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Effect Compartment (effect + compartment)
Selected AbstractsGeneral linearized biexponential model for QSAR data showing bilinear-type distributionJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 11 2005Peter Buchwald Abstract A major impediment of many QSAR-type analyses is that the data show a maximum or minimum and can no longer be adequately described by linear functions that provide unrivaled simplicity and usually give good description over more restricted ranges. Here, a general linearized biexponential (LinBiExp) model is proposed that can adequately describe data showing bilinear-type distribution as a function of not just often-employed lipophilicity descriptors (e.g., log P) but as a function of any descriptor (e.g., molecular volume). Contrary to Hansch-type parabolic models, LinBiExp allows the natural extension of linear models and fitting of asymmetrical data. It is also more general and intuitive than Kubinyi's model as it has a more natural functional form. It was obtained by a differential equation-based approach starting from very general assumptions that cover both static equilibriums and first-order kinetic processes and that involve abstract processes through which the concentration of the compound of interest in an assumed "effect" compartment is connected to its "external" concentration. Physicochemical aspects placing LinBiExp within the framework of linear free energy relationship (LFER) approaches are presented together with illustrative applications in various fields such as toxicity, antimicrobial activity, anticholinergic activity, and glucocorticoid receptor binding. © 2005 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 94:2355-2379, 2005 [source] Pharmacodynamics of S-2150, a Simultaneous Calcium-blocking and ,1 -Inhibiting Antihypertensive Drug, in RatsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 3 2000TORU ISHIBASHI The in-vivo pharmacodynamics of S-2150, a newly developed dual-blocking type antihypertensive drug, was evaluated following intravenous infusion to rats. Previous in-vitro studies showed that the drug has two distinct mechanisms of antihypertensive effect,calcium-channel blocking activity and ,1 -adrenoceptor antagonism,which could be explained by a combination of two different pharmacodynamic models. The present in-vivo study showed that S-2150 also displays a complex pharmacodynamic profile (as measured by the decrease in mean blood pressure), which could be described by a combination of two sigmoid Emax models independently connected with the central compartment and the effect compartment. These results suggested that the dual-blocking mechanism of S-2150, which has been observed in in-vitro experiments, was also evaluated by the pharmacodynamic analysis of in-vivo experimental data. [source] Nonlinear mixed effects pharmacokinetic/pharmacodynamic analysis of the anticonvulsant ameltolide (LY201116) in a canine seizure modelJOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 6 2008P. R. TERRITO The anticonvulsant ameltolide (LY201116) is a novel potential therapy for the treatment of canine epilepsy. Eight dogs were administered five different oral doses of ameltolide and clinical scoring of the maximal electroshock (MES) induced seizures at 3 and 24 h postdosing were determined in two separate crossover design studies. Plasma ameltolide concentrations were determined at the time of seizures in all dogs and complete plasma concentration-time profiles were also determined in a separate study. A nonlinear mixed effects PK/PD model was fit to the resulting data. A one compartment open model with first order absorption was determined to best fit the ameltolide pharmacokinetics. An effect compartment with a cumulative logistic regression equation was used to establish the PK/PD relationship. The mean bioavailability normalized volume of distribution and the elimination half-life were estimated at 1.20 L/kg and 5.46 h, respectively. The fitted model estimated that from 2 to 15 h following a single 3 mg/kg oral ameltolide dose the mean probability of obtaining a 1 unit reduction in the seizure clinical score severity was greater than 0.80. The utilized PK/PD analysis combined with the canine MES model allowed for the rapid and efficient determination of the plasma ameltolide concentration-anticonvulsant relationship preclinically in dogs. [source] Suppression of the human spinal H-reflex by propofol: a quantitative analysisACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 2 2006J. H. Baars Background:, The spinal cord is an important site of anaesthetic action because it mediates surgical immobility. During anaesthesia with volatile anaesthetics, it has been shown that the suppression of the spinal H-reflex correlates with surgical immobility. To evaluate whether the H-reflex could also be a possible candidate for monitoring immobility during propofol anaesthesia, this study assessed the concentration-dependent suppression of the H-reflex by propofol. To discriminate different effect sites, the individual concentration response-curves and the t1/2ke0 of the H-reflex have been compared with those of two EEG parameters. Methods:, In 18 patients, anaesthesia was induced and maintained with propofol infused using a target-controlled infusion pump at stepwise increasing and decreasing plasma concentrations between 0.5 and 4.5 mg/l. The H-reflex of the soleus muscle was recorded at a frequency of 0.1 Hz. Calculated propofol concentrations and H-reflex amplitude were analysed in terms of a pharmacokinetic-pharmacodynamic (PKPD) model with a sigmoid concentration-response function. Results:, For slowly increasing propofol concentrations, computer fits of the PKPD model for H-reflex suppression by propofol yielded the following median parameters: EC50 1.1 (0.8,1.7) mg/l, slope parameter 2.4 (2.0,3.7), and a t1/2ke0 of 6.7 (2.8,7.5, 25,75% quantiles) min. For the bispectral index, the t1/2ke0 was 2.2 (1.8,3.1) min and for the spectral edge frequency at the 95th percentile of the power spectrum 2.8 (1.9,3.2) min. Conclusions:, Propofol, unlike sevoflurane, suppresses the spinal H-reflex at concentrations far lower than the C50 skin incision. The differences in t1/2ke0 -values indicate the presence of different effect compartments for effects on the H-reflex and the EEG. [source] | ||||||||||