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Biomedical subjects

S Gauthier

Publications and source records attributed to S Gauthier.

At least 37 records · Page 2Linked to original sources
PubMed2001

A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease.

OBJECTIVE: To investigate the efficacy and safety of donepezil in patients with moderate to severe AD (standardized Mini-Mental State Examination [sMMSE] scores of 5 to 17; Functional Assessment Staging score < or =6 at baseline). METHODS: Two-hundred ninety patients were randomized to treatment in this 24-week, double-blind, placebo-controlled trial. Patients received either donepezil 5 mg/day for the first 28 days and 10 mg/day thereafter as per the clinician's judgment (n = 144) or placebo (n = 146). The primary outcome measure was the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC+). RESULTS: Patients' mean age was 73.6 years (range 48 to 92 years). Baseline demographics were similar between the treatment groups. Least squares (LS) mean +/- SE sMMSE scores at baseline were 11.7 +/- 0.35 for the donepezil group and 12.0 +/- 0.34 for the placebo group. Patients receiving donepezil showed benefits on the CIBIC+, compared with placebo, at all visits up to week 24 (p < 0.001) and at week 24 last observation carried forward (LOCF) (p < 0.0001). All other secondary measures (including sMMSE, Severe Impairment Battery, Disability Assessment for Dementia, Functional Rating Scale, and Neuropsychiatric Inventory) showed significant differences between the groups in favor of donepezil at week 24 LOCF. Eighty-four percent of donepezil- and 86% of placebo-treated patients completed the trial. Adverse events (AE) were experienced by 83% of donepezil- and 80% of placebo-treated patients, the majority of which were rated mild in severity; 8% of donepezil- and 6% of placebo-treated patients discontinued because of AE. Laboratory and vital sign abnormalities were similar between the treatment groups. CONCLUSION: These data suggest that donepezil's benefits extend into more advanced stages of AD than those previously investigated, with very good tolerability.

Activities of Daily Living↗
PubMed2001

Progression of impairment in patients with vascular cognitive impairment without dementia.

Little is known about progression, short of dementia, in vascular cognitive impairment. In the Canadian Study of Health and Aging, 149 participants (79.3 +/- 6.7 years; 61% women) were found to have vascular cognitive impairment, no dementia (CIND). After 5 years, 77 participants (52%) had died and 58 (46%) had developed dementia. Women were at greater risk of dementia (OR 2.1, 1.0 to 4.5). Of 32 participants alive without dementia, cognition had deteriorated in seven and improved in four. Half of those with vascular CIND developed dementia within 5 years, suggesting a target for preventive interventions.

Aged↗
PubMed2001

Identification of a new chemically induced allele (Lp(m1Jus)) at the loop-tail locus: morphology, histology, and genetic mapping.

Loop-tail (Lp) is a semidominant mutation that affects neurulation in mice. Heterozygous animals are characterized by a looped-tail appearance (pig tail) and wobbly head movements while homozygous embryos exhibit a neural tube closure defect that extends from the caudal midbrain to the tip of the tail. The Lp gene has been finely mapped to the distal part of chromosome 1, and a positional cloning strategy has been initiated to isolate the defective gene. This study represents the characterization of a new Lp allele (Lp(m1Jus)) induced by N-ethyl-N-nitrosurea mutagenesis. Lp(m1Jus)/+ mice have a looped-tail appearance, and both Lp(m1Jus)/Lp(m1Jus) homozygotes and Lp/Lp(m1Jus) compound heterozygotes fail to initiate neural tube closure along most of the embryonic axis. These data indicate that the Lp(m1Jus) allele causes a neural tube defect and overall phenotype similar to that of the original Lp allele. Segregation analysis of 90 (Lp(m1Jus)/+ x C57BL/6J)F(1) x C57BL/6J looped-tail mice with seven markers that define the Lp genetic map (D1Mit455/D1Mit146/D1Mit148/D1Mit270-1 cM-D1Mit113-0.4 cM-Lp-0.2 cM-D1Mit149-0.8 cM-D1Mit115) showed significant linkage between Lp(m1Jus) and all loci analyzed (P < 0.0001). Eight crossovers were detected with the proximal cluster of D1Mit455, D1Mit146, D1Mit148, and D1Mit270, indicating a recombination rate higher than expected in this region, and a single recombinant was encountered with the distal markers D1Mit149 and D1Mit115. Based on these phenotypic and genetic data, Lp(m1Jus) is most likely allelic to Lp, thereby representing a valuable additional tool for the positional cloning of the Lp gene and its subsequent molecular characterization.

Alkylating Agents↗
PubMed2001

Pharmacotherapy of Alzheimer's disease: is there a need to redefine treatment success?

The traditional aim of Alzheimer's disease treatment in clinical trials has been to improve cognitive abilities. It has become increasingly clear, however, that other aspects are important in assessing treatment responses. A group of 10 physicians recently gathered to review the current criteria for assessing treatment success in Alzheimer's disease. While cognition has been previously viewed as the primary measure of efficacy, areas such as functional abilities, behaviour, caregiver burden, quality of life and resource utilization all need to be comprehensively assessed to fully evaluate treatment effects in patients with Alzheimer's disease, as well as their impacts on caregivers and society. Postponing or slowing decline in any of these areas may represent an important benefit and should be considered as an outcome measure in clinical trials, clinical practice and decision-making about healthcare budgets. Accepted instruments are available for assessing outcomes in each aspect of Alzheimer's disease, but they need to be selected carefully to provide valid, meaningful data. Some of the most frequently used outcome measures in Alzheimer's disease are reviewed. Using expanded criteria for treatment success and clinically relevant outcome measures, data from currently available studies show that cholinesterase inhibitors produce clinically meaningful long-term benefits in multiple domains in patients with Alzheimer's disease.

Activities of Daily Living↗
PubMed2001

Say NO to Alzheimer's disease: the putative links between nitric oxide and dementia of the Alzheimer's type.

Alzheimer's disease (AD) is the most common form of dementia, with progressive cognitive deficits being the primary symptom. AD is neuropathologically characterized by amyloid and neurofibrillary tangle depositions, basal forebrain cholinergic deficit, and extensive neuronal loss and synaptic changes in the cortex and hippocampus. Mutations of amyloid precursor protein or presenilin genes or apolipoprotein E gene polymorphism appear to affect amyloid formation, which in turn causes neuronal death via a number of possible mechanisms, including Ca(2+) homeostasis disruption, oxidative stress, excitotoxicity, energy depletion, neuro-inflammation and apoptosis. Nitric oxide (NO) is an enzymatic product of nitric oxide synthase, which exists in three isoforms. In addition to its vasoactive and immunological properties, NO has significant neurophysiological functions. However, NO can also be neurotoxic primarily due to its free radical properties, and it has been implicated in neurodegenerative diseases. Interestingly, there is increasing evidence that NO may have a role in the aforementioned AD pathogenetic mechanisms, and putative links between NO and AD are beginning to be recognized. This review focuses on these issues highlighting the possible relevance of NO in AD, either as a neuroprotective or neurotoxic agent.

Alzheimer Disease↗
PubMed2001

Alzheimer's disease: current and future therapeutic perspectives.

1. A better understanding of the pathophysiology of AD has been made possible through population-based epidemiological studies, human genetic and post-mortem studies, leading to a number of testable hypothesis towards delaying progression. 2. A number of disease milestones have been identified as therapeutic targets, such as conversion from MCI to diagnosable dementia. 3. Clinicians caring for patients with AD have currently available a number of symptomatic drugs, and will have in the future the ability to predict the risk for asymptomatic individuals to develop AD, and provide advice towards prevention.

Alzheimer Disease↗
PubMed2001

The recognition, assessment and management of dementing disorders: conclusions from the Canadian Consensus Conference on Dementia.

OBJECTIVE: i) To develop evidence based consensus statements on which to build clinical practice guidelines for primary care physicians towards the recognition, assessment and management of dementing disorders; ii) to disseminate and evaluate the impact of these statements and guidelines built on these statements. OPTIONS: Structured approach to assessment, including recommended laboratory tests, choices for neuroimaging and referral; management of complications (especially behaviour problems and depression) and use of cognitive enhancing agents. POTENTIAL OUTCOMES: Consistent and improved clinical care of persons with dementia; cost containment by more selective use of laboratory investigations, neuroimaging and referrals; appropriate use of cognitive enhancing agents. EVIDENCE: Authors of each background paper were entrusted to: perform a literature search, discover additional relevant material including references cited in retrieved articles; consult with other experts in the field and then synthesize information. Standard rules of evidence were applied. Based upon this evidence, consensus statements were developed by a group of experts, guided by a steering committee of eight individuals from the areas of Neurology, Geriatric Medicine, Psychiatry, Family Medicine, Preventive Health Care and Health Care Systems. VALUES: Recommendations have been developed with particular attention to the context of primary care and are intended to support family physicians in their ongoing assessment and care of patients with dementia. BENEFITS, HARMS AND COSTS: Potential for improved clinical care of individuals with dementia. A dissemination and evaluation strategy will attempt to measure the impact of the recommendations. RECOMMENDATIONS: See text. VALIDATION: Four other sets of consensus statements and/or guidelines have been published recently. These recommendations are generally congruent with our own consensus statements. The consensus statements have been endorsed by relevant bodies in Canada.

Aged↗
PubMed2001

Assessment of suspected dementia.

At the Second Canadian Consensus Conference on Dementia (CCCD) (February, 1998), a group of neurologists, geriatricians, and psychiatrists met to consider guidelines for evaluation of dementia in Canada. This review paper formed a background paper for their discussion of dementia diagnosis. These experts from across the country concluded that diagnosis of suspected dementia cases continued to rest on skilled clinical assessment. Mental status exam, preferably in some quantifiable form, has become an essential part of the assessment. Selected laboratory tests are advisable in all cases (CBC, TSH, electrolytes, calcium, and glucose), but the CCCD continued to advise that CT scanning was mandatory only in selected cases where clinical findings pointed to another possibility besides Alzheimer's disease. The growing list of other diagnostic measures with potential usefulness in diagnosis of Alzheimer's disease or dementia in general was reviewed, but the evidence was judged as insufficient to support routine use of these tests by physicians. As new treatments for Alzheimer's disease become available, neurologists face new diagnostic challenges--differentiating Mild Cognitive Impairment, Frontotemporal dementias and Mixed dementias, and Lewy Body Dementia. Guidelines to aid in differential diagnosis are presented.

Aged↗
PubMed2001

Neuroprotective and neurorescuing effects of isoform-specific nitric oxide synthase inhibitors, nitric oxide scavenger, and antioxidant against beta-amyloid toxicity.

Beta amyloid (Abeta) is implicated in Alzheimer's disease (AD). Abeta(1 - 42) (5, 10, or 20 microM) was able to increase NO release and decrease cellular viability in primary rat cortical mixed cultures. L-NOARG and SMTC (both at 10 or 100 microM) - type I NOS inhibitors - reduced cellular NO release in the absence of Abeta(1 - 42). At 100 microM, both drugs decreased cell viability. L-NIL (10 or 100 microM), and 1400W (1 or 5 microM) - type II NOS inhibitors - reduced NO release and improved viability when either drug was administered up to 4 h post Abeta(1 - 42) (10 microM) treatment. L-NOARG and SMTC (both at 10 or 100 microM) were only able to decrease NO release. Carboxy-PTIO or Trolox (both at 10 or 100 microM) - a NO scavenger and an antioxidant, respectively - increased viability when administered up to 1 h post Abeta(1 - 42) treatment. Either L-NIL (50 microM) or 1400W (3 microM) and Trolox (50 microM) showed synergistic actions. Peroxynitrite (100 or 200 microM) reduced cell viability. Viabilities were improved by L-NIL (100 microM), 1400W (5 microM), carboxy-PTIO (10 or 100 microM), and Trolox (10 or 100 microM). Hence, the data show that Abeta(1 - 42) induced NO release in neurons and glial cells, and that Abeta neurotoxicity is, at least in part, mediated by NO. NO concentration modulating compounds and antioxidant may have therapeutic importance in neurological disorders where oxidative stress is likely involved such as in AD.

Amyloid beta-Peptides↗
PubMed2001

Methylprednisolone concentrations in the vitreous and the serum after pulse therapy.

PURPOSE: Intravenous (i.v.) pulse of corticosteroids has been used to treat severe eye inflammation from different origins. Whether such large doses result in vitreous levels that differ either in magnitude or duration from more conventional corticotherapy remain unsolved issues. The authors therefore determined levels of methylprednisolone hemisuccinate and methylprednisolone in the vitreous and serum of patients at different times after a single i.v. perfusion of methylprednisolone hemisuccinate. METHODS: Fifty patients scheduled for a first vitrectomy received an i.v. injection of 500 mg hemisuccinate methylprednisolone at different times before surgery (from 15-24 hours). Patients were divided into two groups: those with (n = 21) and without (n = 29) retinal detachment (RD). Pure vitreous samples were analyzed by high-pressure liquid chromatography. RESULTS: Both the ester and the nonester methylprednisolone forms were sampled in the vitreous, showing a slower rate of hydrolysis compared to the serum. On average, the highest concentration of total methylprednisolone in the vitreous was found at 2.5 hours and rapidly decreased for the group of patients with RD. In the group of patients without RD, the highest concentration was reached at 6 hours and then slowly decreased. The antiinflammatory potency in the nondetached retina eyes was approximately 500 times more than in the physiologic vitreous, but despite the route of administration (i.v. or oral), only 1/10 of the corticosteroid serum concentration was measured in the vitreous. CONCLUSION: High concentration of methylprednisolone is achieved by i.v. pulse therapy without changing the kinetic of entry in the vitreous of nondetached retina eyes when compared to conventional oral corticotherapy. Hydrolysis occurs in the vitreous resulting in high rate of active form. Pulse therapy could be considered in cases of severe ocular inflammation involving the posterior segment of the eye.

Adolescent↗
PubMed2001

Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer's disease: epidemiology and management.

Cholinergic adverse effects of acetylcholinesterase inhibitors (AChEIs) are caused by their central and peripheral pharmacological actions on a variety of organ tissues. Gastrointestinal adverse effects predominate and these were relatively common in the phase II and III randomised clinical trials of AChEIs for the treatment of probable Alzheimer's disease. However, in these studies forced and rapid titration of drugs was used, which is not the case in clinical practice. Although there is a risk of pharmacodynamic interactions with other drugs leading to enhanced cholinergic adverse effects, very few of these interactions have proven to be clinically significant. Unresolved issues include the mechanism of syncope and neuromuscular weakness, which should be resolved through structured pharmacovigilance programmes and clinical studies. Loss of bodyweight may prove to be a long term significant complication. As a class, the AChEIs have proven to be well tolerated in the symptomatic treatment of Alzheimer's disease in its mild-to-moderately severe stages. The incidence and clinical significance of cholinergic adverse events will need to be carefully studied if the drugs are used for indications other than Alzheimer's disease.

Alzheimer Disease↗
PubMed2001

Outcome measures for probable vascular dementia and Alzheimer's disease with cerebrovascular disease.

Vascular dementia (VaD) can be defined as dementia associated with cerebrovascular disease (CVD), and accounts for a large proportion of all dementia cases. There is substantial overlap in the clinical symptomatology, pathophysiology and neurochemical mechanisms in VaD compared with Alzheimer's disease, suggesting that an effective treatment for Alzheimer's disease may also offer benefit as a symptomatic treatment in VaD. However, there are currently no explicit guidelines for conducting clinical pharmacotherapy trials in VaD patients. Two important requirements for assessing therapeutic benefits in such trials are 1) the inclusion of appropriate patients and 2) the use of appropriate outcome measures. Debate on the precise definition of VaD in relation to patient selection criteria continues, but many of the recommendations for outcome measures in Alzheimer's disease are already applicable to VaD. There is consensus that cognitive and global function measures, and assessments of abilities to perform activities of daily living (ADL) must be included as part of the optimal assessment battery in VaD trials. A measure of reduced behavioural symptoms with associated reductions in demands on caregivers would also be desirable. However, care must be taken in extrapolating Alzheimer's disease-specific evaluations to VaD, in that important differences in specific domains affected and characteristics of disease course must be taken into account. Between them, measures such as the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog; perhaps with supplemental tests of attention and other frontal lobe functions), evaluations of clinical global impression of change and a functional assessment addressing instrumental as well as basic ADL, e.g. Disability Assessment in Dementia (DAD) scale, should provide a good overall description of VaD-related deficits and sufficient appraisal of treatment effects. The Neuropsychiatric Inventory has also been shown to have good potential utility for measuring behavioural alterations in VaD. These and other assessments are reviewed to provide a balanced and realistic view of the type of treatment outcomes that can be expected in VaD pharmacotherapy trials, and to address the best ways of measuring these outcomes.

Alzheimer Disease↗
PubMed2000

The Nramp2/DMT1 iron transporter is induced in the duodenum of microcytic anemia mk mice but is not properly targeted to the intestinal brush border.

Microcytic anemia (mk) mice and Belgrade (b) rats are severely iron deficient because of impaired intestinal iron absorption and defective iron metabolism in peripheral tissues. Both animals carry a glycine to arginine substitution at position 185 in the iron transporter known as Nramp2/DMT1 (divalent metal transporter 1). DMT1 messenger RNA (mRNA) and protein expression has been examined in the gastrointestinal tract of mk mice. Northern blot analysis indicates that, by comparison to mk/+ heterozygotes, mk/mk homozygotes show a dramatic increase in the level of DMT1 mRNA in the duodenum. This increase in RNA expression is paralleled by a concomitant increase of the 100-kd DMT1 isoform I protein expression in the duodenum. Immunohistochemical analyses show that, as for normal mice on a low-iron diet, DMT1 expression in enterocytes of mk/mk mice is restricted to the duodenum. However, and in contrast to normal enterocytes, little if any expression of DMT1 is seen at the apical membrane in mk/mk mice. These results suggest that the G185R mutation, which was shown to impair the transport properties of DMT1, also affects the membrane targeting of the protein in mk/mk enterocytes. This loss of function of DMT1 is paralleled by a dramatic increase in expression of the defective protein in mk/mk mice. This is consistent with a feedback regulation of DMT1 expression by iron stores. (Blood. 2000;96:3964-3970)

Alleles↗
PubMed2000

Isolation and purification of serum and interfacial peptides of a trypsinolyzed beta-lactoglobulin oil-in-water emulsion.

Information on the conformation of proteins adsorbed to an oil-water interface is usually determined by following the time course of enzymatic hydrolysis of the protein in an oil-in-water emulsion. Unlike previous works reported in the literature, the research presented in this paper provides information on which peptides are actually in contact with the lipid bilayer (interfacial peptides) and those segments that project into the aqueous phase (serum peptides). In order to achieve this classification of peptides, we present a method to separate serum peptides from interfacial peptides by initial centrifugation steps followed by reversed-phase high-performance liquid chromatography. The effectiveness of the method was ascertained by performing proteolysis on beta-lactoglobulin adsorbed to an oil-water interface in a soybean oil-water emulsion. It was found that more peptides are qualitatively and quantitatively found adsorbed to the oil-water interface as compared to peptides released into the serum.

Adsorption↗
PubMed2000

Long-term inhibitory effect of the orally active and pure antiestrogen EM-800 on the growth of human breast cancer xenografts in nude mice.

The antiproliferative effect of the new antiestrogen EM-800 has been studied during 40 weeks of treatment on human breast carcinoma ZR-75-1 xenografts in ovariectomized nude mice supplemented with estrone (0.5 microg, s.c. daily). At the daily 50 microg (approximately 2.5 mg/kg) oral dose, EM-800 caused a complete inhibition of the 680% stimulatory effect of estrone on the growth of the ZR-75-1 human breast cancer xenografts. Complete response, defined as the complete disappearance of the tumors, was observed in 41% of tumors following treatment with the 50 microg dose of the antiestrogen, while a value of 26% was found in ovariectomized animals. The proportion of tumors showing progression at the end of 40 weeks of treatment decreased from 94% in the estrone-supplemented animals to 62%, 61% and 19% in the animals receiving the 5 microg, 20 microg and 50 microg daily doses of the antiestrogen, respectively. None of the tumors that showed a complete or a partial response progressed at later time intervals. The 50 microg daily dose of EM-800 nearly completely (93%) or completely (28% below the value in ovariectomized animals) reversed the stimulatory effect of estrone on uterine and vaginal weight, respectively. The disappearance of 41% of tumors in the group of animals that received the 50 microg daily dose of EM-800 indicates that the antiestrogen induces cell death or apoptosis in ZR-75-1 human breast cancer cells and that its action is cytotoxic and not only cytostatic.

Administration, Oral↗
PubMed2000

Rivastigmine for Alzheimer's disease: Canadian interpretation of intermediate outcome measures and cost implications.

BACKGROUND: Clinical studies have shown that patients with Alzheimer's disease (AD) who are treated with rivastigmine have statistically significantly better scores on 5 scales used to assess AD than control patients receiving placebo. However, the clinical meaning and cost implications of these differences are not clear. OBJECTIVE: The purpose of this study was to assess the clinical meaning and cost implications of statistically significant results obtained in clinical trials of rivastigmine for the treatment of AD. Potential cost implications for the health care system, caregivers, and society are considered. METHODS: Data on clinical effects of rivastigmine were obtained from published North American and European clinical studies of patients with mild to moderately severe AD receiving rivastigmine 6 to 12 mg/d (n = 828) or placebo (n = 647). Differences in scores on the Alzheimer's Disease Assessment Scale-Cognitive Function, Clinician's Interview-Based Impression of Change with both clinical and caregiver information considered, Progressive Deterioration Scale, Mini-Mental State Examination (MMSE), and Global Deterioration Scale were assessed. A convenience panel of 9 Canadian specialists experienced in the treatment of AD provided their opinions on the clinical importance of the trial results. Chart review was performed to identify specific behaviors that improved, and cost implications of improvements were assessed. RESULTS: The panel determined that statistically significant differences in scores on all scales except the MMSE were likely associated with functional or cognitive differences that were clinically relevant for patients, reflecting stabilization that would have beneficial consequences for caregivers and health care resource use. Subsequent chart review showed that improvement on specific scale items confirmed the physician panel's opinion. Analysis of possible cost implications to society indicated that medication expenditures would be offset largely by delays in the need for paid home care and institutionalization, positive effects on caregiver health, and less time lost from work for the caregiver. CONCLUSIONS: From the perspective of a Canadian specialist panel, rivastigmine treatment for AD produces clinically relevant effects for patients that are beneficial to caregivers. These effects suggest decreased use of caregiver resources and delays in the need for institutionalization, both of which reduce societal costs.

Aged↗