RESUMEN
INTRODUCTION: Patient-reported outcomes (PROs) play an increasingly pivotal role in confirmatory clinical trials with pressures to develop drug differentiation strategies. Claims based on primary endpoints that are included in the product label are likely to be fully promoted by the manufacturers; however, the extent to which manufacturers promote claims based on secondary PRO endpoints is unknown. The purpose of this review is to assess the extent of promotion of PRO label claims for 6 pharmaceutical products with nonprimary PRO endpoints. METHODS: Six products were reviewed that received PRO label claims based on nonprimary PRO endpoints between 2006 and 2008. Promotional documents distributed in the United States by the drug manufacturers between the year of launch and 2011 were identified from a PharmaVoxx database. Circulation of these documents was calculated according to quarterly distributions. Two researchers reviewed the documents using standard criteria. Promotional activities based on nonprimary PRO endpoint claims were compared with total number of messages. RESULTS: Manufacturers of the 6 products distributed 973 unique promotional documents 2998 times. Messages based on primary endpoints were distributed 1798 times, whereas messages relating to nonprimary PRO endpoints were distributed 1200 times (40% of distributions) and varied among products (4%-70%). Messages relating to PROs were targeted mostly at patients and consumers (65%) versus physicians and health care professionals (34%). CONCLUSIONS: Promotion of PRO messages based on nonprimary endpoints is much lower than those based on primary endpoints, suggesting that manufacturers do not always optimize the potential of PRO messages.
RESUMEN
Febrile seizures (FSs) typically occur at the onset of fever and do not recur within the same febrile episode despite enduring or increased hyperthermia. Recurrent seizures during the same febrile episode are considered "complex," with potentially altered prognosis. A characterized immature rat model of FS was used to test the hypotheses that (1) a first FS influences the threshold temperature for subsequent ones, and (2) the underlying mechanisms involve the release and actions of the endogenous inhibitory hippocampal neuropeptide Y (NPY). Experimental FSs were induced two or three times, at 3- to 4-h intervals, and threshold temperatures measured. To determine the potential effects of seizure-induced endogenous NPY on thresholds for subsequent seizures, an antagonist of the major hippocampal NPY receptor (type 2) was infused prior to induction of the second seizure. As an indicator of NPY release, NPY expression was determined 4 and 24 h later. Threshold core and brain temperatures for hyperthermic seizures were consistent with those observed during human fever. Threshold temperatures for a second and third seizure were significantly and progressively higher than those required for the first. This "protective" effect involved induction of endogenous NPY because it was abolished by the NPY antagonist. In addition, NPY mRNA expression was increased in dentate gyrus, CA3 and CA1, after an experimental FS, consistent with peptide release. Collectively these data indicate that the absence of repetitive seizures during a febrile episode involves the inhibitory actions of endogenous NPY, suggesting that the signaling cascade triggered by this peptide might provide targets for therapeutic intervention.
Asunto(s)
Neuropéptido Y/fisiología , Convulsiones Febriles/prevención & control , Convulsiones Febriles/fisiopatología , Factores de Edad , Animales , Temperatura Corporal , Modelos Animales de Enfermedad , Fiebre/fisiopatología , Hipocampo/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/fisiología , RecurrenciaRESUMEN
Do seizures cause neuronal death? At least in the immature hippocampus, this may not be the critical question for determining the mechanisms of epileptogenesis. Neuronal injury and death have clearly been shown to occur in most epilepsy models in the mature brain, and are widely considered a prerequisite to seizure-induced epilepsy. In contrast, little neuronal death occurs after even a severe and prolonged seizure prior to the third postnatal week. However, seizures early in life, for example prolonged experimental febrile seizures, can profoundly and permanently change the hippocampal circuit in a pro-epileptogenic direction. These seizure-induced alterations of limbic excitability may require transient structural injury, but are mainly due to functional changes in expression of gene coding for specific receptors and channels, leading to altered functional properties of hippocampal neurons. Thus, in some pro-epileptogenic models in the developing brain, neither the death of neurons nor death-induced abnormalities of surviving neurons may underlie the formation of an epileptic circuit. Rather, findings in the experimental prolonged febrile seizure model suggest that persistent functional alterations of gene expression ('neuroplasticity') in diverse hippocampal neuronal populations may promote pro-epileptogenic processes induced by these seizures. These findings also suggest that during development, relatively short, intense bursts of neuronal activity may disrupt 'normal' programmed maturational processes to result in permanent, selective alterations of gene expression, with profound functional consequences. Therefore, determining the cascade of changes in the programmed expression of pertinent genes, including their temporal and cell-specific spatial profiles, may provide important information for understanding the process of transformation of an evolving, maturing hippocampal network into one which is hyperexcitable.
Asunto(s)
Encéfalo/patología , Epilepsia/patología , Neuronas/patología , Convulsiones/patología , Envejecimiento , Animales , Encéfalo/crecimiento & desarrollo , Modelos Animales de Enfermedad , Epilepsia/etiología , Epilepsia del Lóbulo Temporal/patología , Epilepsia del Lóbulo Temporal/fisiopatología , Hipocampo/patología , Hipocampo/fisiopatología , Convulsiones/complicaciones , Convulsiones Febriles/patologíaRESUMEN
Febrile seizures, in addition to being the most common seizure type of the developing human, may contribute to the generation of subsequent limbic epilepsy. Our previous work has demonstrated that prolonged experimental febrile seizures in the immature rat model increased hippocampal excitability long term, enhancing susceptibility to future seizures. The mechanisms for these profound proepileptogenic changes did not require cell death and were associated with long-term slowed kinetics of the hyperpolarization-activated depolarizing current (I(H)). Here we show that these seizures modulate the expression of genes encoding this current, the hyperpolarization-activated, cyclic nucleotide-gated channels (HCNs): In CA1 neurons expressing multiple HCN isoforms, the seizures induced a coordinated reduction of HCN1 mRNA and enhancement of HCN2 expression, thus altering the neuronal HCN phenotype. The seizure-induced augmentation of HCN2 expression involved CA3 in addition to CA1, whereas for HCN4, mRNA expression was not changed by the seizures in either hippocampal region. This isoform- and region-specific transcriptional regulation of the HCNs required neuronal activity rather than hyperthermia alone, correlated with seizure duration, and favored the formation of slow-kinetics HCN2-encoded channels. In summary, these data demonstrate a novel, activity-dependent transcriptional regulation of HCN molecules by developmental seizures. These changes result in long-lasting alteration of the HCN phenotype of specific hippocampal neuronal populations, with profound consequences on the excitability of the hippocampal network.