Usefulness of administration of non-organophosphate cholinesterase inhibitors before acute exposure to organophosphates: assessment using paraoxon.

Reversible acetylcholinesterase (AChE) inhibitors can protect against the lethal effects of irreversible organophosphorus AChE inhibitors (OPCs), when administered before OPC exposure. We have assessed in vivo the mortality-reducing efficacy of a group of known AChE inhibitors, when given in equitoxic dosage before exposure to the OPC paraoxon. Protection was quantified in rats by determining the relative risk (RR) of death. Best in vivo protection from paraoxon-induced mortality was observed after prophylactic administration of physostigmine (RR = 0.30) or the oxime K-27 (RR = 0.34); both treatments were significantly superior to the pre-treatment with all other tested compounds, including the established substance pyridostigmine. Tacrine (RR = 0.67), ranitidine (RR = 0.72), pyridostigmine (RR = 0.76), tiapride (RR = 0.80) and 7-MEOTA (RR = 0.86) also significantly reduced the relative risk of paraoxon-induced death, but to a lesser degree. Methylene blue, amiloride and metoclopramide had an unfavorable effect (RR ≥ 1), significantly increasing mortality. When CNS penetration by prophylactic is undesirable K-27 is a promising alternative to pyridostigmine.

Practice guidelines for the diagnosis and treatment of Alzheimer's disease in a managed care setting: Part II--Pharmacologic therapy. Alzheimer's Disease (AD) Managed Care Advisory Council.

The progressive loss of social and physical functioning associated with Alzheimer's disease (AD) results in extensive social and economic costs to society. The early diagnosis and treatment of AD may reduce cognitive and behavioral symptoms of this disease and may slow disease progression, thereby alleviating some of these social and economic costs. The Alzheimer's Disease Managed Care Advisory Council, a panel of experts from managed care, academic medicine, and the Los Angeles chapter of the Alzheimer's Association was convened to synthesize current evidence-based recommendations for AD diagnostic and treatment guidelines and to integrate these guidelines for use in MCOs. This paper presents conclusions from this panel and provides an algorithm for the treatment of AD specifically for managed care settings. When combined with other necessary efforts to educate providers, these guidelines should improve the cost-effectiveness and quality of care for individuals with dementia in managed care.

Assessment of the value of therapeutic monitoring of tacrine in Alzheimer's disease.

OBJECTIVES: The purpose of this study was to validate the lower end of the putative therapeutic range of serum tacrine concentrations of 7-20 ng ml(-1) in the treatment of Alzheimer's disease. METHODS: The relationship between dose, steady-state serum tacrine concentrations and change in MMSE score (a measure of cognitive function) was examined in 106 Alzheimer's disease patients who had been treated with the drug for 12 weeks. RESULTS: In all, 72% of patients showed some response, but there was no relationship between dose and the chance of a favourable outcome. The proportion of patients with serum concentrations above 7 ng x ml(-1) who improved (79%) was significantly greater than that of those with serum concentrations below this level (47%) (P < 0.02). Also, a significantly greater proportion of patients with serum concentrations above both 5 ng x ml(-1) and 9 ng x ml(-1) showed improvement in comparison to those with concentrations below these levels. CONCLUSIONS: This study indicates that therapeutic monitoring of serum tacrine concentrations might increase the possibility of responding to tacrine by some 68%. This represents an important contribution to the management of Alzheimer's disease patients with this drug, and may also be relevant to the use of the newer generation of cholinesterase inhibitors.

Cardinal features of cognitive dysfunction in Alzheimer's disease: a factor-analytic study of the Alzheimer's Disease Assessment Scale.

Factor analysis methodology applied to Alzheimer's Disease Assessment Scale (ADAS) subtest profiles for patients in two large-scale clinical trials of the antidementia drug tacrine yielded three oblique factors interpreted as dysfunctions in memory, language, and praxis. The factor structures confirmed reliable assessment of primary dimensions of cognitive impairment in Alzheimer's disease that the original authors of the ADAS proposed to measure and that correspond well to that of the only previously reported factor analysis of the ADAS-COG. The presence of a strong general factor, supported by stable correlations among the oblique primary factors, justifies the recommendation to continue reliance on the ADAS-COG total score as a primary outcome measure in clinical trials, whereas the factor scores are recommended for evaluation of differential treatment effects on more specific aspects of the general cognitive decline. The stability of correlations across time appears to satisfy a primary requirement for application of repeated measures ANOVA to ADAS-COG total score and factor scores in longitudinal clinical trials.