Pharmacodynamics of donepezil

Protocol The study was of a double-blind, randomized, placebo-controlled, single-dose, sequential-group design. Donepezil was administered in single oral doses according to an ascending-dose scheme.

The selection of doses 0. Groups of eight subjects were assigned to each dose level. Within each dose group, two subjects were randomized to receive placebo and six to receive donepezil. Progression to the next higher dose was contingent upon demonstration that the previous dose was well tolerated.

Baseline measurements were taken on study day 1 and the study medication was taken on study day 2. The trial was blinded by using a standard dose of three tablets per patient. The dose consisted of donepezil 0. The tablets were taken with ml of tap water after an 8-h fast. Subjects stayed at the investigational site for an additional 6 days until all of the follow-up assessments had been completed.

During this time, they abstained from caffeine-containing beverages, and physical exertion was limited to normal walking. Sample collection and analysis Venous blood samples for the measurement of donepezil concentrations and AChE activity were collected at min intervals for the first 4 h post-dose, and then at 6, 8, 12, 18, 24 and 36 h.

Thereafter, blood samples were taken once daily 48, 72, 96 and h post-dose. A final sample was taken on day 8 h. Samples were placed on ice immediately upon collection. Plasma donepezil concentrations were measured using a specific and sensitive high-performance liquid chromatography HPLC method with ultraviolet UV detection [ 17 ].

The lowest quantifiable concentration was 2. Pharmacokinetic analysis Model-independent pharmacokinetic parameters were determined using standard techniques. The peak plasma concentration Cmax and the time at which the peak concentration occurred tmax were determined by inspection of individual subject data. For subjects with more than one peak, tmax was defined as the time at which the highest peak occurred. If the multiple peaks were the same height, then tmax was defined for the first peak.

The slope of the terminal disposition phase was calculated from the first time point at which there was no systematic deviation from log-linear decline in plasma concentration to the last quantifiable measurement. The area under the plasma concentration—time curve AUC , for the time t at which the final measurable concentration was obtained AUC 0—t , was calculated by the linear trapezoidal rule.

Pharmacodynamic assessments The pharmacodynamic activity of donepezil was examined by measuring AChE activity in peripheral erythrocyte membranes rbc-AChE taken from the samples used for the pharmacokinetic determinations. After 30 s, the hydrolytic product was extracted into a scintillation cocktail and total radioactivity was counted.

The curves were fit using a third-order polynomial equation. The inter-day precision of this assay was 7. None of the subjects had clinical evidence of gastrointestinal, renal, respiratory, endocrine, haematological, neurological, psychiatric or cardiovascular system abnormalities.

Subjects who had a known or suspected history of alcohol or drug misuse, or a positive urine drug screen, were excluded from entry, as were those who had donated blood within 1 month of study commencement. Patients who were smokers or who were taking products containing nicotine were also excluded. The study was conducted in accordance with the principles stated in the Declaration of Helsinki and the US Code of Federal Regulations. All subjects gave written informed consent prior to study screening.

Protocol This was a randomized, double-blind, multiple-dose study. Subjects were admitted to the study site at least 12 h prior to drug administration. A urine sample for drug screening was collected on admission. Subjects were provided with a standard supper 4 h before dose administration, after which an absolute fast from food and fluids except water was maintained.

The first dose of donepezil was administered with ml of tap water at Fasting continued until the following morning when breakfast was served, 8 h after drug administration. After breakfast, the standard meal schedule for the study site was followed. Drug administration continued at Each blinded dose of donepezil consisted of two tablets.

To minimize reactions to acute, extensive inhibition of AChE, all subjects initially received one 5 mg donepezil tablet and one matching placebo tablet. After 7 days, patients randomized to the 10 mg dose received two 5 mg donepezil tablets for the remaining 21 days of the study.

The subjects stayed at the study centre as in-patients for a total of 37 days in order to ensure compliance with the protocol. During this period they avoided caffeine-containing foods or beverages and abstained from physical activity other than normal walking. None of the subjects had received any prescription drugs for at least 1 month prior to entering the trial.

Over-the-counter products and alcohol consumption were prohibited from 72 h prior to admission until the end of the treatment period. Sample collection and analysis Venous blood samples for analytical determinations were collected in 7 ml evacuated, heparinized tubes, at the following time-points: This same time course for sample collection was repeated on dose administration days 7, 14, 21 and 28 to complete the profile.

After the final dose day 28 , additional samples were collected at 48, 72, , and h day Pre-dose samples were taken immediately prior to drug administration on all dose administration days. Blood samples for protein binding studies were collected in 10 ml, heparinized, evacuated tubes, immediately prior to administration of the final dose day 28 and at 4, 12, 24, 72, and h day 35 afterwards.

Following the removal of plasma for donepezil measurements, the white blood cell and platelet layer and the top 3 mm of rbc were removed from the same tube, using a Pasteur pipette. These cells were used to measure rbc-AChE activity. Plasma concentrations of donepezil HCl were measured by a specific and sensitive high-performance liquid chromatography HPLC method with UV detection nm [ 9 ].

Protein binding was determined by equilibrium dialysis and rbc-AChE activity was measured using a specific and sensitive radioenzyme assay [ 10 ], with pre-treatment baseline activity values used to calculate percentage inhibition of activity in post-treatment samples. Tacrine disposition was maintained with age, and area under the concentration-time curve and clearance in old rats were similar to those in young rats for all drugs tested as was bioavailability.

Enhanced cholinergic-mediated behaviors such as tremor, hypothermia, salivation, and lacrimation were also observed in the old rats, which could not be accounted for by a similar magnitude of change in pharmacokinetics.

A decrease in expression of muscarinic acetylcholine receptor subtype 2 detected in old rat brains was postulated to play a role.

Greater age effects in both pharmacokinetics and pharmacodynamics of donepezil and tacrine were seen in previous studies with Fischer rats, indicating a potential risk in overreliance on this rat strain for aging studies. Introduction The world population is aging at an alarming rate with the number of people aged 60 years and older projected to triple from to , reaching nearly 2 billion United Nations, World Population Ageing: Elderly individuals, having an increased vulnerability to disease, consume a disproportionately larger share of medicines compared with any other age group.

Changes in pharmacological response are known to occur with aging McLean and Le Couteur, ; Hilmer, , and it is vital to understand and preferably predict and manage them to reduce incidents of adverse drug events or states of poor efficacious response. The effect of age on pharmacokinetics has been extensively covered by various reviews Cusack ; McLean and Le Couteur, ; Turnheim, ; Klotz The decline in glomerular filtration rate with aging is probably the most influential change, affecting excretion of most drugs.

Cytochrome P enzymes involved in phase I metabolism have shown some dysregulation with age with varying trends in activity reported. Phase II enzymes involved in conjugation reactions, in contrast, are reportedly maintained with aging.

Pharmacodynamic changes with age are less clearly elucidated compared with pharmacokinetic changes. Investigations on pharmacodynamic changes should measure drug concentrations in blood or plasma to ensure that sensitivity alterations are not due to pharmacokinetics. Elderly individuals are generally more sensitive to pharmacotherapy although bidirectional pharmacodynamic alterations have been observed Mangoni and Jackson, The central nervous system is especially vulnerable with aging and centrally acting drugs consistently shown to produce sensitized reactions in the elderly independent of pharmacokinetic changes include benzodiazepines midazolam , opioids morphine , and anticholinergic tricyclic antidepressants imipramine and amitriptyline Albrecht et al.

Tags: were to buy xanax hydrocodone in oxycodone zoloft treats depression cheap prozac online no prescription hydrocodone without tylenol in it