Catalogo Articoli (Spogli Riviste)

OPAC HELP

Titolo:
An introduction to nucleoside and nucleotide analogues
Autore:
Squires, KE;
Indirizzi:
Univ So Calif, Dept Med Infect Dis, Los Angeles, CA 90089 USA Univ So Calif Los Angeles CA USA 90089 ect Dis, Los Angeles, CA 90089 USA
Titolo Testata:
ANTIVIRAL THERAPY
, volume: 6, anno: 2001, supplemento:, 3
pagine: 1 - 14
SICI:
1359-6535(2001)6:<1:AITNAN>2.0.ZU;2-F
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-IMMUNODEFICIENCY-VIRUS; REVERSE-TRANSCRIPTASE INHIBITORS; HIV-INFECTED PATIENTS; DNA-POLYMERASE-ALPHA; INDUCED MITOCHONDRIAL TOXICITY; PLACEBO-CONTROLLED TRIAL; BLOOD MONONUCLEAR-CELLS; ANTIRETROVIRAL-THERAPY; PHARMACOKINETIC PROPERTIES; CELLULAR-METABOLISM;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Citazioni:
101
Recensione:
Indirizzi per estratti:
Indirizzo: Squires, KE Univ So Calif, Dept Med Infect Dis, Los Angeles, CA 90089 USA Univ So Calif Los Angeles CA USA 90089 Angeles, CA 90089 USA
Citazione:
K.E. Squires, "An introduction to nucleoside and nucleotide analogues", ANTIVIR TH, 6, 2001, pp. 1-14

Abstract

The introduction of newer and more potent agents has diverted attention away from the importance of nucleoside analogue reverse transcriptase inhibitors (NRTIs) in modern antiretroviral drug regimens. As a class, these proviral chain terminators lack the virological potency of either non-nucleosidereverse transcriptase inhibitor (NNRTI) or protease inhibitor (PI) drugs, due largely to their competitive mode of inhibition and requirement for metabolic activation. However, neither NNRTIs nor Pis alone can maintain the complete suppression of HIV replication required for extended therapy, and both suffer from serious class cross-resistance on therapeutic failure. Thus, the NRTIs will remain essential components of highly active antiretroviral therapy (HAART) for the foreseeable future, both for their contribution to a regimen's virological potency and the subsequent preservation of the more potent drug classes used with them. However, it has become apparent in recent years that the current NRTIs exhibit duration-dependent adverse events as a class, which may limit the length of time for which they can be safely used. An independent contribution to peripheral fat Wasting in lipodystrophy syndrome has been established for the use of NRTI drugs. Of greater clinical concern is their established association with potentially fatal lactic acidaemia and hepatic steatosis. Both these class events, as well as several individual drug events, such as peripheral neuropathy, can be linked to progressive mitochondrial destruction with a greater or lesser degree of confidence. Mitochondrial toxicity, due in large part to the high affinity of several NRTI agents for uptake by mitochondrial DNA polymerase gamma, has been demonstrated both in vitro and in vivo. New chain-terminating agentsare urgently needed that address issues of improved virological potency, greater efficacy in NRTI-experienced individuals, and greater long-term safety. The nucleotide class of reverse transcriptase inhibitor (NtRTI), currently under clinical development, addresses improved potency by abbreviating the intracellular activation pathway to allow a more rapid and complete conversion to the active agent. These nucleoside monophosphate analogues are taken as masked prodrugs bearing labile lipophilic groups to facilitate penetration of target cell membranes. Subsequent unmasking by endogenous chemolytic enzymes releases a partially activated nucleoside analogue metabolite. The NtRTI furthest along the developmental process is tenofovir disoproxilfumarate (TDF), an orally available acyclic adenine phosphonate analogue, currently in Phase III clinical trials. This agent has shown high potency and an unusually durable response in trials of single-agent therapy intensification in highly treatment-experienced individuals, and its active metabolite, tenofovir diphosphate, exhibits a long intracellular half-life in bothresting and activated peripheral blood mononuclear cells that permits oncedaily dosing. Tenofovir diphosphate also exhibits a very low affinity for DNA polymerase gamma in vitro, suggesting a low degree of in vivo mitochondrial toxicity may be observed on long-term follow-up, although clinical data to support this inference are not yet available. The introduction of TDF and other NtRTIs as 'second-generation' nucleoside analogues carefully evaluated for potential long-term toxicity, can be expected to significantly improve the therapeutic options for both those currently on HAART and those yet to begin.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 23/01/20 alle ore 18:59:38