BACKGROUND: The acetylcholinesterase inhibitor donepezil is administered as a treatment for Alzheimer's disease (AD). However, the appropriate donepezil dosage is still a matter of debate. METHODS: Forty AD patients receiving 10 mg/day of donepezil were randomly divided into four groups based on the time of plasma and cerebrospinal fluid (CSF) sampling: 6 h (n = 5), 12 h (n = 12), 18 h (n = 6) and 24 h (n = 17) after donepezil administration. High-performance liquid chromatography measured the donepezil concentration in plasma samples and CSF samples collected at 4-time points. RESULTS: Plasma and CSF levels among the groups were not significantly different. Conversely, the CSF/plasma donepezil concentration ratio considerably increased in the 24 h group compared to the 6 h (p < 0.005) and 12 h (p < 0.05) groups. CONCLUSION: The measurement of the CSF/plasma donepezil concentration ratio could be used to better evaluate the optimal dose of donepezil.
- MeSH
- acetylcholinesterasa MeSH
- Alzheimerova nemoc * krev mozkomíšní mok farmakoterapie MeSH
- cholinesterasové inhibitory * krev mozkomíšní mok terapeutické užití MeSH
- donepezil * krev mozkomíšní mok terapeutické užití MeSH
- indany terapeutické užití farmakologie MeSH
- lidé MeSH
- piperidiny farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
Although some studies have described the pharmacokinetics and pharmacodynamics of donepezil in the peripheral compartment, studies focused on drug transport across the blood-brain barrier are still very rare. To our knowledge, the fluctuation in the cerebrospinal fluid concentration of donepezil after administration of the drug has not been described in the literature so far. We recruited 16 patients regularly taking a standard therapeutic dose of donepezil (10 mg per day). All patients (Caucasian race) were treated for at least three months with a stable dose of 10 mg per day prior to sample collection. Patients were divided into two groups depending on the time of plasma and cerebrospinal fluid sampling: 12 h (n = 9; 4 M/5F aged 78.68 ± 7.35 years) and 24 h (n = 7; 3 M/4F aged 77.14 ± 5.87 years) after donepezil administration. The cerebrospinal fluid sample was collected by standard lumbar puncture technique using a single-use traumatic needle. The samples were analysed on an Agilent 1260 Series liquid chromatograph comprising a degasser, a quaternary pump, a light-tight autosampler unit set, a thermostated column compartment, and a UV/VIS detector. Agilent ChemStation software, the statistical software Prism4, version 5.0 (GraphPad Software, USA), and IBM(®) SPSS(®) Statistics were used for the analysis of the results. The difference in plasma concentration of donepezil after 12 h (mean ± SEM; 39.99 ± 5.90 ng/ml) and after 24 h (29.38 ± 1.71 ng/ml) was nonsignificant. In contrast, the donepezil concentration in the cerebrospinal fluid was significantly higher in the 24-h interval (7.54 ± 0.55 ng/ml) compared with the 12-h interval (5.19 ± 0.83 ng/ml, which is ~70 % based on mean cerebrospinal fluid values). Based on these data, it is plausible to predict that donepezil might produce a stronger AChE inhibition in the brain at 24 h compared with 12 h following the administration. This information may help physicians individually adjust the time of drug administration in the patients according to time course of the disease symptoms.
- MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- časové faktory MeSH
- cholinesterasové inhibitory krev farmakokinetika terapeutické užití MeSH
- hematoencefalická bariéra MeSH
- indany krev farmakokinetika terapeutické užití MeSH
- kapilární permeabilita MeSH
- lidé středního věku MeSH
- lidé MeSH
- nootropní látky krev farmakokinetika terapeutické užití MeSH
- piperidiny krev farmakokinetika terapeutické užití MeSH
- rozvrh dávkování léků MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- spinální punkce MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
UNLABELLED: Inhibitors of acetylcholinesterase (AChE) may be used in the treatment of various cholinergic deficits, among them being myasthenia gravis (MG). This paper describes the first in vivo data for promising small quaternary inhibitors (K298 and K524): acute toxicity study, cholinesterase inhibition, absorption, and blood-brain barrier penetration. The newly prepared AChE inhibitors (bis-quinolinium and quinolinium compounds) possess a positive charge in the molecule which ensures that anti-AChE action is restricted to peripheral effect. HPLC-MS was used for determination of real plasma and brain concentration in the pharmacokinetic part of the study, and standard non-compartmental analysis was performed. The maximum plasma concentrations were attained at 30 min (K298; 928.76 ± 115.20 ng/ml) and 39 min (K524; 812.40 ± 54.96 ng/ml) after i.m. APPLICATION: Both compounds are in fact able to target the central nervous system. It seems that the difference in the CNS distribution profile depends on an active efflux system. The K524 brain concentration was actively decreased to below an effective level; in contrast, K298 progressively accumulated in brain tissue. Peripheral AChE inhibitors are still first-line treatment in the mild forms of MG. Commonly prescribed carbamates have many severe side effects related to AChE carbamylation. The search for new treatment strategies is still important. Unlike carbamates, these new compounds target AChE via apparent π-π or π-cationic interaction aside at the AChE catalytic site.
- MeSH
- chinolinové sloučeniny aplikace a dávkování krev farmakokinetika toxicita MeSH
- cholinesterasové inhibitory aplikace a dávkování krev farmakokinetika toxicita MeSH
- cholinesterasy krev MeSH
- hematoencefalická bariéra účinky léků metabolismus MeSH
- krysa rodu rattus MeSH
- LD50 MeSH
- mozek - chemie účinky léků MeSH
- mozek účinky léků metabolismus MeSH
- potkani Wistar MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A simple, rapid and sensitive method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated for the quantitative determination in rat plasma of a new candidate for AD treatment, namely PC 48 (a 7-MEOTA-donepezil like compound) in rat plasma. Sample preparation involved pH adjustment with sodium hydroxide followed by solvent extraction with ethyl acetate:dichloromethane (80:20, v/v). The chromatographic separation was achieved on an Ascentis Express RP-Amide column (75 mm × 2.1mm, 2.7 μm) with a gradient mobile phase consisting of 0.05 M aqueous formic acid and acetonitrile. Detection was carried out using positive-ion electrospray tandem mass spectrometry on an LTQ XL system using the MS/MS CID (collision-induced dissociation) mode. The method was linear in the range 0.1-1000 ng/ml (r(2)=0.999) with a lower limit of quantitation of 0.1 ng/mL. Extraction recovery was in the range 63.5-72.1% for PC 48 and 70.5% for reserpine (internal standard, IS). Intra- and inter-day precisions measured as relative standard deviation were below 10.8% and accuracy was from -7.2% to 7.4%. The method was successfully applied to a pharmacokinetic study involving intramuscular application of 3.86 mg/kg PC 48 to rats for the first time. Pharmacokinetic parameters for PC 48 include Cmax 39.09 ± 4.45 ng/mL,Tmax 5.00 ± 3.08 min, AUC0-t 23374 ± 4045 min ng/mL and t1/2 1065 ± 246 min.
- MeSH
- Alzheimerova nemoc MeSH
- cholinesterasové inhibitory krev MeSH
- indany krev chemie farmakokinetika MeSH
- krysa rodu rattus MeSH
- lineární modely MeSH
- piperidiny krev chemie farmakokinetika MeSH
- potkani Wistar MeSH
- reprodukovatelnost výsledků MeSH
- senzitivita a specificita MeSH
- takrin analogy a deriváty krev chemie farmakokinetika MeSH
- tandemová hmotnostní spektrometrie metody MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antidota terapeutické užití MeSH
- butyrylcholinesterasa aplikace a dávkování farmakologie terapeutické užití MeSH
- chemické bojové látky otrava toxicita MeSH
- cholinesterasové inhibitory chemie krev otrava MeSH
- chronické poškození mozku chemicky indukované prevence a kontrola MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- injekce intramuskulární MeSH
- krysa rodu rattus MeSH
- mozek patologie MeSH
- neurotoxiny antagonisté a inhibitory MeSH
- organofosforové sloučeniny antagonisté a inhibitory toxicita MeSH
- otrava organofosfáty MeSH
- otrava prevence a kontrola MeSH
- reaktivátory cholinesterázy chemie izolace a purifikace MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
The changes in cholinesterase activity in tissues were evaluated and compared with the reactivation potential of reactivators. As reactivators, (E)-1-(4-carbamoylpyridinium- 1-yl)-4-{4-[(hydroxyimino)methyl]pyridinium-1-yl} but-2-ene dibromide (K203) and common 1,3-bis{4- [(hydroxyimino)methyl]pyridinium-1-yl}-2-oxapropane dichloride (obidoxime) were used. The reactivation of both oximes was monitored in blood and blood plasma. The reactivation of tabun-inhibited acetylcholinesterase (AChE) was higher using the newly synthesized K203.
- MeSH
- butyrylcholinesterasa analýza krev MeSH
- cholinesterasové inhibitory analýza krev MeSH
- financování organizované MeSH
- kolorimetrie metody MeSH
- oximy diagnostické užití MeSH
- potkani Wistar MeSH
- reprodukovatelnost výsledků MeSH
- sarin analogy a deriváty analýza krev MeSH
- spektrofotometrie metody MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
