Chronic treatment with reboxetine by osmotic pumps facilitates its effect on extracellular noradrenaline and may desensitize alpha(2)-adrenoceptors in the prefrontal cortex.

1. This study investigated the effect of acute (2 days) and chronic (14 days) treatment with a selective inhibitor of noradrenaline uptake, reboxetine (10 mg kg(-1) day(-1)) by osmotic pumps, on extracellular noradrenaline and the sensitivity of alpha(2)-adrenoceptors in the prefrontal cortex of rats. 2. The effect of continuous infusion of reboxetine for 14 days on cortical extracellular noradrenaline was significantly higher (599% of vehicle levels) than after 2 days (263% of vehicle levels). 3. Brain concentrations of reboxetine after 2 and 14 days of infusion were 37.9+/-17.8 and 37.1+/-7.7 ng g(-1), respectively. 4. Reboxetine infused for 2 and 14 days significantly increased extracellular dopamine in the prefrontal cortex, to a similar extent (257 and 342% of vehicle levels, respectively), whereas extracellular 5-HT was not modified by either treatment. 5. Clonidine (10 and 30 microg kg(-1) i.p.) reduced cortical extracellular noradrenaline similarly in animals treated with reboxetine or vehicle for 2 days whereas the effects in rats infused with reboxetine for 14 days were markedly less than in vehicle-treated animals. 6. Clonidine (0.05 and 0.2 microM), infused through the dialysis probe into the prefrontal cortex, reduced cortical extracellular noradrenaline much less in rats treated with reboxetine for 14 days than in vehicle-treated animals. 7. Reboxetine's effect on extracellular noradrenaline in the prefrontal cortex was greater after chronic treatment and could be associated with desensitization of terminal alpha(2)-adrenoceptors that normally serve to inhibit noradrenaline release.

Long-Term Nicergoline Treatment of Mild to Moderate Senile Dementia : Results of a Multicentre, Double-Blind, Placebo-Controlled Study.

The efficacy and tolerability of nicergoline were evaluated in a long-term, double-blind, placebo-controlled trial. 108 patients, fulfilling DSM III-R criteria for mild to moderate senile dementia of degenerative, vascular or mixed origin, were selected from a pool of outpatients attending five Italian neurological centres and randomised to receive nicergoline 30mg twice daily (54 patients) or placebo (54 patients) for 12 months. Treatment efficacy on cognitive and behavioural performances was assessed by the Sandoz Clinical Assessment Geriatric scale (SCAG) and Mini Mental State Examination (MMSE), at baseline and after 3, 6, 9 and 12 months of treatment. Investigators and patients or caregivers provided a global evaluation of treatment outcome at study end. The efficacy analysis was carried out on 101 patients (51 nicergoline; 50 placebo) who completed the 12-month study. At study end, the SCAG total score and its clusters showed statistically significant improvement in the nicergoline-treated group compared with placebo-treated patients. The MMSE total score was maintained with nicergoline treatment. Global treatment evaluations, both by physician and patients, were consistently in favour of nicergoline (p < 0.001). Nicergoline was well tolerated; incidence of adverse events (7% in the nicergoline and 2% in the placebo group), withdrawals and haemodynamic changes were comparable with placebo.