later from a breakdown of viral latency within a ganglion and subsequent virus spread to the skin producing a unilateral dermatomal vesicular rash accompanied by segmental pain. Treatment with famciclovir, valacyclovir, and high dose acyclovir is beneficial if started within the first 3 days of the rash. All three drugs can be given orally, are equally effective, shorten the duration of viral shedding and time to healing of the rash by 1 to 2 days, and lessen the intensity and duration of the acute neuritic pain. Famciclovir and valacyclovir have more convenient dosing schedules (three times daily) compared to acyclovir (five times daily). Mild cases of shingles in younger healthy individuals often do not require any antiviral treatment. Pain in shingles may have burning, lancinating, or allodynic qualities, ranges in intensity from mild to unbearable, and lasts 2 to 8 weeks. Pain treatment varies on the type and intensity of pain experienced. In a few patients, post-herpetic neuralgia develops and the dermatomal pain persists for months to years. Effective treatment of post-herpetic pain is often difficult.

Journal Article↗
PubMed1999

Determination of acyclovir in plasma by solid-phase extraction and column liquid chromatography.

After oral administration, valacyclovir, the L-valyl ester of acyclovir, converts to the antiherpes virus drug, acyclovir. The bioavailability of acyclovir after valacyclovir administration is between 3- to 4.5-fold higher than that achieved after oral acyclovir administration. Therefore, despite the drug's short terminal half-life (3 hours), acyclovir plasma concentrations obtained after oral administration of the prodrug offer a more convenient dosage regimen in patients with herpes zoster than that required after acyclovir administration. Acyclovir is also used for viral infection prophylaxis in patients with hematologic disorders and in those who have undergone solid organ transplantation. We have described a simple and selective liquid chromatographic method for the determination of acyclovir in plasma using a new polymeric reversed-phase sorbent for solid-phase extraction. A mean acyclovir absolute recovery of 90% was found after elution of the drug from the cartridge with the mobile phase. This procedure allowed us to measure 62.5 ng/mL of acyclovir with an acceptable precision using a plasma volume of 250 microL, and no drug was found to interfere with the assay. This method is suitable for the therapeutic monitoring of acyclovir in patients who have been given a wide variety of coadministered drugs.

Acyclovir↗
PubMed1999

Advances in antiviral therapy.

Multiple agents for the treatment and prevention of viral illnesses have been developed during the past few years. While in many cases this has been in direct response to the human immunodeficiency virus type 1 epidemic, a number of new antiviral agents are relevant to the practice of general pediatrics. This article reviews recent advances in the therapy of some common and a few unusual viral illnesses of children. The indication and efficacy of the newly developed agents valacyclovir, famciclovir, cidofovir, oral and intraocular ganciclovir, adefovir, respiratory syncytial virus immune globulin, palivizumab, and imiquimod are discussed, as well new uses of acyclovir, lamivudine, and ribavirin. Many of the antivirals discussed, including valacyclovir and cidofovir, have not yet been studied in children, but they hold promise for improving the treatment of pediatric viral infections.

Antiviral Agents↗