Background: Gait disorders are common in Parkinson’s disease patients who respond poorly to dopaminergic treatment. Blockade of adenosine A2A receptors is expected to improve gait disorders. Istradefylline is a first-in-class selective adenosine A2A receptor antagonist with benefits for motor complications associated with Parkinson’s disease.
Research design and methods: This multicenter, open-label, single-group, prospective interventional study evaluated changes in total gait-related scores of the Part II/III Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) and Freezing of Gait Questionnaire (FOG-Q) in 31 Parkinson’s disease patients treated with istradefylline. Gait analysis by portable gait rhythmogram was performed.
Results: MDS-UPDRS Part III gait-related total scores significantly decreased at Weeks 4–12 from baseline with significant improvements in gait, freezing of gait, and postural stability. Significant decreases in MDS-UPDRS Part II total scores and individual item scores at Week 12 indicated improved daily living activities. At Week 12, there were significant improvements in FOG-Q, new FOG-Q, and overall movement per 48 h measured by portable gait rhythmogram. Adverse events occurred in 7/31 patients.
Conclusions: Istradefylline improved gait disorders in Parkinson’s disease patients complicated with freezing of gait, improving their quality of life. No unexpected adverse drug reactions were identified.
Objective: Report efficacy findings from three clinical trials (one phase 2 and two phase 3 [OPUS-1, OPUS-2]) of lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease (DED).Research design and methods: Three 84-day, randomized, double-masked, placebo-controlled trials. Adults (≥18 years) with DED were randomized (1:1) to lifitegrast 5.0% or matching placebo. Changes from baseline to day 84 in signs and symptoms of DED were analyzed.Main outcome measures: Phase 2, pre-specified endpoint: inferior corneal staining score (ICSS; 0–4); OPUS-1, coprimary endpoints: ICSS and visual-related function subscale (0–4 scale); OPUS-2, coprimary endpoints: ICSS and eye dryness score (EDS, VAS; 0–100).Results: Fifty-eight participants were randomized to lifitegrast 5.0% and 58 to placebo in the phase 2 trial; 293 to lifitegrast and 295 to placebo in OPUS-1; 358 to lifitegrast and 360 to placebo in OPUS-2. In participants with mild-to-moderate baseline DED symptomatology, lifitegrast improved ICSS versus placebo in the phase 2 study (treatment effect, 0.35; 95% CI, 0.05–0.65; p?=?0.0209) and OPUS-1 (effect, 0.24; 95% CI, 0.10–0.38; p?=?0.0007). Among more symptomatic participants (baseline EDS ≥40, recent artificial tear use), lifitegrast improved EDS versus placebo in a post hoc analysis of OPUS-1 (effect, 13.34; 95% CI, 2.35–24.33; nominal p?=?0.0178) and in OPUS-2 (effect, 12.61; 95% CI, 8.51–16.70; p?<?0.0001).Limitations: Trials were conducted over 12 weeks; efficacy beyond this period was not assessed.Conclusions: Across three trials, lifitegrast improved ICSS in participants with mild-to-moderate baseline symptomatology in two studies, and EDS in participants with moderate-to-severe baseline symptomatology in two studies. Based on the overall findings from these trials, lifitegrast shows promise as a new treatment option for signs and symptoms of DED. 相似文献
Over the past 20 years there has been a growing interest in the neural underpinnings of cost/benefit decision-making. Recent studies with animal models have made considerable advances in our understanding of how different prefrontal, striatal, limbic and monoaminergic circuits interact to promote efficient risk/reward decision-making, and how dysfunction in these circuits underlies aberrant decision-making observed in numerous psychiatric disorders. This review will highlight recent findings from studies exploring these questions using a variety of behavioral assays, as well as molecular, pharmacological, neurophysiological, and translational approaches. We begin with a discussion of how neural systems related to decision subcomponents may interact to generate more complex decisions involving risk and uncertainty. This is followed by an overview of interactions between prefrontal-amygdala-dopamine and habenular circuits in regulating choice between certain and uncertain rewards and how different modes of dopamine transmission may contribute to these processes. These data will be compared with results from other studies investigating the contribution of some of these systems to guiding decision-making related to rewards vs. punishment. Lastly, we provide a brief summary of impairments in risk-related decision-making associated with psychiatric disorders, highlighting recent translational studies in laboratory animals. 相似文献
Immaturities in adolescent reward processing are thought to contribute to poor decision making and increased susceptibility to develop addictive and psychiatric disorders. Very little is known; however, about how the adolescent brain processes reward. The current mechanistic theories of reward processing are derived from adult models. Here we review recent research focused on understanding of how the adolescent brain responds to rewards and reward-associated events. A critical aspect of this work is that age-related differences are evident in neuronal processing of reward-related events across multiple brain regions even when adolescent rats demonstrate behavior similar to adults. These include differences in reward processing between adolescent and adult rats in orbitofrontal cortex and dorsal striatum. Surprisingly, minimal age related differences are observed in ventral striatum, which has been a focal point of developmental studies. We go on to discuss the implications of these differences for behavioral traits affected in adolescence, such as impulsivity, risk-taking, and behavioral flexibility. Collectively, this work suggests that reward-evoked neural activity differs as a function of age and that regions such as the dorsal striatum that are not traditionally associated with affective processing in adults may be critical for reward processing and psychiatric vulnerability in adolescents. 相似文献
OBJECTIVES: To assess the effectiveness and safety of additional bedtime H2‐receptor antagonists (H2RAs) in suppressing nocturnal gastric acid breakthrough (NAB) via a systematic review. METHODS: Eligible trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 2, 2004), MEDLINE (January 1966–June 2004), EMBASE (January 1980–June 2004) and CINAHL (January 1982–June 2004). Additional hand‐searching was conducted on the proceedings of correlated conferences, eight important Chinese journals and references of all included trials. All randomized controlled trials evaluating H2RAs for the control of NAB were eligible for inclusion. The systematic review was conducted using methods recommended by The Cochrane Collaboration. RESULTS: Only two randomized crossover studies, comprising 32 participants, met the inclusion criteria. Because the design, dosage and duration of the treatments were different between the studies, it was not possible to conduct meta‐analysis. There were no consistent conclusions found between the two included studies in evaluating H2RAs for the control of NAB. CONCLUSIONS: No implications for practice at this stage can be concluded. Appropriately designed large‐scale randomized controlled trials with long‐term follow up are needed to determine the effects of additional bedtime H2RAs in suppressing NAB. 相似文献
Four hundred and twenty-three alcohol dependent subjects were enrolled into a 12-week randomized, double-blind, placebo-controlled
study to determine the safety and efficacy of the 5-HT2 receptor antagonist, ritanserin (2.5 mg/day or 5 mg/day), in reducing alcohol intake and craving. All subjects received 1
week of single-blind placebo prior to randomization into the 11-week double-blind phase. Additionally, all subjects received
weekly individual sessions of manual-guided cognitive-behavioral therapy. Comparing the single-blind period with endpoint,
there was approximately a 23% reduction in drinks/day; 34% fall in the total number of drinking days/week; 22% decrease in
drinks/drinking day; and a 37% diminution in alcohol craving for all treatment groups. All treatment groups experienced a
beneficial clinical outcome as assessed by the Clinical Global Impression Scale. There was, however, no significant difference
between treatment groups on any of these measures of alcohol drinking, craving, or clinical outcome. Subjects were of relatively
high social functioning at baseline, and this did not change significantly during treatment. Treatment groups did not differ
significantly on either medication compliance or reported adverse events. Ritanserin treatment was associated with a dose-related
prolongation of subjects’ QTc interval recording on the electrocardiogram. These results suggest that alcohol dependent subjects
can show marked clinical improvement within a structured alcohol treatment program. These findings do not support an important
role for ritanserin in the treatment of alcohol dependence.
Received: 30 April 1996/Final version: 3 July 1996 相似文献
The effects of an indirect dopamine-agonist, d-amphetamine, and a non-selective dopamine receptor antagonist, haloperidol, were investigated in normal male volunteers using
a between-subjects double-blind design in a procedural learning task, thought mainly to involve unconscious/automatic learning.
The results showed: (1) d-amphetamine facilitated response speed, whereas haloperidol inhibited it, in comparison to placebo; (2) the linear increase
in procedural learning corresponded with pharmacological manipulation of degree of dopaminergic activity, i.e. subjects given
haloperidol showed the least, and subjects given d-amphetamine the greatest, procedural learning. The implications of these findings are discussed in relation to investigation
of abnormalities of procedural learning processes in schizophrenia.
Received: 28 June 1996/Final version: 2 October 1996 相似文献