Pharmacokinetic-Pharmacodynamic Disease Progression Model for Effect of Etanercept in Lewis Rats with Collagen-Induced Arthritis

Purpose  

To develop a pharmacokinetic-pharmacodynamic disease progression (PK/PD/DIS) model to characterize the effect of etanercept in collagen-induced arthritis (CIA) rats on rheumatoid arthritis (RA) progression.     

Rencontre de modèles cliniques et robotiques. Du saut entre les organisations psychiques

Clinical models of the mental system and robotic models of artificial thinking show analogies which enable us to compare them. These encounters facilitate the study of the jumps between the various mental organisations. Actually, these jumps are easily observed in current clinic. It is a matter of commonplace observations (the various organisations), of means reflecting them (ladder and systematical module), of natural jumps in mental disturbances (periods of evolution of mental disturbances, structuring of disturbances, integration of the various levels of organisation), and of internal gaps in the system during the formation of the meaning process. Correspondingly, robotics emphasize the specific principles of a system of artificial thinking: the internal structuring of the system, the relations with the external world and self-control; these principles are directly analogous with clinical facts. Furthermore, their realisation shows an efficient structuring of these jumps allowing a better understanding of them. These comparisons show the interest of modeling in three co-active and indissociable levels (biologic, semantic, and linguistic), of taking account of gaps and regulating factors, of refining means of thinking (particularly of intuition and of the matrices of logic knowledge) and of a better grasp of pathologic phenomena.     

Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials

BACKGROUND: Cholinesterase inhibitors and memantine do not have regulatory approval in most of the world for treatment of vascular dementia. A systematic review and meta-analysis was undertaken to assess the evidence for efficacy and safety of cholinesterase inhibitors and memantine in vascular dementia. METHODS: PubMed, BIOSIS, International Pharmaceutical Abstracts, and Cochrane registries were searched for randomised, placebo-controlled trials on cholinesterase inhibitors and memantine in patients with vascular dementia. Trial methods, clinical characteristics, outcomes, and adverse events were extracted and checked. Meta-analytic methods using fixed-effects models were used to give summaries of each drug's effects. FINDINGS: Three donepezil, two galantamine, one rivastigmine, and two memantine trials, comprising 3093 patients on the study drugs and 2090 patients on placebo, met the selection criteria. Trials were of 6-month duration with similar vascular dementia criteria and outcome measures. Cognitive effects on the Alzheimer's Disease Assessment scale were significant for all drugs, ranging from a -1.10 point mean difference (95% CI -2.15 to -0.05) for rivastigmine to -2.17 for 10 mg daily donepezil (95% CI -2.98 to -1.35). Only 5 mg daily donepezil had an effect on the Clinicians' Global Impression of Change scale (odds ratio 1.51 [95% CI 1.11-2.07]). No behavioural or functional benefits were observed, except for a -0.95 point difference (95% CI -1.74 to -0.16) with 10 mg daily donepezil on the Alzheimer's Disease Functional Assessment and Change Scale. Compared with placebo, more dropouts and adverse events (anorexia, nausea, vomiting, diarrhoea, and insomnia) occurred with the cholinesterase inhibitors, but not with memantine. INTERPRETATION: Cholinesterase inhibitors and memantine produce small benefits in cognition of uncertain clinical significance in patients with mild to moderate vascular dementia. Data are insufficient to support widespread use of these drugs in vascular dementia. Individual patient analyses are needed to identify subgroups of patients with vascular dementia who might benefit.     

Midlife C-reactive protein and risk of cognitive decline: a 31-year follow-up

There is evidence for a relationship between raised inflammatory markers, including high sensitivity C-reactive protein (hs-CRP), measured late in life, and an increased risk of cognitive decline and dementia. This study evaluates the association of midlife hs-CRP concentrations with late-life longitudinal trends in cognitive function. Data are from the Honolulu-Asia Aging Study (HAAS), a longitudinal community-based study of Japanese American men. hs-CRP levels were measured on average 25 years before cognitive testing began in 1991. Subjects were followed from up to three follow-up examinations (mean of 6.1 years). At each exam, cognitive function was measured with the Cognitive Abilities Screening Instrument (CASI). This analysis includes a sub-sample of 691 subjects dementia-free in 1991. With incident dementia cases included, those with the highest quartile of hs-CRP had significantly more cognitive decline than those in the lowest quartile, after adjustment for baseline CASI score, demographic and cardiovascular risk factors. When cases were removed, there was no difference in cognitive decline by CRP quartile. This relationship was not modified by the presence of apolipoprotein E varepsilon4. These findings suggest that inflammatory mechanisms during midlife may reflect underlying processes contributing to dementia-related cognitive decline late in life.     

Effect of Walking Distance on 8‐Year Incident Depressive Symptoms in Elderly Men with and without Chronic Disease: The Honolulu‐Asia Aging Study

OBJECTIVES: To determine the effect of walking on incident depressive symptoms in elderly Japanese‐American men with and without chronic disease. DESIGN: Prospective cohort study. SETTING: The Honolulu‐Asia Aging Study. PARTICIPANTS: Japanese‐American men aged 71 to 93 at baseline. MEASUREMENTS: Physical activity was assessed according to self‐reported distance walked per day. Depressive symptoms were measured using an 11‐question version of the Centers for Epidemiologic Studies Depression Scale (CES‐D 11) at the fourth examination (n=3,196) and at the seventh examination 8 years later (1999/00, n=1,417). Presence of incident depressive symptoms was defined as a CES‐D 11 score of 9 or greater or taking antidepressants at Examination 7. Subjects with prevalent depressive symptoms at baseline were excluded. RESULTS: Age‐adjusted 8‐year incident depressive symptoms were 13.6%, 7.6%, and 8.5% for low (<0.25 miles/day), intermediate (0.25–1.5 miles/day), and high (>1.5 miles/day) walking groups at baseline (P=0.008). Multiple logistic regression analyses, adjusted for age, education, marital status, cardiovascular risk factors, prevalent diseases, and functional impairment, showed that those in the intermediate and highest walking groups had significantly lower odds of developing 8‐year incident depressive symptoms (odds ratio (OR)=0.52, 95% confidence interval (CI)=0.32–0.83, P=.006 and OR=0.61, 95% CI= 0.39–0.97, P=.04, respectively). Analysis found that this association was significant only in participants without chronic diseases (coronary heart disease, cerebrovascular accident, cancer, Parkinson's disease, dementia, or cognitive impairment) at baseline. CONCLUSION: Daily physical activity (≥0.25 mile/day) is significantly associated with lower risk of 8‐year incident depressive symptoms in elderly Japanese‐American men without chronic disease at baseline.     

Cocaine effects during D-amphetamine maintenance: a human laboratory analysis of safety, tolerability and efficacy

Agonist replacement therapies are effective for managing substance abuse disorders including nicotine and opioid dependence. The results of preclinical laboratory studies and clinical trials indicate that agonist replacements like D-amphetamine may be a viable option for managing cocaine dependence. This experiment determined the physiological and behavioral effects of cocaine during D-amphetamine maintenance in seven cocaine-dependent participants. We predicted cocaine would be well tolerated during D-amphetamine maintenance. We also predicted D-amphetamine would attenuate the behavioral effects of cocaine. After 3-5 days of D-amphetamine maintenance (0, 15, and 30 mg/day), volunteers were administered ascending doses of cocaine (4, 30, 60 mg, i.n.) within a single session. Cocaine doses were separated by 90 min. Cocaine produced prototypical physiological (e.g., increased heart rate, blood pressure, and body temperature) and subject-rated (e.g., increased ratings of Good Effects) effects. During maintenance on the highest D-amphetamine dose, the heart rate increasing effects of cocaine were larger than observed during placebo maintenance. These effects were not clinically significant and no unexpected or serious adverse events were observed. D-amphetamine attenuated some of the subject-rated effects of cocaine. These results are concordant with those of previous preclinical studies, human laboratory experiments and clinical trials, further suggesting that agonist replacement therapy may be a viable strategy for managing cocaine abuse. Additional research in humans is needed to determine whether D-amphetamine attenuates the effects of cocaine under different experimental conditions (e.g., higher cocaine doses) and behavioral arrangements (e.g., drug self-administration or discrimination).     

多层螺旋CT与冠状动脉造影在诊断心肌桥中的对比性研究

目的：探讨多层螺旋CT（MSCT）对心肌桥（MB）的诊断价值。方法：对203例可疑冠心病患者行16-MSCT冠状动脉成像检查,发现21例患者存在心肌桥,将检查结果与冠状动脉造影（CAG）作对照。结果：两种方法对心肌桥检出的部位及数目具有一致性;21例患者心肌桥均出现在左冠状动脉前降支,位于前降支近段2例,中段16例,远段2例,对角支心肌桥1例。结论：多层螺旋CT对心肌桥诊断与冠状动脉造影具有一致性。