Co-prescription of gastroprotective agents in patients taking non-selective NSAIDs or COX-2 selective inhibitors: analysis of prescriptions.

OBJECTIVE: To evaluate the prevalence of co-prescription of GPAs (proton pump inhibitors - PPIs and H2-receptor antagonists) and non-selective NSAIDs or COXIBs in patients registered under the local health authority (LHA) of Bergamo, a city in the north of Italy. METHODS: A drug utilization analysis was done using the Bergamo prescription Health Services Electronic Database. All patients aged 35 years or older who had received at least one prescription during 2004 for non-selective NSAIDs and/or COXIBs were divided into three groups: occasional, chronic and new users. RESULTS: Among chronic users, 44.8% were treated with non-selective NSAIDs, 11.6% with COXIBs, and 43.6% with both (mixed NSAIDs). For new users, non-selective NSAIDs were prescribed to 82.7%, COXIBs and mixed NSAIDs to 10.8% and 6.5%. PPIs were co-prescribed to 7.1% of COXIB users and 5.8% of non-selective NSAID occasional users. Among chronic users, the figures were 15.6% and 14%. For new users, prescriptions for COXIBs were associated with less use of GPA for patients who received the first and last prescription for NSAIDs and GPAs on the same day, while for patients who became chronic users COXIBs did not reduce the probability of co-prescription of a GPA: the number of co-prescribed medications and antithrombotics or corticosteroids were independent predictors of GPA use. CONCLUSIONS: COXIBs seem to be used in patients at high risk of GI toxicity. However, the fear of GI adverse reactions and the uncertain safety profile of COXIBs leads many physicians to boost the gastroprotection by prescribing a PPI.

Potentially severe drug interactions in elderly outpatients: results of an observational study of an administrative prescription database.

PURPOSE: To estimate the prevalence of potentially severe drug-drug interactions (DDIs) and their relationship with age, sex and number of prescribed drugs. METHODS: We analysed all prescriptions dispensed from 1 January 2003 to 31 December 2003 to individuals aged 65 or more registered under the Local Health Authority of Lecco, a northern Italian province with a population of almost 330 000 persons. Elderly who received at least two co-administered prescriptions were selected to assess the presence of DDIs. RESULTS: The prevalence of potentially severe DDIs was 16%, and rose with increasing patient's age and number of drugs prescribed. At multivariate analysis, the adjusted odds ratios rose from 1.07 (95% CI 1.03-1.11) in patients aged 70-74 to 1.52 (95% CI 1.46-1.60) in those aged 85 or older. Elderly taking more than five drugs on a chronic basis had a statistically significant higher risk of sever DDIs than those receiving less than 3 or 3-5 such drugs. CONCLUSIONS: The elderly constitutes a population at high risk of DDIs. As physicians still have some difficulty in managing this problem, it is essential to highlight for them, which factors raise the risk of DDIs.

Inflammatory markers in Alzheimer's disease and multi-infarct dementia.

Inflammation has been involved in the pathogenesis of dementia. The study evaluates the presence and the source of pro- and anti- inflammatory cytokines in the blood of patients with Alzheimer's disease (AD), multi-infarct dementia (MID) or in non-demented elderly people (controls). Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10, IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor I (sTNF-RI) plasma concentrations and release from blood cells stimulated with lipopolysaccharide (LPS, 1 microg/ml) were determined. The results show that TNF-alpha released from blood cells is significantly decreased (27%) in all demented patients compared to controls. Circulating TNF-alpha is increased (400%) only in MID patients. In these patients plasma levels of sTNF-RI are increased (53%) and IL-10 from stimulated blood cells decreased (47%) compared to non-demented subjects. The results show that: (1) peripheral production of TNF-alpha is blunted in demented (both AD and MID) patients compared to non-demented age-matched subjects; (2) AD patients have a selective disregulation of the peripheral TNF-alpha system; (3) different cytokines are up- or down- regulated in MID patients showing that in this condition the pro- and anti-inflammatory peripheral cytokine system is more widely affected.

Efficacy and safety of eptastigmine for the treatment of patients with Alzheimer's disease.

OBJECTIVE: To evaluate the efficacy and safety of eptastigmine in patients with moderate to moderately severe AD. BACKGROUND: Eptastigmine is a centrally acting cholinesterase inhibitor. METHODS: The study was carried out according a multicenter, randomized, double-blinded, placebo-controlled, parallel-group design. Patients received a 24-week treatment with placebo or eptastigmine 15 mg or 20 mg three times daily after a 4-week, stepwise dose escalation. The effects of treatment on cognition, global function, and activities of daily living were evaluated with the Alzheimer's Disease Assessment Cognitive Subscale (ADAS-Cog), the Clinician's Interview-Based Impression of Change Plus (CIBIC-Plus), and the Instrumental Activities of Daily Living scale (IADL), respectively. RESULTS: Thirty-six centers recruited 491 patients: 164 on placebo, 166 on eptastigmine 15 mg three times daily, and 161 on eptastigmine 20 mg three times daily. Percentages of patients completing double-blinded treatment were 87% in the placebo group and 86% in both the eptastigmine-treated groups. At the end of treatment, the intent-to-treat analysis on 463 patients showed a dose-dependent effect of eptastigmine on all efficacy variables, with a statistically significant effect of the 20 mg three times daily dose compared with placebo on the ADAS-Cog, CIBIC-Plus, and IADL. Patients on eptastigmine 15 mg three times daily performed significantly better than placebo-treated patients only on the ADAS-Cog. Eleven patients on placebo (7%), 13 patients on eptastigmine 15 mg three times daily (8%), and 12 patients on eptastigmine 20 mg three times daily (8%) discontinued study treatment because of adverse events. Adverse events were recorded in 49% of patients on placebo compared with 54% on eptastigmine 15 mg three times daily and 48% on eptastigmine 20 mg three times daily. Cholinergic side effects (nausea, vomiting, diarrhea, and abdominal pain) were reported with similar frequency in the eptastigmine- and placebo-treated patients. There was a dose-dependent transient and mild neutropenic effect associated with eptastigmine treatment, and one patient on 20 mg three times daily had an asymptomatic pancytopenia. CONCLUSIONS: Eptastigmine produces significant cognitive, clinical, and functional benefits in patients with probable AD. Although the cholinergic tolerability of eptastigmine was found to be favorable, its potential adverse hematologic effects limit its clinical utility.

Long-term acetyl-L-carnitine treatment in Alzheimer's disease.

In a double-blind, placebo-controlled, parallel-group, randomized clinical trial, we studied the efficacy of long-term (1-year) oral treatment with acetyl-L-carnitine in 130 patients with a clinical diagnosis of Alzheimer's disease. We employed 14 outcome measures to assess functional and cognitive impairment. After 1 year, both the treated and placebo groups worsened, but the treated group showed a slower rate of deterioration in 13 of the 14 outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, ideomotor and buccofacial apraxia, and selective attention. Adjusting for initial scores with analysis of covariance, the treated group showed better scores on all outcome measures, reaching statistical significance for the Blessed Dementia Scale, logical intelligence, verbal critical abilities, long-term verbal memory, and selective attention. The analysis for patients with good treatment compliance showed a greater drug benefit than for the overall sample. Reported adverse events were relatively mild, and there was no significant difference between the treated and placebo groups either in incidence or severity.

Rate of progression and prognostic factors in Alzheimer's disease: a prospective study.

OBJECTIVE: To study rate of progression and correlates of cognitive and functional/behavioral deterioration in Alzheimer patients. DESIGN: A 1-year multicenter prospective study. SETTING: Outpatients and inpatients at geriatric institutions. PATIENTS: Fifty-six patients with a clinical diagnosis of Alzheimer's disease according to DSM-III criteria of Primary Degenerative Dementia. MAIN OUTCOME MEASURES: Blessed Dementia Scale (BDS) and Blessed Information-Memory-Concentration test (BIMC) measured at baseline, third, sixth, and twelfth month. RESULTS: The mean annual (+/- SD) rate of progression of our sample was 3.5 (+/- 3.7) points on the BDS and 2.6 (+/- 4.9) on the BIMC, with a wide range of variability. The level of cognitive impairment (BIMC score) at baseline predicted functional and behavioral deterioration: the better the initial BIMC score, the less the rate of negative change of BDS (r = 0.37, P = 0.006). Furthermore, the younger the patients at the disease onset, the faster the progression of cognitive impairment (r = 0.48, P = 0.0003), with men having a slower rate of progression (P = 0.004) than women. CONCLUSIONS: The present study confirms previous findings showing a wide individual variability in rate of progression of cognitive and functional/behavioral impairment as assessed by BIMC and BDS. The cognitive profile may predict the clinical evolution better than the functional and behavioral status, with patients with an earlier onset and women having a faster deterioration.

Single-dose safety and pharmacokinetics of a potential cognition-enhancing compound, CL 275,838, in healthy volunteers.

The pharmacokinetics and safety of CL 275,838, a potential cognition-enhancing compound, were studied after single escalating oral doses first in young healthy male volunteers and then in old (60-74 years) and very old (over 75 years) volunteers of both sexes. In all age groups absorption of CL 275,838 was rapid as assessed by the mean time to reach maximum plasma concentrations (Cmax) which averaged 1-2 hr, regardless of the dose administered. In young male volunteers both Cmax and area under the curve (AUC) increased proportionally with dose from 10 to 100 mg. Mean elimination half-lives (t1/2) of the parent compound (18-21 hr) and of its circulating metabolites II (20-22 hr) and IV (27-30 hr) were well comparable for the doses tested (50 and 100 mg). Age did not appreciably affect plasma Cmax of CL 275,838 or its two metabolites. Mean AUC and elimination half-life did not appreciably differ between old and very old subjects given 50 mg CL 275,838, with the limitations dictated by the small number of elderly subjects examined. Compared with younger volunteers receiving comparable doses, however, the elderly had higher mean plasma AUC of the unchanged compound and its two metabolites, although the parameter varied widely between subjects. The mean elimination t1/2 (+/- SD) was longer in the elderly (38.8 +/- 19.6, 50.5 +/- 24.5 and 41.7 +/- 12.1 hr, respectively, for the parent compound and its metabolites II and IV) than in the young subjects. The cause(s) of these variations and the possible clinical implications remain to be established.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple-dose pharmacokinetics and safety of a potential memory-enhancing compound, CL 275,838, in healthy male volunteers.

The pharmacokinetics and safety of CL 275,838, a new potential memory-enhancing compound, were examined after 14 daily doses (50 and 100 mg) in 16 healthy male volunteers, age 20 to 59 years, in a randomized, double-blind, placebo-controlled, parallel group study. Trough blood samples (predose) were collected on days 2, 4, 7, 10, and 14, and further samples were drawn after the final dose (day 14) to define the multiple-dose kinetics of the parent compound and its metabolites II and IV. Intercurrent clinical events, vital functions, EEG, ECG, and cognitive tests (attention, verbal memory, and spatial memory) were considered as outcome measures of safety. Performance in cognitive tests was also studied to collect preliminary information on possible therapeutic action. Predose plasma concentrations of the parent compound and its two metabolites increased approximately in proportion to the dose, and accumulation was complete within 7 days, regardless of the dose. At steady state, mean Cmax and AUC of the parent compound and its two metabolites were dose related. Mean wash-out t1/2 was 18 to 20 hours for the parent compound, 22-23 hours for metabolite II, and 28-33 hours for metabolite IV; these elimination t1/2 are comparable for the two doses, and are similar to those observed in single-dose studies. For the 50-mg-dose group, predicted and observed average plasma concentrations (Css) of CL 275,838 and its two metabolites did not differ significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Statistical analysis of the clinical trial of a therapy for Alzheimer's disease. Univariate tests and logistic regression.

A placebo controlled, randomized, double blind, multicentric clinical trial was carried out in Italy to test the effectiveness of a drug in the therapy of Alzheimer's disease. Informed consensus was gained for the inclusion of 130 patients, whose mental performance was assessed before allocation and after 3, 6, 12 months of continuing assumption of treatment. 14 different outcome variables were used. The main analysis was performed on measures adjusted for baseline, using both univariate and multivariate techniques for each of the three assessing times. The former is mainly descriptive in its scope and allows an analytical view of the results; the latter protects from a too high type I error probability, without implying the loss of power produced by the Bonferroni correction. The techniques are respectively Mann-Whitney test, and analysis of deviance of logistic models, which was suggested by Cupples et al. (1984). In the latter we used the allocation of the patients as response variable, and compared the predictor containing all outcome measures with that having just a constant term. It is shown that a significant difference of fit implies that treatment significantly affects outcome. For the 3 and 6 month follow-up assessment, univariate tests do not show clearcut trends (only 1 outcome measure is significantly better for the drug, none is for the placebo). After 12 months, a trend shows: 13 out of 14 variables are in favour of the drug and 4 of them are significant. Of the three multivariate test carried out, that relative to the 12-month follow-up is significant at the 0.05 level, which is consistent with the univariate results.(ABSTRACT TRUNCATED AT 250 WORDS)

A 25-week placebo-controlled study of eptastigmine in patients with Alzheimer disease.

The efficacy and safety of eptastigmine in patients with probable Alzheimer disease was evaluated in a double-blind, placebo-controlled, parallel group study. Patients with mild to moderate dementia were randomly assigned to placebo, eptastigmine 10 mg three times a day (t.i.d.), or eptastigmine 15 mg t.i.d. over 25 weeks. The Alzheimer Disease Assessment Cognitive Subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change Plus (CIBIC-Plus) were the primary outcome measures for efficacy. Twenty-six centers recruited 320 patients: 106 on placebo, 105 on eptastigmine 10 mg t.i.d., and 109 on eptastigmine 15 mg t.i.d. Six patients on placebo (6%), 18 patients on eptastigmine 10 mg t.i.d. (17%), and 10 patients on eptastigmine 15 mg t.i.d. (9%) discontinued study treatment. The intent-to-treat analysis on 315 patients showed a statistically significant (p=0.047) difference of 2.0 points on ADAS-Cog between the placebo and the eptastigmine 15 mg t.i.d. group at the end of treatment. Patients in the 10 mg t.i.d. group performed better than did placebo-treated patients on the Spontaneous Behavior Interview (SBI) total scores (p=0.015) and on the Activities of Daily Living (ADL, p=0.043) and Behavioral Problems (BP, p=0.028) subscales. The differences in favor of the eptastigmine groups on the CIBIC-Plus did not reach statistical significance. In a post hoc subgroup analysis by staging, the effect size of eptastigmine was found to be greater in the most severely impaired patients (Global Deterioration Scale rating of 4 and 5 at screening) reaching statistical significance in both ADAS-Cog (p=0.007) and CIBIC-Plus (p=0.038). In this patient subgroup (n=222), there was also a significant effect of eptastigmine on SBI (p=0.019). The drug was generally well tolerated, with 8% of patients withdrawing due to adverse events versus 5% on placebo. Adverse events were recorded in 35 patients (33%) on placebo compared with 41 (39%) on eptastigmine 10 mg t.i.d. and 38 (35%) on eptastigmine 15 mg t.i.d. This study shows that eptastigmine doses up to 15 mg t.i.d. for 25 weeks are well tolerated. The drug positively affects cognitive performance of Alzheimer patients. This effect appears greater in more severely impaired patients and also impacts on their behavioral performance.

An example of a clinical trial in patients with Alzheimer's disease: some methodological issues.

UNLABELLED: In ten Italian centers--hospitals and geriatric institutions--130 outpatients and inpatients with a diagnosis of Alzheimer's disease were recruited for a randomized, double blind, placebo controlled clinical trial with 1-acetylcarnitine. In planning the trial, we had to deal with some important and largely open issues. DIAGNOSIS: we decided not to use neuropsychological tests (NPT) in the diagnostic process, both for the unknown risk of false positive and false negative rate and to improve the feasibility of the trial. FOLLOW-UP: it must be representative of the disease and consequently we chose to follow the patients for one year (assessment at baseline, 3rd, 6th and 12th month) in spite of a possible high rate of drop-outs. ASSESSMENT: to assess the patients' outcome we used NPT and behavioural scales. However, the validity, reliability and feasibility of these instruments are rarely discussed and their usefulness as indicators of the relevant aspects of the disease needs a careful evaluation. STATISTICAL ANALYSIS: in this type of trial there is both a high risk of alpha-error, in view of the high number of NPT and behavioural scales used to assess the drug efficacy, and a high risk of beta-error connected with the usually small sample size. Thus, the role of small trials in defining the risk/benefit ratio of a treatment needs to be discussed.

Peripheral inflammatory response in Alzheimer's disease and multiinfarct dementia.

Whether peripheral inflammatory molecules can be considered markers of dementia is still an open issue. We have investigated the presence of circulating cytokines and the ability of blood cells to release them in response to an inflammatory stimulus in patients with different types of dementia and in age-matched controls. A significant increase in circulating interleukin-1beta in moderate Alzheimer and in multiinfarct (145 and 224 times control concentration, respectively) dementia and in circulating tumor necrosis factor-alpha concentration in multiinfarct dementia patient group (156%) were found. Tumor necrosis factor-alpha and interleukin-6 released from blood cells after exposure to lipopolysaccharide were significantly reduced in moderate Alzheimer (60%, both cytokines) and multiinfarct patients (71 and 50%, respectively), while interleukin-10 was decreased only in multiinfarct patients (61%). The results show that patients with Alzheimer disease or multiinfarct dementia have an upregulation of circulating cytokines and a downregulation of cytokines released by blood cells.

Apolipoprotein E and intronic polymorphism of presenilin 1 and alpha-1-antichymotrypsin in Alzheimer's disease and vascular dementia.

Apolipoprotein E (ApoE) genotypes, presenilin 1 (PS-1) and alpha(1)-antichymotrypsin (ACT) polymorphism and the association of the genotypes were examined in patients with Alzheimer's disease (AD, n = 121) or vascular dementia (VD, n = 68) in comparison with elderly controls (n = 125). The frequency of the ApoE epsilon 4 allele was significantly increased both in late-onset AD (0.35) and in VD (0.17); the frequency of ApoE epsilon 2 was significantly reduced in AD, but it was similar in VD and controls. The presence of the allele 1 of PS-1 intronic polymorphism was not associated with AD or VD and was not influenced by the ApoE genotypes. Also, the frequency of allele A of the intronic polymorphism of ACT was similar in AD, VD and controls and it was not altered by ApoE or PS-1 genotypes. The results confirm the association between ApoE epsilon 4 and AD and indicate an increase in ApoE epsilon 4 in Vd, too. A potential protective role of ApoE epsilon 2 is also suggested for late-onset AD but not for VD. No association was shown between ACT allele A and PS-1 allele 1 in AD or VD.

Clinical global measures of dementia. Position paper from the International Working Group on Harmonization of Dementia Drug Guidelines.

Following is the report of the committee working on clinical global measures for antidementia drug guidelines. The concepts involved in global scales, the distinctions between change and severity scales, advantages and disadvantages of structured interviews, and anchoring of change scores are discussed, and selected existing clinical global scales are described. In addition, the committee assessed the utility of global scales in clinical trials for antidementia drugs. There was a consensus among the members of the working group on the following: (1) Clinical global scales are interview based; in most cases, they include information obtained from caregivers as well as directly from patients, but they can rely on information from the subject only. (2) Clinicians' global ratings are intended to assess clinically meaningful change based on multidimensional clinical assessment and take into account the clinical heterogeneity of dementia by assessing at least cognition, behavior, and functioning. (3) There are two distinct types of clinical global measures: (a) clinicians' interview-based global severity scales, which generally incorporate classification by stage or severity of illness and (b) clinicians' interview-based global change scales, which incorporate global assessment ratings of clinical change. The committee could not reach a consensus on whether global scales should be required in phase II and phase III clinical trials, or whether other specific assessments such as well-designed activities of daily living, cognition, and behavior measures could, when used in appropriate combinations, replace the global as assessments of clinical meaningfulness.