RESUMEN
PURPOSE: Preladenant is an orally administered adenosine2A (A2A) receptor antagonist in phase III development for Parkinson's disease treatment. This thorough QT/QTc study evaluated its potential effects on cardiac repolarization. METHODS: This was a randomized, double-blind, positive- and placebo-controlled, four-period crossover study performed under steady-state exposure of clinical and supratherapeutic doses of preladenant (10 mg BID and 100 mg BID, respectively, for 5 days), moxifloxacin (400 mg on day 5), or placebo in 60 healthy adult volunteers. The potential effect on QTcF was measured by the largest upper bound of 95 % one-sided CIs for the mean changes from time-matched baseline ECG recordings compared with placebo. Plasma preladenant concentrations were also determined on day 5. RESULTS: The QTcF difference for moxifloxacin compared with placebo exceeded 5 ms from 1 to 12 h postdose, establishing assay sensitivity. The QTcF interval was similar between the preladenant and placebo treatment groups: the upper bound of the 95 % one-sided CI for the mean difference in QTcF between preladenant and placebo was less than 10 ms at all time points for the supratherapeutic treatment group (1.3 to 5.7 ms, mean difference: -1.3 to 2.7 ms) and the therapeutic treatment group (0.4 to 4.3 ms, mean difference: -2.1 to 1.5 ms), substantially below the threshold of regulatory concern. The supratherapeutic dose (100 mg BID) provided a Cmax margin of 6.1-fold and AUC margin of 6.9-fold, respectively, compared with 10 mg BID. CONCLUSIONS: At clinical and supratherapeutic doses, preladenant is not associated with QTc prolongation.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/efectos adversos , Antiparkinsonianos/efectos adversos , Síndrome de QT Prolongado/inducido químicamente , Pirimidinas/efectos adversos , Triazoles/efectos adversos , Antagonistas del Receptor de Adenosina A2/administración & dosificación , Antagonistas del Receptor de Adenosina A2/farmacología , Adolescente , Adulto , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacología , Compuestos Aza/administración & dosificación , Compuestos Aza/efectos adversos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Electrocardiografía , Femenino , Fluoroquinolonas , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino , Pirimidinas/administración & dosificación , Pirimidinas/farmacología , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Triazoles/administración & dosificación , Triazoles/farmacología , Adulto JovenRESUMEN
The quantal release of glutamate depends on its transport into synaptic vesicles. Recent work has shown that a protein previously implicated in the uptake of inorganic phosphate across the plasma membrane catalyzes glutamate uptake by synaptic vesicles. However, only a subset of glutamate neurons expresses this vesicular glutamate transporter (VGLUT1). We now report that excitatory neurons lacking VGLUT1 express a closely related protein that has also been implicated in phosphate transport. Like VGLUT1, this protein localizes to synaptic vesicles and functions as a vesicular glutamate transporter (VGLUT2). The complementary expression of VGLUT1 and 2 defines two distinct classes of excitatory synapse.
Asunto(s)
Proteínas Portadoras/genética , Expresión Génica , Proteínas de Transporte de Membrana , Sinapsis/química , Proteínas de Transporte Vesicular , Secuencia de Aminoácidos , Animales , Química Encefálica , Proteínas Portadoras/análisis , Proteínas Portadoras/química , Ácido Glutámico/metabolismo , Inmunohistoquímica , Hibridación in Situ , Ratones , Datos de Secuencia Molecular , Neuronas/química , Neuronas/ultraestructura , Células PC12 , Fosfatos/metabolismo , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Alineación de Secuencia , Sinapsis/fisiología , Vesículas Sinápticas/química , Vesículas Sinápticas/metabolismo , Distribución Tisular , Proteína 1 de Transporte Vesicular de Glutamato , Proteína 2 de Transporte Vesicular de GlutamatoRESUMEN
Ceruloplasmin (CP), the major plasma anti-oxidant and copper transport protein, is synthesized in several tissues, including the brain. We compared regional brain concentrations of CP and copper between subjects with Alzheimer's disease (AD, n = 12), Parkinson's disease (PD, n = 14), Huntington's disease (HD, n = 11), progressive supranuclear palsy (PSP, n = 11), young adult normal controls (YC, n = 6) and elderly normal controls (EC, n = 7). Mean CP concentrations were significantly increased vs. EC (P < 0.05) in AD hippocampus, entorhinal cortex, frontal cortex, and putamen. PD hippocampus, frontal, temporal, and parietal cortices, and HD hippocampus, parietal cortex, and substantia nigra. Immunocytochemical staining for CP in AD hippocampus revealed marked staining within neurons, astrocytes, and neuritic plaques. Increased CP concentrations in brain in these disorders may indicate a localized acute phase-type response and/or a compensatory increase to oxidative stress.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Encéfalo/fisiología , Ceruloplasmina/metabolismo , Cobre/metabolismo , Degeneración Nerviosa/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Estudios de Casos y Controles , Recuento de Células , Hipocampo/patología , Humanos , Enfermedad de Huntington/metabolismo , Enfermedad de Huntington/patología , Enfermedad de Huntington/fisiopatología , Persona de Mediana Edad , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Enfermedad de Parkinson/fisiopatología , Parálisis Supranuclear Progresiva/metabolismo , Parálisis Supranuclear Progresiva/patología , Parálisis Supranuclear Progresiva/fisiopatologíaRESUMEN
Focal, freeze-induced lesions were made in isolated hemispheres of turtle cerebral cortex in vitro, permitting the investigation of epileptiform discharges in a preparation with preserved intracortical circuitry. Freeze lesions resulted in interictal discharges and occasional ictal-like events. The interictal discharges were dependent upon activation of non-NMDA excitatory amino acid receptors and were affected by but did not require NMDA receptor activation. Voltage clamp and current clamp recordings revealed abnormal bursts of low-amplitude action potentials in 36% of recorded neurons, while large, repetitive inhibitory potentials, mediated by GABAA receptors, were recorded in 90% of the neurons. Thus, prominent findings in this model include abnormalities of both excitatory and inhibitory activity. Since these changes in neuronal excitability resulted from a localized physical injury, they may resemble the changes that occur in acute posttraumatic epilepsy.