Comparison of the pharmacokinetics of apricitabine in the presence and absence of ritonavir-boosted tipranavir: a phase I, open-label, controlled, single-centre study.

Background And Objective: Apricitabine is a deoxycytidine analogue nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. The aim of this phase I study was to investigate whether administration of apricitabine with the HIV protease inhibitor tipranavir (ritonavir-boosted) affects the pharmacokinetic profile of apricitabine.

Methods: This phase I study was conducted in 18 healthy adult male subjects.

Apricitabine--a novel nucleoside reverse transcriptase inhibitor for the treatment of HIV infection that is refractory to existing drugs.

Background: Apricitabine (ATC) is a nucleoside reverse transcriptase inhibitor (NRTI) being developed for the treatment of HIV. ATC has promising antiviral activity, including against HIV-1 containing reverse transcriptase mutations that confer resistance to other NRTIs.

Objectives: This paper describes the development of ATC, including its in vitro activity, pharmacokinetics and clinical efficacy and safety.

Repression of alpha-actinin SM exon splicing by assisted binding of PTB to the polypyrimidine tract.

Polypyrimidine tract binding protein (PTB) acts as a regulatory repressor of a large number of alternatively spliced exons, often requiring multiple binding sites in order to repress splicing. In one case, cooperative binding of PTB has been shown to accompany repression. The SM exon of the alpha-actinin pre-mRNA is also repressed by PTB, leading to inclusion of the alternative upstream NM exon.

Regulation of alternative splicing by PTB and associated factors.

PTB (polypyrimidine tract-binding protein) is a repressive regulator of alternative splicing. We have investigated the role of PTB in three model alternative splicing systems. In the alpha-actinin gene, PTB represses the SM (smooth muscle) exon by binding to key sites in the polypyrimidine tract.

The PTB interacting protein raver1 regulates alpha-tropomyosin alternative splicing.

Regulated switching of the mutually exclusive exons 2 and 3 of alpha-tropomyosin (TM) involves repression of exon 3 in smooth muscle cells. Polypyrimidine tract-binding protein (PTB) is necessary but not sufficient for regulation of TM splicing. Raver1 was identified in two-hybrid screens by its interactions with the cytoskeletal proteins actinin and vinculin, and was also found to interact with PTB.