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Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of -amyloid (A) peptides may cause Alzheimers disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting A have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating A clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-A monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating A formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, -secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of -secretase, the protease that regulates the last metabolic step generating A, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate -secretase, the enzyme responsible for the nonamyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of A aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-A approaches in clinical testing, we will know in few years if the Av hypothesis of AD is correct.

Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit β-amyloid1-42 (Aβ42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Aβ42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Aβ42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Aβ42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.

Rapid and reliable measurement of acetylcholinesterase (AChE) activity is of crucial importance to the pharmacodynamic monitoring of anti-cholinesterase drugs. A new assay has been developed to measure AChE from 10 μl samples of capillary blood. AChE activity was calculated from the change in pH of the reaction medium caused by the hydrolysis of acetylcholine and measured with a highly sensitive differential pH apparatus (CL-10, Eurochem, Rome, Italy). Interference by butyrylcholinesterase was eliminated by a specific inhibitor, quinidine sulfate. The assay lasts 1 min. The coefficient of variation (CV) for replicated measurements was 2.8 (3267 U/L, n = 33). Linearity ranged from 0 to 10,000 U/L. The correlation coefficient between the new technique and Ellman's colorimetric method on washed erythrocytes was r= 0.987 (y = 1.299x – 63, n = 29). The correlation coefficient between assays on capillary and venous samples was r= 0.979 (y = 0.974x 174, n = 47). A cross-laboratory validation study was performed in 10 centers using glycerol-stabilized hemolysates with normal and reduced AChE activity. Samples were assayed in triplicate. The within- and between-laboratory CVs for samples with normal AChE activity (6,018 U/L) were 2.2 and 8.1, respectively. The new method was applied to a double-blind, placebo-controlled multicenter study of eptastigmine in Alzheimer patients and proved to be a simple, noninvasive, rapid, and reliable method for pharmacodynamic monitoring of this drug.

The effectiveness of cimetropii bromidum (10 or 20 mg i.v.) as premedication for upper gastro-intestinal tract endoscopy was examined and compared with that of placebo in a double-blind crossover study involving 160 patients. The drug effects were assessed from the degree of opening of the pyloric sphincter and the endoscopist's rating of drug performance. The study showed that the effects of cimetropii bromidum differed highly significantly (p < 0·0001) from those of placebo, on either count. No adverse effects were noted.

SummaryA study was carried out to evaluate the efficacy of two different doses of a new hypotonizing agent, cimetropium bromide, as a premedication for X-ray of the stomach and duodenum. Forty consecutive patients were allocated at random to two groups and treated intravenously in double-blind fashion with 5 mg or 10 mg cimetropium bromide. The drug was administered immediately after the first phase of an upper gastro-intestinal series had been completed. Duration of the drug-induced hypokinesia was recorded fluoroscopically. The hypotonizing effect was evaluated by measuring the diameters of the gastric antrum, duodenal bulb and loop on the pre-injection and post-injection radiographs. In both groups, the relaxant effect started promptly (within 1 minute of injection) and lasted for an average of 10 minutes, which was considered adequate for the study. There were no statistically significant differences between the two groups in relaxant activity. The treatments were scored arbitrarily as ‘excellent’ in 75% of the examinations after the 10 mg dose and in 60% after the 5 mg dose. The difference between the two groups was not significant. Side-effects were few, of mild entity and not dose-related.