L’apomorphine par voie sous-cutanée en perfusion continue est de plus en plus utilisée dans la prise en charge des complications motrices de la maladie de Parkinson lorsque les fluctuations deviennent gênantes. Jusqu’à présent, sa mise en place était réalisée en hospitalisation, le plus souvent dans un centre expert, ce qui, dans certaines régions pouvait en limiter l’accessibilité. Une meilleure maîtrise de ce traitement par les praticiens, l’implication accrue des prestataires proposant ce type de service et l’amélioration des dispositifs concourent à une plus grande accessibilité de cette thérapeutique, jusqu’à permettre dans certains cas sa mise en place à domicile. Toutefois, cette prescription doit obéir à un certain nombre de règles. Ainsi, pour permettre à l’ensemble des patients éligibles de bénéficier de ce traitement dans de bonnes conditions, des recommandations sont proposées détaillant le rôle des différents acteurs de santé et les modalités de prescriptions.

Background In patients with acute ischemic stroke, early treatment with thrombolytic agents is thought to permit reperfusion of ischemic neurons and to promote recovery of function. The Multicenter Acute Stroke-Trial - Europe (MAST-E) was designed to assess the efficacy and safety of streptokinase in patients with acute ischemic stroke.Methods Patients with moderate-to-severe ischemia in the territory of the middle cerebral artery were randomly assigned to receive streptokinase (1.5 million units over a period of one hour) or placebo within six hours after the onset of stroke. The primary efficacy outcome was a binary criterion combining mortality and severe disability at six months, with severe disability defined as a score of 3 or higher on the Rankin scale. The primary safety outcomes were mortality at 10 days and cerebral hemorrhage.Results All randomized patients (156 in the streptokinase group and 154 in the placebo group) were evaluated at six months. The incidence of the primary efficacy outcome was similar in the two groups (124 patients in the streptokinase group and 126 in the placebo group died or had a Rankin score greater than or equal to 3). However, the mortality rate at 10 days was significantly higher in the streptokinase group than in the placebo group (34.0 percent vs. 18.2 percent, P=0.002). The higher rate in the streptokinase group was mainly due to the hemorrhagic transformation of ischemic cerebral infarcts. At six months, more deaths had occurred in the streptokinase group than in the placebo group (73 vs. 59, P=0.06).Conclusions In patients with acute ischemic stroke, treatment with streptokinase resulted in an increase in mortality. The routine use of streptokinase cannot be recommended in acute ischemic stroke. (C) 1996, Massachusetts Medical Society.

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.

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.

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.

The French selegiline (S) multicenter trial was conducted in 1990 to test the possibility to improve symptomatology of de novo parkinsonian patients (PP) during the first three months of treatment by monotherapy S 10 mg/day.A randomized double blind placebo, parallel controlled trial was carried out on 93 patients in 13 neurologic centers. S appears superior to placebo. Global scores and motor subscores of UPDRS are improved (p < 0.001, p < 0.01) from the first to the third month.Side effects are minor (nausea, dysgueusia, vertigo, lipothymia) and hardly different in both groups. S thus appears as inducing a rapid and moderate symptomatic effect in de novo PP, during a 3 months long period of treatment.

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 μM 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.

Cerebral ischemia alters the tissue concentrations of aminergic neurotransmitters and their metabolites, and at the same time produces an edematous reaction. The predominant role played by calcium ion shift in inducing these deleterious events indicates that calcium blockers may have a protective effect. The effects of four molecules (nimodipine, 2-mu-g/kg/min; flunarizine, 3-mu-g/kg/min; diproteverine, 50-mu-g/kg/min; verapamil, 100-mu-g/kg/min) was investigated on the four-vessel occlusion model in rats. The levels of monoamines (NA, DA, 5HT) and their metabolited (DOPAC, HVA, 5HIAA) were measured with HPLC in four areas of the brain, and edema was evaluated from proton magnetic resonance measurement of relaxation times and tissue water content. The results obtained showed nimodipine, and to a lesser extent verapamil, as having an anti-edematous effect, as evaluated by direct measurement of cortical and subcortical hydration. Three of the four molecules also decreased metabolite cellular content, which reflects improved drainage; no molecule influenced the level of parent molecules.

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.

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.

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.

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.

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.

The pharmacology of cerebral ischemia features 100 molecules and 20 potentially interesting mechanisms for preventing the tissue damage induced by anoxia-ischemia. The intricacy and complexity of the mechanisms involved probably account for the absence of definite evidence for effectiveness in man. The molecules which act on mechanisms qualifying as common denominators or triggering off cascade reactions, appear to be the best candidates. In this respect, the action of calcium, neurotransmitters, excitatory amino acids and pyrimidinergic or purinergic processes has to be given priority. Guidelines for the development of anti-ischemic molecules should be issued urgently, insisting on models, evaluation criteria, intervention timing and the parameters to be monitored (e.g. temperature, glycemia, choice of animal species).

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.