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 (CRF1), 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 (fMRI) 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. While 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 following placebo compared to HCs, and BOLD signal decreases in the left hypothalamus following 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/CRF1 signaling and its role in IBS pathophysiology. The unique state anxiety effects observed suggest a potential pathway for therapeutic benefit of CRF1 receptor antagonism for patients with stress-sensitive disorders.

Background & Aims Alterations in central corticotropin-releasing factor (CRF) signaling pathways have been implicated in the pathophysiology of anxiety disorders and irritable bowel syndrome (IBS). We aimed to characterize the effects of the CRF receptor 1 (CRF-R1) antagonist, GW876008, on brain and skin conductance responses (SCR) 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 y old) and 15 healthy women (controls) given a single oral dose (20 or 200 mg) of the CRF-R1 antagonist or placebo. Blood-oxygen-level-dependent (BOLD) responses were analyzed using functional magnetic resonance imaging in a tertiary care setting. Results Controls had greater SCR during acquisition than extinction, validating the fear conditioning paradigm. In contrast, during extinction, the women with IBS had greater SCR 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 BOLD activity in a wide range of brain regions in IBS patients during extinction, including the medial prefrontal cortex, pons, hippocampus, and anterior insula. Conclusion 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 upregulated in patients with IBS. This upregulation might contribute to the previously reported abnormal brain responses to expected abdominal pain.

In HIV-infected subjects who have received little or no prior antiretroviral therapy, treatment with abacavir alone or in combination with ZDV is well tolerated and resulted in sustained improvements in key immunologic and virologic efficacy parameters through 12 weeks.

Higher baseline levels of HIV-1 replication determine the magnitude of first phase CD4 cell increases after suppression of HIV-1 replication. Second phase (primarily naive) CD4 cell increases are not related to HIV-1 replication but are inversely relate to age suggesting that thymic potential is a major determinant of long term cellular restoration in HIV-1 infected persons receiving antiretroviral therapy.