piperidines and Sensation-Disorders

To investigate if a central cholinesterase inhibitor will reduce falling frequency in subjects with Parkinson disease (PD) with advanced postural instability.. Falling due to postural instability is a significant problem in advancing PD, and is minimally impacted by dopaminergic therapy. Anticholinergic medications increase falling in the elderly. Further, CNS cholinergic neuron loss occurs in PD. We hypothesized that acetylcholine augmentation may reduce frequent falling in subjects with PD.. We enrolled 23 subjects with PD who reported falling or nearly falling more than 2 times per week. In a randomized, placebo-controlled, crossover design, subjects were given 6 weeks of donepezil or placebo with a 3-week washout between phases. The primary outcomes were daily falls and near falls reported on postcards. Secondary outcomes included scores on the Activities of Balance Confidence Scale, Berg Balance Scale, Clinical Global Impression of Change, Folstein Mini-Mental State Examination, and the motor section of the Unified Parkinson's Disease Rating Scale.. Fall frequency per day on placebo was 0.25 ± 0.08 (SEM) compared with 0.13 ± 0.03 on donepezil (p < 0.05). The frequency of near falls was not significantly different between phases. The secondary outcomes did not differ; however, there was a trend to improvement on the subject-completed Global Impression of Change scale.. Subjects with PD fell approximately half as often during the 6 weeks on donepezil than on placebo. Larger trials of cholinergic augmentation are warranted in subjects with PD with frequent falls.. This study provides Class II evidence that donepezil (maximum 10 mg per day) significantly reduced the number of falls in patients with PD (0.13 falls/day, SEM = 0.03) than when taking placebo (0.25 falls/day, SEM = 0.08, p = 0.049).

Topics: Aged; Cholinesterase Inhibitors; Cross-Over Studies; Disability Evaluation; Donepezil; Double-Blind Method; Female; Humans; Indans; Male; Middle Aged; Parkinson Disease; Piperidines; Postural Balance; Sensation Disorders; Severity of Illness Index; Statistics, Nonparametric

Topics: Aged; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Dystonia; Female; Humans; Indans; Memory Disorders; Piperidines; Postural Balance; Sensation Disorders

Clinical and laboratory findings suggest that cannabinoids and their receptors are implicated in schizophrenia. The role of cannabinoids in schizophrenia remains however poorly understood, as data are often contradictory. The primary aim of this study was to investigate whether the cannabinoid CB1 receptor antagonists rimonabant and AM251 are able to reverse deficits of sensorimotor gating induced by phencyclidine and to mimic the 'atypical' antipsychotic profile of clozapine. The prepulse inhibition (PPI) of the startle reflex was used to measure deficits of sensorimotor gating. PPI-disruptive effects of phencyclidine and their antagonism by rimonabant, AM251, and clozapine were studied in rats. The effects of rimonabant were carefully examined taking into account dose ranges, vehicle, and route of administration. We also examined the ability of rimonabant to reduce the PPI-disruptive effects of dizocilpine and apomorphine. Rimonabant as well as AM251 significantly counteracted the phencyclidine-disruptive model of PPI, comparable to the restoring effect of clozapine; no augmentation effect was observed with rimonabant and clozapine as cotreatment. Rimonabant also significantly attenuated the PPI disruptive effects of dizocilpine and apomorphine. Taken together, our results indicate that CB1 receptor antagonists do produce 'atypical' antipsychotic profile mimicking that of clozapine in the phencyclidine disruption of sensorimotor gating. Our findings further suggest that CB1 receptor antagonism may be involved in restoring disturbed interactions between the activity of the endocannabinoid system and glutamate neurotransmitter system implied in schizophrenia.

Topics: Animals; Brain; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Drug Synergism; Excitatory Amino Acid Antagonists; Glutamic Acid; Male; Phencyclidine; Piperidines; Psychoses, Substance-Induced; Pyrazoles; Rats; Receptors, Cannabinoid; Reflex, Startle; Rimonabant; Schizophrenia; Sensation Disorders; Synaptic Transmission

Topics: Anesthetics; Humans; Mental Disorders; Perception; Piperidines; Sensation Disorders