3-(1-dimethylaminoethyl)phenol and Alzheimer-Disease

A transdermal patch has been developed for the cholinesterase inhibitor rivastigmine. This study investigated the pharmacokinetics and pharmacodynamics of rivastigmine and NAP226-90, and compared drug exposure between patch and capsule administrations. This was an open-label, parallel-group study in Alzheimer's disease patients randomized to receive either capsule (1.5-6 mg Q12H, i.e., 3-12 mg/day) or patch (5-20 cm2) in ascending doses through four 14-day periods. The patch showed lower Cmax (ca. 30% lower at 20 cm2, 19.5 versus 29.3 ng/ml), longer tmax (8.0 versus 1.0 h), and greater AUC (ca. 1.8-fold at 20 cm2, 345 versus 191 ng x h/ml) compared with the 6 mg Q12H capsule dose, with markedly less fluctuation between peak and trough plasma levels (80% at 20 cm2 versus 620% at 1.5 mg Q12H). Plasma butyrylcholinesterase inhibition rose slowly after patch administration, whereas two distinct peaks were seen after capsule administration. Average exposure with the 10 cm2 patch was comparable to the highest capsule dose (6 mg Q12H, i.e., 12 mg/day).

Topics: Administration, Cutaneous; Administration, Oral; Aged; Alzheimer Disease; Benzylamines; Butyrylcholinesterase; Capsules; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Models, Biological; Phenethylamines; Phenols; Phenylcarbamates; Rivastigmine; Treatment Outcome

Rivastigmine patches are used for patients with Alzheimer's disease (AD), but little is known about the serum concentration of rivastigmine and its metabolite or clinical adherence in relation to skinfold thickness after rivastigmine patch application.. The aim of this study was to examine the association between rivastigmine and NAP 226-90 serum concentration and skinfold thickness and to determine the appropriate skinfold thickness for the use of rivastigmine patch in patients with AD.. Patients with AD who continuously used rivastigmine patches (4.6 mg/24 h, 5 cm. In total, 91 patients with AD (40 men and 51 women) participated in this study on skinfold thickness measurement. Among them, 27 patients were examined for rivastigmine and NAP 226-90 serum concentrations, with mean concentrations of 1.0 ± 0.6 ng/mL and 3.6 ± 3.6 ng/mL, respectively. The skinfold thickness in the subscapular area was significantly negatively correlated with the NAP 226-90 serum concentration (Spearman's rank correlation coefficient = - 0.47, P = .01). In addition, patients with AD and a subscapular skinfold thickness of ≥25 mm exhibited a significantly high risk of decreased Mini-Mental Status Examination score and nonadherence to a rivastigmine patch (odds ratio 3.00; 95% confidence interval = 1.076-8.366, P = .03).. Subscapular skinfold thickness was significantly negatively correlated with the NAP 226-90 serum concentration and may be considered an appropriate predictor of response and adherence to clinical application of a rivastigmine patch.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Female; Humans; Male; Middle Aged; Phenethylamines; Phenols; Rivastigmine; Skinfold Thickness

The aim of this small pilot study was to evaluate the association between plasma concentrations of rivastigmine and its metabolite, NAP 226-90, and cognitive function in patients with Alzheimer's disease (AD). Rivastigmine-treated AD patients, who had been maintained on a fixed regimen of twice daily rivastigmine (6 to 12 mg/d) for ≥6 months, were eligible for evaluation. The assessments included cognitive assessment screening instrument (CASI) and clinical dementia rating scale, conducted at baseline and at 6-month follow-up. The 9 subdomains of CASI at baseline and follow-up were analyzed in relation to the plasma concentrations of rivastigmine and NAP 226-90, as measured by capillary electrophoresis. Logistic regression was performed to adjust for age, gender, education level, apolipoprotein E ε4 genotype status, and baseline CASI score to investigate the association between plasma rivastigmine and NAP 226-90 concentrations and the cognitive response. The total sample consisted of 53 clinically diagnosed AD patients taking rivastigmine only at doses of 6 mg to 9 mg/d because of intolerability at 12 mg/d. Higher rivastigmine concentration was significantly associated with improved or preserved short-term memory and worsened abstraction/judgment (p < 0.05), but not with changes in other domains (p > 0.05). Higher NAP 226-90 concentration was significantly associated with worsened abstraction/judgment (p < 0.05), but not with changes in other domains. Higher plasma rivastigmine concentration was significantly associated with improved or preserved short-term memory but worsened abstraction/judgment. An optimal concentration of rivastigmine should be quantified for each patient because of differential cognitive responses.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cognition Disorders; Female; Follow-Up Studies; Humans; Male; Phenethylamines; Phenols; Phenylcarbamates; Pilot Projects; Rivastigmine; Taiwan

A simple and sensitive MEKC with UV detection was developed and validated for the simultaneous determination of acetylcholinesterase inhibitors including galantamine, rivastigmine and major metabolite NAP 226-90 in plasma. A sample pretreatment by liquid-liquid extraction with diethylether and subsequent quantification by MEKC was used. The optimum separation for these analytes was achieved in <10 min at 25 degrees C with a fused-silica capillary column of 30.2 cm x 50 microm id (effective length 20 cm) and a run buffer containing 25 mM Tris buffer (pH 5.0) with 160 mM sodium octanesulfonate, 20% ACN and 0.01% PVP as a dynamic coating to reduce analytes' interaction with the capillary wall. For sensitivity consideration regarding the determination of linearity, LOD, quantitation and monitoring drugs concentration in patients, the detection wavelengths for galantamine or rivastigmine and NAP 226-90 were set at 214 or 200 nm, respectively. One male volunteer (26-year-old) was orally administered a single dose of 4.5 mg rivastigmine (Exelon, Novartis) in capsule, and blood samples were drawn over a 12 h period for concentration-time profile study. The method was also successfully applied for monitoring galantamine or rivastigmine and its metabolite NAP 226-90 in 11 Alzheimer's disease patients' plasma after oral administration of the commercial products Reminyl (8 mg galantamine/capsule) or Exelon (3 mg rivastigmine/capsule), respectively.

Topics: Adult; Alzheimer Disease; Benzylamines; Buffers; Cholinesterase Inhibitors; Chromatography, Micellar Electrokinetic Capillary; Drug Monitoring; Galantamine; Humans; Male; Phenethylamines; Phenols; Phenylcarbamates; Phosphoric Acids; Reproducibility of Results; Rivastigmine; Sensitivity and Specificity; Solvents; Surface-Active Agents

It has been shown that combining memantine and a cholinesterase inhibitor, which each affect different neurotransmitter systems, may offer further improvements in efficacy over either treatment alone in patients with Alzheimer's disease. The present study was conducted to determine if memantine has any effects on the steady-state pharmacokinetics of rivastigmine in patients with mild to moderate Alzheimer's disease.. Rivastigmine-treated Alzheimer's disease patients who had been maintained on a fixed regimen of twice-daily rivastigmine for >or=2 months were eligible to enter the study. Sixteen patients (seven males and nine females, age range 64-88 years, weight range 51.8-104 kg) were enrolled in this open-label, crossover study, which consisted of a 28-day screening period, a 36-hour baseline period, and a 35-day combination treatment phase. The patients spent the baseline period and day 35 at the study centre, where plasma samples for pharmacokinetic evaluation were taken at specified time intervals over a 10-hour time period. In addition, 10-hour (evening pre-dose) memantine plasma samples were taken on days 21, 34 and 35.. The combination of memantine (10 mg twice daily) with rivastigmine (1.5-6 mg twice daily) was safe and well tolerated. At each dose level of rivastigmine, the area under the concentration-time curve (AUC) values of rivastigmine and its metabolite as well as the metabolite-to-parent AUC ratios were unaffected by co-administration of memantine, confirming the absence of a meaningful pharmacokinetic drug-drug interaction.. Under the study conditions, the extent of systemic exposure to rivastigmine and its metabolite NAP226-90 at steady state did not appear to be affected by concomitant administration of memantine.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Area Under Curve; Benzylamines; Cholinesterase Inhibitors; Cross-Over Studies; Excitatory Amino Acid Antagonists; Female; Humans; Male; Memantine; Middle Aged; Phenethylamines; Phenols; Phenylcarbamates; Rivastigmine