[Prescription of olanzapine in children and adolescent psychiatric patients]. / Prescription de l'olanzapine chez l'enfant et l'adolescent.

INTRODUCTION: A review of the literature from 1996-2004 on the indications and adverse reactions concerning the use of olanzapine, a second generation antipsychotic agent, in children and adolescents with psychiatric illness is made in this article. Studies lasted for 2 to 3 months and a few had a follow up period up to a year. Olanzapine, dosed from 2.5 to 20 mg/day, is shown to be a useful drug in the treatment of child and adolescent onset schizophrenia, bipolar disorder, anorexia nervosa with delusions, pervasive developmental disorder, tic disorders, and aggression. OPEN AND DOUBLE-BLIND STUDIES: In 4 open labeled studies (26, 34, 39, 43) and 2 case reports (25), 53 patients, aged from 6-18 years old, afflicted by child onset schizophrenia, were treated with olanzapine for 1 1/2 weeks to one year; 19 had treatment resistant childhood schizophrenia and 34 a first episode. In the first group 13/19 showed improvement whereas, in the second group 27/34 were considered responders. Four patients in the first group who had responded to clozapine (stopped because of adverse events) did less well on olanzapine. In 5 studies, 4 open labeled (15, 20, 44) and 1 double blind (27), 59 adolescent onset schizophrenic patients were treated by olanzapine from 8 to 26 weeks; 50/59 patients were considered responders. In the open label study (20) comparing 43 adolescents treated by olanzapine (19 patients), risperidone (17 patients), or haloperidol (7 patients), improvement was significant in the three groups after 4 weeks of treatment and continued after 8 weeks. It is most interesting to mention that 2 months after the end of the study 71% (12/17) of the olanzapine group that had completed the study, 10/15 (67%) of the risperidone group, and 43% (3/7) of the haloperidol group had continued their treatment. Dropouts were for inefficacy and non-compliance in the olanzapine and risperidone groups whereas they were also for adverse events in the haloperidol group (2/4). A final double blind study of 263 adult and adolescent schizophrenic patients (latter are not separated from the former) confirmed the superiority of olanzapine compared to haloperidol and its use for a long period: 67% of the olanzapine and 54% of the haloperidol patients completed the 12-week study. CASE-REPORTS: 12 case reports of children and adolescents diagnosed with acute mania (8, 25, 46, 47) and 23 in an open labeled study (16) were treated by olanzapine; 26/35 were considered to respond well. Some of the patients were on mood stabilizers before adjunction of olanzapine, others on olanzapine monotherapy; 10 case reports of patients with anorexia nervosa associated with psychotic symptomatology, aged from 10-17 years old, relate the use of olanzapine as adjuvant treatment. Improvement was spectacular in these patients who not only gained considerable weight, but were also more compliant to the therapeutic program and their obsessions, delusions, agitation and anxiety became less intense. In this form of anorexia nervosa, olanzapine appears to have an interesting therapeutic role and, in particular, its most important adverse effect, weight gain, became a therapeutic goal. In 2 preliminary studies (24, 30) 31 children and adolescents diagnosed with pervasive developmental disorder were treated by olanzapine from 6 to 13 weeks; 18/25 had good or moderate symptomatic improvement: they were less irritable and hyperactive, and their speech less excessive. In 17 case reports of children and adolescents with aggression (42, 45), associated with tics in 10 patients (49), treatment with olanzapine from 2 weeks to 10 months lowered the presenting symptoms, enhanced the cooperation, and improved the mood of the patients. Only one patient's treatment was changed for inefficacy. DISCUSSION: No matter what the disorder treated, when olanzapine was compared to haloperidol and risperidone, it proved to be as effective as risperidone, and as or more effective than haloperidol; but when compared to clozapine, it was less effective. The most prominent adverse reaction was excessive weight gain, even more so than in adult patients treated with olanzapine. Also weight gain was greater in children and adolescents treated by olanzapine than those treated by risperidone or haloperidol. Though few treatments had to be interrupted because of this side effect, child and adolescent psychiatrists are wary of the long-term disease related to obesity and glucose dysregulation. All should be done to under-stand the process of weight gain better and to prevent or stall excessive caloric intake, encourage activity, and eventually treat by corrector drugs. Secondly, sedation may bother up to 50% of patients even at the end of the study periods, as many as those treated by haloperidol and more than those treated by risperidone. Extrapyramidal symptoms were mild or moderate compared to those that appear with haloperidol, but may be more frequent than in adult patients. Liver enzymes and blood sugar may be slightly elevated. Prolactemia may be elevated but less so with risperidone and haloperidol. CONCLUSION: All the authors emphasized the unfortunate lack of randomized double blind studies for the use of olanzapine in this age group.

Effects of phlebotomy therapy on cytochrome P450 2e1 activity and oxidative stress markers in dysmetabolic iron overload syndrome: a randomized trial.

AIM: To assess the effects of iron removal on cytochrome P450 2E1 activity and oxidative stress in dysmetabolic iron overload syndrome. METHODS: Forty-eight patients were randomized to phlebotomy therapy consisting of removal of 300-500 mL of blood every 14 days until serum ferritin levels dropped under 100 microg/L or to follow-up without phlebotomy therapy. Cytochrome P450 2E1 activity was measured at baseline and at the end of treatment by using the 6-hydroxychlorzoxazone/chlorzoxazone blood metabolic ratio, 2 h after the intake of 500 mg of chlorzoxazone. RESULTS: In the treatment group, a mean of 3.9 +/- 1.3 L of blood was removed and serum ferritin levels dropped from 715 +/- 397 to 74 +/- 34 microg/L. Variation of cytochrome P450 2E1 activity was not significantly different between the 2 groups (0.07 +/- 0.26 vs. 0.03 +/- 0.19, P = 0.36). In the treatment group, low-density lipoprotein cholesterol and vitamin E were lowered after treatment compared with control group (-0.15 +/- 0.51 vs. 0.24 +/- 0.58, P = 0.002 and -1.3 +/- 4.4 vs. 2.3 +/- 5.2, P = 0.03, respectively). Inversely, vitamin C was increased (0.5 +/- 3.5 vs. -1.8 +/- 3.9, P = 0.03). CONCLUSIONS: In dysmetabolic iron overload syndrome, reduction of iron stores does not significantly influence cytochrome P450 2E1 activity but is associated with a significant decrease of low-density lipoprotein cholesterol, suggesting that venesection therapy may be a suitable option in these patients.

Does subthalamic nucleus stimulation induce apathy in Parkinson's disease?

BACKGROUND: Subthalamic Nucleus Deep Brain Stimulation (STN-DBS) has been shown to significantly improve motor symptoms in advanced Parkinson's disease (PD). Only few studies, however, have focused on the non-motor effects of DBS. METHODS: A consecutive series of 15 patients was assessed three months before (M-3), then three months (M3) and six months (M6) after surgery. Mean (+/- SD) age at surgery was 59.7 (7.6). Mean disease duration at surgery was 12.2 (2.8) years. The Mini International Neuropsychiatric Inventory was used to assess psychiatric disorders three months before surgery. Depression was evaluated using Montgomery and Asberg Rating Scale (MADRS). Anxiety was evaluated using the AMDP system (Association for Methodology and Documentation in Psychiatry). Apathy was particularly evaluated using the Apathy Evaluation Scale (AES) and the Starkstein Scale. All these scales were performed at every evaluation. RESULTS: Apathy worsened at M3 and M6 after STN-DBS in comparison with the preoperative evaluation: the AES mean score was significantly impaired between the preoperative (38.4+/-7.1) and both the postoperative M3 (44.6+/-9.5, p = 0.003) and M6 scores (46.0+/-10.9, p = 0.013). Significant worsening of apathy was confirmed using the Starkstein scale. There was no evidence of depression: the mean MADRS score did not differ before surgery (9.1+/-7.4) and at both M3 (8.6+/-8.2) and M6 (9.9+/-7.7) after STN-DBS. The anxiety level did not change between preoperative (9.4+/-9.2) and both M3 (5.5+/-4.5) and M6 (6.6+/-4.6) postoperative states. CONCLUSION: Although STN-DBS constitutes a therapeutic advance for severely disabled patients with Parkinson's disease, we should keep in mind that this surgical procedure may contribute to the inducing of apathy. Our observation raises the issue of the direct influence of STN- DBS on the limbic system by diffusion of stimulus to the medial limbic compartment of STN.

Purification and electrospray mass spectrometry of aldose reductase from pig lens.

Aldose reductase (alditol: NADP+ 1-oxidoreductase, EC 1.1.1.21) has been purified from pig lens to homogeneity by a rapid and efficient three-step procedure involving poly(ethylene glycol) fractionation, ion-exchange chromatography and chromatofocusing. The homogeneity of the purified enzyme was examined by polyacrylamide gel electrophoresis under native and denaturing conditions, by isoelectric focusing and by high-performance liquid chromatography on a size-exclusion column. The highly purified enzyme is a monomeric protein with a molecular mass of 35,775 +/- 3 Da as determined by electrospray mass spectrometry (ESMS). This purification procedure is particularly suited for the preparation of triclinic single crystals of pig lens aldose reductase, which are currently used in X-ray studies of this enzyme.

Differential effects of two types of antidepressants, amitriptyline and fluoxetine, on anorectal motility and visceral perception.

BACKGROUND: Although antidepressants are used for functional gastrointestinal disorders, the mechanisms of their effects on gut are incompletely understood. AIM: To assess the effects of two types of antidepressants (tricyclic, serotoninergic) on anorectal motility and visceral perception. METHODS: A placebo-controlled, randomized, double-blind, crossover study was performed in 12 healthy male volunteers who received a single oral dose of amitriptyline (80 mg), fluoxetine (40 mg) or placebo. Drug effects were assessed using phasic isobaric distensions of the rectum with an electronic barostat (11 levels from 1 to 51 mmHg) 4 h after drug intake. Maximal rectal volume and pressure, mean and residual pressures at upper anal canal, mean pressure at lower anal canal, defecation sensation (5-level scale) and visceral perception (visual analogue scale) were recorded at each level of distending pressure. RESULTS: Ten subjects completed the study. Compared with placebo, neither amitriptyline nor fluoxetine modified rectal compliance or visceral perception. Compared with placebo, antidepressants significantly reduced mean and residual pressures at upper anal canal (-18%, P = 0.0019, and -27%, P = 0.0002, respectively, for amitriptyline; -26%, P = 0.0001, and -33%, P = 0.0001, respectively, for fluoxetine) whereas only amitriptyline significantly reduced mean pressure at lower anal canal (-16%, P = 0.0008). CONCLUSION: Both antidepressants similarly relaxed the internal anal sphincter, probably through a non-specific mechanism, without modifying visceral perception. Only amitriptyline relaxed the external anal sphincter.

The use of bromocriptine for testing central dopaminergic reactivity.

A single oral intake of 10 mg of Bromocriptine can modify both plasma renin activity (PRA) and arterial blood pressure (BP). The changes in both variables depend on the integrity of the central dopaminergic systems. The parkinsonians whose extrapyramidal symptoms are markedly improved by L-Dopa in association with a decarboxylase inhibitor (IDC) and the untreated parkinsonians are the only patients whose PRA and BP are lowered 1 h after Bromocriptine ingestion. The results obtained in the L-dopa-induced dyskinetic parkinsonians are similar to those obtained in the group of L-Dopa-resistant patients. This points to the paradoxical hypothesis of dopaminergic hyposensitivity in the dyskinetic patients. In spite of the absence of correlation between PRA and BP, it is possible that lowering of BP by Bromocriptine is linked to the parallel decrease of PRA. An increase of the BP may be obtained in the dyskinetic and L-Dopa-resistant groups. These data point to a possible involvement of central dopaminergic systems in some aspects of hypertension.

Plasmatic renin activity in patients treated with L-dopa and inhibitor of dopa decarboxylase (IDC).

Plasmatic renin activity (PRA) was studied in patients receiving L-dopa, together with a decarboxylase inhibitor, at rest times and after periods of physical exertion. Although we can superimpose the results from unrelated Parkinson's disease patients on those of the control group, the results are inversed in stabilized patients (lowered PRA) and dyskinetic patients (increased PRA). There is a definite correlation between the increase in PRA and intensity of the dyskinesia. Dosage is the only other factor differentiating the two groups of Parkinsonians treated. The figures relative to arterial pressure are studied in the various groups.

Impairment of acquired temporal response regulation of rats under normobaric hypoxia.

Effects of hypoxia on learning involving temporal regulation of behaviour was investigated. Under 10% hypoxia there was a decrease in the number of conditioned responses, and the 'efficiency' of reinforcement, but no modification of temporal discrimination. Normobaric hypoxia may be a useful model for studying certain behavioural and pharmacological effects of cerebral circulatory insufficiency, and their implications at the level of the central nervous system, but it would be incorrect to use such a model to study factors that might prevent the loss of acquired knowledge.

Reversal of learning and memory impairments following lesion of the nucleus basalis magnocellularis (NBM) by concurrent noradrenergic depletion using DSP4 in the rat.

In the following study the behavioural effects of simultaneous lesion of the nucleus basalis magnocellularis (NBM) using ibotenic acid and noradrenergic depletion following a single i.p. administration of DSP4 (50 mg/kg) were examined in the rat. NBM lesion induced a deficit in acquisition of a reinforced T-maze alternation task, a working memory adaptation of a spatial navigation task in a water maze and 24 h retention in a passive avoidance task compared to sham controls. No effect of the lesion on a reference memory version of spatial navigation in a water maze task was found. Animals that received a combination of NBM lesion and DSP4 treatment showed no impairment on any of the tasks that were impaired by NBM lesion alone. This indicates a reversal of the learning and memory deficits consequent to NBM lesion by simultaneous noradrenergic depletion. NBM lesion induced a significant reduction in choline-acetyltransferase activity in the frontal cortex, and DSP4 induced a significant decrease in noradrenaline concentration in occipital cortex and hippocampus, confirming the effects of these treatments. These results suggest an interaction between central noradrenergic and cholinergic systems in learning and memory processes.

Lisuride prevents learning and memory impairment and attenuates the increase in extracellular dopamine induced by transient global cerebral ischemia in rats.

In this experiment, we tested the efficacy of neuroprotection with lisuride, a dopamine agonist, using the 4-vessel occlusion rat model. Functional improvement was evaluated with two behavior tests exploring learning and memorization capacity in the rat, the Morris water maze and the 14-unit T-maze, 18 days after ischemia. Extracellular dopamine levels during ischemia were determined in search of a possible neuroprotection mechanism. Dopamine and its metabolites, DOPAC and HVA, as well as the serotonin metabolite, 5-HIAA, were assayed with HPLC-EC, in striatal extracellular fluid obtained by in vivo microdialysis in the awake rat. Lisuride was administered at a total dose of 10 ng by continuous intrastriatal infusion or at the dose of 0.5 mg/kg by i.p. infusion, 160 minutes before onset of ischemia for the neurochemical study and at the dose of 0.5 mg/kg via i.p. infusion, 1 hour before occlusion of the carotid arteries, for the behavior tests. Behavioral testing showed significantly better recovery in both sets of behavioral tests, with more pronounced positive results with the 14-unit T-maze, in comparison with the saline-treated animals. Microdialysis confirmed a significant attenuation of the ischemia-induced dopamine surge, whatever the mode of administration, compared with saline-treated animals. These results show that lisuride offers significant neuroprotection from the effect of experimental transient global forebrain cerebral ischemia in the rat; the mechanism would imply, at least in part, reduced levels of extracellular dopamine.

Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia.

To characterise the role played by dopamine receptors in ischaemic brain damage, we have evaluated the effects of pergolide, bromocriptine and lisuride (dopamine D2 receptor agonists), haloperidol (a dopamine D2 receptor antagonist), 2,3,4,5-tetrahydro-7,8,dihydroxy-1-phenyl-1H-3-benzazepine (SKF 38393; a dopamine D1 receptor agonist) and (R)-(+)-8-chloro 2,3,4,5-tetra-hydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol (SCH 23390; a dopamine D1 receptor antagonist) in the gerbil model of global cerebral ischaemia. Ischaemia was induced by 5 min of bilateral carotid artery occlusion under halothane anaesthesia. Sham operated animals were used as controls. Pergolide (0.5 or 1.0 mg/kg i.p), bromocriptine (0.5 or 1.0 mg/kg i.p.), lisuride (0.5 or 1.0 mg/kg i.p.), SCH 23390 (0.1 or 1.0 mg/kg i.p.), haloperidol (0.5, 1.0 or 2 mg/kg i.p.) and SKF 38393 (1.0 or 2 mg/kg i.p.) were administered 1 h before occlusion. Five-minute-occluded animals had extensive damage in the CA1 region of the hippocampus 5 days after surgery. Pergolide 0.5 and 1.0 mg/kg i.p. provided significant (P < 0.05 and P < 0.01, respectively) neuroprotection against the ischaemia-induced hippocampal damage. Bromocriptine and lisuride also provided significant (P < 0.05) neuroprotection, but only at the higher 1.0 mg/kg dose. In contrast, the dopamine D2 receptor antagonist (haloperidol), the dopamine D1 receptor agonist (SKF 38393) and the dopamine D1 receptor antagonist (SCH 23390) failed to provide any neuroprotection in the model. These results support studies indicating that dopamine is important in ischaemic situations. The results also indicate that dopamine D2 receptor agonists are neuroprotective against ischaemia-induced brain injury and may play a role in neurodegenerative disorders.

5-HT-moduline, a 5-HT(1B/1D) receptor endogenous modulator, interacts with dopamine release measured in vivo by microdialysis.

5-Hydroxytryptamine-moduline (5-HT-moduline) is an endogenous tetrapeptide (Leu-Ser-Ala-Leu) recently isolated and characterized from mammalian brain. This compound interacts with 5-HT1B receptors as a non-competitive, high-affinity antagonist and has the properties of an allosteric modulator. 5-HT-moduline could play an important role in the regulation of serotonergic transmission and also, through heteroreceptors, dopaminergic transmission. The aim of this work was to examine the potential ability of 5-HT-moduline to modify the basal extracellular concentration of dopamine and its metabolites (3-methoxytyramine, dihydroxyphenylacetic acid and homovanillic acid), in the rat striatum and to determine its potential interaction with the stimulating activity of a specific 5-HT1B receptor agonist, 3-(1,2,5,6-tetrahydropyrid-4-yl) pyrrolo [3,2-b] pyrid-5-one (CP-93,129), on the release of dopamine. The technique is based on in vivo microdialysis using probes implanted in the striatum of the conscious rat. Results showed that the perfusion of 5-HT-moduline directly into this structure (1.25 mM) increased the striatal level of dopamine by two-fold (104% of the absolute basal release values, P = 0.0015) and that of 3-methoxytyramine by 3-fold (293%, P = 0.0001) without any change in the terminal metabolite concentrations. The intrastriatal administration of CP-93,129 induced a statistically significant, dose-dependent increase of dopamine levels (P < 0.0001). Coperfusion of 5-HT-moduline did not significantly alter the effect of CP-93,129 at 0.1 and 0.5 mM, but appeared to have an additive effect on the lowest dose (P = 0.0406). The results obtained show that 5-HT-moduline directly administered into the striatum increases the release of dopamine in this area. Presumably, this effect results from the desensitization of 5-HT1B receptors located on dopamine terminals. However, the fact that a 5-HT1B receptor agonist (CP-93,129) also increased the release of dopamine in the striatum and that 5-HT-moduline exhibited a slight additive effect with that of a low concentration of CP-93,129 suggests that the two substances interact with different mechanisms.

Assessment of procedural memory in Parkinson's disease.

1. Findings in cognitive psychology and neuropsychology have led to consider the existence of several mnestic systems. This study focuses on a now clearly established distinction between the procedural and the declarative memories. 2. The aim of the present study was to try and determine which of the two acquisition steps (learning and automation) is affected by Parkinsonians' mnestic difficulties, and to verify if these difficulties are linked to the skill content (declarative or motor). 3. To answer these questions, 20 Parkinsonians under treatment underwent specific tests: the maze test and the arithmetic alphabet test. 4. Results show that, by comparison with 20 matched healthy individuals, the deficiencies observed in Parkinson's disease affect both the declarative and the motor skills. In addition, Parkinsonians suffer difficulties in both acquisition steps: learning and automation. 5. These results could account for the cognitive and motor disturbances observed in Parkinson's disease; these abnormalities should be among the pharmacological targets in future.

Role of dopaminergic and serotonergic systems on behavioral stimulatory effects of low-dose alprazolam and lorazepam.

Several recent studies have demonstrated that alprazolam and lorazepam, administered at low doses to healthy volunteers, improve cognitive functions and psychomotor performances. Paradoxical effects of low-dose benzodiazepines have been also observed in mice, in experimental pharmacology. The aim of this work was to determine, in rat, the effect of similar low-doses of benzodiazepines on spontaneous locomotor activity and performance in the elevated zero-maze, and to investigate the underlying neurobiological mechanisms. The dose-effect and the time-course of the action were studied for both compounds. Spontaneous locomotor activity was measured using a photoelectric actimeter. The level of anxiety of the animals was assessed in the elevated zero-maze. Dopamine, serotonin, and their metabolites were assayed in the extracellular striatal fluid of the awake rat, obtained by microdialysis, by HPLC--EC. Spontaneous locomotor activity observed in rats given low-dose alprazolam and lorazepam evidenced a stimulatory effect only with alprazolam. The effect was maximum 90 min after administration of 0.0050 mg/kg alprazolam. An anxiogenic-like action was evidenced with the elevated zero-maze for the two compounds. We observed a statistically significant increase in striatal dopamine concentrations only with alprazolam, during the period corresponding to the behavioral stimulatory effects. We also showed a marked trend towards increased levels of serotonin with alprazolam but this modification was not significant, in spite of statistically significant variations of 5-HIAA. In the rat, behavioral stimulatory effects of low-dose benzodiazepines is evidenced with alprazolam but not lorazepam. This effect could be explained, at least in part, by increased extracellular dopamine concentrations in the striatum. Their different structures could explain the different pattern observed for the two benzodiazepines.

Experimental and clinical methods in the development of anti-Alzheimer drugs.

Methodology used for the development of anti-Alzheimer's disease (AD) drugs raises specific problems which are rarely examined in the literature. While the general development scheme is similar to that required for most drugs, some specific aspects must be analyzed, highly dominated by the dual goal of pharmacology, i.e., to obtain both symptomatic and etiopathogenic drugs. During preclinical studies, aged or lesioned animals are mainly useful for symptomatic drugs, whereas transgenic models or neurodegeneration-induced techniques would probably lead to etiopathogenic drugs potentially slowing down the process of AD. The first administrations of a new compound to human beings raise the question of the activity measurement techniques. Psychometry remains the most informative procedure to detect and analyze the activity of the drugs on the different components of cognition. Electrophysiology and neuroimaging need some complementary studies before they can be proposed as surrogate criteria in phase III trials. At this stage of development, American and the recently published European guidelines are of great help while insisting on long-term (6 months) placebo controlled trials with the use of the triple efficacy criterion: an objective cognition scale, a global assessment, and the opinion of the caregiver. In the long term, pharmacoepidemiology and pharmacoeconomy will have to confirm the rationale of this recent progress in the methodology of anti-AD drug development.

Comparative evaluation of scavenger properties of exifone, piracetam and vinburnine.

The involvement of radical reactions in the ageing process, physiological as well as pathological, is well demonstrated. It is accepted that alloxan cyto-toxicity is linked to a production of hydroxylated free radicals and that a substance preventing the development of alloxanic diabetes possesses scavenger properties. The objective of this work was to demonstrate, in this model, the anti-radical effect of 3 molecules recommended in the treatment of cerebral insufficiency and a reference substance (+)-catechin. We observed a protective action with catechin (P less than 0.05) at the highest dose (100 mg/kg). PEG alone was moderately active but comparison of PEG-alloxan and PEG-exifone-alloxan showed a highly significant difference (P less than 0.001) at the two highest doses (60 and 120 mg/kg). Piracetam (200 and 400 mg/kg) and vinburnine (7.5 and 15 mg/kg) were inactive. Under these experimental conditions, exifone demonstrated remarkable anti-radical properties.

Randomized double-blind trial of injectable heptaminol for controlling spontaneous or bromocriptine-induced orthostatic hypotension in parkinsonians.

Heptaminol is a molecule with experimental cardiovascular analeptic properties. In this double-blind vs placebo trial, the potency, so far unproven, of the injectable form of a 626 mg dose of heptaminol chlorhydrate on spontaneous or induced orthostatic hypotension (OH), was assessed. Nineteen patients were included in the study: 7 displayed spontaneous OH, and in the other 12 OH was induced by bromocriptine, as monitored 103 min/after an oral intake of 6.6 mg on average. Neither spontaneous nor induced OH were recorded in 32% of the Parkinsonian population registered, with no obvious distinctive characteristics. Potency tilt-trials, performed 15, 30 and 45 min after parenteral administration of heptaminol, revealed a significant and expressive potency of the molecule on the systolic blood pressure after 15 min (P less than 0.05). Clinical and biological tolerance was excellent. Low plasma renin activity and the absence of response to orthostatism indicated, in this population of Parkinsonian extrapyramidal syndromes, a loss in positive tonus likely to be of sympathetic origin. The anti-hypotensive action of heptaminol does not seem to be related to any renal or even sympathetic interaction.

Randomized, double-blind trial of exifone versus cognitive problems in Parkinson's disease.

Exifone is a novel substance of the benzophenone group that possesses potent scavenging properties. Initial findings demonstrate beneficial effects on age-related cognitive disorders. In this double-blind clinical trial versus placebo, the efficacy of 2 dosages (600 and 1200 mg/d) was evaluated with regard to Parkinson's disease (PD)-related cognitive disorders, for which there is increasing suspicion of a free-radicals origin. Despite disparities between the treatment groups as assessed by validated scales and subtests, and a considerable placebo effect on main parameters, both dose levels of exifone produced statistically significant improvement of the cognitive items most commonly impaired by PD: immediate recall, naming of objects presented, spatiotemporal orientation, and calculation. These properties suggest a new slot for exifone in the range of therapeutics available.

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.

Explicit and procedural memory in Parkinson's disease.

One of the aims of cognitive psychology is to breakdown complex tasks into their most basic components. The components of explicit (declarative) and implicit (procedural) memory were thus analyzed in undemented, non-depressed Parkinsonian patients under anti-Parkinsonian treatment, and compared with young and elderly healthy subjects. Three series of experiments were conducted in 61 patients in total. Statistically significant results revealed an impairment of explicit memory (verbal recall of words and drawings) with preserved recall of faces, in Parkinsonians. Implicit memory was also deficient, only in association tests (sound-form; arithmetical alphabet) and maze tests. Braille reading tests and Toronto tower tests did not discriminate between Parkinsonians and elderly subjects. Lastly, analyzing learning and automation revealed a dysfunctioning in Parkinsonian patients. All these data indicate a dysregulation of the cortical-sub-cortical systems, not essentially pre-frontal, and not necessarily dopaminergic. Cognitively, it appears that procedural and implicit memories should be dissociated conceptually.