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Human models of anxiety are useful to develop new effective anxiolytics. The objective of this study was to use functional magnetic resonance imaging (fMRI) to test the hypothesis that a single dose of lorazepam modifies brain activation during an anxiety challenge. Eighteen healthy male subjects underwent fMRI associated with a challenge based on the anticipation of aversive electrical stimulations after pretreatment, either with placebo or with 1.0 mg of oral lorazepam. Anxiety was rated before fMRI and after, referring to the threat condition periods, using State Trait Anxiety Inventory (STAI) and Hamilton scales. The conditioning procedure induced anxiety, as indicated by clinical rating score changes. Lorazepam did not modify anxiety rating as compared to placebo. Lorazepam reduced cerebral activity in superior frontal gyrus, anterior insula/inferior frontal gyrus and cingulate gyrus. The current finding provides the first evidence of the modulatory effects of an established anxiolytic agent on brain activation related to anticipatory anxiety.

Objectives: The aim of this study was to get insight into the central effects of TC-1734 (renamed AZD3480), a selective agonist at the neuronal nicotinic receptor of the alpha4beta2 subtype., Materials and Methods: Electroencephalography (EEG) techniques and computerized cognitive tests were performed in young, healthy male volunteers during two double-blind and placebo-controlled studies: a rising single dose crossover study (from 2 to 320 mg) and a rising repeated dose study with a parallel group design (50, 100, and 200 mg)., Results: In contrast to acute administration, administration of AZD3480 over 10 days produced statistically significant enhancement of several cognitive measures (attention and episodic memory) compared to placebo. Regarding EEG data, AZD3480 showed acceleration of the alpha centroid and of the alpha peak in the single-dose study. This EEG profile of the acceleration type was confirmed in the repeated dose study on both day 1 and day 10, with the greatest effect observed with the highest dose. The EEG pattern shown for AZD3480 was consistent with that previously described with other drugs known to improve attention and vigilance (including nicotine). In addition, subjects dosed with AZD3480 showed a statistically significant increase in mismatch negativity (MMN) amplitude at 50 and 200 mg while reducing MMN latency (200 mg only), suggesting an improvement of pre-attentional mechanisms., Conclusion: These early data in healthy subjects provide encouragement to consider development of AZD3480 as a novel agent for the treatment of cognitive decline in the elderly, including age-associated memory impairment and/or dementia of the Alzheimer's type.

Recent research suggests that drugs activating nicotine acetylcholine receptors might be promising therapy in cognitive decline seen in the elderly, including Alzheimer's disease. Ispronicline (TC-1734), a brain-selective alpha4beta2 nicotine acetylcholine receptor partial agonist, has shown memory-enhancing properties in rodents and a good tolerability profile. The safety and the full pharmacokinetic profile of TC-1734 and its N-desalkylated metabolite, TC-1784, were investigated in 2 phase I studies, and results are reported in this article. Study A used a double-blind, placebo-controlled, crossover design with a rising single-dose scheme (2-320 mg). Study B used a double-blind, placebo-controlled, parallel-group design with a rising multiple-dose scheme (doses: 50, 100, and 200 mg, once daily, x 10 days). Cmax of TC-1734 was reached around 1 to 2 hours postdose, and mean terminal half-life (t1/2) ranged from 3 to 5.3 hours (single doses) and from 2.7 to 8.8 hours (repeated doses). No accumulation of TC-1734 was observed after 10 days. Renal clearance appeared to be a minor method of elimination of TC-1734 and TC-1784. A high interindividual variability was noted for all parameters. Across the dose ranges explored, TC-1734 was safe and well tolerated. No changes of clinical significance were seen on laboratory and cardiovascular parameters. Adverse events were generally of mild to moderate intensity, with dizziness and headache being reported most frequently.

Rationale: Cyamemazine (Tercian) is an antipsychotic drug with anxiolytic properties. Recently, an in vitro study showed that cyamemazine possesses high affinity for serotonin 5-HT(2A) receptors, which was fourfold higher than its affinity for dopamine D(2) receptors (Hameg et al. 2003)., Objectives: The aim of this study is to confirm these previous data in vivo in patients treated with clinically relevant doses of Tercian., Methods: Eight patients received 37.5, 75, 150 or 300 mg/day of Tercian depending on their symptomatology. Dopamine D(2) and serotonin 5-HT(2A) receptor occupancies (RO) were assessed at steady-state plasma levels of cyamemazine with positron emission tomography (PET), using [(11)C]raclopride and [(11)C]N-methyl-spiperone, respectively. The effective plasma level of the drug leading to 50% of receptor occupancy was estimated by fitting RO with plasma levels of cyamemazine at the time of the PET scan., Results: Cyamemazine induced near saturation of 5-HT(2A) receptors (RO=62.1-98.2%) in the frontal cortex even at low plasma levels of the drug. On the contrary, occupancy of striatal D(2) receptors increased with plasma levels, and no saturation was obtained even at high plasma levels (RO=25.2-74.9%). The effective plasma level of cyamemazine leading to 50% of D(2) receptor occupancy was fourfold higher than that for 5-HT(2A) receptors. Accordingly, individual 5-HT(2A)/D(2) RO ratios ranged from 1.26 to 2.68. No patients presented relevant increased prolactin levels, and only mild extrapyramidal side effects were noticed on Simpson and Angus Scale., Conclusion: This in vivo binding study conducted in patients confirms previous in vitro findings indicating that cyamemazine has a higher affinity for serotonin 5-HT(2A) receptors compared to dopamine D(2) receptors. In the dose range 37.5-300 mg, levels of dopamine D(2) occupancy remained below the level for motor side effects observed with typical antipsychotics and is likely to explain the low propensity of the drug to induce extrapyramidal side effects.

In the present study, we investigated the effects of a single and a repeated (5 days) administration of naftidrofuryl, a serotonin 5-HT2 receptor inhibitor having neuroprotective properties, on functional brain physiology in male healthy elderly subjects, using quantitative electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Twelve subjects aged 60 +/- 3.8 years completed the quantitative EEG study, where the effects of 400 and 600 mg were assessed, and 12 other subjects (aged 56 +/- 4.7 years) completed the fMRI study, where the effect of 400 mg was assessed on the brain activation induced by the continuous performance test (CPT). Naftidrofuryl induced a transient reduction in alpha activity followed by a specific synchronisation of the 9.5- to 11-Hz EEG activity most pronounced after repeated administration. Such regimen also increased the CPT-induced brain activation visualized by way of fMRI. The results of the present study can be interpreted at the functional level that naftidrofuryl induced an improved level of vigilance or an increased capacity of alertness in healthy elderly subjects., (Copyright 2003 S. Karger AG, Basel)

In the present study, we investigated the effects of a single and a repeated (5 days) administration of naftidrofuryl, a serotonin 5-HT2 receptor inhibitor having neuroprotective properties, on functional brain physiology in male healthy elderly subjects, using quantitative electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Twelve subjects aged 60 ± 3.8 years completed the quantitative EEG study, where the effects of 400 and 600 mg were assessed, and 12 other subjects (aged 56 ± 4.7 years) completed the fMRI study, where the effect of 400 mg was assessed on the brain activation induced by the continuous performance test (CPT). Naftidrofuryl induced a transient reduction in alpha activity followed by a specific synchronisation of the 9.5- to 11-Hz EEG activity most pronounced after repeated administration. Such regimen also increased the CPT-induced brain activation visualized by way of fMRI. The results of the present study can be interpreted at the functional level that naftidrofuryl induced an improved level of vigilance or an increased capacity of alertness in healthy elderly subjects.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]