Two distinct double-blind randomized multicentre studies were undertaken at the same time using the same design. Patients treated for insomnia with zopiclone 7.5 mg or zolpidem 10 mg for at least three months were allocated to two groups: gradual withdrawal or control. In each study the two groups were compared but there was no comparison between zopiclone and zolpidem. The main criteria was the number of patients in each group with “withdrawal syndrome” defined as: the occurrence of an adverse event, or premature discontinuation of treatment or a total score increase of at least 3 points on the Tyrer questionnaire. In both studies the incidence of “withdrawal syndrome” as defined above was significantly higher in the “withdrawal” groups than in the “control” groups 38% vs 20% for zopiclone p = 0.008 and 38% vs 24% for zolpidem P = 0.049. In most cases, the notified symptoms were sleep complaints.

The quality of human cognitive performance appears today as one of the main components of quality of life, whatever the age. Ageing by itself and most of the diseases affecting the central nervous system alter higher brain functions such as memory, vigilance and attention. Dementia is the most acute example, with a cascade of behavioral and psychological consequences (BPSD), which are the main cause of the caregiver’s burden and need specific pharmacotherapy. In this respect, the problem will be the choice of the best drug in situations such as wandering, agitation, violence, and screaming. The psychotropics, however, should not deteriorate the already disturbed cognition of the patients. This is the reason why we propose to establish for each drug, and notably for the antipsychotics, a precise and exact ‘cognitive mapping’; in other words, to measure the effects of drugs on the different components of cognition. The results of such studies will be predictive of the future phase III clinical trials and therapeutic responses. As an illustration of this approach we shall relate two studies, TIATEM (phase I) and TIAGE (phase III/IV), leading to the determination of a good cognitive safety profile of an atypical neuroleptic drug, tiapride.

The adverse effects of insomnia on health and quality of life are matters receiving increasing attention. Yet, surveys have consistently shown that most people suffering from insomnia do not seek medical help, perhaps, in part, because of a concern of becoming dependent on hypnotic medication. The treatment of chronic insomnia poses a particular dilemma in that continuous hypnotic treatment is restricted in many countries to a maximum of 4 weeks, and behavioural treatment is not readily available. Non-nightly hypnotic treatment of chronic insomnia offers a promising alternative option for the many patients whose symptoms do not necessitate nightly drug intake, allaying fears of psychological dependence on medication and respecting regulatory constraints on hypnotic use while providing patients with adequate symptom relief. The practical feasibility and efficacy of this approach has been demonstrated with zolpidem using various treatment regimens and study designs. So far, six clinical trials have been completed on over 4000 patients. Published results show effective treatment of insomnia without any evidence of either adverse event associated with a discontinuous regimen or increased hypnotic use over the treatment period.

Agitated behaviors such as uncooperativeness with necessary care, motor hyperactivity, and verbal or physical aggression are some of the most commonly reported complications in dementia and organic disorders in elderly subjects. These symptoms present greater clinical challenges and management issues than the cognitive deficits. Antipsychotics are the most commonly used psychotropic agents for treating these types of symptoms.

The aims of this article are to review clinical studies with tiapride, a substituted benzamide, and more specifically to present recent data coming from two double-blind, randomized studies in elderly subjects.

The first study versus melperone was conducted in Germany, with over 176 hospitalized demented patients, and indicated that tiapride was as effective and safe as melperone.

More recently, a multicentre, international, double-blind, three-parallel group study compared a 21-day treatment of tiapride to haloperidol and placebo and included 306 demented elderly patients with agitation and aggressiveness. The results showed that tiapride and haloperidol were significantly effective in the treatment of agitation and aggressiveness compared to placebo. The tiapride safety profile was found to be better than haloperidol for clinical acceptability, particularly for significantly fewer extrapyramidal symptoms in the tiapride group.

Les données neurochimiques directes ou indirectes obtenues dans différentes affections du système nerveux central (SNC) constituent la base rationnelle de I'utilisation des médicaments dans des indications précises. Les antidépresseurs (AD) tricycliques agissant sur les principales amines du SNC trouvent ainsi des applications thérapeutiques variées en dehors de la dépression. L'arrivée de nouveaux AD au mécanisme d'action, soit plus cibé (la sérotonine), soit différent (IMAO) pose de nouveau cette question des indications psychiatriques et neurologiques, qui ne peut être résolue que par des essais méthodologiquement irréprochables. Une telle approche évitera d'ignorer pendant des années des effets thérapeutiques incontestables d'une molécule ancienne, tel que ce fut le cas de la clomipramine dans les troubles obsessifs-compulsifs.

The different aspects of general safety of zolpidem are reviewed after analysing the safety data obtained in adults as well as in elderly patients. The low incidence of reported adverse events during the first three years of utilisation of zolpidem have corroborated the results of the clinical studies. The most frequent adverse effects are central nervous system (CNS) related but they can be largely prevented by respecting the recommended doses and prescription rules. In cases of acute overdoses, no severe complications have been attributed to zolpidem taken alone. In most of the studies carried out within the recommended treatment duration, abrupt treatment discontinuation was not associated with clinically significant rebound insomnia, and the available pre-clinical and clinical data indicate that the risk of abuse or dependence is minimal when prescribed according to the recommended doses of 10 mg in adults and 5 mg in elderly. Thus, with now well-established arguments on a large patient basis going in the same direction, the safety of zolpidem can authorise and justify its wide prescription in the short-term treatment of insomnia.

The effect of zopiclone (7.5 mg) on attention, vigilance and memory components was evaluated during a nocturnal period in comparison to a placebo, to zolpidem (10 mg) and to flunitrazepam (1 mg) in a double blind, randomized study, after administration of a single dose in 16 young healthy volunteers. It appears that there is a clear effect on attention and vigilance; this effect is apparent during the kinetic phase of the absorption of the medication. The effect on memory is transient and is absent four hours after the ingestion of the drug. The objective results are not strictly consistent with the chronology of the subjective parameters (Leeds scale — Visual Analogue Scale). The three hypnotics under comparison do not fundamentally differ except in their kinetic/pharmacodynamic effect relationship. One important fact, taking the parameters as a whole, is that there is no objective “residual” effect.

Alcohol-dependent individuals usually favor instant gratification of alcohol use and ignore its long-term negative consequences, reflecting impaired decision-making. According to the somatic marker hypothesis, decision-making abilities are subtended by an extended brain network. As chronic alcohol consumption is known to be associated with brain shrinkage in this network, the present study investigated relationships between brain shrinkage and decision-making impairments in alcohol-dependent individuals early in abstinence using voxel-based morphometry. Thirty patients performed the Iowa Gambling Task and underwent a magnetic resonance imaging investigation (1.5T). Decision-making performances and brain data were compared with those of age-matched healthy controls. In the alcoholic group, a multiple regression analysis was conducted with two predictors (gray matter [GM] volume and decision-making measure) and two covariates (number of withdrawals and duration of alcoholism). Compared with controls, alcoholics had impaired decision-making and widespread reduced gray matter volume, especially in regions involved in decision-making. The regression analysis revealed links between high GM volume in the ventromedial prefrontal cortex, dorsal anterior cingulate cortex and right hippocampal formation, and high decision-making scores (P < 0.001, uncorrected). Decision-making deficits in alcoholism may result from impairment of both emotional and cognitive networks.

A quantitative trait loci (QTL) analysis of wool traits from experimental half-sib data of Merino sheep is presented. A total of 617 animals distributed in 10 families were genotyped for 36 microsatellite markers on four ovine chromosomes OAR1, OAR3, OAR4 and OAR11. The markers covering OAR3 and OAR11 were densely spaced, at an average distance of 2.8 and 1.2 cM, respectively. Body weight and wool traits were measured at first and second shearing. Analyses were conducted under three hypotheses: (i) a single QTL controlling a single trait (for multimarker regression models); (ii) two linked QTLs controlling a single trait (using maximum likelihood techniques) and (iii) a single QTL controlling more than one trait (also using maximum likelihood techniques). One QTL was identified for several wool traits on OAR1 (average curvature of fibre at first and second shearing, and clean wool yield measured at second shearing) and on OAR11 (weight and staple strength at first shearing, and coefficient of variation of fibre diameter at second shearing). In addition, one QTL was detected on OAR4 affecting weight measured at second shearing. The results of the single trait method and the two-QTL hypotheses showed an additional QTL segregating on OAR11 (for greasy fleece weight at first shearing and clean wool yield trait at second shearing). Pleiotropic QTLs (controlling more than one trait) were found on OAR1 (clean wool yield, average curvature of fibre, clean and greasy fleece weightand staple length, all measured at second shearing).

Los efectos adversos del insomnio sobre la salud y la calidad de vida son asuntos que reciben una atención cada vez mayor. Sin embargo, los estudios han mostrado uniformemente que la mayoría de las personas que sufren de insomnio no buscan ayuda médica, quizá, en parte, a causa de una preocupación por volverse dependientes de la medicación hipnótica. El tratamiento del insomnio crónico plantea un dilema particular, ya que el tratamiento hipnótico continuo está limitado en muchos países a un máximo de cuatro semanas, y no es fácil disponer de tratamiento conductual. El tratamiento hipnótico discontinuo del insomnio crónico ofrece una opción distinta prometedora para los numerosos pacientes cuyos síntomas no requieren el consumo de fármacos todas las noches, aliviando los temores de dependencia psicológica de la medicación y respetando los límites regulatorios sobre el uso de hipnóticos al tiempo que proporciona a los pacientes alivio adecuado de los síntomas. La viabilidad práctica y la eficacia de este enfoque se han demostrado con zolpidem, utilizando diversos regímenes de tratamiento y diseños de estudio. Hasta ahora, se han finalizado seis ensayos clínicos en más de 4.000 pacientes. Los resultados publicados muestran que el tratamiento del insomnio es efectivo, sin datos de asociación de acontecimientos adversos con un régimen discontinuo o de aumento de uso del hipnótico durante el periodo de tratamiento.

More accurate definition of Angora rabbit breeding objectives has been investigated by considering multiple expression of different traits. Data on 9672 fleece harvests produced by 1343 Angora does which had at least one wool harvest were analysed in order to study genetic variability according to age. The animals of the French breed were defleeced and weighed at 8 and 21 weeks of age for the first and second time respectively. Thereafter, does were defleeced every 14 weeks and weighed 9 weeks before defleecing. Total fleece weight and live body weight were recorded at each harvest.

Direct heritability estimates of total fleece weight were similar accross ages and ranged from 0·31 to 0·42 . A significant maternal heritability was also observed at all ages of harvest. Maternal genetic estimates decreased with age from 0·44 at the first harvest to 0·10 for an adult harvest. Except for 8 weeks of age, genetic correlations between total fleece weight and live weight were generally not significantly different from zero. Genetic correlations of total fleece weight between the first and subsequent harvests were low (from 0·22 to 0·39) but genetic correlation estimates between consecutive harvests after the first were high, and ranged from 0·68 to 0·89 . The results suggest that the second harvest would be the first good predictor of breeding value for total fleece weight in the adult Angora rabbit.

Se revisan los diferentes aspectos de la seguridad general de zolpidem después de analizar los datos de seguridad obtenidos en adultos y en pacientes ancianos. La baja incidencia de comunicaciones de acontecimientos adversos durante los tres primeros años de utilización de zolpidem ha corroborado los resultados de los estudios clínicos. Los efectos adversos más frecuentes están relacionados con el sistema nervioso central (SNC), pero se pueden prevenir en gran medida respetando las dosis recomendadas y las reglas de prescripción. En los casos de sobredosis aguda, no se han atribuido complicaciones graves a zolpidem en monoterapia. En la mayoría de los estudios realizados en el período de tratamiento recomendado, la interrupción brusca del mismo no se asociaba con insomnio de rebote clínicamente significativo. Los datos preclínicos y clínicos disponibles indican que el riesgo de abuso o dependencia es mínimo cuando se prescribe según las dosis recomendadas de 10 mg en adultos y 5 mg en ancianos. Así, con argumentos ahora bien establecidos que van en la misma dirección sobre una gran base de pacientes, el perfil de seguridad de zolpidem puede autorizar y justificar su prescripción amplia en el tratamiento a corto plazo del insomnio.