[Consensus statement on severe dementia]. / Consensus sur la démence de type Alzheimer au stade sévère.

Under the auspices of the French Society of Gerontology and Geriatrics, a multidisciplinary team including geriatritians, neurologists, epidemiologists, psychiatrists, pharmacologists and public health specialists developed a consensus on care for patients with severe dementia. They defined 21 recommendations for general practitioners, long-term care physicians and specialists based on knowledge available in 2005. At all stages of the disease, the objective of care is to improve as much as possible quality-of-life for the patient and his/her family, including a life project until the end of life. It is always possible to do something for these patients and their family: nutritional status, behavior disorders, and incapacities to deal with basic activities of daily life have to be taken in consideration. Resource allocation and proximity care have to be targeted. Research areas necessary to improve the care of patients with severe dementia has been selected.

[Consensus statement on severe dementia]. / Consensus sur la démence de type Alzheimer au stade sévère.

Under the auspices of the French Society of Gerontology and Geriatrics, a multidisciplinary group of experts, including geriatricians, neurologists, epidemiologists, psychiatrists, pharmacologists, and public health specialists developed consensus recommendations about care for patients with severe dementia. They defined 21 recommendations for general practitioners, long-term care physicians, and specialists, based on the knowledge currently available (2005). The aim of care at all stages is to mitigate the quality-of-life of patient, caregiver, and family insofar as possible, combining care and future planning until the end of life. Management, to take into account problems including nutritional status, behavior disorders, and ability (or inability) to perform activities of daily living, must be global, multidisciplinary, and coordinated and must optimize use of local medical and social resources. The group also stressed the importance of clinical research to improve knowledge of disease course and assess management strategies and recommended specific area for research.

Selegiline in de novo parkinsonian patients: the French selegiline multicenter trial (FSMT).

The French selegiline multicenter trial was conducted in 1990 to test the possibility to improve disability of de novo parkinsonian patients (P.P.) during the first three months of treatment with selegiline (S) (10 mg/day) monotherapy. 93 P.P. were included in this double-blind, randomized, placebo controlled, clinical trial, in which 13 centers participated. Both parallel groups were followed up from inclusion (D0) to D30, D60 and D90. Drug efficacy was judged with Hoehn and Yahr (HY), Hamilton Depression Rating Scale (HDRS), Unified Parkinson's Disease Rating Scale (UPDRS), Schwab and England scores, decision to introduce levodopa and selfassessment. Biological and clinical parameters (cardio- vascular, weight, side-effects reports) were assessed for tolerability. 84 P.P. (38 P, 46 S) were evaluable for efficacy at D90. When considering the main parameters, S appears superior to placebo: HY scores (p less than 0.001), global UPDRS scores (p less than 0.001) and UPDRS subscores: mental (p less than 0.001), daily living activities (p less than 0.01), motor activities (p less than 0.01). Depressive scores (HDRS) are significantly improved only at D90 (p = 0.005). Levodopa therapy was introduced in 45% of the cases in S groups versus 18.4% in P group. Global impression of efficacy was largely in favor of S; failure was noted in half of the cases in P group and only in 1/5th of the cases in S group. Side-effects were rare and minor. S 10 mg/day monotherapy is statistically superior to placebo in improving de novo P.P. during the first three months treatment. Motor symptoms rapidly improve; mood is only modified after 3 months. S appears to be well tolerated. S may be considered as a good candidate for the initial treatment of P.P.

Octreotide acts on anorectal physiology: a dynamic study in healthy subjects.

BACKGROUND: Somatostatin is localized in the intestinal and pelvic nerves of the anorectum and it seems to act as an important neurotransmitter. However, previous analyses of octreotide (a somatostatin analog) effects on anal function showed conflicting results. By use of a dynamic model in healthy subjects, with comparison to the myogenic effect of glucagon, the aim of our study was to further investigate the pharmacologic targets of octreotide. METHODS: This was a placebo-controlled, randomized, double-blinded crossover study performed in 12 healthy volunteers who received octreotide, glucagon, or placebo intravenously on separate days. During each sequence, several pressure steps in 3 different protocols of rectal isobaric distension were applied with an electronic barostat. Manometric responses of the anal canal, adaptative volumes, and perception scores of the rectum were recorded. RESULTS: During both phasic and stepwise distensions, a significant drug effect was encountered at the anal level. Compared with placebo, octreotide significantly increased pressures at both upper and lower levels of the anal canal. In contrast, glucagon decreased pressures at the upper part of the anal canal. Octreotide significantly decreased rectal volumes to phasic distension, but glucagon did not induce any change on rectal adaptation. In addition, neither drug modified perception scores. CONCLUSION: This study suggests that octreotide acts on reflex arcs and rectal myenteric neurons rather than on anal myogenic targets that respond to glucagon.

Cognitive performance in elderly subjects after a single dose of befloxatone, a new reversible selective monoamine oxidase A inhibitor.

BACKGROUND: Patients with depression often have cognitive and psychomotor performance impairments. Antidepressive treatments can correct these deficits, provided sedative and anticholinergic adverse effects do not add to the preexisting condition, particularly in elderly patients. Newly developed antidepressants therefore should be without deleterious effects on cognitive functions, including memory. Befloxatone is a new antidepressant with a potent, selective, competitive, and reversible inhibitory activity on the A isoform of monoamine oxidase (MAO-A). METHODS: The effects on cognition and psychomotor performance of single oral doses of befloxatone (10 mg) and amitriptyline (50 mg) were compared in a randomized, double-blind, placebo-controlled, three-way crossover design trial in 12 healthy elderly (65 to 85 years) volunteers. The performances of the subjects were evaluated by a comprehensive battery of validated psychometric tests that explored alertness, psychomotor performance, information processing, and memory. Subjective feelings on mood and sleep were rated on visual analog scales. MAO-A inhibition was estimated by multiple titrations of 3,4-dihydrophenylglycol (DHPG) in plasma. RESULTS: Amitriptyline displayed the expected deleterious effects on performance tasks, critical flicker fusion threshold, digit symbol substitution, and body sway, and it deteriorated memory (immediate and delayed free recall of words). In contrast, befloxatone did not impair cognition or psychomotor performance but instead significantly improved the delayed free recall. Amitriptyline adversely affected subjective feelings of alertness and contentedness, but befloxatone permitted sustained alertness and did not alter other subjective feelings or sleep. Concurrently, a single dose of 10 mg befloxatone markedly decreased the DHPG concentration in plasma. CONCLUSION: Contrary to tricyclic antidepressants, whose deleterious effects are greater in elderly subjects, this study demonstrated the safety of befloxatone on cognition and psychomotor performance in elderly subjects.

Study of the mechanisms involved in adenosine-5'-O-(2-thiodiphosphate) induced relaxation of rat thoracic aorta and pancreatic vascular bed.

1. The endothelium-dependent relaxation of blood vessels induced by P2Y-purinoceptor activation has often been shown to involve prostacyclin and/or nitric oxide (NO) release. In this work, we have investigated the mechanisms involved in the relaxant effect of the P2Y agonist, adenosine -5'-O-(2-thiodiphosphate) (ADP beta S) using two complementary preparations: rat pancreatic vascular bed and aortic ring. 2. On the pancreatic vascular bed, ADP beta S (1.5 and 15 microM) infused for 30 min induced a concentration-dependent vasodilatation; it was progressive during the first 10 min (first period) and sustained from 10 to 30 min (second period). Indomethacin (10 microM) delayed ADP beta S-induced vasodilatation (1.5 and 15 microM) by about 6 min. N omega-nitro-L-arginine methyl ester (L-NAME) (200 microM) suppressed the relaxation for about 5 min but thereafter ADP beta S at the two concentrations progressively induced an increase in the flow rate. Even the co-administration of L-NAME and indomethacin did not abolish the ADP beta S-induced vasorelaxation. 3. On 5-hydroxy tryptamine (5-HT) precontracted rings mounted in isometric conditions in organ baths, we observed that ADP beta S induced a concentration-dependent relaxation of rings with a functional endothelium; this effect was stable for 25 min. The ADP beta S relaxant effect was strongly inhibited by Reactive Blue 2 (30 microM) and was suppressed by pretreatment of rings with saponin (0.05 mg ml-1 for 30 min), which also abolished the acetylcholine-induced relaxation. 4. ADP beta S-induced relaxation of 5-HT precontracted rings is largely inhibited by indomethacin (100 or 10 microM) or L-NAME (100 microM). 5. We conclude that: the ADP beta S-induced relaxation is endothelium-dependent, mediated by P2Y-purinoceptors, and at least in part linked to NO and prostacyclin release, depending on the preparation used. Furthermore, on the pancreatic vascular bed, (an)other mechanism(s) than prostacyclin and NO releases may be involved in ADP beta S-induced vasodilatation.

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.

Effects of cholinergic agents on anorectal physiology.

BACKGROUND: Despite their potential therapeutic benefit, the effects of cholinergic agents on anal function have been poorly investigated. AIM: To analyse the effects of neostigmine and atropine on anorectal responses to rectal isobaric distension. METHODS: This was a placebo-controlled, randomized, double-blind crossover study, performed in 12 healthy volunteers who received intravenously, on 3 separate days, neostigmine, atropine or the placebo. During each day of the experiment, seven pressure steps (ranging from 1 to 31 mmHg) in three different protocols of rectal isobaric distension (phasic, stepwise and tonic) were applied using an electronic barostat. Manometric responses of the anal canal, adaptative volumes and perception scores of the rectum were recorded. RESULTS: During stepwise distension, a significant drug effect was encountered at the anal level. No drug effect was observed on the other investigated parameters (rectal volumes and rectal perception scores) or for the other modes of distension. Compared to placebo, neostigmine significantly decreased pressures at the upper level of the anal canal for both recto anal inhibitory reflex and mean resting pressures. In contrast, atropine significantly increased pressures at the lower part of the anal canal but did not modify upper anal pressures. CONCLUSION: The present study suggests that cholinergic effects result more from an indirect action on intermediate neurotransmitters and rectal myenteric neurons, than from a direct action on anal targets.

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.

Double blind study of tiapride versus haloperidol and placebo in agitation and aggressiveness in elderly patients with cognitive impairment.

OBJECTIVE: The aim of the present study was to compare the efficacy and safety of tiapride versus haloperidol and placebo in the treatment of agitation and aggressiveness in elderly patients with mild or moderate mental impairment. METHOD: This international, multicentre, randomized, double blind, three parallel groups study compared efficacy and safety of a 21 -day regimen of tiapride 100-300 mg/day versus haloperidol 2-6 mg/day and placebo in 306 elderly patients with mild or moderate dementia according to DSM III R and behavioural troubles with the Multidimensional Observation Scale for the Elderly Subjects (MOSES) irritability/aggressiveness subscore ranging from 16 to 30. RESULTS: The percentage of responders (defined as patients with at least a 25% MOSES irritability/aggressiveness subscore decrease between the inclusion and the end of the treatment) was significantly greater in the tiapride (63%, P=0.04) and haloperidol (69%, P=0.004) groups than in the placebo group (49%), with no significant difference between the active drugs. Similar results were observed for the mean MOSES irritability/aggressiveness subscores on D7, D21 and at D(end) which were significantly smaller in the tiapride and haloperidol groups than in the placebo group. The decrease between D0 and D(end) was significantly greater in the tiapride (6.57, P=0.009) and haloperidol groups (6.75, P=0.005) than in the placebo group (4.71). The global improvement CGI was significantly better in the tiapride and haloperidol groups than in the placebo group (P=0.03 and P=0.02). No significant difference was observed between the two active drugs or among the three treatment groups for the Folstein's Mini Mental Status scale (MMS) total score, and there was no notable change during treatment. The number of patients with adverse events, assessed on the Udvalg Kliniske Undersogelser scale (UKU), and the number of UKU symptoms were smaller in the tiapride group (62 patients, 61%, 212 events) than in the haloperidol group (77 patients, 76%, 305 events) and identical to that observed in the placebo group (69 patients, 67%, 234 events). Of interest, the number of patients with at least one extrapyramidal symptom was significantly lower (P=0.003) in the tiapride group (16 patients, 16%) than in the haloperidol group (34 patients, 34%) and similar to that of the placebo group (18 patients, 17%); the difference observed between the haloperidol and placebo groups was significant (P=0.008). CONCLUSION: Tiapride is not different from haloperidol in the treatment of agitation and aggressiveness in elderly patients and better tolerated, in particular with significantly fewer extrapyramidal symptoms.

Effects of risperidone on psychometric and cognitive functions in healthy elderly volunteers.

RATIONALE: Dementia includes not only cognitive deficit but may also include psychiatric and behavioral symptoms. These psychological symptoms of dementia require specific treatment without deleterious effects on cognitive functions. OBJECTIVE: The aim of the present study was to assess the effects of a single dose of risperidone (0.25 or 0.5 mg) on psychomotor performances and cognitive functions compared to a placebo and to a positive control, lorazepam 1 mg, in 12 healthy elderly subjects. METHODS: This study was a randomized, double-blind, four-way crossover clinical trial involving four 8-h long treatment periods. The pharmacodynamic assessment criteria included a battery of psychomotor tests, a subjective evaluation and an electroencephalogram. Safety was evaluated by clinical laboratory tests, electrocardiogram and recording of adverse events. Concentrations of risperidone, 9-hydroxy-risperidone and lorazepam were determined before and 2 h after dosing. RESULTS. Few significant effects were observed on psychomotor tests with risperidone at all dosages. Risperidone was devoid of any deleterious effects on speed of reaction, vigilance and sustained attention, working and long-term memory and increased cortical arousal. Risperidone demonstrated minor impairment on motor activity (decreased finger taping), postural stability, and information processing (impaired digit symbol substitution). Contentedness subjective evaluation was decreased with risperidone 0.5 mg, 6 h after dosing. No significant difference was observed on EEG frequencies and no sedative activity was detected with risperidone. At 2 h after dosing, risperidone plasma concentrations were 1.54+/-0.99 ng/ml and 2.80+/-1.41 ng/ml; 9-hydroxy-risperidone concentrations were 0.77+/-0.46 ng/ml and 1.54+/-0.85 ng/ml after intake of 0.25 mg and 0.5 mg doses, respectively. Well-known detrimental effects of lorazepam on psychomotor performances were observed and sedative effects were confirmed by the EEG findings. At 2 h following lorazepam 1 mg administration, plasma concentrations were 13.40+/-2.17 ng/ml. None of both compounds induced serious adverse events. CONCLUSION: The results of this clinical trial conducted on healthy subjects demonstrated that low doses of risperidone, but not low doses of lorazepam, did not disturb the cognitive functions in the elderly.

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.

Antidepressants and cognition: comparative effects of moclobemide, viloxazine and maprotiline.

The respective effects of three antidepressant drugs (moclobemide, 450 mg/j; viloxazine, 300 mg/j; maprotiline, 150 mg/j) on vigilance, attention, and memory were compared. Young depressed outpatients (n = 46) entered a double-blind, randomized, monocentre clinical trial lasting for 6 weeks. Drug actions were assessed through the regular determination of critical flicker fusion point (CFF), reaction times (SRT), and a battery to measure memory components. None of the three drugs caused deterioration in cognitive functions. On the other hand, moclobemide improved both vigilance and attention (CFF, SRT) and some crucial components of memory (general memory scores, delayed word recall, recognition of familiar faces). This effect was rapid, stable, and superior to those of viloxazine and maprotiline. It may be explained by moclobemide's selective and reversible inhibition of monoamine oxidase A, as well as by the lack of any anticholinergic action.

Absolute bioavailability and electroencephalographic effects of conventional and extended-release formulations of venlafaxine in healthy subjects.

Venlafaxine is currently marketed for treatment of depressive disorders as a conventional tablet formulation with a twice or three times daily dosage regimen. The absolute bioavailability of the conventional (CF) and extended-release (XR) formulations and their effects on electroencephalograms (EEG) and on a visual analog scale (VAS) for nausea were assessed in a randomized, double-blind, four-way crossover, placebo-controlled study of 16 healthy young men who were given either a single oral dose of 50 mg of CF venlafaxine, 75 mg of XR venlafaxine, or an intravenous dose of 10 mg of venlafaxine, or a placebo at 1-week intervals. The absolute bioavailability of venlafaxine was between 40% and 45% and was similar for both the CF and XR formulations. Venlafaxine produced central effects of a desipramine-like antidepressant. Regardless of formulation tested, the main EEG changes were an increase in fast beta (20-30 Hz) energy, which was more pronounced over the frontotemporal regions and extended within the full beta range (16-40 Hz). Maximum effect was reached at 6 hours for the CF and reached a plateau from 10 to 24 hours for the XR formulation. A dose-proportional increase in central activity, expressed as area under the effect curve (AUE) of the beta band, was observed between the CF (50 mg) and XR (75 mg) formulations. Compared with the CF tablet, the XR formulation also produced a much less intense maximum effect and a decrease of 63% in the AUE of nausea normalized by dose. The XR formulation has the same absolute bioavailability and the same central activity as assessed by EEG, but produced less intensive nausea than CF venlafaxine. The present findings suggest that a once-daily dosage regimen should be sufficient. This was confirmed by several clinical trials in depressive patients.

Pharmacodynamics and pharmacokinetics of two dose regimens of befloxatone, a new reversible and selective monoamine oxidase inhibitor, at steady state in healthy volunteers.

The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO-A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double-blind, three-way crossover, placebo-controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3-4 dihydroxyphenylglycol (DHPG), as measured by high-performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose-related reduction in plasma DHPG levels, as shown by the decrease in the 24-hour area under the concentration-time curve (AUC0-24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO-A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration-time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady-state levels of DHPG.

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.

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.

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.

Drugs used in Alzheimer's disease and neuroplasticity.

Drugs indicated for use in Alzheimer's disease (AD) must clinically improve the cognitive symptomatology of the disorder, although nonexclusively. From a neurochemical standpoint, these drugs must oppose the multiple processes recognized as stigmata of AD. In these two ways, so-called AD drugs may be considered substances modifying cerebral plasticity. Long-term evaluation of anticholinesterases and of tacrine, in particular, provides arguments in support of this initially purely biologic, theoretical approach. This concept of neuroplasticity applied to dementia may modify the traditional pharmaceutical drug development programs.

Effect of two doses of ginkgo biloba extract (EGb 761) on the dual-coding test in elderly subjects.

The subjects of this double-blind study were 18 elderly men and women (mean age, 69.3 years) with slight age-related memory impairment. In a crossover-study design, each subject received placebo or an extract of Ginkgo biloba (EGb 761) (320 mg or 600 mg) 1 hour before performing a dual-coding test that measures the speed of information processing; the test consists of several coding series of drawings and words presented at decreasing times of 1920, 960, 480, 240, and 120 ms. The dual-coding phenomenon (a break point between coding verbal material and images) was demonstrated in all the tests. After placebo, the break point was observed at 960 ms and dual coding beginning at 1920 ms. After each dose of the ginkgo extract, the break point (at 480 ms) and dual coding (at 960 ms) were significantly shifted toward a shorter presentation time, indicating an improvement in the speed of information processing.