OBJECTIVES: The study aimed to evaluate cognitive function and emotional reactivity in 18 patients with ALS, compared to 19 matched controls, and assess their evolution over a 12-month period.METHODS: 18 ALS patients and 19 matched controls were included, and assessed at inclusion, six months and twelve months later. Depression was evaluated with the Geriatric Depression Scale, and cognitive function with the Folstein Mini Mental State. A battery of psychometric tests ( Wisconsin Card Sorting Test (WCST), the numerical Empan test, the Trail-making test, the Boston Naming Test, the 15-word Rey memory test, the Benton visual retention test and the Raven Progressive Matrix) was used to measure frontal processing and non-frontal function. Emotional reactivity was measured with the film-evoked emotions test.RESULTS: ALS patients were significantly more depressed than controls, as measured on the Geriatric Depression Scale, and depression increased over the study period. There was a very mild defect in cognitive function, and a performance deficit in the Trail-making test, a measure of frontal processing. These deficits, unlike neuromuscular function and depression, did not aggravate over the 12 months of the study. There was no observable change in non-frontal function. Emotional reactivity did not differ significantly between ALS patients and controls.CONCLUSIONS: This study provides further evidence for a mild defect in frontal cognitive processing in ALS patients that evolves only slowly, if at all, with time.

Lormetazepam is a short-acting benzodiazepine hypnotic which is beneficial in shortening the time to onset of sleep. The aim of the study was to assess a new formulation of lormetazepam (oral solution) in comparison with lormetazepam tablets in out-patients with insomnia. This trial was an open randomized parallel group study conducted by 30 general practitioners. One hundred and eight patients took 0.5 mg on the first night and were allowed to increase their dosage by 0.25 mg (for oral solution) and 0.5 mg (for tablets), respectively, each day and every 2 days. The patients assessed the efficacy, acceptability and tolerance of lormetazepam using a diary card and a set of visual analogue scales assessing their sleep. Over 14 days of treatment, the mean daily dose of lormetazepam was lower in the oral solution group than in the tablets group (0.78 mg versus 0.97 mg). The cumulated dose of lormetazepam was lower with the oral solution (18% reduction). No significant difference between the two groups was found in the assessment of sleep characteristics. The occurrence of side effects did not differ between the two groups. These results suggest that a unitary dose as achieved by an oral solution of lormetazepam allows easier determination of the minimal individual effective dose. Copyright (C) 2004 John Wiley Sons, Ltd.

This paper describes the psychomotor and amnesic effects of single oral doses of etifoxine (50 and 100 mg) and lorazepam (2 mg) in healthy subjects.Forty‐eight healthy subjects were included in this randomized double blind, placebo controlled parallel group study. The effects of drugs were assessed by using a battery of subjective and objective tests that explored mood and vigilance (Visual Analog Scale), attention (Barrage test), psychomotor performance (Choice Reaction Time) and memory (digit span, immediate and delayed free recall of a word list).Whereas vigilance, psychomotor performance and free recall were significantly impaired by lorazepam, neither dosage of etifoxine (50 and 100 mg) produced such effects.These results suggest that 50 and 100 mg single dose of etifoxine do not induce amnesia and sedation as compared to lorazepam.

BACKGROUND:Dyskinesias are a frequent adverse effect of long-term levodopa therapy. The relative contribution of dopamine D(1) and D(2) receptor function to the pathophysiology of levodopa-induced dyskinesias remains a matter of controversy.OBJECTIVE:To establish whether a selective D(1) dopamine agonist induces more or less dyskinesia than levodopa in primed dyskinetic patients with Parkinson disease.METHODS:We studied ABT-431, the prodrug of a fully selective D(1) agonist, in 20 subjects with advanced Parkinson disease and a fluctuating response to levodopa complicated by dyskinesias. Eight patients were studied in a double-blind, randomized design (French centers); 12, in an open, randomized design (US centers). We assessed and compared the antiparkinsonian (Unified Parkinson's Disease Rating Scale) and dyskinetic (response induced by an acute challenge of a suprathreshold dose of levodopa and by 4 different ascending doses (5, 10, 20, and 40 mg) of ABT-431 during the 6 hours after the challenge.RESULTS:The separate analysis of the double-blind and open data led to the same findings, ie, the antiparkinsonian and dyskinetic responses induced by ABT-431 were dose related. At the most effective doses (20 and 40 mg), ABT-431 exhibited similar antiparkinsonian benefit and produced similar dyskinesias as levodopa.CONCLUSION:Dopamine D(1) agonists can induce a full antiparkinsonian response but do not support previous hypotheses suggesting that D(1) agonists are more or less likely to produce dyskinesias than levodopa.

Objectives: This double-blind, randomized, two-way crossover study in 12 healthy male subjects investigated the influence of caprylocaproyl macrogolglycerides on the pharmacokinetics of IS-159 (serotonin-carboxylmethyleneoxy-L-tyrosylglycinamide) , a peptide serotonin 1B/1D-receptor agonist, after intranasal administration.Methods: A dose of 4 mg IS-159 was administered in a volume of 200 mu L, once in the presence and once in the absence of 2% caprylocaproyl macrogolglycerides. Plasma concentrations of IS-159 were measured over a period of 12 hours for determination of pharmacokinetic parameters. Systemic and local tolerability were assessed at regular time points, the latter by rhinoscopy and visual analog scales,Results: Caprylocaproyl macrogolglycerides significantly increased the maximum plasma concentration (from 4.7 +/- 1.7 to 48 +/- 17 ng/mL) and the area under the plasma concentration-time curve (from 12 +/- 4.7 to 56 +/- 22 ng . h/mL) of IS-159, The time to maximum concentration (15 to 20 minutes) and the elimination half-life (2.0 to 2.3 hours) were not different between the two treatments, Rhinoscopic examination revealed no differences between treatments, but in the presence of caprylocaproyl macrogolglycerides subjects reported more local and systemic adverse events and on the visual analog scales greater nasal obstruction and rhinorrhea,Conclusion: 2% caprylocaproyl macrogolglyceride markedly increased the absorption of IS-159 through the nasal mucosa and elicited only mild irritant effects.

In a placebo-controlled, double-blind study, we measured the effects of low dose lorazepam on attentional and motor factors involved in saccadic and smooth pursuit eye movements. We manipulated the temporal interval between the extinction of the central fixation target and the appearance of a second eccentric target (gap/overlap step paradigm). The second target was either stationary (saccade trial) or moving in a direction opposite to the step (pursuit trial). Gap/overlap effects on the latency of saccadic and smooth pursuit eye movements were measured before and after oral intake of either lorazepam or placebo. Pharmacological effects on the dynamics and the accuracy of both types of eye movements were also investigated. In 14 healthy volunteers, we found that the temporal interval between fixation target offset and eccentric target onset modulates the latency of saccadic and smooth pursuit eye movements in a similar way. As compared to placebo, lorazepam significantly increased the latency of both types of eye movements, but did not modify the gap/overlap effect. Moreover, lorazepam significantly decreased the peak velocity of the first saccade towards the eccentric stationary target, as well as the gain of tracking towards the eccentric moving target. However, the overall accuracy of both behaviors was not significantly affected, indicating that systematic errors in foveating or tracking were detected and corrected by appropriate corrective or catch-up saccades, respectively. Results are discussed in terms of shared/different mechanisms for saccadic and pursuit systems in primates.

Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease. Ann Neurol 1999;45:736–741

Ce travail qui se veut didactique rappelle les differentes familles de recepteurs, les principales caracteristiques des recepteurs serotoninergiques et dopaminergiques ainsi que leur implication dans l'etiologie et la pathophysiologie des schizophrenies. Les connaissances actuelles sur les interactions entre systemes serotoninergiques et dopaminergiques sont ensuite resumees, de meme que le role potentiel de ces interactions dans la limitation des syndromes extra-pyramidaux induits par les neuroleptiques et leur interet theorique dans le traitement des signes negatifs de la schizophrenie.

This didactic paper reviews the different receptors families, the principal characteristics of the dopaminergic and serotoninergic receptors and their role in the aetiology and pathophysiology of schizophrenia. The current knowledge on interactions between serotoninergic and dopaminergic systems is also summarized. The theoretical and potential interests of these interactions in alleviating neuroleptic-induced extrapyramidal symptoms and improving negative signs in schizophrenia are also examined.

Ce travail qui se veut didactique rappelle les differentes familles de recepteurs, les principales caracteristiques des recepteurs serotoninergiques et dopaminergiques ainsi que leur implication dans l'etiologie et la pathophysiologie des schizophrenies. Les connaissances actuelles sur les interactions entre systemes serotoninergiques et dopaminergiques sont ensuite resumees, de meme que le role potentiel de ces interactions dans la limitation des syndromes extra-pyramidaux induits par les neuroleptiques et leur interet theorique dans le traitement des signes negatifs de la schizophrenie.

Many theories about dopaminergic function in Parkinson's disease are based upon the effects of the D2 receptor. Standard treatments mostly involve dopaminergic D2 agonists. However, the recent development of dopaminergic D1 agonists should help to clarify the role of the D1 receptor in the treatment of Parkinson's disease. The authors review the physiopathological, behavioural and therapeutic data on D1 agonists administered in animal models and in patients.

This didactic paper reviews the different receptors families, the principal characteristics of the dopaminergic and serotoninergic receptors and their role in the aetiology and pathophysiology of schizophrenia. The current knowledge on interactions between serotoninergic and dopaminergic systems is also summarized. The theoretical and potential interests of these interactions in alleviating neuroleptic-induced extrapyramidal symptoms and improving negative signs in schizophrenia are also examined.

The dopaminergic hypothesis in schizophrenia has progressively shifted to a bipolar hypothesis. Furthermore, there are numerous interactions between dopaminergic systems and other neurotransmission systems. Therefore, several pharmacological approaches are possible either through the specific antagonism of different dopaminergic receptors subclasses, partial dopaminergic agonists or indirect modulation or through the combined blockade of dopaminergic and serotoninergic, cholinergic or adrenergic receptors. The challenge today is to link a given clinical effect to one specific pharmacological property.

The dopaminergic hypothesis in schizophrenia has progressively shifted to a bipolar hypothesis. Furthermore, there are numerous interactions between dopaminergic systems and other neurotransmission systems. Therefore, several pharmacological approaches are possible either through the specific antagonism of different dopaminergic receptors subclasses, partial dopaminergic agonists or indirect modulation or through the combined blockade of dopaminergic and serotoninergic, cholinergic or adrenergic receptors. The challenge today is to link a given clinical effect to one specific pharmacological property.

Expression of some developmentally regulated cytoskeleton components (desmin, vimentin and myosin heavy chain isoforms) and cell surface proteins (including neural cell adhesion molecule (NCAM), its polysialylated (PSA) isoform and CD24) have been studied by immunohistochemical detection in a series of 23 infantile spinal muscular atrophies (SMA). According to the clinical classification established by Byers and Banker in 1961, 8 cases were type I SMA (Werdnig-Hoffmann's disease), 10 cases were type II (intermediate form), and 5 cases were type III (Kugelberg-Welander's disease). In 15 cases, the percentage of immunoreactive fibers with the various antibodies used has been quantified and the results correlated with clinical data. The aim of the study was to search for variations in the pattern of expression of the proteins to improve the accuracy of diagnosis and prognosis, and to gain an understanding of the pathological processes involved in SMA. The results showed that the pattern of expression of these cytoskeleton and cell surface proteins is abnormal in all types of SMA. However, it was strikingly different in type I and II SMA as opposed to type III. In type I and II SMA, strong NCAM and developmental myosin heavy chain (MHC) expression was observed in atrophic fibers. Numerous atrophic fibers co-expressed desmin and vimentin as well as slow and fast adult MHC. Very few of them expressed PSA NCAM, fetal MHC and CD24. In type III SMA, the number of fibers expressing NCAM, developmental MHC and co-expressing slow and fast adult MHC was low and virtually none of them expressed vimentin or desmin. These findings are in favor of a denervation process occurring very early in life, probably even in utero, in type I and II SMA and leading to a severe impairment of muscle fibers maturation. In contrast, in type III SMA, the process is initiated well after birth and affects mature muscle fibers. In all types of SMA, the ability of muscle fibers to regenerate is low, although some fibers may be reinnervated. Immunohistochemical data was not related to the patients follow-up and thus has no prognostic value.