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Physiologically based pharmacokinetic modeling of SNU-0039, an anti-Alzheimer's agent, in rats
Abstract
The objective of this study was to characterize the systemic and tissue kinetics of 2-(3,4-dimethoxyphenyl)-5-(3-methoxypropyl) benzofuran (SNU-0039), an inhibitor of β-amyloid protein aggregation, in rats. Simultaneous fitting of the data to polyexponential equations indicated that the systemic clearance and steady state volume of distribution were estimated to be 0.0220 l/min/kg and 2.33 l/kg. The clearance and volume of distribution were not dependent on the intravenous dose, in the range from 5 to 20 mg/kg. The tissue (i.e., the brain, liver, kidneys, heart, spleen, lungs, gut, muscle and adipose tissue) to plasma partition coefficients (K
p
) for SNU-0039 in rats ranged from a low of 0.779 ± 0.314 (muscle) to a high of 5.71 ± 1.66 (liver). The recoveries of DMB were less than 1% of the dose for the renal and biliary excretion, indicative of minor involvements of these pathways in overall elimination. The fraction of bound SNU-0039 to plasma protein was approximately 95.9% and the fraction of SNU-0039 distributed to blood cells was approximately 45.3%. Assuming a flow-limited distribution, the simulated concentration profiles for SNU-0039 in the physiologically based pharmacokinetic model were in reasonable agreement with the observed concentrations in plasma and nine tissues in rats.
... Plasma samples and tissue homogenates were stored at −80 • C until analysis [10]. The tissue-toplasma concentration ratio at steady state (K P,ss ) was then calculated for each tissue using the following equation [23][24][25]: ...
IDP-73152, a novel peptide deformylase inhibitor with an antibacterial effect against Gram-positive bacteria, is in phase I development. The objective of this study was to develop a physiologically-based pharmacokinetic model (PBPK) for IDP-73152 in animals, and to extend the model to humans. Biopharmaceutical properties of IDP-73152 are determined using in vitro/in vivo experimentations for the PBPK model. A transit model consisting of gastrointestinal segments is applied for an estimation of the intestinal absorption kinetics. The PBPK model of IDP-73152 in rats is able to appropriately predict the plasma concentration–time profiles after the administration of IDP-73152 at different doses and by different routes (combined absolute average fold error (cAAFE), 1.77). The model is also found to be adequate in predicting the plasma concentration–time profiles of IDP-73152 in mice (cAAFE 1.59) and dogs (cAAFE 1.42). Assuming the oral administration of IDP-73152 to humans at doses of 640 and 1280 mg, the model is able to reproduce the concentration–time profiles obtained in humans (cAAFE 1.38); therefore, these observations indicate that the PBPK model used for IDP-73152 is applicable to animal species and humans. This model may be useful in predicting efficacious doses of IDP-73152 for the management of infectious disease in humans.
... For PA and NAPA, the PBPK model consisted of eleven major tissues (i.e., adipose, bone, brain, gut, heart, kidney, liver, lung, muscle, skin, and spleen), which were assumed to be connected to the circulatory system (i.e., arterial and venous blood compartments). In the PBPK calculation, the rate of PA and NAPA distribution to tissues was assumed to be perfusion-rate limited and the corresponding standard mass balance differential equations were used [43,44] ...
Previous observations demonstrated that cimetidine decreased the clearance of procainamide (PA) and/or N-acetylprocainamide (NAPA; the primary metabolite of PA) resulting in the increased systemic exposure and the decrease of urinary excretion. Despite an abundance of in vitro and in vivo data regarding pharmacokinetic interactions between PA/NAPA and cimetidine, however, a mechanistic approach to elucidate these interactions has not been reported yet. The primary objective of this study was to construct a physiological model that describes pharmacokinetic interactions between PA/NAPA and cimetidine, an inhibitor of rat organic cation transporter 2 (rOCT2) and rat multidrug and toxin extrusion proteins (rMATE1), by performing extensive in vivo and in vitro pharmacokinetic studies for PA and NAPA performed in the absence or presence of cimetidine in rats. When a single intravenous injection of PA HCl (10 mg/kg) was administered to rats, co-administration of cimetidine (100 mg/kg) significantly increased systemic exposure and decreased the systemic (CL) and renal (CLR) clearance of PA, and reduced its tissue distribution. Similarly, cimetidine significantly decreased the CLR of NAPA formed by the metabolism of PA and increased the AUC of NAPA. Considering that these drugs could share similar renal secretory pathways (e.g., via rOCT2 and rMATE1), a physiologically-based pharmacokinetic (PBPK) model incorporating semi-mechanistic kidney compartments was devised to predict drug-drug interactions (DDIs). Using our proposed PBPK model, DDIs between PA/NAPA and cimetidine were successfully predicted for the plasma concentrations and urinary excretion profiles of PA and NAPA observed in rats. Moreover, sensitivity analyses of the pharmacokinetics of PA and NAPA showed the inhibitory effects of cimetidine via rMATE1 were probably important for the renal elimination of PA and NAPA in rats. The proposed PBPK model may be useful for understanding the mechanisms of interactions between PA/NAPA and cimetidine in vivo.
CYP enzymes and hOATP1B1 are reported to be involved in the pharmacokinetics of lobeglitazone (LB), a new PPARγ agonist. Atorvastatin (ATV), a substrate for CYP3A and hOATP1B1, is likely to be co-administered with LB in patients with the metabolic syndrome. We report herein on a study of potential interactions between LB and ATV in rats. When LB was IV-administered with ATV, the systemic clearance (CL; 2.67 ± 0.63 mL/min/kg) and volume of distribution at steady-state (Vss; 289 ± 20 mL/kg) for LB remained unchanged, compared to those of LB without ATV (CL, 2.34 ± 0.37 mL/min/kg; Vss, 271 ± 20 mL/kg). While the Kp of LB was not affected by ATV in most major tissues, the liver Kp for LB was decreased by the co-administration of ATV. The liver Kp values at the steady state for three levels of LB were significantly decreased as the result of the co-administration of ATV. LB uptake was inhibited by ATV in rOatp1b2-overexpressing MDCK cells and in isolated rat hepatocytes in vitro. After incorporating the kinetic parameters for the in vitro studies into a PBPK model, the characteristics of LB distribution to the liver were consistent with the findings of the in vivo study. It thus appears that the distribution of LB to the liver is mediated by the hepatic uptake of transporters such as rOatp1b2, and the carrier- mediated transport is involved in the liver specific DDI between LB and ATV in vivo.
1. This study evaluated the pharmacokinetics of the novel TAZ modulator TM-25659 in rats following intravenous and oral administration at dose ranges of 0.5-5 mg/kg and 2-10 mg/kg, respectively. Plasma protein binding, plasma stability, liver microsomal stability, CYP inhibition, and transport in Caco-2 cells were also evaluated. 2. After intravenous injection, systemic clearance, steady-state volumes of distribution, and half-life were dose-independent, with values ranging from 0.434-0.890 mL·h(-1)·kg(-1), 2.02-4.22 mL/kg, and 4.60-7.40 h, respectively. Mean absolute oral bioavailability was 50.9% and was not dose dependent. Recovery of TM-25659 was 43.6% in urine and <1% in bile. In pharmacokinetic modeling studies, the three-compartment (3C) model was appropriate for understanding these parameters in rats. 3. TM-25659 was stable in plasma. Plasma protein binding was approximately 99.2%, and was concentration-independent. TM-25659 showed high permeation of Caco-2 cells and did not appear to inhibit CYP450. TM-25659 was metabolized in phase I and II steps in rat liver microsomes. 4. In conclusion, the pharmacokinetics of TM-25659 was characterized for intravenous and oral administration at doses of 0.5-5 and 2-10 mg/kg, respectively. TM-25659 was eliminated primarily by hepatic metabolism and urinary excretion.
The prediction of clinical drug-drug interactions (DDIs) due to mechanism-based inhibitors of CYP3A is complicated when the inhibitor itself is metabolized by CYP3Aas in the case of clarithromycin. Previous attempts to predict the effects of clarithromycin on CYP3A substrates, e.g., midazolam, failed to account for nonlinear metabolism of clarithromycin. A semiphysiologically based pharmacokinetic model was developed for clarithromycin and midazolam metabolism, incorporating hepatic and intestinal metabolism by CYP3A and non-CYP3A mechanisms. CYP3A inactivation by clarithromycin occurred at both sites. K(I) and k(inact) values for clarithromycin obtained from in vitro sources were unable to accurately predict the clinical effect of clarithromycin on CYP3A activity. An iterative approach determined the optimum values to predict in vivo effects of clarithromycin on midazolam to be 5.3 microM for K(i) and 0.4 and 4 h(-1) for k(inact) in the liver and intestines, respectively. The incorporation of CYP3A-dependent metabolism of clarithromycin enabled prediction of its nonlinear pharmacokinetics. The predicted 2.6-fold change in intravenous midazolam area under the plasma concentration-time curve (AUC) after 500 mg of clarithromycin orally twice daily was consistent with clinical observations. Although the mean predicted 5.3-fold change in the AUC of oral midazolam was lower than mean observed values, it was within the range of observations. Intestinal CYP3A activity was less sensitive to changes in K(I), k(inact), and CYP3A half-life than hepatic CYP3A. This semiphysiologically based pharmacokinetic model incorporating CYP3A inactivation in the intestine and liver accurately predicts the nonlinear pharmacokinetics of clarithromycin and the DDI observed between clarithromycin and midazolam. Furthermore, this model framework can be applied to other mechanism-based inhibitors.
Prediction of the extent and time course of drug-drug interactions (DDIs) between the mechanism-based inhibitor diltiazem (DTZ) and the CYP3A4 substrate midazolam (MDZ) is confounded by time- and concentration-dependent clearance of the inhibitor. Semiphysiologically based pharmacokinetic (PBPK) models were developed for DTZ and MDZ with the major metabolite of DTZ, N-desmethyldiltiazem (nd-DTZ), incorporated in the DTZ model. Enzyme kinetic parameters (k(inact) and K(I)) for DTZ and nd-DTZ were estimated in vitro and used to model the time course of changes in the amount of CYP3A4 in the liver and gut wall, which in turn, determined the nonlinear elimination of MDZ and DTZ, and the corresponding DDI. The robustness of the model prediction was assessed by comparing the results of the prediction to published DTZ pharmacokinetic and DTZ/MDZ interaction data. A clinical study was conducted to further validate the predicted increase of MDZ exposure after DTZ treatment. The model predicted the nonlinear disposition of DTZ after single and multiple oral doses. The clinical study showed that DTZ treatment resulted in 4.1- and 1.6-fold increases in MDZ exposure after oral and intravenous MDZ administration, respectively, suggesting that the DDI in the gut wall plays an important role in the DTZ/MDZ interaction. The semi-PBPK model incorporating the DDI at the gut wall, and the effect of nd-DTZ successfully predicted the nonlinear disposition of DTZ and its interaction with MDZ. Moreover, model simulation suggested that both DTZ and nd-DTZ contributed to the overall inhibitory effect after DTZ administration, and the values of the in vitro estimated inhibition parameters and CYP3A4 turnover rate are critical for the prediction.
The kinetics and mechanism by which tacrine is distributed in the rat brain were examined. Tacrine levels in plasma and striatal extracellular fluid were used to evaluate the pharmacokinetics of this process. The K(D,brain) was decreased with the dose for tacrine, indicating that the distribution to the brain is saturable. The uptake of organic cations such as choline, 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), and carnitine was inhibited by the addition of tacrine to cultures of mouse immortalized brain capillary endothelial cells. In addition, the apical to basal transport and basal to apical transport of tacrine were inhibited by the addition of organic cations to cultures of LLC-PK1 cells, suggesting that tacrine transport across the blood-brain barrier (BBB) is mediated by organic cation transport system(s). Consistent with the in vitro results, a standard reverse transcription-polymerase chain reaction procedure was able to amplify the message of mOCT2 and mOCTN2, but not mOCT1, in MBEC4 (mouse brain microvessel endothelial cell line 4) cells. Similarly, mRNAs for rOCT2 and rOCTN2 were present in representative rat brain samples. To determine whether OCT2 and/or OCTN2 transport tacrine, these transporters were cloned and then transfected in SK-HEP1 and HEK 293 cells. The uptake of choline, MPP, and TEA was inhibited by the presence of tacrine in rOCT2-expressing SK-HEP1 cells, whereas the uptake of carnitine was inhibited by the presence of tacrine in rOCTN2-expressing HEK 293 cells. Collectively, these observations suggest that the transport of tacrine across the BBB is mediated, at least in part, by multiple organic cation transport systems in rats.
Apart from the damago to ascending cholinergic projections in Alzheimer's disease, biochemical studies on human brain post mortem have revealed a number of other neurochemical abnormalities. These include reductions in 5-hydroxytryptamine (5-HT) and 5-HT receptors, and in noradrenaline. There is also evidence of selective damage to somatostatin-containing elements in cerebral cortex, especially in the temporal lobe. Such other cortical peptides as enkephalins, neurotensin, cholecystokinin, thyrotropin-releasing hormone, substance P and vasoactive intestinal polypeptide are unaffected. Some regions of cerebral cortex show reduced concentrations of GABA.
The reduction in cortical somatostatin appears to be the most marked of these changes, and is the most clearly related to seventy of illness. All of the neurochemical deficits were most pronounced in younger patients.
Background: Whole-body physiologically-based pharmacokinetic (WB-PBPK) models mathematically describe an organism as a closed circulatory system consisting of compartments that represent the organs important for compound absorption, distribution, metabolism and elimination. Objectives: To review the current state of WB-PBPK model use in the clinical phases of drug development. Methods: A qualitative description of the WB-PBPK model structure is included along with a review of the varying methods available for input parameterisation. Current and potential WB-PBPK model application in clinical development is discussed. Conclusions: This modelling tool is at present used for small and large molecule drug development primarily as a means to scale pharmacokinetics from animals to humans based on physiology. The pharmaceutical industry is active in employing these models to clinical drug development although the applications in use now are narrow in comparison to the potential. Expanded integration of WB-PBPK models into the drug development process will only be achieved with staff training, managerial will, success stories and regulatory agency openness.
Cholinergic markers, neuropeptides, and amines and their metabolites were sampled from identical specimens across 10 neocortical regions in a large sample of Alzheimer's disease (AD) cases and controls. Levels of choline acetyltransferase, acetylcholinesterase, somatostatin, corticotropin-releasing factor, serotonin, and 5-hydroxyindoleacetic acid were significantly reduced in AD versus controls. After data reduction, the most descriptive neurochemical indices were used to examine the relationship of neurochemical measures and dementia severity within the AD sample, controlling for age effects. Dementia severity ratings were based on antemortem assessments (46.9% of AD sample) and postmortem chart review (53.1% of the AD sample). Choline acetyltransferase activity was highly correlated with clinical dementia ratings across the neocortex of the AD cases. Somatostatin and corticotropin-releasing factor levels were correlated with dementia severity only when control cases were included in the analyses. None of the amines, their metabolites, or the neuropeptides quantified related significantly to dementia severity in the AD cohort. These data (a) confirm the strong association of cholinergic deficits with functional impairment in AD and show that this association is independent of age and (b) suggest that of all the neurochemical species quantified, the cholinergic indices may be unique in their association with dementia severity.
An important parameter in the development of pharmacokinetic models is the ratio of tissue drug concentration to the concentration of the drug in the arterial plasma or the effluent plasma. The relationship between these two tissue/plasma ratios is derived analytically for different routes of drug administration. The two are equal only in compartments with no elimination when the drug is infused at constant rate. For other routes of administration, the two ratios are identical in all compartments only when there is no elimination process. The tissue/plasma concentration ratios for infusion equilibrium are not equal to the corresponding values for the postdistribution phase after an intravenous bolus injection. When the plasma concentration for infusion and injection are the same, more drug will appear in the lung during infusion steady state than during the postdistribution equilibrium. The reverse is true for the other organs. The importance of properly defining the tissue/plasma ratio and its implication for pharmacokinetic modeling are discussed. The results may have important therapeutic implications for the availability of drugs using different routes of administration.
An important parameter used in physiologically based pharmacokinetic models is the partition coefficient (Kp), which is defined as the ratio of tissue drug concentration to the concentration of drug in the emergent venous blood of the tissue. Since Kp is governed by reversible binding to protein and other constituents in blood and tissue, an attempt was made here to estimate the Kp values for a model drug ethoxybenzamide (EB) by means of in vitrobinding studies and to compare these Kp values to those obtained from in vivokinetic parameters observed following the administration of EB by two different routes, i.e., i.v. bolus injection and constant rate infusion. The Kp values obtained by using these three different methods were in reasonably good agreement suggesting that binding data obtained in vitrocan successfully be used to estimate in vivodistribution.
The primary pathology in Alzheimer's disease (DAT) occurs in the basal forebrain cholinergic system (BFCS), which provides the major cholinergic innervation to the neocortex, hippocampus and amygdala. Consistent with the 'cholinergic hypothesis' of dementia in DAT, the most effective treatments so far developed for DAT are drugs which act to boost the functions of the BFCS. These include the centrally acting cholinesterase inhibitor tacrine, and the cholinergic agonist nicotine, acute administration of which leads to an improvement in attentional functions, in line with recent animal studies of the role of the BFCS in cognition. We conclude that future research should include the development of more potent, longer-lasting, less toxic cholinergic agents, which appear to be the best candidates for alleviating the cognitive symptomatology of DAT. Such drugs may also be useful in the treatment of a number of other cognitive disorders, including Lewy body dementia, attention deficit/hyperactivity disorder, and schizophrenia.
The disposition of ketoconazole was characterized in the rat over a wide dose/concentration range. Bolus dose (0.03–10 mg/kg) studies indicate that plasma concentration–time profiles for ketoconazole are not superimposable when dose normalized because of nonlinearities occurring in both volume of distribution and clearance. The volume of distribution decreases from 3 to less than 1 L/kg, while the plasma clearance decreases 10-fold from 25 mL/min/kg as the dose is escalated. From these results, infusion rates were calculated to maintain the plasma concentrations achieved with particular bolus doses. The curvilinear relationship between steady-state plasma concentration (0.015–8.3 mg/L) and ketoconazole infusion rate (0.021–2.45 mg/hr/kg) was analyzed in terms of Michaelis–Menten kinetics. A V
max of 3.2 mg/hr/kg and K
m of 2.1 mg/L were obtained by nonlinear regression analysis. At the end of the ketoconazole infusion, liver, adrenals and kidneys were removed and assayed for ketoconazole. Tissue-to-plasma partition coefficients for the liver and adrenals showed a marked dependence upon steady-state plasma concentration. Both parameters (liver, 22; and adrenals, 53) showed a decrease of approximately 10-fold as the plasma concentrations were increased. In contrast, the kidney:plasma partition coefficient (1.8), blood:plasma concentration ratio (0.6), and plasma binding (96%) of ketoconazole did not show a concentration dependence over the range studied. It is concluded that the liver is an important determinant of ketoconazole's volume of distribution and that saturation of this process accounts largely for the reduction in volume of distribution with increasing dose. The characterization of ketoconazole's hepatic clearance and binding in the rat helps resolve the apparent discrepancy between in vitro and in vivo observations on this azole's interaction with cytochrome P450.
This site is a pdf document for analytical scientists detailing what is necessary to make a methodology acceptable to the FDA. As such it should provide an \\\\\\\"eye\\\\\\\" opener to students trying to learn the analytical mindset. This site will be especially useful for instructors presenting material on method validation. It is also a valuable resource for students considering employment in the pharmaceutical industry.
The objective of this study was to characterize the mechanism that controls the transport of donepezil into the brain. The apparent brain uptake clearance (CL(app,br)) was decreased as a function of the dose of donepezil, suggesting an involvement of a saturable transport process via transporter(s) in the penetration across the blood-brain barrier (BBB). Consistent with in vivo results, the uptake of substrates for organic cation transporters was significantly reduced by donepezil in both MBEC4 cells (i.e., a model for BBB) and HEK 293 cells expressing the transporters found in the brain, indicative of the involvement of organic cation transporters in the transport of the drug. Furthermore, donepezil transport was enhanced (p < 0.01) in HEK 293 cells expressing rOCNT1, rOCTN2, or rCHT1. The CL(app,br) was reduced up to 52.8% of the control in rats that had been pretreated with choline, while the CL(app,br) was unaffected with pretreatments with organic cations other than choline, suggesting that choline and donepezil share a common transport mechanism in the penetration across the BBB in vivo. Taken together, these observations suggest that the transport of donepezil across the BBB is mediated by organic cation transporters such as choline transport system(s).
Hepatobiliary excretion mediated by transporters, organic anion-transporting polypeptide (OATP) 1B1 and multidrug resistance-associated protein (MRP) 2, is the major elimination pathway of an HMG-CoA reductase inhibitor, pravastatin. The present study examined the effects of changes in the transporter activities on the systemic and liver exposure of pravastatin using a physiologically based pharmacokinetic model. Scaling factors, determined by comparing in vivo and in vitro parameters of pravastatin in rats for the hepatic uptake and canalicular efflux, were obtained. The simulated plasma and liver concentrations and biliary excretion profiles were very close to the observed data in rats under linear and nonlinear conditions. In vitro parameters, determined in human cryopreserved hepatocytes and canalicular membrane vesicles, were extrapolated to in vivo parameters using the scaling factors obtained in rats. The simulated plasma concentrations of pravastatin were close to the reported values in humans. Sensitivity analyses showed that changes in the hepatic uptake ability altered the plasma concentration of pravastatin markedly but had a minimal effect on the liver concentration, whereas changes in the ability of canalicular efflux altered the liver concentration of pravastatin markedly but had a small effect on the plasma concentration. In conclusion, the model allows the prediction of the disposition of pravastatin in humans. The present study suggests that changes in the OATP1B1 activities may have a small and a large impact on the therapeutic efficacy and side effect (myopathy) of pravastatin, respectively, whereas those in the MRP2 activities may have opposite impacts (i.e., large and small impacts on the therapeutic efficacy and side effect).
Whole-body physiologically-based pharmacokinetic (WB-PBPK) models mathematically describe an organism as a closed circulatory system consisting of compartments that represent the organs important for compound absorption, distribution, metabolism and elimination.
To review the current state of WB-PBPK model use in the clinical phases of drug development.
A qualitative description of the WB-PBPK model structure is included along with a review of the varying methods available for input parameterisation. Current and potential WB-PBPK model application in clinical development is discussed.
This modelling tool is at present used for small and large molecule drug development primarily as a means to scale pharmacokinetics from animals to humans based on physiology. The pharmaceutical industry is active in employing these models to clinical drug development although the applications in use now are narrow in comparison to the potential. Expanded integration of WB-PBPK models into the drug development process will only be achieved with staff training, managerial will, success stories and regulatory agency openness.
An important parameter in the development of pharmacokinetic models is the ratio of tissue drug concentration to the concentration of the drug in the arterial plasma or the effluent plasma. The relationship between these two tissue/plasma ratios is derived analytically for different routes of drug administration. The two are equal only in compartments with no elimination when the drug is infused at constant rate. For other routes of administration, the two ratios are identical in all compartments only when there is no elimination process. The tissue/plasma concentration ratios for infusion equilibrium are not equal to the corresponding values for the postdistribution phase after an intravenous bolus injection. When the plasma concentration for infusion and injection are the same, more drug will appear in the lung during infusion steady state than during the postdistribution equilibrium. The reverse is true for the other organs. The importance of properly defining the tissue/plasma ratio and its implication for pharmacokinetic modeling are discussed. The results may have important therapeutic implications for the availability of drugs using different routes of administration.
The distribution of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) was mapped in 39 cortical areas of 11 brains of patients with Alzheimer's disease (AD). Whole hemisphere blocks were embedded in polyethylene glycol (Carbowax), sectioned coronally, and stained with thioflavin S and thionin. The densities of NFTs and NPs were assessed using a numerical rating scale for each area. Scores were grouped by type of cortex and by lobe for statistical analysis. Highly significant differences were obtained. For example, limbic periallocortex and allocortex had more NFTs than any other type of cortex. In descending order, the density of NFTs was as follows: periallocortex (area 28) greater than allocortex (subiculum/CA1 zones of hippocampal formation, area 51) greater than corticoid areas (accessory basal nucleus of amygdala, nucleus basalis of Meynert) greater than proisocortex (areas 11, 12, 24, 23, anterior insula, 38, 35) greater than nonprimary association cortex (32, 46, superior temporal sulcus, 40, 39, posterior parahippocampal cortex, 37, 36) greater than primary sensory association cortex (7, 18, 19, 22, 21, 20) greater than agranular cortex (44-5, 8, 6, 4) greater than primary sensory cortex (41-2, 3-1-2, 17). The laminar distribution of NFTs tended to be selective, involving primarily layers III and V of association areas and layers II and IV of limbic periallocortex. There were far more NFTs in both limbic and temporal lobes than in frontal, parietal, and occipital lobes. In general, NPs were more evenly distributed throughout the cortex, with the exceptions of limbic periallocortex and allocortex, which had notably fewer NPs than other cortical areas. Temporal and occipital lobes had the highest NP densities, limbic and frontal lobes had the lowest, and parietal lobe was intermediate. No significant left-right hemispheric differences for NFT or NP densities were found across the population, and there was no relationship between duration of illness and densities of NFTs or NPs. The regional and laminar distribution of NFTs (and, to a lesser degree, that of NPs) suggests a consistent pattern of vulnerability within the cerebral cortices that seems correlated to the hierarchies of cortico-cortical connections. The higher-order association cortices, especially those in the anterior and ventromedial sectors of temporal lobe, are the most vulnerable, while other cortices appear less vulnerable to a degree commensurate with their connectional "distance" (i.e., synapses removed) from the limbic areas.
Changes in the cholinergic, serotonergic, noradrenergic, dopaminergic, GABAergic and somatostatinergic neurons were investigated to determine their roles in Alzheimer's disease (AD). Markers for these systems were analyzed in postmortem brain samples from 20 patients with AD and 14 controls. In the CSF study, markers for the cholinergic neurons (choline esterase, ChE) and for the somatostatinergic neurons (somatostatin-like immunoreactivity, SLI) were assayed for 93 and 75 probable AD patients and 29 and 19 controls, respectively. Activity of choline acetyltransferase (CAT) was decreased by 50-85% in four cortical areas and hippocampus in patients with AD, but not in other areas of the brain, indicating a profound deficit in the function of cholinergic projections ascending from the nucleus basalis to the cerebral cortex and hippocampus in AD. Muscarinic receptor binding was reduced by 18% in the frontal cortex but not in other areas of the brain in AD. Serotonin (5HT) concentrations were reduced (by 21-37%) in hippocampal cortex, hippocampus and striatum; and 5HT metabolite levels were lowered (by 39-54%) in three cortical areas, thalamus and putamen in AD patients. Concentrations of noradrenaline (NA) were reduced (18-36%) in frontal and temporal cortex and putamen. These data imply that serotonergic and noradrenergic projections are also affected in AD but less than the cholinergic neurons. Dopamine (DA) concentrations in AD patients were reduced by 18-27% in temporal and hippocampal cortex and hippocampus, while HVA, the metabolite of DA, was unaltered. Glutamic acid decarboxylase activity was not altered in AD. SLI was decreased (28-42%) in frontal, temporal and parietal cortex, but not in thalamus and putamen in patients with AD. Frontal tangle scores correlated most strongly with cortical CAT activity reduction and less so with decreases of 5HT, NA and DA, indicating a closer correlation with the cholinergic changes and severity of AD than with other neurotransmitter deficiencies. ChE activity and SLI were reduced by 20% and 35%, respectively, in CSF of the whole group of AD patients as compared to the controls. Comparison of CSF findings between four subgroups of dementia severity indicated that the SLI was already reduced in the group of mildest AD (-31%), while ChE activity was not. Although ChE activity in CSF declined in relation to dementia severity, however, the maximal reduction was only modest (-30%). On the other hand, SLI in CSF showed only a slight further reduction (up to -41%) as the dementia become more severe.(ABSTRACT TRUNCATED AT 400 WORDS)
A physiologic pharmacokinetic model of cyclosporin has been developed in the rat aimed at predicting the time course of drug concentrations in blood, organs, and tissues. The model assumes that tissue distribution is perfusion-rate limited and that each tissue acts as a well-stirred compartment. The unbound equilibrium distribution ratios as well as the values of the fraction unbound and the distributon isotherm of cyclosporin between erythrocytes and plasma are included in the rate equations describing the time course of the drug concentration in each tissue. Parameter values for the rat were obtained experimentally from a continuous infusion study, in which 2.7 and I3.9mg/kg per day doses of cyclosporin were administered subcutaneously to each of two groups of rats by osmotic pumps for 6 days. Steady-state cyclosporin concentrations in blood, CSF, and 18 different organs and tissues, were determined by a monoclonal antibody RIA. Differences in values of the unbound equilibrium distribution ratios in some tissues and unbound clearance indicated that both the processes of distribution and elimination may have elements of nonlinearity over the range of dosing rales tested. The model was evaluated in the rat with a kinetic experiment in which a 6-mg/kg dose of cyclosporin was infused intravenously over 15 min, with measurements of blood concentrations until 56 hr. Good agreement was obtained for the volume of distribution at steady state (blood), Vxs
between the perfusion model and that calculated from the kinetic experiment. Also, the model prediction of the blood concentration temporal profile agreed closely with that observed except in the early moments, when distribution out of blood occurred considerably slower than predicted. On scaling the model up to humans, good agreement was found between the predicted plasma concentration-time profile and Vss
,and experimental data from the literature. Both rat and human data suggest that partition into adipose tissue plays an important role in the pharmacokinetics of cyclosporin.
Apart from the damage to ascending cholinergic projections in Alzheimer's disease, biochemical studies on human brain post mortem have revealed a number of other neurochemical abnormalities. These include reductions in 5-hydroxytryptamine (5-HT) and 5-HT receptors, and in noradrenaline. There is also evidence of selective damage to somatostatin-containing elements in cerebral cortex, especially in the temporal lobe. Such other cortical peptides as enkephalins, neurotensin, cholecystokinin, thyrotropin-releasing hormone, substance P and vasoactive intestinal polypeptide are unaffected. Some regions of cerebral cortex show reduced concentrations of GABA. The reduction in cortical somatostatin appears to be the most marked of these changes, and is the most clearly related to severity of illness. All of the neurochemical deficits were most pronounced in younger patients.
Aizheimer's disease (AD) is a major mental health problem involving abnormalities of several neurotransmitter systems in the brain. The most consistent and pervasive abnormality involves the cholmergic system, and correlates with severity of illness in AD. Pharmacological enhancement of cholinergic activity includes presynaptic agents which increase acetylcholine (ACh) synthesis and release; synaptic agents which increase ACh by limiting its breakdown; and postsynaptic agents which directly stimulate ACh receptors. Valid trials of cholinergic agents in AD require a specialized study design in which individualized optimal drug doses are tested in a large population of stringently diagnosed AD patients. Testing devices must be suitable for each patient's capabilities, and should measure alterations of function in several areas.
Clinical trials with choline and lecithin, ACh precursors, have not shown cognitive improvements in AD patients. Combination of precursors with agents that enhance the firing rate of presynaptic neurons, such as piracetam, may have some beneficial effect in a subgroup of AD patients with remaining functionally intact cholinergic neurons. Red cell-plasma choline ratio appears to be higher in treatment responders. Presynaptic approaches have the advantage of mimicking the phasic action of cholinergic cells, but require the presence of functionally intact cholinergic neurons.
Physostigmine, an acetycholinesterase (AChE) inhibitor, augments available synaptic ACh. Studies with intravenous physostigmine show significant but moderate transient improvement in memory test, but applicability is limited by short half-life. Oral, like intravenous, physostigmine has a narrow therapeutic window, necessitating the use of a dose-finding phase in study design. Oral physostigmine has yielded modest improvements in specific cognitive areas and overall functioning in a majority of AD patients. Biochemical measures of central cholinergic activity such as plasma cortisol and cerebrospinal fluid AChE activity have been correlated with symptom improvement, and may identify likely responders. Cholinergic agonists such as Rs 86, erecoline and oxotremorine have been used in preliminary trials with AD patients, yielding modest results with significant side effects. Future directions include the development of more specific, long-acting cholinergic agents with fewer side effects; differentiating M-1 and M-2 receptor sites; delineation of parameters that can predict response, and possibly the use of combined neurotransmitter enhancement treatments.
Various pharmacokinetic parameters—disposition half-life, t
1/2,z, metabolic clearance CLm, volume of distribution V, intrinsic clearance of unbound drug CLut, and unbound volume of distribution of tissues (distributive tissue volume / fraction of drug in tissue unbound, VT/fuT—are compared in rat and human for nine weakly acidic drugs, phenytoin, hexobarbital, pentobarbital, phenylbutazone, warfarin, tolbutamide, valproate, phenobarbital, and amobarbital, and six weakly basic drugs, quinidine, chlorpromazine, propranolol, pentazocin, antipyrine, and diazepam. With regard to all parameters, statistically significant correlations are obtained when parameters are plotted on a log-log plot. Correlation coefficients between the intrinsic parameters (CLuint or VT/fuT) were higher than those between the hybrid parameters (t1/2,z, CLm, or V). In general, these drugs were metabolized ten times more rapidly in rat than in human. With regard to the tissue distribution of these drugs, there was little difference between rat and human. Predictions of CLm, V, and t1/2, in humans using rat data were successful for most drugs, with a few marked exceptions.
Single intravenous dosages of 200 mg/kg DMSO to anesthetized cats produced apnea and a transient fall in blood pressure. Subsequent doses of DMSO caused only transient hypotension; apnea was no longer observed. Hemolysis resulting in hemoglobinuria and methemoglobinuria also occurred. The intraperitoneal administration of DMSO or the dilution of DMSO with isotonic saline prior to intravenous administration reduced hemolytic activity.
An important parameter used in physiologically based pharmacokinetic models is the partition coefficient (Kp), which is defined as the ratio of tissue drug concentration to the concentration of drug in the emergent venous blood of the tissue. Since Kp is governed by reversible binding to protein and other constituents in blood and tissue, an attempt was made here to estimate the Kp values for a model drug ethoxybenzamide (EB) by means of in vitro binding studies and to compare these Kp values to those obtained from in vivo kinetic parameters observed following the administration of EB by two different routes, i.e., i.v. bolus injection and constant rate infusion. The Kp values obtained by using these three different methods were in reasonably good agreement suggesting that binding data obtained in vitro can successfully be used to estimate in vivo distribution.
This review starts with an historical background of the pharmacological development of tacrine almost fifty years ago (1949). Tacrine is the first drug to be tested, clinically, on a large scale and to be registered (1993) for treatment of Alzheimer's disease. For the first time, clinical results of four second generation cholinesterase inhibitors (ChEI) (donepezil, ENA 713, eptastigmine and metrifonate) are reviewed and compared with other ChEI such as tacrine, physostigmine and galanthamine. Data based on more than 6000 patients show that second generation drugs are well tolerated and show evidence of clinical efficacy. Differences are mainly due to frequency of side effects, number of drop outs and percentage of improved patients. These results also demonstrate the presence of clinical efficacy for all ChEI tested so far. Clinical mechanism of action, levels of efficacy and differences among various ChEI are discussed. Future potential indications are suggested. The present data indicate that optimization of effects prolongation and maintenance of clinical gains will depend on further knowledge of the compounds pharmacodynamic properties.
Alzheimer's disease (AD) is the most common cause of dementia in the elderly. One of the most successful therapeutic strategies for Alzheimer's disease has been the use of acetylcholinesterase inhibitors to enhance surviving cholinergic neurotransmission by inhibiting breakdown of released acetylcholine. The first generation acetylcholinesterase inhibitors, such as tacrine, revealed major limitations to use including hepatotoxicity. Several second generation acetylcholinesterase inhibitors have now been introduced, including rivastigmine, which are believed to have superior proprieties. The mode of action and metabolism of rivastigmine suggest that it is unlikely to interact significantly with other medications. This is of particular relevance in elderly AD patients, the majority of whom are likely to be receiving concomitant medication. Large multi-centre trials have been completed in the USA, Canada, Europe and South Africa. Rivastigmine has received EU approval for use in all member states. It has approval in 30 countries but not the US. It is currently under review by the Food and Drug Administration, who requested additional analyses in 1998.
To determine the clinical efficacy and safety of rivastigmine for patients with dementia of the Alzheimer's type.
The Cochrane Controlled Trials Register, the Dementia Group Register of Clinical Trials, other electronic databases and other sources of reports were searched using the terms ENA 713, EXELON, and rivastigmine in addition to the terms for controlled trials in dementia (see the Group's search strategy for full details).
All unconfounded, double-blind, randomised trials in which treatment with rivastigmine was administered for more than one day and compared to placebo for patients with dementia of the Alzheimer's type.
Data were extracted by the reviewer (JSB) and entered into an appropriate meta-analysis. The data extracted were cross-checked by the second reviewer (VI). For each outcome measure, data were sought on every patient randomised. To allow an intention-to-treat analysis, the data were sought irrespective of compliance, whether or not the patient was subsequently deemed ineligible, or otherwise excluded from treatment or follow-up. If these data were not available, an analysis of data on patients who completed treatment was conducted.
There are seven included trials. There are no published reports for two large phase III trials, B304 and B351, although they were completed more than 3 years ago. These are part of the Novartis ADENA programme and comprise 1379 (49%) out of 2803 phase III patients. It is unclear how missing data are replaced in ITT analyses, as reports from the ADENA programme provide no description of the use of this method. This has a profound effect on the results: if the method is substantially the same as LOCF, the benefits of treatment inferred from the analyses described in the publications as ITT, may be exaggerated. The meta-analysis reveals benefits on cognitive function as measured by ADAS-Cog test scores for the higher dose of rivastigmine compared to placebo at 26 weeks and for the lower dose. An additional analysis of ADAS-Cog dichotomised into those showing less than 4 points improvement and those showing 4 or more points improvement at 26 weeks shows benefit for cognitive function for the higher dose of rivastigmine compared to placebo and not for the lower dose. Global clinical state, dichotomised, counting those showing no change or decline, against those showing improvement shows benefit due to lower dose rivastigmine compared to placebo at 26 weeks and not for the higher dose. One trial reported results at 18 weeks and there are no significant differences between higher dose rivastigmine and placebo. One trial reported results at 13 weeks, and there are no significant differences between the 4 or 6 mg/d rivastigmine group and p
Alzheimer's disease (AD) is the commonest cause of dementia affecting older people. One of the therapeutic strategies aimed at ameliorating the clinical manifestations of Alzheimer's disease is to enhance cholinergic neurotransmission in relevant parts of the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts. Tacrine, the first of the cholinesterase inhibitors to undergo extensive trials for this purpose, was associated with significant adverse effects including hepatotoxicity. Several other cholinesterase inhibitors, including rivastigmine, with superior properties in terms of specificity of action and low risk of adverse effects, have now been introduced. Rivastigmine has received approval for use in 60 countries including all member States of the European Union and the USA.
To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer's type.
The Cochrane Controlled Trials Register (April 2000) the Cochrane Dementia and Cognitive Improvement Group Register of Clinical Trials (July 2000), other electronic databases and other sources of reports were searched.
All unconfounded, double-blind, randomized trials in which treatment with rivastigmine was administered to patients with dementia of the Alzheimer's type for more than two weeks and its effects compared with those of placebo in a parallel group of patients.
One reviewer (JSB) applied study selection criteria, assessed the quality of studies and extracted data.
Seven trials, involving 3370 participants, were included. Use of rivastigmine in high doses was associated with statistically significant benefits on several measures. High-dose rivastigmine (6 to 12 mg daily) was associated with a 2.1 point improvement in cognitive function on the ADAS-Cog score compared with placebo (weighted mean difference -2.09, 95% confidence interval -2.65 to -1.54, on an intention-to-treat basis) and a 2.2 point improvment in activities of daily living assessed on the Progressive Deterioration Scale (weighted mean difference -2.15, 95% confidence interval -3.16 to -1.13, on an intention-to-treat basis) at 26 weeks. Fewer patients were graded as having severe dementia at 26 weeks (55% of patients taking rivastigmine compared with 59% on placebo; odds ratio 0.78, 95% confidence interval 0.64 to 0.94). At lower doses (4 mg daily or lower) differences were in the same direction but were statistically significant only for cognitive function. There were statistically significantly higher numbers of events of nausea, vomiting, diarrhoea, anorexia, headache, syncope, abdominal pain and dizziness among patients taking high-dose rivastigmine than among those taking placebo. There was some evidence that adverse events might be less common with more frequent, smaller doses of rivastigmine.
Rivastigmine appears to be beneficial for people with mild to moderate Alzheimer's disease. In comparisons with placebo, improvements were seen in cognitive function, activities of daily living, and severity of dementia with daily doses of 6 to 12 mg. Adverse events were consistent with the cholinergic actions of the drug. Further resarch is desirable on dosage (frequency and quanitity) in a search for ways to minimize adverse effects. This review has not examined economic data.
The acute oral and intravenous toxicity of dimethyl sulfoxide (DMSO) was determined in mice and rats. Anemia and peritoneal inflammation were the main complications noted when rats were given a series of 24 intraperitoneal injections. No fatalities occurred in dogs that received a series of 24 daily intravenous injections of DMSO at dosage levels of 1.2 g/kg and below. Perivascular inflammation and local thrombosis resulted from the repeated intravenous administration of undiluted DMSO, but these reactions did not occur when the material was adequately diluted before use. In addition, a reversible hemolytic anemia was noted in dogs that received repeated intravenous injections of DMSO.DMSO seems to have a relatively low order of systemic toxicity. It has excellent solvent properties and other characteristics that make it a useful solvent for the administration of waterinsoluble drugs. Because of its local toxic action, DMSO should be diluted before parenteral use. Unfortunately, this limits its usefulness somewhat because additions of even small amounts of water may drastically lessen the solvent action. From an esthetic standpoint, the characteristic odor of DMSO may be undesirable.
Alzheimer's disease is a neurodegenerative disorder associated with a decline in cognitive abilities. Patients also frequently have noncognitive symptoms, such as anxiety, depression, apathy, and psychosis, that impair daily living. The most commonly prescribed treatments for Alzheimer's disease are acetylcholinesterase inhibitors, such as donepezil and galantamine. Enhanced cholinergic functions caused by these compounds are believed to underlie improvements in learning, memory, and attention. The noncognitive aspects of dementia, however, are usually linked to serotonin and dopamine rather than acetylcholine because those neurotransmitter systems most directly influence mood, emotional balance, and psychosis. Fast-scan cyclic voltammetry applied to mouse striatal brain slices was used to measure the real-time release of dopamine arising from spontaneous activity or from single electrical stimulations. At concentrations that include their prescribed dosage ranges, donepezil (1-1000 nM) and galantamine (50-1000 nM) increase action potential-dependent dopamine release. Consistent with previous literature, the data support slightly different modes of action for donepezil and galantamine. The ability of these commonly prescribed drugs to alter catecholamine release may underlie their influence over noncognitive symptoms of dementia. Furthermore, these results suggest that acting via nicotinic receptors, these drugs may serve presently untapped therapeutic roles by altering dopamine release in other disorders involving dopaminergic systems.
Aims To create a general physiologically based pharmacokinetic (PBPK) model for drug disposition in infants and children, covering the age range from birth to adulthood, and to evaluate it with theophylline and midazolam as model drugs.
Methods Physiological data for neonates, 0.5-, 1-, 2-, 5-, 10- and 15-year-old children, and adults, of both sexes were compiled from the literature. The data comprised body weight and surface area, organ weights, vascular and interstitial spaces, extracellular body water, organ blood flows, cardiac output and glomerular filtration rate. Tissue: plasma partition coefficients were calculated from rat data and unbound fraction (fu) of the drug in human plasma, and age-related changes in unbound intrinsic hepatic clearance were estimated from CYP1A2 and CYP2E1 (theophylline) and CYP3A4 (midazolam) activities in vitro. Volume of distribution (Vdss), total and renal clearance (CL and CLR) and elimination half-life (t1/2) were estimated by PBPK modelling, as functions of age, and compared with literature data.
Results The predicted Vdss of theophylline was 0.4-0.6 l kg−1 and showed only a modest change with age. The median prediction error (MPE) compared with literature data was 3.4%. Predicted total CL demonstrated the time-course generally reported in the literature. It was 20 ml h−1 kg−1 in the neonate, rising to 73 ml h−1 kg−1 at 5 years and then decreasing to 48 ml h−1 kg−1 in the adult. Overall, the MPE was − 4.0%. Predicted t1/2 was 18 h in the neonate, dropping rapidly to 4.6-7.2 h from 6 months onwards, and the MPE was 24%. The predictions for midazolam were also in good agreement with literature data. Vdss ranged between 1.0 and 1.7 l kg−1 and showed only modest change with age. CL was 124 ml h−1 kg−1 in the neonate and peaked at 664 ml h−1 kg−1 at 5 years before decreasing to 425 ml h−1 kg−1 in the adult. Predicted t1/2 was 6.9 h in the neonate and attained ‘adult’ values of 2.5-3.5 h from 1 year onwards.
Conclusions A general PBPK model for the prediction of drug disposition over the age range neonate to young adult is presented. A reference source of physiological data was compiled and validated as far as possible. Since studies of pharmacokinetics in children present obvious practical and ethical difficulties, one aim of the work was to utilize maximally already available data. Prediction of the disposition of theophylline and midazolam, two model drugs with dissimilar physicochemical and pharmacokinetic characteristics, yielded results that generally tallied with literature data. Future use of the model may demonstrate further its strengths and weaknesses.
Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed (Birks 2005, Birks 2005b and Loy 2005). Despite the evidence from the clinical studies and the intervening clinical experience the debate on whether ChEIs are effective continues.
To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease.
The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases.
All unconfounded, blinded, randomized trials in which treatment with a ChEI was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease.
Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment estimated.
The results of 13 randomized, double blind, placebo controlled trials demonstrate that treatment for periods of 6 months and one year, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.7 points (95%CI -3.0 to -2.3), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians blind to other measures rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large. There is nothing to suggest the effects are less for patients with severe dementia or mild dementia, although there is very little evidence for other than mild to moderate dementia.More patients leave ChEI treatment groups, approximately 29 %, on account of adverse events than leave the placebo groups (18%). There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo. There are four studies, all supported by one of the pharmaceutical companies, in which two ChEIs were compared, two studies of donepezil compared with galantamine, and two of donepezil compared with rivastigmine. In three studies the patients were not blinded to treatment, only the fourth, DON vs RIV/Bullock is double blind. Two of the studies provide little evidence, they are of 12 weeks duration, which is barely long enough to complete the drug titration. There is no evidence from DON vs GAL/Wilcock of a treatment difference between donepezil and galantamine at 52 weeks for cognition, activities of daily living, the numbers who leave the trial before the end of treatment, the number who suffer any adverse event, or any specific adverse event. There is no evidence from DON vs RIV/Bullock of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine.
The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. It is not possible to identify those who will respond to treatment prior to treatment. There is no evidence that treatment with a ChEI is not cost effective. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. There appears to be less adverse effects associated with donepezil compared with rivastigmine. It may be that galantamine and rivastigmine match donepezil in tolerability if a careful and gradual titration routine over more than three months is used. Titration with donepezil is more straightforward and the lower dose may be worth consideration.
The purpose of this study was to examine the feasibility of applying a sample pooling method to the accelerated estimation of the uptake clearance of drugs to the brain in rats. Brain uptake clearances (CL(uptake)) were estimated for five model compounds using the sample pooling method and an integration plot analysis. CL(uptake) was also evaluated for caffeine and theophylline by brain microdialysis. The parameters and throughput of the pooling method were compared with those of typically used standard methods. The correlation for CL(uptake) was statistically significant (P<0.005) between the integration plot and the current method; the throughput of evaluation was 15-fold higher for the sample pooling method. A comparison of CL(uptake) values indicated that the three methods showed comparable results for caffeine while the CL(uptake) of theophylline using the proposed method was significantly different from those of the other methods. A kinetic analysis indicated that a compound with a slower CL(uptake) and longer half-life (e.g., theophylline) is more prone to error and that the lower limit of the CL(uptake) of 0.17 mL min(-1) (g brain)(-1) may be set so as to have an error less than 20% of the estimation. These results suggest that the sample pooling method is applicable for use in the accelerated estimation of the uptake clearance of compounds in the brain for which the value is greater than 0.17 mL min(-1) (g brain)(-1).
Pharmacokinetics: revised and expanded. Series in drugs and the pharmaceutical sciences
- M Gibaldi
- D Perrier