Single- and multiple-ascending-dose studies of the NS3 protease inhibitor asunaprevir in subjects with or without chronic hepatitis C.

Hepatitis C virus (HCV) protease inhibitors combined with pegylated alfa interferon-ribavirin have demonstrated improved efficacy compared with pegylated alfa interferon-ribavirin alone for the treatment of chronic hepatitis C. Asunaprevir (BMS-650032), a novel HCV NS3 protease inhibitor in clinical development, was evaluated for safety, antiviral activity, and resistance in four double-blind, placebo-controlled, sequential-panel, single- and multiple-ascending-dose (SAD and MAD) studies in healthy subjects or subjects with chronic HCV genotype 1 infection. In SAD studies, subjects (healthy or with chronic HCV infection) were randomized to receive asunaprevir in dose groups of 10 to 1,200 mg or a placebo. In MAD studies, healthy subjects were randomized to receive asunaprevir in dose groups of 10 to 600 mg twice daily or a placebo for 14 days; subjects with HCV infection received asunaprevir in dose groups of 200 to 600 mg twice daily, or a placebo, for 3 days. Across all four studies, headache and diarrhea were the most frequent adverse events in asunaprevir recipients. Asunaprevir at doses of 200 to 600 mg resulted in rapid HCV RNA decreases from the baseline; maximal mean changes in HCV RNA over time were 2.7 and 3.5 log(10) IU/ml in the SAD and MAD studies, respectively. No enrichment of signature asunaprevir-resistant viral variants was detected. In conclusion, the novel NS3 protease inhibitor asunaprevir, when administered at single or multiple doses of 200 to 600 mg twice daily, is generally well tolerated, achieving rapid and substantial decreases in HCV RNA levels in subjects chronically infected with genotype 1 HCV.

Influence of executive function on locomotor function: divided attention increases gait variability in Alzheimer's disease.

OBJECTIVES: To evaluate how cognitive function and divided attention affect gait in Alzheimer's disease (AD). DESIGN: Cross-sectional intervention study with subjects serving as their own controls. SETTING: Inpatient unit and outpatient clinic for patients with dementia located at a Veterans Affairs Medical Center. PARTICIPANTS: Twenty-eight patients diagnosed with probable AD. INTERVENTION: Performance of a cognitive task (repeating random digits) while walking. MEASUREMENTS: Neuropsychological measures including clock drawing, verbal fluency, and digit span were obtained along with the Clinical Dementia Rating and Mini-Mental State Examination, the measures of dementia severity. Gait speed and stride-to-stride variability of gait rhythm were measured, once during normal walking and once during dual-task walking. RESULTS: During usual walking, subjects walked slowly and with greater gait variability than older adults without AD. Gait speed was significantly reduced (P<.012) and gait variability increased with dual-task walking (P<.007). The effect on gait variability was larger than the effect on gait speed (P<.015). Executive and neuropsychological function were significantly (P<.02) associated with the increased gait variability that occurred when walking with divided attention but not with gait speed or usual, single-task walking measures of gait. CONCLUSION: Divided attention markedly impairs the ability of patients with AD to regulate the stride-to-stride variations in gait timing. This susceptibility to distraction and its effect on stride time variability, a measure of gait unsteadiness, could partially explain the predilection to falling observed in patients with dementia. The results also support the concept that persons with AD have significant impairments in the cognitive domain of attention and that locomotor function relies upon cognitive, especially executive, function.

Influence of African American elders' age stereotypes on their cardiovascular response to stress.

Although it has been shown that White elders are vulnerable to the influence of age stereotypes, it was not known whether this effect applied to African American elders. In the present study, African American elders were randomly assigned to negative or positive implicit-age-stereotype groups. Compared to participants in the positive age-stereotype group, those in the negative age-stereotype group demonstrated significantly more elevated cardiovascular response to stress, as measured by blood pressure and heart rate following mental challenges. These results suggest that negative age stereotypes generate a susceptibility to stress among African American elders, whereas positive age may provide them with a defense against this stress.

The role of higher-level cognitive function in gait: executive dysfunction contributes to fall risk in Alzheimer's disease.

Alzheimer's disease (AD) is generally understood as primarily affecting cognition while sparing motor function, at least until the later stages of the disease. Studies reported over the past 10 years, however, have documented a prevalence of falls in AD patients significantly higher than in age-matched normal elders; also persons with AD have been observed to have different walking patterns with characteristics that increase gait instability. Recent work in cognitive neuroscience has begun to demonstrate the necessity of intact cognition, particularly executive function, for competent motor control. We put the pieces of this puzzle together and review the current state of knowledge about gait and cognition in general along with an exploration of the association between dementia, gait impairment and falls in AD. We also briefly examine the current treatment of gait instability in AD, mainly exercise, and propose a new approach targeting cognition.