In contrast, haloperidol showed a smaller overall impairment, on the first day, which had increased dramatically by the fourth day and was still marked on many measures after 48 hours of washout. This study predicted a clear difference between the two compounds in cognitive toxicity with repeated dosing in patients, which has been largely borne out, by subsequent clinical trials. Interestingly, despite being markedly impaired with haloperidol after 48 hours of washout, the volunteers reported no lowering of self-rated alertness CCI-779 mw compared with predosing, which is the opposite pattern to that described in the previous trial.

Inhibitors,research,lifescience,medical Despite this clear impairment with haloperidol 3 mg in the elderly, another trial in this population, which used a 2-mg dose in an attempt to avoid this extreme cognitive toxicity, found Inhibitors,research,lifescience,medical relatively little overall impairment.27 On two measures, haloperidol 2 mg was shown to be inferior to amisulpride 50 and 200 mg, the latter drug showing no impairment and some occasional Inhibitors,research,lifescience,medical signs of enhancement. In another trial in elderly volunteers, acute doses of moclobemide 100 and 300 mg were shown to produce little overall impairment and some

enhancement of memory processes compared with trazodone 150 mg, which produced widespread and marked impairment.28 Remacemide, a noncompetitive Af-methyl-D-aspartate (NMDA) antagonist under development for the treatment of epilepsy, was found to lead to dose-dependent cognitive impairment in acute doses up to 400 mg in a 5-way, placebo-controlled, crossover design in 16 young volunteers.29 Diazepam 10 mg was used as an internal control, and produced a similar Inhibitors,research,lifescience,medical range of impairments as remacemide 400 mg, though the profile of these impairments in terms of the magnitudes of actions on various aspects of function

was quite distinct. However, in subsequent repeated dosing trials, no Inhibitors,research,lifescience,medical effects of remacemide have been discovered, despite the doses being equivalent to therapeutically relevant equivalents in enzyme-activated patients.30 This suggests that, for some compounds, such as olanzapine mentioned previously, tachyphylaxis for cognitive impairment can occur with repeated dosing. The benzodiazepine antagonist flumazenil has been shown to reverse the effects of midazolam Metalloexopeptidase on cognitive function in healthy volunteers.31 Interestingly, despite this effect, when given alone in three infusions of 0.5, 2.5, and 5 mg, flumazenil produced a wide range of cognitive impairment, in a placebo-controlled, double -blind, crossover trial.32 Similar effects when flumazenil is administered to patients with Alzheimer’s disease (AD) will be reported in a later section.33 There is obvious interest in the cognitive effects of the opioids when used to treat cancer pain.