Donepezil-treated patients with probable vascular dementia demonstrate cognitive benefits.
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Biomedical subjects
C A Perdomo
Publications and source records attributed to C A Perdomo.
Donepezil: tolerability and safety in Alzheimer's disease.
The tolerability and safety of donepezil HCI in patients with mild to moderate Alzheimer's disease (AD) were examined in an integrated analysis of phase II/III placebo-controlled trials. Patients with mild to moderately severe AD (n=1,920) were randomised to receive donepezil (n=1,291) or placebo (n=629). Adverse events, physical examinations and clinical laboratory tests were assessed. A high completion rate (79%) was achieved in these trials. Of the 1,291 patients receiving donepezil only, 142 (11%) withdrew because of an adverse event compared with 43 of the 629 (7%) placebo patients. The most common adverse events included nausea, diarrhoea, headache, insomnia, dizziness, rhinitis, vomiting, asthenia/fatigue and anorexia. Donepezil had no clinically significant effect on any laboratory evaluations and was not associated with hepatotoxicity. These results demonstrate that donepezil is well tolerated and has a favourable safety profile at clinically effective, once-daily doses of 5 mg and 10 mg.
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A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients.
OBJECTIVE: To examine the effects of donepezil compared with placebo on the preservation of function in patients with AD over a 1-year period. METHODS: This was a prospective, 54-week, double-blind, placebo-controlled, survival to endpoint study. Patients were required to have at entry: a diagnosis of probable AD (National Institute of Neurological and Communicative Disorders and Stroke criteria); Mini-Mental State Examination score of 12 to 20; Clinical Dementia Rating of 1 or 2; modified Hachinski ischemia score < or =4; and capability of performing 8 of 10 instrumental activities of daily living and 5 of 6 basic activities of daily living. Patients (n = 431) were randomized to placebo or donepezil (5 mg/day for 28 days, 10 mg/day thereafter). Outcome measures were the AD Functional Assessment and Change Scale, the Mini-Mental State Examination, and Clinical Dementia Rating scale. At each visit, investigators determined whether predefined criteria for clinically evident decline in functional status had been met. Patients who met the endpoint criteria were discontinued per protocol. RESULTS: Donepezil extended the median time to clinically evident functional decline by 5 months versus placebo. The probability of patients treated with donepezil remaining in the study with no clinically evident functional loss was 51% at 48 weeks, compared with 35% for placebo. The Kaplan-Meier survival curves for the two treatment groups were different (p = 0.002, log-rank test). CONCLUSIONS: Patients with AD continue to show detectable disease progression over time, but treatment with donepezil for 1 year was associated with a 38% reduction in the risk of functional decline compared with placebo.
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Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer disease.
BACKGROUND: Donepezil hydrochloride is a selective acetylcholinesterase inhibitor approved for the symptomatic treatment of mild to moderately severe Alzheimer disease (AD). Controlled clinical trials of up to 24 weeks have demonstrated that donepezil treatment (5 and 10 mg/d) significantly improves cognition and global function. OBJECTIVE: To investigate the long-term benefits of donepezil treatment in patients with AD. DESIGN: Multicenter, open-label, 144-week extension of 2 US phase 3, double-blind, placebo-controlled clinical trials: a 15-week study (12 weeks of treatment followed by a 3-week placebo washout) and a 30-week study (24 weeks of treatment followed by a 6-week placebo washout). INTERVENTIONS: All patients (N = 763) initially received donepezil, 5 mg/d, for 6 weeks, after which an increase to 10 mg/d was encouraged. MEASURES: Primary efficacy measures were the Alzheimer's Disease Assessment Scale-cognitive subscale and the Clinical Dementia Rating-Sum of the Boxes. RESULTS: After the shorter 3-week placebo washout, donepezil-associated benefits remained above original baseline values for an additional 24 weeks of open-label treatment. Benefits on Alzheimer's Disease Assessment Scale-cognitive subscale scores for patients who received 10 mg/d in the double-blind study were evident compared with the other groups for 108 weeks of open-label treatment. In contrast, donepezil-associated benefits were lost after the 6-week placebo washout, and scores decreased below original baseline values for all patient groups. Although scores improved relative to the new open-label study baseline scores after drug use was restarted, patients remained below original baseline values. The most common adverse events were associated with the nervous and digestive systems and were generally mild and transient; 17% of patient discontinuations were associated with adverse events. CONCLUSIONS: Donepezil is an effective and safe drug for the long-term symptomatic treatment of mild to moderately severe AD for up to 144 weeks (2.8 years), and sustained treatment may confer some advantages.
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A randomized, double-blind, placebo-controlled study of the efficacy and safety of donepezil in patients with Alzheimer's disease in the nursing home setting.
OBJECTIVES: To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimer's disease (AD) residing in nursing home facilities. DESIGN: Twenty-four-week, randomized, multicenter, parallel-group, double-blind, placebo-controlled trial. SETTING: Twenty-seven nursing homes across the United States. PARTICIPANTS: Two hundred eight nursing home patients with a diagnosis of probable or possible AD, or AD with cerebrovascular disease; mean Mini-Mental State Examination (MMSE) score 14.4; mean age 85.7. MEASUREMENTS: The primary outcome measure was the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). Secondary efficacy measures were the Clinical Dementia Rating (Nursing Home Version)-Sum of the Boxes (CDR-SB), MMSE, and the Physical Self-Maintenance Scale (PSMS). Safety was monitored by physical examinations, vital signs, clinical laboratory tests, electrocardiograms (ECGs), and treatment-emergent adverse events (AEs). RESULTS: Eighty-two percent of donepezil- and 74% of placebo-treated patients completed the trial. Eleven percent of donepezil- and 18% of placebo-treated patients withdrew because of AEs. Mean NPI-NH 12-item total scores improved relative to baseline for both groups, with no significant differences observed between the groups at any assessment. Mean change from baseline CDR-SB total score improved significantly with donepezil compared with placebo at Week 24 (P < .05). The change in CDR-SB total score was not influenced by age. Differences in mean change from baseline on the MMSE favored donepezil over placebo at Weeks 8, 16, and 20 (P < .05). No significant differences were observed between the groups on the PSMS. Overall rates of occurrence and severity of AEs were similar between the two groups (97% placebo, 96% donepezil). Gastrointestinal AEs occurred more frequently in donepezil-treated patients. In general, AEs were similar in older and younger donepezil-treated patients, with the majority of patients experiencing only AEs that were transient and mild or moderate in severity. Weight loss was reported as an AE more frequently in older patients, although a loss at last visit of >or=7% of screening weight occurred at the same rate in older and younger patients (9% of donepezil- and 6% of placebo-treated patients). No significant differences between groups in vital sign changes, bradycardia, or rates of clinically significant laboratory or ECG abnormalities were observed. CONCLUSION: Patients treated with donepezil maintained or improved in cognition and overall dementia severity in contrast to placebo-treated patients who declined during the 6-month treatment period. The safety and tolerability profile was comparable with that reported in outpatient studies of donepezil. These findings also suggest that advanced age, comorbid illnesses, and high concomitant medication usage should not be barriers to donepezil treatment. Given the apparent improvement in behavior in the placebo group, and the high use of concomitant medications in both groups, the impact of donepezil on behavior in the nursing home setting is unresolved and merits further investigation. In summary, effects on cognition, overall dementia severity, and safety and tolerability findings are consistent with previous findings in outpatients and support the use of donepezil in patients with AD who reside in nursing homes.
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A lipid A analog, E5531, blocks the endotoxin response in human volunteers with experimental endotoxemia.
BACKGROUND: Endotoxin (lipopolysaccharide [LPS]) has been associated with sepsis and the high mortality rate seen in septic shock. The administration of a small amount of LPS to healthy subjects produces a mild syndrome qualitatively similar to that seen in clinical sepsis. We used this model to test the efficacy of an endotoxin antagonist, E5531, in blocking this LPS-induced syndrome. METHODS: In a placebo-controlled, double-blind study, we randomly assigned 32 healthy volunteers to four sequential groups (100, 250, 500, or 1000 microg of E5531). Each group of eight subjects (six assigned to E5531, two assigned to placebo) received a 30-min intravenous infusion of study drug. LPS (4 ng/kg) was administered to all subjects as an intravenous bolus in the contralateral arm at the midpoint of the infusion. Symptoms, signs, laboratory values, and hemodynamics (by echocardiogram) were evaluated at prospectively defined times. RESULTS: In subjects receiving placebo, LPS caused headache, nausea, chills, and myalgias. E5531 led to a dose-dependent decrease in these symptoms that was statistically significant (p < .05) except for myalgias. The signs of endotoxemia (fever, tachycardia, and hypotension) were consistently inhibited at the three higher doses (250, 500, and 1000 microg, p < .05). Tumor necrosis factor-alpha and interleukin-6 blood levels were both lower in those who received E5531 (p < .0001). The C-reactive protein level and white blood cell count response were decreased at all doses (p < .0001). The hyperdynamic cardiovascular state (high cardiac index and low systemic vascular resistance) associated with endotoxin challenge was significantly inhibited at the higher doses of E5531. CONCLUSIONS: E5531 blocks the symptoms and signs and cytokine, white blood cell count, C-reactive protein, and cardiovascular response seen in experimental endotoxemia. This agent is a potent inhibitor of endotoxin challenge in humans and may be of benefit in the prevention or treatment of sepsis and septic shock.
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Metabolism and elimination of 14C-donepezil in healthy volunteers: a single-dose study.
AIM: The aim of this study was to investigate the metabolism and elimination of donepezil HCl in humans, following the administration of a single 5 mg (liquid) oral dose containing a mixture of unlabelled and 14C-labelled donepezil. METHODS: This was an open-label, non-randomized study in healthy male volunteers (n = 8). Characterization of donepezil metabolism and elimination was performed by analysing blood, urine and faecal samples collected over a 10-day period following drug administration. Each collected sample was assayed for total radioactivity, and aliquots from specified time-points and/or pooled samples were assayed for the presence of donepezil metabolites by thin-layer chromatography (TLC). Donepezil concentrations in plasma were determined by HPLC. RESULTS: Recovery of radioactivity in subject samples averaged 72% of the administered dose. Recovery of the administered dose in urine (57%) was significantly greater than that recovered in faeces (15%). Unchanged donepezil accounted for the largest component of the recovered dose in each matrix. Three metabolic pathways were identified: (i) O-dealkylation and hydroxylation to metabolites M1 and M2, with subsequent glucuronidation to metabolites M11 and M12; (ii) hydrolysis to metabolite M4; and (iii) N-oxidation to metabolite M6. In plasma, the parent compound accounted for about 25% of the dose recovered during each sampling period, as well as of the cumulative dose recovered. The recovered residue showed higher levels of the hydroxylated metabolites M1 and M2 than of their glucuronide conjugates M11 and M12, respectively. In urine, the parent compound accounted for 17%, on average, of the dose recovered from each pooled sample, as well as of the total recovered dose. The major metabolite was the hydrolysis product M4, followed by the glucuronidated conjugates M11 and M12. In faeces, the parent compound also predominated, although it accounted for only 1%, of the recovered dose. A large percentage of the radioactivity in faeces consisted of unidentified very polar metabolites, which were retained at the TLC origin. Of the extracted metabolites, the hydroxylation products M1 and M2 were the most abundant, followed by the hydrolysis product M4 and the N-oxidation product M6. CONCLUSIONS: Donepezil is hepatically metabolized and the predominant route for the elimination of both parent drug and its metabolites is renal, as 79% of the recovered dose was found in the urine with the remaining 21% found in the faeces. Moreover, the parent compound, donepezil, is the predominant elimination product in urine. The major metabolites of donepezil include M1 and M2 (via O-dealkylation and hydroxylation), M11 and M12 (via glucuronidation of M1 and M2, respectively), M4 (via hydrolysis) and M6 (via N-oxidation).
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Concurrent administration of donepezil HCl and cimetidine: assessment of pharmacokinetic changes following single and multiple doses.
AIM: The aim of this study was to examine the pharmacokinetics of donepezil HCl and cimetidine separately, and in combination, following administration of multiple oral doses. METHODS: This was an open-label, randomized, three-period crossover study in healthy male volunteers (n=19). During each treatment period, subjects received single daily doses of either donepezil HCl (5 mg), cimetidine (800 mg), or a combination of both drugs for 7 consecutive days. Pharmacokinetic comparisons were made between groups for the day 1 and day 7 profiles. Each treatment period was followed by a 3-week, drug-free washout period. RESULTS: On both day 1 and day 7, a statistically significant difference was observed between the donepezil and the donepezil + cimetidine groups in terms of the Cmax and AUC(0-24) values for donepezil. The combination group had an 11-13% greater Cmax and a 10% greater AUC(0-24) than the donepezil-only group. No significant difference was observed between the tmax of the two treatment groups on day 1, and no significant differences in tmax, t1/2 or the rate of drug accumulation (RA) were observed between the groups on day 7. Cimetidine pharmacokinetics were essentially unchanged by co-administration of the two drugs. The donepezil + cimetidine treatment group had a 20% greater maximum cimetidine concentration (Cmax) than the cimetidine-only group (P= 0.001) on day 1, but not on day 7, and no difference was observed in any of the other pharmacokinetic parameters examined. CONCLUSIONS: Co-administration of donepezil HCl (5 mg) and cimetidine (800 mg) did not produce clinically significant changes in the pharmacokinetic profiles of either drug.
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Concurrent administration of donepezil HCl and ketoconazole: assessment of pharmacokinetic changes following single and multiple doses.
AIM: The aim of this study was to examine the pharmacokinetics of donepezil HCl and ketoconazole separately, and in combination, following administration of single and multiple oral doses. METHODS: This was an open-label, randomized, three-period crossover study in healthy volunteers (n=21). During each treatment period, subjects received single daily doses of either donepezil HCl (5 mg), ketoconazole (200 mg), or a combination of both drugs for 7 consecutive days. Pharmacokinetic comparisons were made between treatment groups for the day 1 and day 7 profiles. Each treatment period was followed by a 3-week, drug-free washout period. RESULTS: On both day 1 and day 7, a statistically significant difference was observed between the donepezil and the donepezil + ketoconazole treatment groups in terms of Cmax and AUC(0-24) of donepezil. The concurrent administration of both drugs resulted in a 12% greater Cmax (9.5 ng ml(-1) versus 8.4 ng ml(-1); P=0.01) and a 12% greater AUC(0-24) (135.2 ng h ml(-1) versus 118.7 ng h ml(-1); P=0.001) than donepezil alone on day 1, and a 26.8% greater Cmax (37.7 ng ml(-1) versus 27.6 ng ml(-1); P < 0.0001) and a 26.4% greater AUC(0-24) (680.9 ng h ml(-1) versus 501.0 ng h ml(-1); P<0.0001) than donepezil alone on day 7. In contrast, ketoconazole plasma concentrations were unaffected by the concurrent administration of donepezil, and there were no statistically significant differences in ketoconazole pharmacokinetics when ketoconazole administered alone was compared with ketoconazole administered with donepezil. CONCLUSIONS: The concurrent administration of ketoconazole and donepezil produces no change in ketoconazole plasma concentrations, but a statistically significant change in donepezil plasma concentrations. These observed changes, which are smaller than those produced by ketoconazole for other agents sharing the CYP-3A4 pathway, are most likely the result of donepezil also being metabolized by CYP-2D6, as well as its slow rate of clearance from plasma.
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Concurrent administration of donepezil HCl and digoxin: assessment of pharmacokinetic changes.
AIM: The aim of this study was to examine the pharmacokinetics of donepezil HCl and digoxin separately, and in combination, following administration of single oral doses. Changes in cardiac conduction parameters following drug administration were also assessed. METHODS: This was an open-label, randomized, three-period crossover study in healthy male volunteers (n=12). During each treatment period, subjects received a single dose of either donepezil HCl (5 mg), digoxin (0.25 mg), or a combination of both drugs. Each treatment period was followed by a 2-week, drug-free washout period. RESULTS: All 12 volunteers completed the study without incident. No statistically significant differences in donepezil pharmacokinetics (Cmax, tmax, AUC(0-120), AUC(0-infinity) or t1/2) were observed when donepezil administered alone was compared with donepezil administered in combination with digoxin. Similarly, no statistically significant differences in digoxin pharmacokinetics were observed when digoxin was administered alone or in combination with donepezil. No clinically relevant changes in cardiac conduction (lead II ECG) were observed in any subject during any treatment period. CONCLUSIONS: Co-administration of single doses of donepezil HCl (5 mg) and digoxin (0.25 mg) produced no changes in the pharmacokinetic profile of either drug. In addition, co-administration produced no changes in cardiac conduction parameters during the 24 h of telemetry monitoring following drug administration.
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An evaluation of the pharmacokinetics of donepezil HCl in patients with impaired hepatic function.
AIM: The aim of this study was to evaluate the pharmacokinetic profile of donepezil HCl (5 mg) in patients with impaired hepatic function, following the administration of single oral doses. METHODS: This was an open-label, non-randomized study comparing the pharmacokinetic profile of donepezil in male volunteers with chronic compensated cirrhosis of the liver (n = 10) to that in healthy age- and sex-matched controls (n = 10). Each subject received a single 5 mg oral dose of donepezil. Blood samples for pharmacokinetic analyses were taken at specified intervals up to 120-h post-dose. Concentrations of donepezil in plasma were determined by HPLC with UV detection. RESULTS: No statistically significant differences in donepezil pharmacokinetics were observed between hepatically impaired patients and normal subjects, with the exception of Cmax. The hepatically impaired patients showed a statistically significant, but not clinically significant, higher mean Cmax value of 6.6 ng ml(-1) compared with the control group, which had a mean Cmax value of 4.8 ng ml(-1) (P=(0.022). This represented an increase of 37.5%. The observed changes in AUC values were smaller and not statistically different. The AUC(0-120) and AUC(0-infinity) were 7% and 21% larger in the hepatically impaired patients than in the normal subjects, respectively, although clearance and volume of distribution were almost identical in the two groups. The t1/2 increased by 20%, but this change was also not statistically significant. Donepezil was equally well tolerated by all subjects. CONCLUSIONS: This study demonstrates that compromised hepatic function does not produce clinically significant changes in the pharmacokinetics of donepezil following single-dose administration. These results suggest that the administration of donepezil to patients with hepatic disease in clinical practice should not require any dosing modifications.
Administration, Oral↗
Etodolac, aspirin, and gastrointestinal microbleeding.
The effects of etodolac, a new nonsteroidal anti-inflammatory drug, on gastrointestinal (GI) microbleeding were quantitatively assessed in two studies in healthy adult men. The first was a two-group, open-label, parallel comparison of etodolac, 600 mg/day, aspirin, 2600 mg/day, and placebo in 20 subjects; the second was a four-group, double-blind, parallel comparison of etodolac, 600, 800, and 1200 mg/day, aspirin, 2600 mg/day, and placebo in 41 subjects. Subjects in both studies received a single-blind placebo on days 1 through 7, either etodolac or aspirin on days 8 through 14, and a single-blind placebo on days 15 through 19. GI blood loss (milliliters per day) was estimated by the radiolabeled (51Cr) erythrocyte method and was based on daily radioactivity counts of stool specimens and regression-estimated daily blood radioactivity. Etodolac, 600 mg/day, induced no significant GI blood loss at any time during the experiments, nor was there significant blood loss after 800 and 1200 mg/day in experiment 2. Blood loss was noted after aspirin in both.
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Gastrointestinal microbleeding associated with the use of etodolac, ibuprofen, indomethacin, and naproxen in normal males.
Etodolac, a nonsteroidal antiinflammatory and analgesic drug, was used in a randomized, parallel group, open-label design study, with stool analysis conducted in a blind fashion, to compare its effect in normal men in doses of 400 mg (N = 11) and 600 mg (N = 12) b.i.d. on gastrointestinal microbleeding with that of 600 mg ibuprofen, q.i.d. (N = 12), 50 mg indomethacin in the morning, 50 mg at noon, and 100 mg h.s. (N = 9), and 375 mg naproxen b.i.d. (N = 9). Etodolac was given at about 2 1/2 and 3 1/2 times the mean effective dose used for treating patients with rheumatoid arthritis. The other drugs were given at their manufacturers' maximum recommended doses. Lead-in placebo was given for one week, active drug for one week, and washout placebo for one week. Fecal blood loss was measured by the 51Cr-tagged red cell method, and was averaged over days 4-7 (baseline), 11-14 (treatment period), and 17-20 (washout). The mean increase in blood loss for the treatment period for the 400 mg etodolac b.i.d. group (0.13 ml) and 600 mg etodolac b.i.d. group (0.10 ml) was significantly less (P = 0.001) than the corresponding values for ibuprofen (1.14 ml), indomethacin (1.20 ml), and naproxen (0.87 ml). There was no tendency for greater blood loss at higher doses of etodolac. Etodolac at doses in excess of the mean effective dose in osteoarthritis and rheumatoid arthritis caused significantly less microbleeding in normal male volunteers during the seven-day treatment period than the other drugs tested, and not clinically more than that occurring during baseline placebo.
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