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1.
Gastroenterology ; 145(6): 1253-61.e1-3, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-23954313

RESUMEN

BACKGROUND & AIMS: Alterations in central corticotropin-releasing factor signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the corticotropin-releasing factor receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses during acquisition and extinction of conditioned fear to the threat of abdominal pain in subjects with IBS and healthy individuals (controls). METHODS: We performed a single-center, randomized, double-blind, 3-period crossover study of 11 women with IBS (35.50 ± 12.48 years old) and 15 healthy women (controls) given a single oral dose (20 mg or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen level-dependent responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. RESULTS: Controls had greater skin conductance responses during acquisition than extinction, validating the fear-conditioning paradigm. In contrast, during extinction, women with IBS had greater skin conductance responses than controls-an effect normalized by administration of a CRF-R1 antagonist. Although the antagonist significantly reduced activity in the thalamus in patients with IBS and controls during acquisition, the drug produced greater suppression of blood-oxygen level-dependent activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. CONCLUSIONS: Although CRF signaling via CRF-R1 is involved in fear acquisition and extinction learning related to expected abdominal pain in patients with IBS and controls, this system appears to be up-regulated in patients with IBS. This up-regulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.


Asunto(s)
Trastornos de Ansiedad/fisiopatología , Hormona Liberadora de Corticotropina/fisiología , Extinción Psicológica/fisiología , Síndrome del Colon Irritable/fisiopatología , Receptores de Hormona Liberadora de Corticotropina/fisiología , Transducción de Señal/fisiología , Dolor Abdominal/fisiopatología , Dolor Abdominal/psicología , Adulto , Trastornos de Ansiedad/psicología , Encéfalo/fisiología , Mapeo Encefálico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Miedo/fisiología , Miedo/psicología , Femenino , Respuesta Galvánica de la Piel/efectos de los fármacos , Respuesta Galvánica de la Piel/fisiología , Humanos , Persona de Mediana Edad , Pirazoles/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
2.
PLoS One ; 7(12): e50716, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23284643

RESUMEN

UNLABELLED: Umeclidinium bromide (GSK573719; UMEC), a new long-acting muscarinic receptor antagonist (LAMA), is in development with vilanterol (GW642444; VI), a selective long-acting ß(2) agonist (LABA), as a once-daily inhaled combination therapy for the treatment of chronic obstructive pulmonary disease (COPD). A single dose healthy volunteer study was conducted to assess the safety and tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of inhaled umeclidinium (500 µg) and vilanterol (50 µg) when administered separately and in combination using a novel dry powder inhaler (NDPI). Co-administration of single inhaled doses of umeclidinium and vilanterol to healthy Japanese subjects was well tolerated and not associated with meaningful changes in systemic exposure or PD effects compared with administration of either compound individually. Pharmacokinetic assessments showed rapid absorption for both drugs (Tmax = 5 min for both umeclidinium and vilanterol) followed by rapid elimination with median tlast of 4-5 h for umeclidinium and median tlast of 1.5-2.0 h for vilanterol. Assessments of pharmacokinetic interaction were inconclusive since for umeclidinium, Cmax following combination was higher than umeclidinium alone but not AUC whereas for vilanterol, AUC following combination was higher than vilanterol alone but not Cmax. There were no obvious trends observed between individual maximum supine heart rate and umeclidinium Cmax or vilanterol Cmax when delivered as umeclidinium 500 µg and vilanterol 50 µg combination or when delivered as umeclidinium or vilanterol alone. TRIAL REGISTRATION: Clinicaltrials.gov NCT00976144.


Asunto(s)
Alcoholes Bencílicos/efectos adversos , Alcoholes Bencílicos/farmacocinética , Clorobencenos/efectos adversos , Clorobencenos/farmacocinética , Quinuclidinas/efectos adversos , Quinuclidinas/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Adulto , Anciano , Alcoholes Bencílicos/administración & dosificación , Alcoholes Bencílicos/farmacología , Clorobencenos/administración & dosificación , Clorobencenos/farmacología , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Inhaladores de Polvo Seco/instrumentación , Humanos , Masculino , Persona de Mediana Edad , Antagonistas Muscarínicos/administración & dosificación , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacología , Seguridad del Paciente , Quinuclidinas/administración & dosificación , Quinuclidinas/farmacología , Adulto Joven
3.
J Neurosci ; 31(35): 12491-500, 2011 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-21880911

RESUMEN

Alterations in corticotropin-releasing factor (CRF) signaling pathways have been implicated in irritable bowel syndrome (IBS) pathophysiology. We aimed to (1) determine the effect of the selective CRF receptor 1 antagonist (CRF(1)) GW876008 relative to placebo, on regional activation and effective connectivity of a stress-related emotional-arousal circuit during expectation of abdominal pain using functional magnetic resonance imaging in human subjects with a diagnosis of IBS and healthy controls (HCs), and (2) examine GW876008 effects on state-trait anxiety and hypothalamic-pituitary-adrenal (HPA) axis response. Although there were no drug-related effects on peripheral HPA activity, significant central effects were observed in brain regions associated with the stress response. Effective connectivity analysis showed drug-induced normalizations between key regions of the emotional-arousal circuit in patients. During pain expectation, orally administered GW876008 relative to placebo produced significant blood oxygen level-dependent (BOLD) signal reductions in the amygdala, hippocampus, insula, anterior cingulate, and orbitomedial prefrontal cortices across groups. Patients showed significantly greater BOLD responses in the left locus coeruleus and hypothalamus after placebo compared with HCs, and BOLD signal decreases in the left hypothalamus after drug. The inhibitory effects of GW876008 in the hypothalamus in patients were moderated by anxiety; patients having average and high levels of state anxiety showed drug-related BOLD decreases. GW876008 represents a novel tool for elucidating the neuronal mechanisms and circuitry underlying hyperactivation of CRF/CRF(1) signaling and its role in IBS pathophysiology. The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF(1) receptor antagonism for patients with stress-sensitive disorders.


Asunto(s)
Dolor Abdominal , Mapeo Encefálico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Pirazoles/uso terapéutico , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Estrés Psicológico/tratamiento farmacológico , Estrés Psicológico/etiología , Dolor Abdominal/complicaciones , Dolor Abdominal/patología , Dolor Abdominal/psicología , Administración Oral , Adolescente , Hormona Adrenocorticotrópica/sangre , Adulto , Encéfalo/irrigación sanguínea , Encéfalo/efectos de los fármacos , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Persona de Mediana Edad , Vías Nerviosas/irrigación sanguínea , Oxígeno/sangre , Dimensión del Dolor , Umbral del Dolor/efectos de los fármacos , Adulto Joven
4.
J Clin Pharmacol ; 50(3): 338-49, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-19797535

RESUMEN

Alvimopan is a novel, oral, peripherally acting mu-opioid receptor (PAM-OR) antagonist that blocks the effects of opioids on the gastrointestinal tract, without blocking opioid-induced analgesic effects. It is metabolized by gut microflora to an active amide-hydrolysis metabolite, which is equipotent to alvimopan. The objective of this study was to characterize the pharmacokinetics of alvimopan and metabolite before, during, and after administration of a short course of antibiotics in healthy adult participants. Simulations were conducted to determine the feasibility for this study. An open-label, sequential drug interaction study was conducted in 45 participants who received twice-daily dosing of alvimopan with and without ciprofloxacin. Metabolite concentrations were reduced by 99.2% (90% confidence interval: 98.8-99.5) in the presence of ciprofloxacin. The interaction occurred rapidly, and recovery was slow. The interaction may be of relevance for patients with relatively high metabolite plasma concentrations prior to antibiotic administration but of little relevance for patients with little or no plasma metabolite exposure initially. Administration of ciprofloxacin decreased alvimopan C(max) by 24%, which is of no clinical relevance. There was no effect of ciprofloxacin on alvimopan trough concentrations or AUC. Alvimopan was well tolerated.


Asunto(s)
Antibacterianos/farmacología , Ciprofloxacina/farmacología , Fármacos Gastrointestinales/farmacocinética , Piperidinas/farmacocinética , Receptores Opioides mu/antagonistas & inhibidores , Administración Oral , Adolescente , Adulto , Antibacterianos/administración & dosificación , Área Bajo la Curva , Presión Sanguínea/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Ciprofloxacina/administración & dosificación , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Fármacos Gastrointestinales/administración & dosificación , Fármacos Gastrointestinales/sangre , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Piperidinas/administración & dosificación , Piperidinas/sangre , Espectrometría de Masas en Tándem , Factores de Tiempo , Adulto Joven
5.
Am J Physiol Gastrointest Liver Physiol ; 294(5): G1114-9, 2008 May.
Artículo en Inglés | MEDLINE | ID: mdl-18372395

RESUMEN

beta(3)-Adrenoceptors(beta(3)-AR) are expressed by cholinergic myenteric neurons and beta(3)-AR agonists are effective in experimental models of diarrhea. Our aim was to explore the effects of a beta(3)-AR agonist, solabegron, on gastrointestinal transit, safety, bowel function, plasma somatostatin, and solabegron pharmacokinetics (PK) following single and multiple doses. In a single-center, double-blind, parallel-group trial, 36 healthy volunteers were randomized to oral solabegron (50 or 200 mg twice daily) or placebo. Transit was measured by a validated method ((99m)Tc-labeled egg meal and (111)In charcoal delivered to the colon via delayed-release capsule). Stool frequency, form, and ease of passage were measured on a validated daily diary; plasma somatostatin by radioimmunoassay and plasma solabegron and its active metabolite by validated liquid chromatography-tandem mass spectroscopy analysis followed by PK analysis using noncompartmental methods. There were no overall or dose-related effects of solabegron on gastric, small bowel, or colonic transit, plasma somatostatin levels, stool frequency, form, or ease of passage in healthy volunteers. Solabegron and active metabolite exposures (area under the curve and maximum serum concentration) at both dose levels were consistent with PK at similar doses in previous phase I studies. We concluded that 7 days of the beta(3)-AR agonist, solabegron, 50 or 200 mg twice daily, did not significantly alter gastrointestinal or colonic transit or bowel function. In this study, medication was generally well tolerated with few adverse events reported and no clinically significant changes in vital signs observed. Further studies on clinical efficacy, visceral sensitivity, and gastrointestinal transit are required in irritable bowel syndrome patients.


Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Compuestos de Anilina/farmacología , Benzoatos/farmacología , Defecación/efectos de los fármacos , Tránsito Gastrointestinal/efectos de los fármacos , Somatostatina/sangre , Adulto , Compuestos de Anilina/efectos adversos , Compuestos de Anilina/farmacocinética , Antidiarreicos/efectos adversos , Antidiarreicos/farmacocinética , Antidiarreicos/farmacología , Área Bajo la Curva , Benzoatos/efectos adversos , Benzoatos/farmacocinética , Compuestos de Bifenilo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Heces/química , Femenino , Tránsito Gastrointestinal/fisiología , Cefalea/inducido químicamente , Humanos , Masculino , Tasa de Depuración Metabólica
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