Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe.

BACKGROUND: There is some evidence that statins may have a protective and symptomatic benefit in Alzheimer disease (AD). The LEADe study is a randomized controlled trial (RCT) evaluating the efficacy and safety of atorvastatin in patients with mild to moderate AD. METHODS: This was an international, multicenter, double-blind, randomized, parallel-group study. Subjects had mild to moderate probable AD (Mini-Mental State Examination score 13-25), were aged 50-90 years, and were taking donepezil 10 mg daily for > or 3 months prior to screening. Entry low-density lipoprotein cholesterol levels (LDL-C) were > 95 and < 195 mg/dL. Patients were randomized to atorvastatin 80 mg/day or placebo for 72 weeks followed by a double-blind, 8-week atorvastatin withdrawal phase. Coprimary endpoints were changes in cognition (Alzheimer's Disease Assessment Scale-Cognitive Subscale [ADAS-Cog]) and global function (Alzheimer's Disease Cooperative Study Clinical Global Impression of Change [ADCS-CGIC]) at 72 weeks. RESULTS: A total of 640 patients were randomized in the study. There were no significant differences in the coprimary endpoints of ADAS-cog or ADCS-CGIC or the secondary endpoints. Atorvastatin was generally well-tolerated. CONCLUSIONS: In this large-scale randomized controlled trial evaluating statin therapy as a treatment for mild to moderate Alzheimer disease, atorvastatin was not associated with significant clinical benefit over 72 weeks. This treatment was generally well-tolerated without unexpected adverse events. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intensive lipid lowering with atorvastatin 80 mg/day in patients with mild to moderate probable Alzheimer disease (aged 50-90), taking donepezil, with low-density lipoprotein cholesterol levels between 95 and 195 mg/dL over 72 weeks does not benefit cognition (as measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale) (p = 0.26) or global function (as measured by Alzheimer's Disease Cooperative Study Clinical Global Impression of Change) (p = 0.73) compared with placebo.

Economic evaluation of donepezil in moderate to severe Alzheimer disease.

OBJECTIVE: To investigate the costs to society of Alzheimer disease (AD) care in a multinational, randomized, placebo-controlled trial of donepezil in patients with moderate to severe AD. METHODS: A total of 290 patients with AD (screening standardized Mini-Mental State Examination score 5 to 17) were randomized to receive either donepezil (n = 144; 5 mg/day for 28 days, followed by 10 mg/day as per clinician's judgment) or placebo (n = 146) for 24 weeks. The authors collected data on patient and caregiver health resource utilization prospectively using the Canadian Utilization of Services Tracking questionnaire. Costs were calculated for patients and caregivers in each group based on resource utilization multiplied by the unit prices for each resource. A cost (the average Ontario minimum wage for 1998 [Can 6.85 dollars per hour]) was assigned to unpaid time that caregivers spent assisting the patient with activities of daily living (ADL). RESULTS: Patient and caregiver demographics at baseline were similar across the two groups. After adjusting for baseline total cost per patient, the mean total societal cost per patient for the 24-week period was donepezil, Can 9,904 dollars (US 6,686 dollars) and placebo, Can 10,236 dollars (US 6,910 dollars). This net cost saving of Can 332 dollars (US 224 dollars) included the average 24-week cost of donepezil treatment. Most of the cost-saving with donepezil treatment was due to less use of residential care by patients, and caregivers spending less time assisting patients with ADL. CONCLUSION: This cost-consequence analysis reveals economic benefits of treatment of moderate to severe AD with donepezil.

A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting.

OBJECTIVES: To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimer's disease (AD) residing in nursing home facilities. DESIGN: Twenty-four-week, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial. SETTING: Twenty-seven nursing homes across the United States. PARTICIPANTS: Two hundred eight nursing home patients with a diagnosis of probable or possible AD, or AD with cerebrovascular disease; mean Mini-Mental State Examination (MMSE) score 14.4; mean age 85.7. MEASUREMENTS: The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). Secondary efficacy measures were the Clinical Dementia Rating (Nursing Home Version)-Sum of the Boxes (CDR-SB), MMSE, and the Physical Self-Maintenance Scale (PSMS). Safety was monitored by physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and treatment-emergent adverse events (AEs). RESULTS: Eighty-two percent of donepezil- and 74% of placebo-treated patients completed the trial. Eleven percent of donepezil- and 18% of placebo-treated patients withdrew because of AEs. Mean NPI-NH 12-item total scores improved relative to baseline for both groups, with no significant differences observed between the groups at any assessment. Mean change from baseline CDR-SB total score improved significantly with donepezil compared with placebo at Week 24 (P < .05). The change in CDR-SB total score was not influenced by age. Differences in mean change from baseline on the MMSE favored donepezil over placebo at Weeks 8, 16, and 20 (P < .05). No significant differences were observed between the groups on the PSMS. Overall rates of occurrence and severity of AEs were similar between the two groups (97% placebo, 96% donepezil). Gastrointestinal AEs occurred more frequently in donepezil-treated patients. In general, AEs were similar in older and younger donepezil-treated patients, with the majority of patients experiencing only AEs that were transient and mild or moderate in severity. Weight loss was reported as an AE more frequently in older patients, although a loss at last visit of >or=7% of screening weight occurred at the same rate in older and younger patients (9% of donepezil- and 6% of placebo-treated patients). No significant differences between groups in vital sign changes, bradycardia, or rates of clinically significant laboratory or ECG abnormalities were observed. CONCLUSION: Patients treated with donepezil maintained or improved in cognition and overall dementia severity in contrast to placebo-treated patients who declined during the 6-month treatment period. The safety and tolerability profile was comparable with that reported in outpatient studies of donepezil. These findings also suggest that advanced age, comorbid illnesses, and high concomitant medication usage should not be barriers to donepezil treatment. Given the apparent improvement in behavior in the placebo group, and the high use of concomitant medications in both groups, the impact of donepezil on behavior in the nursing home setting is unresolved and merits further investigation. In summary, effects on cognition, overall dementia severity, and safety and tolerability findings are consistent with previous findings in outpatients and support the use of donepezil in patients with AD who reside in nursing homes.

Fulminant meningococcal supraglottitis: An emerging infectious syndrome?

We report a case of fulminant supraglottitis with dramatic external cervical swelling due to associated cellulitis. Blood cultures were positive for Neisseria meningitidis. The patient recovered completely after emergency fiberoptic intubation and appropriate antibiotic therapy. We summarize five other cases of meningococcal supraglottitis, all reported since 1995, and discuss possible pathophysiologic mechanisms.

Intravenous flumazenil following acute and repeated exposure to lorazepam in healthy volunteers: antagonism and precipitated withdrawal.

The effects of i.v. administered flumazenil (3.0 mg) were studied in healthy male subjects who received pretreatment with p.o. placebo or lorazepam. The duration of placebo or lorazepam (3.0 mg single p.o. daily dose) pretreatment before a flumazenil or placebo injection was 1, 3, 7 or 14 days in four sequential groups of subjects. Initial administration of lorazepam produced a classic sedative profile of effects on various psychomotor/behavioral performance, observer-rated and subject-rated measures. Tolerance to repeated daily administration of lorazepam was suggested by a progressive diminution of performance disrupting effects. In subjects pretreated with placebo, flumazenil increased subject-ratings of dizziness over preinjection ratings. Flumazenil produced an immediate reversal of lorazepam effects in subjects who were not tolerant to lorazepam (1- and 3-day pretreatment groups). Flumazenil did not precipitate withdrawal symptoms in subjects who received a single administration of lorazepam. Precipitated withdrawal symptoms were evident after 3 and 7 days of lorazepam pretreatment, and there was a tendency toward precipitated withdrawal symptoms (that included one panic attack) after 14 days of lorazepam pretreatment. Precipitated withdrawal was characterized by an elevation in subject-rated symptoms including dizziness, tenseness, tachycardia, perceptual disturbance and sweating. Symptoms were maximal immediately after injection, usually mild in severity and usually resolved within 1 hr. There was no evidence of precipitated withdrawal on psychomotor/behavioral performance or observer ratings. The present study provides the strongest human experimental evidence to date that flumazenil can precipitate withdrawal symptoms after a history of repeated benzodiazepine exposure.

Validity and reliability of the Observer's Assessment of Alertness/Sedation Scale: study with intravenous midazolam.

The Observer's Assessment of Alertness/Sedation (OAA/S) Scale was developed to measure the level of alertness in subjects who are sedated. This scale was tested in 18 subjects in a three-period crossover study to assess its reliability and its criterion, behavioral, and construct validity. After receiving either placebo or a titrated dose of midazolam to produce light or heavy sedation, each subject was administered two sedation scales (OAA/S Scale and a Visual Analogue Scale) and two performances tests (Digit Symbol Substitution Test and Serial Sevens Subtraction). Two raters individually evaluated the subject's level of alertness on each of the two sedation scales. The results obtained on the OAA/S Scale were reliable and valid as measured by high correlations between the two raters and high correlations between the OAA/S Scale and two of the three standard tests used in this study. The OAA/S Scale was sensitive to the level of midazolam administered; all pairwise comparisons were significant (p less than 0.05) for all three treatment levels at both test periods.

Flumazenil: US clinical pharmacology studies.

Flumazenil, a benzodiazepine antagonist, blocks the central effects of benzodiazepines by competitive interaction at the receptor site. Two double-blind, placebo-controlled, randomized studies in healthy volunteers (110/study) were performed to determine the minimal effective dose of flumazenil required to reverse the sedative, psychomotor and amnesic effects of benzodiazepines used to produce conscious sedation. Conscious sedation was produced by i.v. diazepam (12-30 mg) in one study and i.v. lorazepam (0.045 mg kg-1) in the other. Intravenous flumazenil (0.001, 0.003, 0.007 or 0.014 mg kg-1) or placebo was administered after diazepam or lorazepam. Assessment of sedation, psychomotor performance and recall/recognition were made both before and after the benzodiazepine as well as serially after flumazenil or placebo. Doses as low as 0.007 and 0.014 mg kg-1 flumazenil consistently reversed diazepam- and lorazepam-induced effects, respectively. The duration of reversal produced by varying doses of flumazenil (0.2, 0.6, 1.0 or 3 mg) was evaluated in 50 volunteers in a double-blind, placebo-controlled, parallel group study. A constant level of conscious sedation was produced by a continuous infusion of midazolam. Assessments of sedation and psychomotor performance were assessed both before and at varying times after the administration of flumazenil or placebo. Preliminary results indicate that the duration of reversal produced by 3.0 mg flumazenil was longer than that produced by any of the lower doses. While the mean duration of reversal produced by the lower doses was comparable, the 0.2 mg dose resulted in the greatest between subject variability and only partial rather than complete reversal. Two further double-blind, placebo-controlled studies were done in healthy volunteers (45/study) to evaluate the safety of flumazenil 1.0 mg or placebo given i.v. to reverse midazolam-induced sedation in subjects who had been treated for up to 14 days with either oral diazepam or triazolam. No clinically significant changes were noted in laboratory test values, electrocardiograms or vital signs monitored for up to 36 h after flumazenil or placebo in any pre-treatment group.

Senile plaques in aged squirrel monkeys.

Aged squirrel monkeys develop senile plaques in the brain that are similar to those occurring in aged rhesus monkeys and aged humans. These plaques consist of abnormal, swollen neurites around an amyloid core. In whole-hemisphere coronal sections through the level of the rostral temporal lobe, plaques are present in temporal cortex, amygdala, hippocampal formation and, occasionally, in other cortical regions. In more rostral sections through the frontal lobe, plaques are most common in orbitofrontal and frontal opercular cortical regions. In immunocytochemical preparations, some neurites show immunoreactivity with antibodies directed against phosphorylated neurofilaments and neuropeptide Y. Thus, plaques in these New World primates are similar in distribution and composition to those occurring in aged Old World primates.

Autoshaping and automaintenance of a key-press response in squirrel monkeys.

Following exposure for a minimum of 500 to 600 trials, three of four naive squirrel monkeys eventually pressed a response key, illumination of which always preceded delivery of a food pellet. Three other naive monkeys did not press the key when the pellets were delivered randomly with respect to key illumination. Despite some similarities to autoshaping using pigeons, the data indicate many points of difference when squirrel monkeys are used as subjects. Although key-food pairings were shown to be important in the acquisition of the key-press response, they were ineffective in maintaining the response when either a negative response-reinforcer dependency was introduced, or when there was no scheduled response-reinforcer dependency (fixed trial). Not all demonstrations of autoshaping can be considered to be under the control of those processes that are primarily responsible for the phenomena obtained in pigeons.