Tolerability of ORM-12741 and effects on episodic memory in patients with Alzheimer's disease.

INTRODUCTION: ORM-12741 is a novel selective antagonist of alpha-2C adrenoceptors. This trial evaluated the safety and efficacy of ORM-12741 in patients with Alzheimer's disease (AD). METHODS: A randomized, double-blind, placebo-controlled, exploratory phase 2a trial was conducted in 100 subjects with AD and neuropsychiatric symptoms. Participants were randomized to receive one of two flexible doses of ORM-12741 (30-60 mg or 100-200 mg) or placebo b.i.d. for 12 weeks in addition to standard therapy with cholinesterase inhibitors. Efficacy was assessed primarily with the Cognitive Drug Research (CDR) computerized assessment system and secondarily with the Neuropsychiatric Inventory (NPI). RESULTS: A statistically significant treatment effect was seen in one of the four primary CDR system end points, Quality of Episodic Memory (P = .030; not adjusted for multiple comparisons), favoring ORM-12741 over placebo. NPI caregiver distress scores also favored ORM-12741 (P = .034). ORM-12741 was well tolerated. DISCUSSION: This is the first clinical trial providing evidence on an acceptable safety profile for ORM-12741 in patients with AD and neuropsychiatric symptoms. In addition, the trial provided hints of potential therapeutic benefit, primarily on episodic memory, in this patient population.

Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa when administered four or five times daily.

OBJECTIVES: To compare plasma levodopa concentrations after repeated doses of levodopa/carbidopa/entacapone (LCE) and levodopa/carbidopa (LC). METHODS: Open-label, randomized, two-period, active-controlled, cross-over study with four dosing regimens: groups I and II (healthy volunteers and Parkinson's disease patients) received levodopa 100 mg or 150 mg four times daily, respectively, and groups III and IV (healthy volunteers) received the same strengths of levodopa five times daily. Pharmacokinetic (PK) parameters determined for levodopa included Cmin, Cmax, Cmax - Cmin, AUC, t(1/2), and tmax. RESULTS: In healthy volunteers and PD patients, mean trough levels (Cmin), Cmax, and AUC of levodopa were, in general, significantly higher during LCE compared to LC administration. Compared to Cmin, Cmax, and AUC, differences between the treatments in variability of levodopa concentrations (Cmax - Cmin) were less consistent. CONCLUSIONS: The present results on the differences in levodopa PK between LCE and LC provide a basis to evaluate the relationship of levodopa PK and the induction of motor complications in an on-going study in early Parkinson's disease using similar dosing regimens.

Effect of the novel anxiolytic drug deramciclane on cytochrome P(450) 2D6 activity as measured by desipramine pharmacokinetics.

BACKGROUND: In vitro findings have indicated that the novel anxiolytic drug, deramciclane, is an inhibitor of the cytochrome P(450) (CYP) 2D6 enzyme and co-administration of deramciclane and the CYP2D6 probe drug desipramine is possible in clinical practice. OBJECTIVE: To evaluate the effects of deramciclane on CYP2D6 activity as measured by desipramine pharmacokinetics and pharmacodynamics using paroxetine as a positive control for CYP2D6 inhibition. METHODS: Fifteen healthy subjects received either 60 mg deramciclane, 20 mg paroxetine or matched placebo for 8 days in randomized order in this double-blind, cross-over study. On day 8 of each study phase, the subjects received a 100-mg single dose of desipramine. Desipramine and its CYP2D6-dependent metabolite, 2-OH-desipramine, concentrations were measured for 240 h. Measurement of secretion of saliva, Visual Analogue Scale assessment of dryness of mouth and tiredness were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane or paroxetine co-administration with desipramine. RESULTS: Repeated administration of deramciclane doubled the AUC of desipramine ( P<0.001), while paroxetine caused a 4.8-fold increase in the AUC of desipramine ( P<0.001). Significant correlations were observed with paroxetine (r(s)=0.84, P<0.001) and deramciclane (r(s)=0.51, P=0.0498) concentrations and the magnitude of increase of desipramine AUC. Both deramciclane and paroxetine decreased the formation of 2-OH-desipramine in the first-pass phase. The AUC ratio of 2-OH-desipramine/desipramine was decreased by 39% ( P<0.001) by deramciclane and by 74% ( P<0.001) by paroxetine. There were no changes in the secretion of saliva during co-administration of desipramine with deramciclane compared with placebo. CONCLUSION: Although deramciclane seems to be a weaker inhibitor of CYP2D6 than paroxetine, dose adjustment of drugs metabolized by CYP2D6 may be needed when used concomitantly with deramciclane.

Effect of the novel anxiolytic drug deramciclane on the pharmacokinetics and pharmacodynamics of the CYP3A4 probe drug buspirone.

RATIONALE: Preliminary in vitro findings indicated that the novel anxiolytic drug, deramciclane is a substrate for the cytochrome P(450) (CYP) 3A4 isoenzyme. Moreover, its co-administration with buspirone, another anxiolytic drug, is likely in clinical practice. OBJECTIVES: The primary objective of the present study was to evaluate the in vivo effects of deramciclane on CYP3A4 activity as measured by buspirone pharmacokinetics. The secondary objective was to study the possible pharmacodynamic interaction between these two anxiolytic drugs. METHODS: Sixteen healthy subjects received 60 mg deramciclane or matched placebo for 8 days in this randomized, double-blind, cross-over study. On day 8 of both phases, the subjects received a 20-mg single dose of buspirone. Buspirone and its active metabolite, 1-pyrimidylpiperazine (1-PP), concentrations were measured for 24 h. Pharmacodynamic testing and measurement of plasma prolactin concentrations were carried out on day 7 and day 8 to assess the pharmacodynamic consequences of deramciclane and buspirone co-administration. RESULTS: Repeated administration of deramciclane had no effect on CYP3A4 activity as measured by buspirone pharmacokinetics. However, deramciclane administration caused an inhibition of the further, not CYP3A4-dependent, metabolism of 1-PP as evidenced by 84% increase in the AUC ( P<0.001) and 20% increase in the elimination half-life ( P=0.0012) of 1-PP. Deramciclane did not potentiate the buspirone-induced increase in prolactin secretion. No significant differences were found in the psychomotoric testing or the subjective maximum sedation between the deramciclane phase and the placebo phase, either before or after buspirone administration. Of 16 subjects, 5 experienced dizziness during both study phases. CONCLUSION: Deramciclane does not inhibit CYP3A4 activity as measured by buspirone pharmacokinetics, and there were no indications of relevant pharmacodynamic interaction after multiple doses of deramciclane and a single dose of buspirone.