Postmarketing surveillance of zopiclone in insomnia: analysis of 20,513 cases.

The subjective response to the prescription drug zopiclone, an hypnotic agent belonging to the cyclopyrrolone family, was assessed under the usual conditions of prescription of an hypnotic in general practice. The study included 20,513 insomniac outpatients with at least two of the following symptoms: sleep onset latency longer than 1 hour, more than two nocturnal awakenings, early morning awakening 1 hour or more before scheduled time, total sleep time of less than 6 hours, complaint of tiredness on awakening. Insomniac patients were treated with zopiclone and followed for 21 consecutive days within the context of a follow-up surveillance study. The population was predominantly female (62.6%), and the mean age was 52.3 years. The dosage of zopiclone prescribed at the inclusion visit was 7.5 mg per day in 87.5% of the cases and 3.75 mg per day in 10.5%. A total of 93.8% of the patients completed the survey. Spiegel questionnaire improved during the 21-day survey, and 9.2% of the patients reported at least one adverse event that led to treatment discontinuation in only 2.8% of the population. No serious or unexpected adverse events were reported.

Effect of brain microdialysis on aminergic transmitter levels in repeated cerebral global transient ischemia in rat.

The effect of repeated transient global ischemia and microdialysis on changes in aminergic neurotransmitter release was investigated using the rat four-vessel occlusion model of global ischemia. To examine the possible transient or permanent changes in neurotransmitter release, ischemia was induced at varying time points in 5 groups of rats. The first ischemia occurred either 24 h (groups I, II, IV, V) or 96 h (group III) following vertebral artery electro-coagulation and guide probe implantation(s), and the second ischemia was induced either 48 h (groups I, IV, V) or 72 h (group II) following the first ischemia. To assess the consequence of repeated microdialysis on the results, one group of rats (group IV) was not dialysed during the first ischemia and another group (group V) was bilaterally dialysed during the second ischemia. Finally, amphetamine-induced neurotransmitter release was also studied in rats submitted to ischemia and compared with that in normal rats. In each case, dopamine, serotonin and their main metabolites were measured by HPLC with electrochemical detection. Monoamine release was inhibited during the second episode of transient ischemia; this non-release was linked to the repeated microdialysis and not to the repeated ischemia. Although the results of chronic studies using brain microdialysis have been widely recognized as valid, the findings presented here indicate that combined with ischemia, probe reinsertion modifies the level of neurotransmitter release.

Choosing a target for cognitive enhancers.

The development of drugs to improve cognitive functions (cognitive enhancers) has been hampered by the failure to define pharmacologic targets. The justifications for the development of cognitive enhancers for medicine, the pharmaceutical industry, and society are outlined. The procedures required for the development of these drugs and their therapeutic objectives are discussed. It is concluded that a better definition of the direct targets of cognitive enhancers can guarantee cost and time savings for the industry and produce a therapeutically effective agent.

Cardiac beta-adrenoceptor sensitivity and Parkinson's disease.

Certain clinical manifestations of Parkinson's disease (PD) (speech or/and balance disturbances) are not linked to brain dopamine deficiency. The purpose of the present study was to search for a possible relationship between those so-called "non-dopamine-dependent" extrapyramidal manifestations and the sensitivity of cardiac beta-adrenoceptors. Fourteen patients aged 51 to 69 were included in the study after having given their informed consent. Any factor or pathology susceptible to modify receptor sensitivity entailed exclusion. In the absence of a reference model for measuring the reactivity of central beta-adrenoceptors, a computation of the isoprenalin dose necessary to increase the resting heart rate by 20 bpm was used as an index for beta-adrenergic system reactivity. In addition to that test, other parameters were recorded: disease duration, motor status scale (Columbia), some cognitive functions (MMS and image differed recall). The cardiac beta-receptor decrease in reactivity to isoproterenol is correlated to PD duration (r = 0.8, P less than 0.001). Conversely, the sensitivity of these receptors appeared to be unrelated to the extrapyramidal severity of the disease, hence to the degree of the so-called "non dopamine-dependent" disturbances. Furthermore, such results raise the meaning of the impairment of peripheral aminergic receptors in the cognitive disturbances linked to ageing and/or PD.

Progress in understanding the pathophysiology of cerebral ischemia: the almitrine-raubasine approach.

Cerebral ischemia occurs frequently and is disabling. In addition to preventing and correcting risks factors, drugs prevent cell death induced by ischemia-hypoxia. Precise knowledge of the pathophysiology of cerebral ischemia is the prerequisite for drug development, and the main proofs of efficiency are histopathological and clinical (i.e., the results of controlled studies). Different animal models are considered valid for global, focal, or multifocal ischemia. These models have enabled the identification of deleterious phenomena that could be corrected or neutralized by drugs: hypoxia, lactic acidosis, release of neurotransmitters, influx of calcium, activation of phospholipase A2, release of excitatory amino acids, excess of free radicals, and neuronal cell metabolic paralysis (decrease of oxygen and glucose consumption). The chronology of these events clearly described herein will prompt the choice of the best drug, based on the delay between the ischemic event and the decision to treat. The main pharmacological effects required are the following: antagonism of hypoperfusion, oxygenation improvement, blockade of calcium influx and neurotransmitters action, reduction of acidosis and potassium efflux, blockade of arachidonic cascade and free radicals production, and antiedematous effect. The analysis of almitrine-raubasine (Duxil) pharmacological properties will be used as an example of these potentially anti-ischemic drugs. Almitrine-raubasine pharmacological studies indicate that this drug has several beneficial effects on cerebral ischemic processes. These studies have dealt with effects of hypobaric hypoxia on deoxyglucose uptake in the rat, protective effects on permanent or temporary cerebral ischemia-induced neurobehavioral problems in the gerbil, and preservation of the glycogen content and of the swelling in astrocytes after bilateral occlusion of the carotid arteries in the rabbit.

Alteration of aminergic neurotransmitter release after two consecutive transient global ischaemias: an in vivo microdialysis study in rat.

This study was designed to evaluate the effects of two consecutive ischaemias on extracellular monoaminergic neurotransmitter concentrations. The data on the neuroamine changes induced by the second ischaemia could be used to assess the delay in aminergic neurotransmission subsequent to the primary injury. Dopamine (DA), serotonin (5HT) and their metabolites, homovanillic acid (HVA), dihydroxyphenyl-acetic acid (DOPAC) and 5-hydroxyindolacetic acid (5-HIAA) were measured in vivo through striatal microdialysis of awake rats, using HPLC and electrochemical detection. Pulsinelli and Brierley's four-vessel occlusion model was used to induce a 20-minute global transient ischaemia in the forebrain. Two experimental groups were formed: the second ischaemic period was induced 3 h after the first one in group I (n = 5) and after 24 h in group II (n = 5). Dramatic increases in DA (150 times the baseline level) and 5HT (10 times the baseline level) were recorded during the first ischaemia, consistent with literature data. Metabolites of DA and 5HT (HVA and 5HIAA) decreased significantly. Baseline values were restored after 40 min of reperfusion. There was no significant difference between the effects of the first and second ischaemias on neurotransmitter release in group I. In group II, the second ischaemia did not significantly alter the baseline aminergic neurotransmitter content, although all the clinical signs of global ischaemia were present (in particular the loss of righting reflex). These original data could be explained by delayed impairment of release mechanisms, rather than by exhaustion of the releasable pools of these neurotransmitters one day after the first ischaemia.

[Pharmacology of cellular ischemia]. / Pharmacologie de l'ischémie cellulaire.

Knowledge of cellular disturbances provoked by an ischemic aggression conditions the use of a pharmacologic strategy that could possibly protect the cell from necrosis. Whatever the type of cell, the basic mechanisms are very similar: energy failure, acidosis, loss of electrolytic homeostasis, particularly of calcium, formation of free radicals and, of more recent knowledge, genetic induction. Different molecules have been shown to be effective at each of these stages in one or other of the many experimental models available. The therapeutic approach is not very forthcoming at present but the field of applications is vast. Ischemic disease is not restricted to cerebral or cardiac ischemia and, although the lesions are mainly those of senescence, it is observed in other etiologic frameworks, if only in the perinatal period. Finally, the great increase in the use of organ transplants opens up another field of application with research on the best method for organ preservation and optimization of its acceptance by the host organism.

[Pharmacology of central cholinergic synapse]. / Pharmacologie de la synapse cholinergique centrale.

Because it intervenes in normal and pathological cerebral ageing, plays a role in late dyskinesias of Parkinson's syndrome and is involved in the memorization processes, central cholinergic neurotransmission deserves to be known with precision. Its physiological approach deals with the anatomical organization of the central cholinergic system and with the mechanisms of synthesis, release and degradation of acetylcholine and its interaction with its receptors. The pharmacological changes (inhibition or stimulation) conceivable at different levels lead to therapeutic applications.

[Memory deficit in Parkinson's disease. Precocious aging of recall processes]. / Déficit mnésique au cours de la maladie de Parkinson. Vieillissement accéléré des processus de rappel.

In this study, the various components of the memory process were analysed in 25 non-demented parkinsonian patients (PP). A battery of tests was used to explore words, drawings and semantic organization of items. Results were compared with young (n = 22) and elderly (n = 11) healthy controls. Scores were correlated with the characteristics of Parkinson disease. Recall of words and drawings was significantly disturbed in PP. In contrast, the recognition of drawings and faces was not impaired. A high degree of interindividual difference in performance was observed; it was strictly correlated with age but not with the features of parkinsonism. A specific pattern of memory impairment can be described in parkinsonism, which would suggest and support the theory that different pathogenic mechanisms are involved in ageing and in parkinsonian patients.

Temporal profile of aminergic neurotransmitter release in striatal dialysates in rats with post-ischemic seizures.

The temporal profiles of aminergic neurotransmitter levels and of their acid metabolites after transient global cerebral ischemia in awake rats with and without subsequent seizures were compared using a microdialysis approach. In seizure animals, the post-ischemic levels of dopamine and serotonin were higher than the levels observed in the non-seizure controls. Inversely, the levels of the three neurotransmitter metabolites increased rapidly in the controls but not in seizure animals, where they remained at the low levels observed during and immediately after ischemia. This particular pattern is similar to that observed in rats submitted to prolonged ischemia or pretreated with monoamine oxidase inhibitors. In the seizure animals, neurotransmitter metabolites remained at low levels, as if the hypoxia had continued after the period of ischemia, inhibiting monoamine oxidase activity and, perhaps, neurotransmitter recapture.

L-type voltage-dependent calcium channels do not modulate aminergic neurotransmitter release induced by transient global cerebral ischaemia: an in vivo microdialysis study in rat.

Cerebral ischaemia induces considerable neurotransmitter exocytosis, mediated by calcium entry in neurones, essentially via the N-type, voltage-dependent channels, which are insensitive to calcium blockers. Nonetheless, these blockers, by unclear mechanisms, exert a neuroprotective effect when used in experimental ischaemic models. On the other hand, the existence of L-type, voltage-dependent channels, the only ones responding to the action of calcium blockers on synapses, argues in favour of their possible concomitant action in certain highly pathological situations. We studied the action of three calcium blockers, nimodipine, diltiazem and verapamil (administered at a concentration of 100 microM directly into the striatum of rats), on the extracellular release of dopamine and serotonin, and on the level of their main metabolites, in a model of transient global cerebral ischaemia (four-vessel occlusion). The total absence of effect of these molecules on neurotransmitter release induced by ischaemia proves the non-involvement of this mechanism in the protective action of calcium entry blockers on ischaemic lesions, and the absence or very weak action of L-type, voltage-dependent presynaptic channels in the striatum of rats.

Importance of catecholamine release for the functional action of intrastriatal implants of adrenal medullary cells: pharmacological analysis and in vivo electrochemistry.

The aim of the present experiments was to test whether adrenal chromaffin cells implanted into the striatum of rats could exert a functional effect through a release of catecholamines. A cell suspension obtained from bovine adrenal medulla was implanted unilaterally into the striatum. The striatal dopaminergic input was extensively destroyed beforehand to preclude the possibility of reinnervation of the striatum by endogenous dopaminergic neurons. The functional influence of the implant was tested through the measurement of drug-induced rotation, while catecholamine release was measured subsequently in the same animals by in vivo electrochemistry. Transplant survival, as shown by the immunohistochemical analysis performed at the end of the in vivo experiments, was highly variable. Surviving chromaffin cells maintained their endocrine morphology and no reinnervation of the host striatum could be detected. Rotation of the animals evoked by apomorphine (0.1 mg/kg, sc) or amphetamine (5.0 mg/kg, ip) following the lesion was left uninfluenced following transplantation, even when a large transplant was recovered. On the other hand, nicotine (0.5 mg/kg, sc) evoked a strong contraversive rotational response in the transplant-bearing animals. This response could not be ascribed to the central effect of substances released peripherally and entering the nervous system through the blood-brain barrier opened by the implantation procedure, as it could not be found in animals bearing implants of other peripheral endocrine tissue, viz, pituitary. The effect of nicotine was not blocked by the pretreatment of the animals with either the opiate antagonist naloxone (2.5 mg/kg, 10 min) or the dopamine receptor blocker pimozide (0.5 mg/kg, 1 h), although the latter pretreatment blocked the amphetamine-evoked rotation. No spontaneous catecholamine release could be detected from the implanted chromaffin cells by in vivo electrochemistry, while treatment with amphetamine or nicotine did evoke a release. The results suggest that the functional effects of such intrastriatal grafts of chromaffin cells, reported in previous studies, cannot be explained by the secretion from the grafted cells of catecholamines into the denervated striatum. On the other hand the results obtained following the pharmacological stimulation of these cells indicate that adrenal grafts can, under suitable conditions, influence the functioning of the host nervous system.

[Anxiolytic agents and hypnotic drugs in Bretagne. Pharmaco-epidemiological study]. / Les anxiolytiques et les hypnotiques en Bretagne. Etude pharmaco-épidémiologique.

A pharmacoepidemiological survey was carried out in a rural region of France (Brittany) with the help of 54 general practitioners, all of whom belong to a clinical research group. The aim of the survey was 3-fold: to determine the frequency (incidence and prevalence) of anxiolytic and hypnotic drug prescriptions, the sociological characteristics of these drug consumers, and the indications and reasons for prescribing this class of drugs. The population of hypnotic drug and sedative consumers was strikingly dominated by women, 60 years old and over, retired or without a profession. Prescription analysis revealed that these drugs were essentially benzodiazepines whose prevalence and incidence were 17 and 1.76%, respectively. A high frequency of prescription renewals (78%) and an elevated percentage of long-term treatments (more than 9 years) were also noted. Insomnia and dependence are the two main "risk factors" for drug treatments lasting more than one year.

[Development of memory-improving drugs]. / Le développement de médicaments pro-mnésiants.

Knowledge on the diverse processes involved in memory has been gained from multiple approaches, all necessary for the development of molecules aimed at enhancing memory. However, the neurobiological aspects of apprenticeship and memory remain to be fully elucidated. Long-term storage of information in the nervous system is under the control of glycoprotein synthesis. The chemistry of storage has been extensively studied in mollusks because of their simple neuroarchitecture. In mammals, the phenomenon of hippocampic long-term potentialization (HLTP), to a large extent linked to modification of glutamatergic transmissions, has been demonstrated. Stimulation of N-methyl-DL-aspartase (NMDA) receptors induces an influx of calcium, which is needed for HLTP maintenance, as are the activation of protein kinase C (PKC) and the synthesis of new proteins, for example calmodulin. At the molecular level, a cascade of biochemical events leads to modifications of neuronal connections, thus constituting the basis of memory. Memory-improving substances can be classified according to their theoretical mechanism of action: molecular pharmacology (agents inducing phenomena that mimic HLTP), neurotransmission (molecules acting on the cholinergic, noradrenergic, serotoninergic, GABAergic or dopaminergic systems), pathophysiology (substances antagonizing or correcting anomalies responsible for the memory deficiency, i.e., the cognitive enhancers). The development of memory-enhancing drugs has encountered many obstacles, notably the difficulty in evaluating the effectiveness of a medication in improving memory. It is imperative that guidelines be established for the clinical and experimental development of such substances as well as the standardization of tests in animals and man.

Comparison of three regimens of Parlodel-SRO in levodopa-treated parkinsonians: a randomized double-blind crossover study.

Parlodel-SRO is a newly developed slow-release formulation of bromocriptine, which prevents initial plasma peak--a known source of adverse events--and extends the half-life of the compound, an interesting feature for the management of motor symptoms in Parkinsonians. This study was designed to determine the best daily administration schedule for 30 mg Parlodel-SRO in 18 parkinsonians previously treated with levodopa and standard Bromocriptine (Br). The 30 mg dose was replaced from one day to the next, in a randomized, double-blind latin square design trial. Three consecutive 7-day courses were implemented, during which a total daily dose of 30 mg P-SRO was administered in one dose, two intakes (b.i.d.) and three intakes, (t.i.d.) respectively. The b.i.d. schedule produced the best improvement in UPDRS scores, especially as to postural stability, walking, bradykinesia; it also provided greater pharmacological stability throughout the assessment day. Adverse event analysis was not in favor of a single daily dose. It appeared that P-SRO administered in two 15 mg intakes (morning and evening) produces the best benefit-risk ratio in Parkinsonians who were already being treated with levodopa.