RESUMO
BACKGROUND: The current direction of the US Food and Drug Administration (FDA) policy on direct-to-consumer advertising (DTCA) of pharmaceuticals is a subject of debate. The literature addresses the benefits and drawbacks of DTCA, but the foundations for such policies have not been investigated in detail. OBJECTIVE: This paper explores the most recent FDA guidance on broadcast DTCA based on a critical examination of the principle of autonomy. CONCLUSIONS: Autonomy is determined not by the ability to choose a therapy, but by the ability to actively participate in choices about health care. DTCA can be an effective tool to increase patient awareness of their therapeutic choices, encourage patients to seek more information, and help them draw closer to autonomous choices, but only if the presentations provide fair and balanced information on the benefits and risks of therapy.
Assuntos
Publicidade/legislação & jurisprudência , Indústria Farmacêutica , Autonomia Pessoal , United States Food and Drug Administration , Humanos , Relações Médico-Paciente , Estados UnidosRESUMO
The proteasome is a large multicatalytic proteinase that plays a role in the generation of peptides for presentation by major histocompatibility complex class I molecules. The 20S proteolytic core of mammalian proteasomes is assembled from a group of 17 protein subunits that generate a distinctive pattern of spots upon two-dimensional gel electrophoresis. The genes for most of these subunits have been cloned from humans and rats. We isolated cDNA clones for the mouse orthologues of ten of the subunits [PSMA1 (C2), PSMA2 (C3), PSMA3 (C8), PSMA4 (C9), PSMA5 (ZETA), PSMA6 (IOTA), PSMA7 (C6-I), PSMB2 (C7-I), PSMB3 (C10-II), and PSMB5 (X)] to complete the cloning of all of the mouse subunits. Using antisera raised against these subunits or their orthologues, we verified the identity of these proteins by two-dimensional NEPHGE-PAGE.
Assuntos
Cisteína Endopeptidases/genética , Complexos Multienzimáticos/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Clonagem Molecular , Cisteína Endopeptidases/química , Cisteína Endopeptidases/isolamento & purificação , Primers do DNA/genética , DNA Complementar/genética , Eletroforese em Gel Bidimensional , Humanos , Camundongos , Dados de Sequência Molecular , Complexos Multienzimáticos/química , Complexos Multienzimáticos/isolamento & purificação , Filogenia , Complexo de Endopeptidases do Proteassoma , Conformação Proteica , Ratos , Homologia de Sequência de Aminoácidos , Especificidade da EspécieRESUMO
The assembly of individual proteasome subunits into catalytically active mammalian 20S proteasomes is not well understood. Using subunit-specific antibodies, we characterized both precursor and mature proteasome complexes. Antibodies to PSMA4 (C9) immunoprecipitated complexes composed of alpha, precursor beta and processed beta subunits. However, antibodies to PSMA3 (C8) and PSMB9 (LMP2) immunoprecipitated complexes made up of alpha and precursor beta but no processed beta subunits. These complexes possess short half-lives, are enzymatically inactive and their molecular weight is approximately 300 kDa. Radioactivity chases from these complexes into mature, long-lived approximately 700 kDa proteasomes. Therefore, these structures represent precursor proteasomes and are probably made up of two rings: one containing alpha subunits and the other, precursor beta subunits. The assembly of precursor proteasomes occurs in at least two stages, with precursor beta subunits PSMB2 (C7-I), PSMB3 (C10-II), PSMB7 (Z), PSMB9 (LMP2) and PSMB10 (LMP10) being incorporated before others [PSMB1 (C5), PSMB6 (delta), and PSMB8 (LMP7)]. Proteasome maturation (processing of the beta subunits and juxtaposition of the two beta rings) is accompanied by conformational changes in the (outer) alpha rings, and may be inefficient. Finally, interferon-gamma had no significant effect on the half-lives or total amounts of precursor or mature proteasomes.
