An Overview of the Development of SDZ ENA 713, A Brain Selective Cholinesterase Inhibitor

Anand, Ravi; Hartman, Richard D.; Hayes, Peggy E.; Gharabawi, M.

doi:10.1007/978-1-4612-4116-4_35

Cited by 8 publications

(5 citation statements)

References 2 publications

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“…The results from this study show that the pharmacokinetics of donepezil are linear and stationary over a 28‐day course of once‐daily, oral evening administration. Unlike other cholinesterase inhibitors, such as tacrine [ 11], physostigmine [ 12] and rivastigmine [ 13], donepezil has a long mean half‐life and slow clearance. However, this slow clearance is unrelated to capacity‐limited metabolism.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration

Tiseo

Rogers

Friedhoff

1998

Brit J Clinical Pharma

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AimsThe primary objective of this study was to characterize the pharmacokinetics and pharmacodynamics of single daily doses of donepezil (5 and 10 mg) each evening for 28 consecutive days. A secondary objective was to measure the plasma protein binding of donepezil at steady state. Methods This was a double-blind, randomized, multiple-dose study in healthy male (n=13) and female (n=3) volunteers. Subjects were randomized to receive, once daily, either oral doses of 5 mg donepezil for 28 days or doses of 5 mg donepezil for 7 days followed by 10 mg donepezil for 21 days. All doses were administered in the evening. Donepezil concentrations and protein binding in plasma were determined by HPLC with UV detection and equilibrium dialysis, respectively. Inhibition of acetylcholinesterase (AChE) activity in red blood cell (rbc) membranes was assessed using a specific radioenzyme assay. Results The pharmacokinetics of donepezil were linear, dose proportional and stationary over the course of the study. Mean C max , t max , AUC , t D and V lz /F at steady state were 34.1 ng ml −1 , 3.0 h, 634.8 ng h ml −1 , 72.7 h, and 11.8 l kg −1 , respectively, for the 5 mg group and 60.5 ng ml −1 , 3.9 h, 1127.8 ng h ml −1 , 73.5 h and 11.6 l kg −1 , respectively, for the 10 mg group. Accumulation of the drug was observed for 14-21 days, until steady state was achieved. A direct consistent relationship was observed between donepezil plasma concentration and percentage rbc-AChE inhibition during each 24 h evaluation period, indicating no hysteresis in donepezil pharmacodynamics. The pharmacodynamic parameters, E min , E max and E ss , were 62.2%, 71.8% and 65.3%, respectively, for the 5 mg donepezil dose, and 74.7%, 83.6% and 77.8%, respectively, for the 10 mg donepezil dose. Donepezil was 95.6% bound to plasma protein at steady state. The binding was high capacity and low affinity, and neither concentration nor time dependent. Both dosage regimens were well tolerated; no clinically significant changes in laboratory or vital sign parameters were observed in any subject. Conclusions The measured pharmacokinetic and pharmacodynamic parameters for both 5 and 10 mg day −1 donepezil administered in the evening are in good agreement with previous results obtained with morning administration, indicating no time of dosing effect.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration

Tiseo

Rogers

Friedhoff

1998

Brit J Clinical Pharma

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“…Looking at the 6-months data one could say that patients treated with the active compound do not change significantly from the baseline determined at the begin ning of treatment (6 months earlier). As an example in a US study with ENA-713, patients given placebo for 26 weeks would deteriorate approximately 4 points on the ADAS-cog compared to only 0.3 in patients given 6-12 mg/day of the drug (29). The difference seen after 6 months between placebo-treated and drug treated groups seems to depend more on the deterioration of the placebo group (3-4 points) than on true additional improvement.…”

Section: Molecular Design Of New Cholinesterase Inhibitorsmentioning

confidence: 99%

From Molecular Structure to Alzheimer Therapy.

Giacobini

1997

Jpn.J.Pharmacol

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ABSTRACT-Clinical trials in the USA, Japan and Europe have confirmed the hypothesis that a steady state increase of acetylcholine resulting from cholinesterase inhibition in the brain results in an improve ment of cognitive function in mild to moderate Alzheimer disease (AD) patients. During the last decade, a systematic effort to develop a pharmacological treatment for AD has resulted in two drugs being registered for the first time in the USA and Europe for this specific indication. Both are cholinesterase inhibitors (ChEI). Based on these first positive results, several second generation ChEI are being developed. An ad ditional effect of certain ChEI is to maintain cognitive function at a constant level during a 6 months to one year period of treatment as compared to placebo. It is possible that the drug effect is one of slowing down cognitive deterioration. Comparison of clinical effects of 5 ChEI demonstrates a rather similar magnitude of improvement. For some drugs, this may represent a limit, while for others it may be possible to increase the benefit further. To maximize and prolong positive drug effects, it is important to start early and adjust the dosage during the treatment. Other strategies may involve combinations with other cholinergic drugs such as muscarinic or nicotinic agonists. A second important class of drugs which is being developed is that of muscarinic ml agonists. However, their clinical use is still limited by side effects. The increased knowledge and recognition of the beta-amyloid molecule as a central focus of AD pathology has strongly stimulated research with the hope of finding ways of influencing its processing and deposition. At this point, no product in this line of development has reached clinical trial level. Other pharmacological approaches are related to preventive and neuroprotective interventions (estrogens, anti-oxidants and anti-inflammatories). In conclusion, given the relatively short time of research in this field, results are encouraging.

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“…1,67 The results of the largest multi-center phase III trial involving over 2,600 Alzheimer patients are not yet available. 68 The early results of the 2,600 patient study suggest Exelon is a safe medication in AD patients, including those with physical ailment. 69 Whether rivastigmine has clinical benefit in this large study waits final reporting, however preliminary information suggests it showed significant cognitive improvement in AD patients.…”

Section: Rivastigmine (Exelon)mentioning

confidence: 99%

Current and the near future medications for Alzheimer's disease: What can we expect from them?

Shua-Haim¹,

Ross

1999

American Journal of Alzheimer's Disease

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An Overview of the Development of SDZ ENA 713, A Brain Selective Cholinesterase Inhibitor

Cited by 8 publications

References 2 publications

Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration

Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration

From Molecular Structure to Alzheimer Therapy.

Current and the near future medications for Alzheimer's disease: What can we expect from them?

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