Effects of prolonged-release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers.

BACKGROUND: Melatonin is an important regulator of the sleep-wake cycle. A prolonged-release formulation of melatonin (PR-M) that essentially mimics the profile of the endogenous production of the hormone is effective in the treatment of insomnia in patients aged 55 years and older. Because hypnotics result in impairments of various cognitive skills, it is important to examine the cognitive effects associated with the use of PR-M. OBJECTIVES AND METHODS: The effects of therapeutic oral doses of PR-M (2 mg), zolpidem (10 mg) and their combination administered at bedtime on cognitive functions in healthy subjects aged 55 years and older (12 males + 4 females, age 59.4 +/- 3.2 years) were assessed in a randomized, double-blind, placebo-controlled, and four-way crossover study. Psychomotor functions, memory recall, and driving skills were assessed at 1 and 4 h following administration and the next morning. RESULTS: Compared to placebo, PR-M alone did not impaired performances on any cognitive tasks. Zolpidem significantly impaired psychomotor and driving performance 1 h and 4 h post-dosing, and early memory recall; these impairment were exacerbated with PR-M co-administration. No effects on next morning psychomotor or driving performance were observed except that the decline in memory recall after zolpidem was more pronounced in the next day. No pharmacokinetic interactions were found. CONCLUSIONS: This study extends previous researches showing impairment of cognitive functions by zolpidem within 5 h post-administration. Further, PR-M use was not found associated with impairment of psychomotor functions, memory recall, and driving skills, and point to a pharmacodynamic interaction between melatonin and GABA-A modulators.

Effects of TC-1734 (AZD3480), a selective neuronal nicotinic receptor agonist, on cognitive performance and the EEG of young healthy male volunteers.

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.

Psychotropic profile of S 17092, a prolyl endopeptidase inhibitor, using quantitative EEG in young healthy volunteers.

The central activity of S 17092, a prolyl endopeptidase (PEP) inhibitor, was investigated by quantitative electroencephalography (qEEG) in 48 young healthy men participating in a double-blind, randomized, placebo-controlled, cross-over study. S 17092 (100, 200, 400 or 600 mg) and placebo were administered once daily for 10 days in a rising multiple-dose scheme. EEG recordings were performed before and repeatedly from 0.5 to 24 h after dose on day 1 and day 10. PEP activity in plasma was also measured for the same periods. S 17092 appeared as a potent inhibitor of PEP activity at all doses, after both single and repeated administrations. EEG changes after acute doses were slight and of short duration, mainly characterized by increased relative alpha 1 power, suggesting a vigilance-promoting EEG profile. After repeated doses and more strikingly after a superimposed dose, increases in relative alpha 1 power were still present with additional increase in relative delta power and decreases in absolute fast alpha, fast beta, theta powers and total power at all doses. These EEG findings suggest that S 17092 might possess some mood-stabilizing potential in addition to its cognition-enhancing properties.

Pharmacokinetics and safety profile of ispronicline (TC-1734), a new brain nicotinic receptor partial agonist, in young healthy male volunteers.

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.

Ability of a new oral nicotine substitute to reduce smoking urge in moderate smokers.

The aim of this study was to assess the effectiveness of a new nicotine lozenge ( Nicopass 1.5 mg) in reducing smoking urge after an overnight abstinence. Twenty-four moderate smokers participated in a randomized, double-blind, placebo-controlled, 2-period crossover trial. The results showed that 1.5 mg-nicotine lozenge is superior to placebo in reducing smoking urge (p = 0.0001). In addition, nicotine lozenge, but not placebo, significantly improved vigilance and psychomotor performances (p < 0.05) and displayed a cardiac chronotropic effect. Thus, the 1.5-mg nicotine lozenge appears as an effective aid to alleviate acute tobacco withdrawal symptoms in moderate smokers.

A positron emission tomography (PET) study of cerebral dopamine D2 and serotonine 5-HT2A receptor occupancy in patients treated with cyamemazine (Tercian).

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.

Planning of pharmacodynamic trials: I. Specificity and possible solutions. II. Stability considerations under placebo and interpretation of drug effects on EEG.

This workshop deals with the concept of quantitative electroencephalography (QEEG) to characterize the central effects of drugs. For proper interpretation, the circumstances under which data are obtained play an important role. To infer the size of variability in standard practice, we elaborated some computations for "placebo-treatment" in healthy volunteers, which helps to determine the threshold of drug effect detection. Simple rules for interpretation of multiple statistical comparisons were proposed and validation of dose effects were carried out with accepted reference compounds. Furthermore, psychotropic agents with comparable therapeutic indications often present similar modifications in EEG spectral composition (pharmaco-EEG profile). To extrapolate this concept, quantified wake-EEG is a rapid, validated technique for early psychopharmacological investigation of new psychotropic compounds (Phase I, healthy volunteers). Classification of drug-induced changes in cerebral activity at this stage forms a useful decision instrument in planning the long-term clinical scenario of drug development (Phases II and higher).

Effects of lorazepam on brain activity pattern during an anxiety symptom provocation challenge.

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.

Pharmacodynamic effects of acamprosate on markers of cerebral function in alcohol-dependent subjects administered as pretreatment and during alcohol abstinence.

Animal studies suggested that acamprosate modulates neuronal hyperexcitability of acute alcohol withdrawal, acting through the glutamatergic neurotransmission. In the present study, we further investigated whether treatment with acamprosate could attenuate the post-alcohol withdrawal hyperexcitability or hyperarousal in humans using brain magnetoencephalography mapping of spontaneous fields. A double-blind, randomised, placebo-controlled study with a parallel group design comparing 2,000 mg/day of acamprosate versus placebo was conducted in alcohol-dependent subjects meeting DSM-IV criteria for alcohol dependence. Treatments were initiated 8 days before alcohol withdrawal and prolonged during the 15 following (abstinence) days. The study demonstrated that during alcohol withdrawal, acamprosate decreased the arousal level as reflected by alpha slow-wave index (ASI) measurement. This effect was mostly evidenced in left parietotemporal regions and, to a lesser extent, in the contiguous anterior, posterior and right-sided regions. In the placebo group, on the contrary, ASI measures increased between day 2 (acute withdrawal) and day 14 (prolonged withdrawal). The present results suggest a sustained effect of acamprosate on the hyperexcitability state due to alcohol withdrawal in alcohol-dependent patients and that acamprosate may have a protective effect when administered 8 days before alcohol withdrawal.

Characterization of the CNS effects of naftidrofuryl (Praxilène) by quantitative EEG and functional MRI: a study in healthy elderly subjects.

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.