The measured CSF/plasma donepezil concentration ratio but not individually measured CSF and plasma concentrations significantly increase over 24 h after donepezil treatment in patients with Alzheimer's disease.

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.

Concentration of Donepezil in the Cerebrospinal Fluid of AD Patients: Evaluation of Dosage Sufficiency in Standard Treatment Strategy.

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.

Epidural administration of neostigmine-loaded nanofibers provides extended analgesia in rats.

BACKGROUND: In this study, neostigmine-loaded electrospun nanofibers were prepared and then their efficacy and duration of analgesic action were studied after epidural administration in rats by repeated tail flick and formalin tests. METHODS: The neostigmine poly vinyl alcohol (PVA) nanofibers were fabricated by electrospinning methods. The nanofibers (1 mg) were injected into the lumbar epidural space (L5-L6) of rats (n = 6). Cerebrospinal fluid samples of rats were collected 1, 5 and 24 hours after injection and then were sampled once weekly for 4 weeks. Free-neostigmine concentration was measured in the samples spectrophotometrically. Rat nociceptive responses were evaluated by repeated tail-flick and formalin tests for 5 weeks after the nanofibers (1 mg) injection. Locomotor activity of rats was measured in the open-field at the same period. RESULTS: The cerebrospinal fluid concentration of free neostigmine reached 5 µg/ml five hours after injection and remained constant until the end of the experiments. The tail-flick latency of treated rats was significantly (p < 0.01) increased and remained constant up to 4 weeks. Pain scores of the rats in both phases of formalin test were significantly (p < 0.01) reduced during the same periods, Epidural injection of the nanofibers had no effect on locomotor activity of rats in an open-field. CONCLUSIONS: Our results indicate that the neostigmine nanofibers can provide sustained release of neostigmine for induction of prolonged analgesia after epidural administration. High tissue distribution and penetration of the nanofibers in dorsal horn can increase thermal and chemical analgesia duration without altering locomotor activity in rats for 4 weeks.

Huperzine A in rat plasma and CSF following intranasal administration.

This paper presents to investigate the levels of Huperzine A in plasma and CSF of rats after three different kinds of administrations and to find out whether intranasal administration is the best route to transfer the drug into the CNS. The drugs of two doses (167 and 500 microg/kg) were administered to male Sprague-Dawley rats intravenously, intranasally and intragastricly, respectively. Series plasma and cerebrospinal fluid (CSF) samples were collected from femoral artery and cisterna magna for 6h. The drug concentrations were determined by HPLC-fluorescence method. The AUC(plasma) and the AUC(CSF) of intranasal administration were 90.3% and 127.7% in low dose group (167 microg/kg) and 91.3% and 69.4% in high dose group (500 microg/kg) compared with intravenous administration. The AUC(plasma) and the AUC(CSF) of intragastric administration were 98.9% and 52.1% in high dose group (500 microg/kg) compared with intravenous administration.

Pharmacokinetic characterization of dehydroevodiamine in the rat brain.

The objective of this study was to examine the kinetics of the distribution of dehydroevodiamine (DHED) in the rat brain. After an intravenous infusion of 15 min (dose of 1-10 mg/kg), the temporal profiles of the plasma levels of DHED declined in a multiexponential manner. Moment analysis indicated that the clearance and steady-state volume of distribution for DHED were not statistically different with the dose, indicating that the pharmacokinetics for DHED is linear in the range examined. Nonlinear regression analysis of DHED concentrations in the plasma and the brain revealed that the linear kinetics into and out from the brain reasonably described the data and that the clearances for influx into and efflux from the brain were comparable. Transport clearances for DHED across MBEC4 monolayers, an in vitro model of the blood-brain barrier, were also comparable for influx and efflux, and were independent of the medium concentration. The concentration of DHED in cerebrospinal fluid was negligible compared with that found in plasma, indicating that the drug is not primarily distributed to the brain via the blood-cerebrospinal fluid barrier. These observations indicate that DHED is transported from the systemic circulation to the brain via the blood-brain barrier by linear kinetics.

Pharmacokinetic-pharmacodynamic modeling of rivastigmine, a cholinesterase inhibitor, in patients with Alzheimer's disease.

Rivastigmine is a cholinersterase inhibitor approved recently for the treatment of Alzheimer's disease (AD). The objective of this study is to characterize the pharmacokinetics-pharmacodynamics of rivastigmine in patients with AD. Eighteen AD patients received doses ranging from 1 to 6 mg bid for about 11 weeks. Rivastigmine and its active (major) metabolite (ZNS 114-666, also called NAP 226-90), plasma, and cerebrospinal fluid (CSF) concentrations were determined together with the AChE activity and computerized neuropsychological test battery (CNTB) scores. Nonlinear mixed-effects modeling of pharmacokinetic and pharmacodynamic data was conducted using NONMEM. Rivastigmine and its metabolite exhibited dose-disproportional pharmacokinetics. The apparent clearance and volume of distribution (plasma) of rivastigmine were estimated to be 120 L/h and 236 L, respectively. The relative bioavailability at the 6 mg dose was about 140%. The metabolite had a clearance of about 100 L/h and a volume of distribution of 256 L. The kinetics of the parent and metabolite in CSF showed an equilibration half-life of about 0.2 and 0.5 hours, respectively. The metabolite levels in CSF correlated very well with the acetylcholinesterase inhibition, with a ZNS 114-666 concentration of about 5.4 microg/L required for half-maximal inhibition of acetylcholinesterase activity. No statistically significant correlation of the CNTB scores with enzyme inhibition, parent or metabolite concentration (plasma/CSF), or rivastigmine dose could be established. The PK-PD model presented in this study can provide valuable information to optimize the drug development of rivastigmine and other related compounds and also in rationalizing dosing recommendations.

Determination of neostigmine in human plasma and cerebrospinal fluid by high-performance liquid chromatography with ultraviolet detection.

A high-performance liquid chromatographic assay coupled with ultraviolet detection has been developed for the determination of neostigmine in human plasma and cerebrospinal fluid. A novel solid-phase extraction procedure was first used for this analyte and allowed good recovery (89+/-4.5%) together with ease and speed of execution. The method was sensitive, reproducible (C.V.<4.5%) and accurate (100+/-6.6%) over the range 2.6-167.0 ng/ml neostigmine concentrations in plasma or cerebrospinal fluid, and was applied successfully to study the pharmacokinetics of neostigmine in patients suffering from chronic postoperative abdominal pain.

Cerebrospinal fluid pharmacokinetics and pharmacodynamics of intrathecal neostigmine methylsulfate in humans.

BACKGROUND: This study defines the cerebrospinal fluid (CSF) pharmacokinetics of neostigmine after intrathecal injection in humans and its effect on CSF acetylcholine, and it correlates physiologic effects with neostigmine dose and CSF acetylcholine concentrations. METHODS: The CSF was sampled via an indwelling spinal catheter in 12 volunteers receiving intrathecal neostigmine (50-750 microg) and analyzed for neostigmine and acetylcholine. Pharmacokinetic and pharmacodynamic analyses were performed with NONMEM. Effect-site models linked the time course of the neostigmine concentration with the time course of analgesia. RESULTS: Acetylcholine concentrations increased from <20 pmol/ml at baseline to >100 pmol/ml within 15 min of neostigmine injection. The pharmacokinetics of intrathecal neostigmine were best described by a triexponential function with an absorption phase. Individual predicted concentrations varied 100-fold. Post hoc Bayesian estimates described the observed neostigmine concentrations with a median error of 22% and did not show systematic model misspecification. Individual estimates of effect site concentration producing a 50% maximal effect for foot visual analog scale analgesia correlated with the magnitude of individual CSF neostigmine concentrations. CONCLUSIONS: Intrathecal neostigmine concentrations can be well described by a triexponential disposition function, but the intersubject variability is large. The correlation between intersubject variability in concentration and intersubject variability in 50% maximal effect for foot analgesia suggests that both are offset by a common scalar, possibly the distance from the site of injection to the sampling and effect sites. These data provide the basis for the hypothesis of "observation at a distance" to describe the pharmacodynamics of intrathecally administered drugs.

Toxicokinetics of soman in cerebrospinal fluid and blood of anaesthetized pigs.

The toxicokinetics of the four stereoisomers of the nerve agent C(+/-)P(+/-)-soman was analysed in cerebrospinal fluid (CSF) and blood in anaesthetized, spontaneously breathing pigs during a 90-min period after injection of soman. The pigs were challenged with different intravenous (i.v.) doses of C(+/-)P(+/-)-soman corresponding to 0.75-3.0 LD50 (4.5, 9.0 and 18 microg/kg in a bolus injection and 0.45 microg/kg per min as a slow infusion). Artificial ventilatory assistance was given if, after soman intoxication, the respiratory rate decreased below 19 breaths/min. Blood samples were taken from a femoral artery and CSF samples from an intrathecal catheter. The concentrations of the soman isomers were determined by gas chromatography coupled with high resolution mass spectrometry. All four isomers of soman were detected in both blood and CSF samples. The relatively non-toxic C(+/-)P(+) isomers disappeared from the blood stream and CSF within the first minute, whereas the levels of the highly toxic C(+/-)P(-) isomers could be followed for longer, depending on the dose. Concurrently with the soman analyses in blood and CSF, cholinesterase (ChE) activity and cardiopulmonary parameters were measured. C(+/-)P(-) isomers showed approx. 100% bioavailability in CSF when C(+/-)P(+/-)-soman was given i.v. as a bolus injection. In contrast, C(+/-)P(-) isomers displayed only 30% bioavailability in CSF after slow i.v. infusion of soman. The ChE activity in blood decreased below 20% of baseline in all groups of pigs irrespective of the soman dose. The effect of soman intoxication on the respiratory rate, however, seems to be dose-dependent and the reason for ventilatory failure and death. Artificial ventilation resulted in survival of the pigs for the time-period studied.

Dose-dependent CSF acetylcholinesterase inhibition by SDZ ENA 713 in Alzheimer's disease.

INTRODUCTION: This study evaluates the activity of SDZ ENA 713, a centrally-selective acetylcholinesterase (AChE) inhibitor, in the cerebral spinal fluid (CSF) of patients with Alzheimer's disease (AD), and its relationship to central and peripheral pharmacokinetic parameters. METHODS: Eighteen AD patients were enrolled in this open-label, multiple-dose study. Patients were titrated in 1 mg bid/week increments to target doses of 1, 2, 3, 4, 5, or 6 mg bid SDZ ENA 713. After patients had been maintained at their target dose for at least 3 days, continuous CSF samples were obtained via a lumbar catheter for 12.5 h, beginning 0.5 h prior to the final dose of SDZ ENA 713. RESULTS: Dose-dependent inhibition of CSF AChE was significantly correlated (P < 0.05) with plasma drug and metabolite concentrations. The 6 mg bid treatment group showed a maximum mean inhibition of 62% at 5.6 h post-dose. CONCLUSION: Rapid, sustained, dose-dependent inhibition of CSF AChE suggests that SDZ ENA 713 has therapeutic potential in AD patients.

Penetration of tacrine into cerebrospinal fluid in patients with Alzheimer's disease.

Tacrine is widely used for the treatment of Alzheimer's disease, but data are limited regarding cerebrospinal fluid (CSF) concentrations at steady state. To evaluate CSF penetration, seven patients with Alzheimer's disease who were receiving tacrine at doses of 40 to 140 mg/day as a part of a double-blind trial were studied. After 6 weeks of tacrine therapy, concomitant plasma and CSF samples were collected 30 minutes after the morning dose of tacrine. Although this time point is before the peak oral absorption in most patients, the critical issue for this study is that the plasma and CSF samples were collected concomitantly so that a percentage of tacrine penetration could be derived. The morning dose of tacrine ranged from 10 to 40 mg, which was given in the fasting state. Mean (+/-SD) plasma levels of tacrine were 8.01+/-7.07 ng/mL, whereas mean (+/-SD) CSF levels of tacrine were 5.21+/-6.00 ng/mL. The mean (+/-SD) ratio of CSF to plasma tacrine concentration was 0.50+/-0.45, with wide interindividual variability. No relationship between dose and percentage of penetration was observed. Plasma concentrations ranged from 0.99 to 22.6 ng/mL and were unrelated to dose, suggesting erratic oral absorption and/or rapid metabolism. CSF concentrations ranged from not detectable to 15.92 ng/mL. The authors support that penetration of tacrine into CSF is highly variable in patients with Alzheimer's disease and that disparity in tacrine concentrations at the site of action may be one reason for conflicting results from studies of the efficacy of tacrine in Alzheimer's disease.

Anticholinesterase action of a bromine compound isolated from human cerebrospinal fluid.

L-1- Methylheptyl -gamma- bromoacetoacetate was found to be a competitive inhibitor of the acetylcholinesterases (electric eel, Ki = 17.2 microM; rat brain, Ki = 32.6 microM) and of butyrylcholinesterase (horse serum, Ki = 1.2 microM). The L-isomer was a more effective inhibitor than the D-isomer. The bromine atom at the gamma-position of the acidic moiety, the specific length of the carbon chain constituting the secondary alcohol moiety, and the presence of the ketone radical at the acidic moiety of the ester were necessary for the anticholinesterase action. 1- Methylheptyl -gamma- bromoacetoacetate formed a complex with acetylcholinesterase or butyrylcholinesterase without hydrolysis of its own molecule.