valacyclovir and 5-propynylarabinofuranosyluracil

Topics: 2-Aminopurine; Acyclovir; Amines; Antidepressive Agents, Tricyclic; Antiviral Agents; Arabinofuranosyluracil; Cyclohexanecarboxylic Acids; Famciclovir; Gabapentin; gamma-Aminobutyric Acid; Humans; Neuralgia, Postherpetic; Valacyclovir; Valine

Topics: 2-Aminopurine; Acyclovir; Amines; Antidepressive Agents, Tricyclic; Antiviral Agents; Arabinofuranosyluracil; Cyclohexanecarboxylic Acids; Famciclovir; Gabapentin; gamma-Aminobutyric Acid; Herpes Zoster; Humans; Neuralgia; Valacyclovir; Valine

Until recently aciclovir has been the only licensed drug for the treatment of herpes zoster. A number of new drugs have emerged over the past few years which offered the potential for improved efficacy or ease of administration. With the completion of the first efficacy trials for each of these agents it has become apparent that, whilst less frequent dosing can he accomplished, it is not easy to significantly improve on the efficacy of aciclovir. Increasing age, the presence of prodromal pain and more severe pain at presentation have, however, been found to predispose to a longer duration of pain. Taking cessation of pain as the single most important parameter, at least for the older immunocompetent population as a whole, only valaciclovir has, to date, been shown to be superior to standard therapy with aciclovir. This review utilises primarily intent-to-treat data to illustrate the relative efficacy of the different therapies.

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Arabinofuranosyluracil; Controlled Clinical Trials as Topic; Drug Approval; Famciclovir; Herpes Zoster; Humans; Prodrugs; Treatment Outcome; United States; Valacyclovir; Valine

Topics: 2-Aminopurine; Acyclovir; Antiviral Agents; Arabinofuranosyluracil; Chickenpox; Drug Resistance, Microbial; Famciclovir; Herpes Simplex; Herpes Zoster; Humans; Valacyclovir; Valine

Over the past 15 years, acyclovir has become established as standard therapy for the management of herpes simplex virus infections, but there are areas where improvements might be made. Acyclovir has a relatively low oral bioavailability. As a result, valaciclovir, the L-valine ester of acyclovir, is being developed. This new drug produces enhanced plasma levels of acyclovir following oral dosing, which will not only allow more convenient dosing for the treatment of herpes simplex virus and varicella zoster virus (VZV) infections, but also mean that valaciclovir has the potential for superior clinical efficacy over acyclovir. This may broaden the potential utility of the drug to include human cytomegalovirus prophylaxis. Other new drugs in the antiherpes area include penciclovir and its pro-drug famciclovir, which have antiviral characteristics similar to acyclovir but no clinical benefit over and above that seen with acyclovir has been demonstrated. The synthesis of new specific antiherpes compounds has led to the discovery of a novel nucleoside analogue, 882C87, which has significantly greater activity against VZV than acyclovir. The compound also has a longer plasma half-life than acyclovir which may permit less frequent dosing.

Topics: Acyclovir; Arabinofuranosyluracil; Cytomegalovirus Infections; Ganciclovir; Guanine; Herpes Simplex; Herpesvirus 3, Human; Humans; Valacyclovir; Valine

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)

Topics: Acyclovir; Antiviral Agents; Arabinofuranosyluracil; Drug Design; Herpesvirus 3, Human; Prodrugs; Valacyclovir; Valine