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Biomedical subjects

P Veng-Pedersen

Publications and source records attributed to P Veng-Pedersen.

At least 37 records · Page 2Linked to original sources
PubMed1997

A tracer interaction method for nonlinear pharmacokinetics analysis: application to evaluation of nonlinear elimination.

A drug tracer is most commonly applied to get information about the pharmacokinetics (PK) of a drug that is not confounded by an endogenously produced drug or an unknown drug input. An equally important use of tracers that has not been fully recognized is their use in the study of nonlinear PK behavior. In the present study a system analysis is applied to examine the interaction between drug molecules characteristic and intrinsic to any nonlinear process which enables the nonlinearity to be identified and modeled using a drug tracer. The proposed Tracer Interaction Methodology (TIM) forms a general developmental framework for novel methods for examining nonlinear phenomena. Such methods are potentially much more sensitive and accurate than previous methods not exploiting the tracer principle. The methodology proposed is demonstrated in a simulation study and with real data in a specific implementation aimed at determining the Michaelis-Menten (MM) parameters of nonlinear drug elimination while accounting for drug distribution effects. The simulation study establishes that the TIM-based, MM parameter evaluation produces substantially more accurate parameter estimates than a nontracer (NT) conventional method. In test simulations the accuracy of the TIM was in many cases an order of magnitude better than the NT method without evidence of bias. The TIM-based, MM parameter estimation methodology proposed is ideally suitable for dynamic, non-steady-state conditions. Thus, it offers greater applicability and avoids the many problems specific to steady state evaluations previously proposed. TIM is demonstrated in an evaluation of the nonlinear elimination behavior of erythropoietin, a process that likely takes place via receptor-based endocytosis. Due to its high sensitivity, accuracy, and intrinsic nonlinearity the TIM may be suitable for in-vivo studies of receptor binding of the many biotechnology produced peptide drugs and endogenous compounds displaying receptor-mediated elimination.

Computer Simulation↗
PubMed1996

Erythropoietin pharmacokinetics in premature infants: developmental, nonlinearity, and treatment effects.

Erythropoietin (EPO) pharmacokinetic studies were performed in premature infants (birth weight < 1.25 kg) and normal adults. Infants were divided into two subgroups on the basis of whether they received chronic treatment with recombinant human EPO (rhEPO; 500 IU.kg-1.wk-1 for 6 wk) beginning at 2-4 wk of life. Ten adults and seven rhEPO-treated infants underwent intravenous pharmacokinetic studies at escalating rhEPO doses: 10, 100, and 500 IU/kg. To test for pharmacokinetic developmental and treatment effects, an equal number of non-EPO- and EPO-treated infants were studied with 100 IU/kg on the last day of treatment. Compared with adults, very low birth weight infants demonstrated significantly greater plasma clearance and distribution volume and significantly shorter fractional elimination times (FET) and mean residence time (MRT) at all three rhEPO doses. Both infants and adults demonstrated nonlinear EPO elimination, i.e., increasing rhEPO dosing was associated with decreasing plasma clearance and increasing FET and MRT. In the absence of rhEPO treatment there were no pharmacokinetic differences between the two subgroups of infants studied 6 wk apart. In contrast, the rhEPO-treated infant subgroup demonstrated a significant increase in clearance and a decrease in FET and MRT following 6 wk of treatment. Enhancement of rhEPO efficacy in the prevention and treatment of anemia in premature infants may require higher doses administered in a progressively increasing fashion.

Adult↗
PubMed1996

In vivo 125I-erythropoietin pharmacokinetics are unchanged after anesthesia, nephrectomy and hepatectomy in sheep.

Knowledge regarding the in vivo metabolic fate of the glycoprotein erythropoietin (EPO) is incomplete. To determine whether EPO pharmacokinetics are perturbed by ablation of the kidneys or liver or by anesthesia, EPO pharmacokinetic parameters were determined in adult sheep. Animals were studied in a paired manner, with and without deep barbiturate anesthesia and before and immediately after nephrectomy or hepatectomy accompanied by deep barbiturate anesthesia. Hepatectomy was accomplished with the liver left in situ, by occlusion of the arterial hepatic blood supply and diversion of portal venous flow to the jugular vein. After i.v. administration of tracer amounts of 125I-labeled recombinant human EPO, multiple blood samples were taken over 6 to 7 hr and analyzed for EPO immunoprecipitable radioactivity. EPO pharmacokinetic parameters were derived using a noncompartmental system analysis applied to the data on EPO immunoprecipitable radioactivity. No significant differences were detected for plasma clearance, distribution volume, mean residence time and alpha and beta half-lives examined under each of the three paired study conditions. Contrary to speculation by others, results of the present study make it highly unlikely that removal of the terminal sialic acid moieties of EPO contributes significantly to the metabolism of EPO. Because removal of the liver and kidney had no effect on EPO elimination, the metabolic degradation of EPO occurs in a tissue compartment that is yet to be defined. We speculate that the bone marrow is the most likely tissue with primary responsibility for the metabolism of EPO.

Anesthetics↗
PubMed1995

Kinetic evaluation of nonlinear drug elimination by a disposition decomposition analysis. Application to the analysis of the nonlinear elimination kinetics of erythropoietin in adult humans.

The disposition-decomposition analysis (DDA) methodology enables isolation of the overall elimination and distribution effects in pharmacokinetics and facilitates analysis which focuses on drug elimination kinetics and does not require a specific structured modeling of drug distribution processes. A computer algorithm enables a curve fitting and a kinetic estimation by integration of the convolution type integrodifferential equation in the DDA. The approach is demonstrated in an analysis of the nonlinear disposition kinetics of erythropoietin (Epo) in 10 healthy, adult human subjects who each received 10, 100, and 500 U/kg i.v. bolus doses of Epo. The nonlinearity is analyzed according to a Michaelis-Menten type nonlinear elimination function, considering simultaneous fitting to the data from all three doses in each subject. The simultaneous fittings produced estimates of the Michaelis-Menten parameters (mean, % cv) Vm (901 mU/mL/h, 19.4%) and km (4814 mU/mL, 24.6%). A linear clearance parameter is defined as the asymptotic clearance value approached when the drug level decreases toward zero. The degree of nonlinearity reached from various dosings was quantified in terms of a clearance ratio which is defined as the ratio between the linear clearance and the clearance estimated for the maximum drug concentration encountered at the given dose level. The subjects showed very little nonlinearity at the 10 U/kg dosing with a mean clearance ratio of 1.07 (2.1% CV) A statistically significant increase in the degree of nonlinearity was observed in the Epo elimination kinetics as the dosing level was increased to 100 and 500 U/kg, reaching clearance ratios of 1.66 (14% CV) and 4.33 (27% CV), respectively. A zero value for the global elimination rate parameter in all 30 dosings indicates that Epo's elimination is entirely accounted for by nonlinear pathway(s).

Adult↗
PubMed1995

Duration of opioid antagonism by nalmefene and naloxone in the dog: an integrated pharmacokinetic/pharmacodynamic comparison.

A continuous fentanyl infusion was administered to eight adult, male beagle dogs for a duration of approximately 400 min at a rate of 30 micrograms/kg/h. The extent of respiratory depression was quantified by continuous, noninvasive, transcutaneous pCO2 recordings. Upon reaching a pseudosteady-state of respiratory depression at approximately 120 min of fentanyl infusion, the animals then received, in a 2 x 2 crossover fashion separated by approximately 3 weeks, 30-minute equiefficacious infusions of nalmefene (12 micrograms/kg/h) or naloxone (48 micrograms/kg/h). Multiple venous blood samples were taken throughout the dosing regimen, and the resulting fentanyl, nalmefene, or naloxone plasma concentrations were determined. The concentration-time data were analyzed by noncompartmental methods and subsequently linked to the pharmacodynamic effect data by a competitive antagonism link model. Separately, the biophase concentrations were linked to the plasma concentration-time profiles through a single-exponential conduction function. The various pharmacokinetic/pharmacodynamic parameters resulting from this semiparametric analysis were analyzed by ANOVA, using a statistical model that considers carryover effects. The results of these analyses indicate that several pharmacokinetic/pharmacodynamic parameters of the two antagonists were comparable. However, nalmefene had a significantly more protracted terminal disposition and a significantly greater persistency in the biophase evaluated over the experimental time frame from 0 to 450 min.

Animals↗
PubMed1995

Duration of opioid antagonism by nalmefene and naloxone in the dog. A nonparametric pharmacodynamic comparison based on generalized cross-validated spline estimation.

The opioid antagonist nalmefene was compared in its pharmacodynamic properties to the structurally similar antagonist naloxone in a 2 x 2 cross-over study with 8 dogs. Opioid-induced respiratory depression was produced for ca. 7 hours with a constant rate intravenous infusion of 30 micrograms/kg/hr fentanyl and quantified using noninvasive transcutaneous pCO2 recordings. Upon reaching a pseudo-steady state of respiratory depression at 2 hours post fentanyl infusion initiation, the animals then received either nalmefene (12 micrograms/kg/hr) or naloxone (48 micrograms/kg/hr) for 30 minutes. The pharmacodynamic pCO2 responses produced by the combined agonist/antagonist regimen were fitted with a cubic spline function using a generalized cross-validation technique. Various quantities that describe the onset, duration and relative potency of each antagonist were determined directly from the estimated response curves in a model-independent, nonparametric way. The 2 antagonists were compared in terms of these quantities using a statistical model that considers carry-over effects typically arising from a possible development of tolerance. The results indicate that nalmefene: 1. is approximately 4-fold more potent than naloxone, 2. has an onset of reversal as rapid as naloxone, and 3. has a significantly longer (2-fold) pharmacodynamic duration of action than does naloxone. The mean time required for the agonist to regain 30% or 50% of its effect present at the start of the antagonist infusion was 66 and 112 minutes and 37 and 55 minutes for nalmefene and naloxone, respectively. Early, effective pharmacodynamic screening of new drug compounds is a valuable way of accelerating the drug discovery process and reducing escalating drug development costs. This study exemplifies a novel, endpoint oriented pharmacodynamic comparison procedure that can be done expeditiously before starting the time consuming development and validation of a drug level assay, and before engaging in considerably more involved integrated PK/PD studies.

Analysis of Variance↗
PubMed1994

Application of a variable direction hysteresis minimization approach in describing the central nervous system pharmacodynamic effects of alfentanil in rabbits.

The relationship between the concentration of a drug and its pharmacologic effect is of central interest in pharmacodynamics. Various compartmental and noncompartmental methods have been proposed for elucidating this relationship when the plasma drug concentration and effects are both measured. Although the relationship between drug input and the pharmacologic effect is equally useful, it has not received as much attention. A system analysis hysteresis minimization pharmacodynamic method was developed to describe the central nervous system effects of alfentanil in rabbits. The spectral edge frequency (SEF) was used as the effect measure and the infusion rate as the pharmacokinetic variable. The sigmoid Emax and cubic polynomial representations of the transduction relationship were investigated in modeling the collapsed hysteresis loop. The results indicated that alfentanil has a relatively rapid biophase equilibration time (t50 = 6 min). Both the sigmoid Emax and cubic polynomial transduction relationships were equally effective in describing the observed effect data and gave similar predictions. The proposed approach has the advantage of not assuming a specific compartmental structure for the pharmacokinetic-pharmacodynamic link. A particular advantage of the method is that no functional relationship is assumed a priori for the transduction relationship, and errors in both regression variables are considered in the optimization. The system analysis pharmacodynamic approach assumes linear disposition pharmacokinetics, an instantaneous and time-invariant transduction, and that inductive effects like tolerance or sensitization do not develop significantly in the time frame studied.

Alfentanil↗
PubMed1994

Quantitative structure-pharmacokinetic relationships for systemic drug distribution kinetics not confined to a congeneric series.

Many attempts have been made to describe quantitative structure-pharmacokinetic relationships within a congeneric series of drug molecules. The goal is to develop a predictive relationship that could predict in vivo results for other drugs within that series. These studies typically evaluate pharmacokinetic parameters that are reflective of both distribution and elimination processes. This work utilizes the results from 17 noncongeneric drugs reported in 18 pharmacokinetic studies. The objective was to determine if drug distribution parameters that were independent of elimination could be predicted from easily measured physicochemical parameters with a data base that included a wide variety of drugs that were not congeners of one another. Regression models utilizing a linear and a quadratic response surface were used to predict the various distribution parameters from physicochemical parameters, including molecular weight, intrinsic solubility, alcohol solubility, protein binding, and the distribution coefficient. Analogous to the extent of absorption, the extent of drug distribution can be predicted reasonably well by the probability that the drug will distribute into the peripheral system before being eliminated and by the volume of distribution at steady state. The duration of distribution, analogous to the rate of absorption, can be predicted by the mean transit time through the peripheral system the mean residence time of the drug in the peripheral system and the intrinsic mean residence time in the peripheral system. The ability to use statistical models to approximate drug distribution parameters without the constraints of working within a congeneric series provides some valuable opportunities.

Chemical Phenomena↗
PubMed1994

Validation of a variable direction hysteresis minimization pharmacodynamic approach: cardiovascular effects of alfentanil.

An important goal in therapeutics is the quantitative prediction of drug effects. Although several comprehensive pharmacodynamic models have been proposed, relatively few of these have attempted to assess objectively the application of the models to predict pharmacologic responses. A variable-direction hysteresis minimization approach was proposed recently that allowed the pharmacodynamics of drugs to be modeled using information about drug input. The application and validation of this approach are demonstrated using the pharmacodynamic effect of alfentanil, a short-acting narcotic analgesic agent, in New Zealand White rabbits. A parameter is proposed to assess the ability of the pharmacodynamic model to predict responses.

Alfentanil↗
PubMed1994

Phenobarbital removal characteristics of three brands of activated charcoals: a system analysis approach.

The in vivo phenobarbital removal characteristics of three brands of activated charcoal (Actidose, Charcoaid, Superchar) were studied in normal volunteers using a system analysis approach. The subjects received a 200-mg dose of oral or intravenous phenobarbital followed by a single oral dose of 30 g of one of the three charcoals in a randomized crossover design. The relative merits of the three charcoals in enhancing the removal of oral and intravenous phenobarbital were assessed using a system analysis approach. The removal clearance, time to peak (tp), peak removal clearance (Rmax), percentage of dose removed (PCT infinity), and phenobarbital removal clearance (CLr) were calculated for the oral and intravenous treatments. Superchar had a pulse-like effect, with the shortest tp and the largest Rmax. Actidose and Charcoaid had similar effects, with Actidose inducing slightly greater phenobarbital removal. Superchar has the highest surface area and relative percentage of surface hydroxyl groups, whereas Actidose has the lowest surface area and relative percentage of surface hydroxyl groups of the three charcoals studied. Although correlations between the in vitro and the in vivo phenobarbital adsorption characteristics of the three charcoals may be difficult due to the presence of preservatives and palatibility enhancers in the commercial preparations, it appears that the in vivo effectiveness decreases as the surface area and the concentration of surface hydroxyl groups decrease. The proposed system analysis approach requires fewer assumptions than methods based on compartmental or physiologic approaches and has the advantage of describing the phenobarbital removal in a dynamic manner.

Absorption↗
PubMed1993

A system approach to pharmacodynamics. Input-effect control system analysis of central nervous system effect of alfentanil.

Virtually all biological variables, including those affected by drugs, are subject to adaptive self regulation. In the description of the pharmacodynamics (PD) of drugs, it may be necessary to consider the endogenous control system (ECS) as an integral part of the PD. A PDECS model based on system analysis principles is presented and tested on PD data for alfentanil considering the central nervous system activity quantified by a power spectrum analysis of the electroencephalogram. The model was tested in terms of a proposed relative prediction performance criterion that measures the accuracy of future predictions relative to how well the model describes (fits) the past effect data. A mean value of 80% (standard deviation, 28) for relative prediction performance indicates that the model performs well when challenged by the complex multiple infusion scheme used in the test. The overshoot phenomenon observed in the data is considered by the PDECS model as a ECS-based tolerance phenomenon. The proposed development of tolerance is modeled as a variable gain in the ECS processing that influences the effect. Although the development and loss of tolerance is determined by a single rate constant in the tolerance model, the rates of increase and decrease of tolerance may be substantially different. Contrary to other PD tolerance models, the proposed PDECS approach models the tolerance in terms of an effect deviation from an ECS set point. The intrinsic (no tolerance) effect of the drug is isolated in terms of an open loop (no feedback) effect.

Alfentanil↗
PubMed1993

Application of a system analysis approach to population pharmacokinetics and pharmacodynamics of nicardipine hydrochloride in healthy males.

Nicardipine hydrochloride, a dihydropyridine calcium channel blocker, possesses antihypertensive and arterial vasodilator properties. A system analysis approach, which makes fewer structural assumptions than compartmental methods, is presented for determining the pharmacokinetics and pharmacodynamics of nicardipine hydrochloride in healthy males following a discontinuous infusion at four dose levels. The results indicate that the average total body clearance of nicardipine is 0.920 L/h/kg and the volume of distribution is 0.275 L/kg. Nicardipine hydrochloride has a mean residence time in the body of 1.27 h, of which 0.324 h were spent in the systemic circulation and the remainder in the periphery. The determined pharmacokinetic model was linked to a pharmacodynamic model that allowed the change in the mean arterial blood pressure and heart rate to be described and predicted. A population pharmacokinetic-pharmacodynamic model was derived and the predictive power of the proposed model was assessed with a cross-validation technique that employs a relative predictive quotient for comparing the predictions to the fitted model. The results indicate that the proposed model describes the pharmacodynamics of nicardipine in healthy males and has good predictive ability when tested with a cross-validation procedure.

Adult↗
PubMed1993

A system approach to pharmacodynamics. Plasma iron mobilization by endogenous erythropoietin in the sheep fetus; evidence of threshold response in spontaneous hypoxemia.

At present, nearly all infants with birth weights of < 1 kg receive blood transfusions for treatment of clinical signs of tissue hypoxia resulting from anemia of prematurity. In contrast to the successful use of recombinant human erythropoietin (rhEp) in adults, treatment of anemic neonates with rhEp to stimulate red cell production and reduce the need for transfusions that pose serious infectious and immunologic risk has not been effective. The present study investigates the pharmacodynamics (PD) of endogenous erythropoietin (Ep) in sheep fetuses to determine possible causes for the poor rhEp response in early development. The dynamic relationship between plasma Ep and plasma iron resulting from spontaneous hypoxemic episodes is investigated by PD system analysis. The erythropoietic effect of Ep is measured in terms of the mobilization of plasma iron needed in the production on new erythrocytes. A hysteresis minimization approach is employed to determine the intrinsic PD dose-response relationship (transduction) of Ep. The dose-response relationship shows a well-defined threshold level that has to be exceeded before Ep begins to show a significant effect on plasma iron. It is postulated that the threshold mechanism may serve a useful purpose during early development by reducing the risk of the fetus developing a pathological degree of polycythemia and hyperviscosity in the relatively hypoxemic fetal environment. At the same time, the threshold serves the purpose of providing a needed response to more severe pathologic hypoxemic episodes. The occurrence of anemia during subsequent postnatal life when PaO2 levels increase markedly may be the inevitable, but unfortunate corollary of a continuation of this mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Application of neural networks to pharmacodynamics.

Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems. A synopsis is presented of the operational characteristics, structures, and applications of NN. The NN technology has primarily been aimed at recognition science (e.g., handwriting, voice, signal, picture, image, pattern, etc.). It is pointed out that NN may also be particularly suitable to deal with pharmacokinetic (PK) and pharmacodynamic (PD) systems, especially in cases such as multivariate PK/PD population kinetics when the systems are so complex that modeling by a conventional structured model building technique is very troublesome. The main practical advantage of NN is the intrinsic ability to closely emulate virtually any multivariate system, including nonlinear systems, independently of structural/physiologic relevance. Thus, NN are most suitable to model the behavior of complex kinetic systems and unsuitable to model the structure. In a practical sense, this structure limitation may be inconsequential because NN in its multivariate formulation may consider any physiologic, clinical, or population variable that may influence the kinetic behavior. The application of NN in PD is demonstrated in terms of the ability of an NN to predict, by extrapolation, the central nervous system (CNS) activity of alfentanil. The drug was infused by a complex computer-controlled infusion scheme over 180 min with simultaneous recording of the CNS effect quantified by a fast Fourier transform power spectrum analysis. The NN was trained to recognize (emulate) the drug input-drug effect behavior of the PD system with the input-effect data for the 180 min as a training set.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗
PubMed1992

An algorithm for constrained deconvolution based on reparameterization.

The method of deconvolution is the most general method of evaluating drug absorption. Deconvolution does not normally subscribe to a particular structured model for the input function that would ensure non-negativity of the calculated input rate. Unfortunately, the increased flexibility gained by this "model independence" sometimes results in a calculated input rate that becomes negative in the late absorption phase. A method for constrained deconvolution is proposed to overcome this deficiency. The method is based on a reparameterization of the input function in a "model-free" context. The reparameterization schemes proposed are optimal in the sense that they give the input function its maximum flexibility possible while at the same time ensuring non-negativity. The method makes use of "deconvolution through convolution." The basic procedure of this technique is, during the curve fitting, to iteratively adjust the input function so that when it is convolved with the unit impulse response function it results in a curve that best fits the data from the extravascular administration. Cimetidine data from oral and iv administrations are deconvolved by the proposed method to demonstrate the basic procedures involved. The proposed method is easy to implement since it relies on simple curve-fitting procedures as routinely performed in pharmacokinetics. The procedure can be carried out using any of the many curve-fitting programs available that allow the user to supply the function to be fitted and allow simple bounds to be specified for the fitted parameters. The convolution required by the method can be done analytically using a previously published computer program.

Algorithms↗
PubMed1992

Pharmacodynamic system analysis of the biophase level predictor and the transduction function.

This work deals with the pharmacodynamic problem of relating a drug effect E(t) to an observable pharmacokinetic (PK) predictor variable r(t), which may be a venous and/or arterial drug level, some other PK variable, or a drug infusion scheme. It is proposed that the relationship between E(t) and r(t) may, in many cases, be appropriately modeled as E(t) = N(F(r(t))) [for practical analysis reasons, F(r(t)) is denoted the biophase level, cb(t), the operator F() is accordingly denoted the biophase level predictor (BLP), and N() is denoted the transduction function (TF)]. This work proposes a method for determining the two fundamental components, BLP and TF, that define the E(t)-r(t) relationship. The BLP is determined by a hysteresis minimization (HM) technique with the following features: (1) the method considers errors in both HM variables; (2) the method is suitable for dealing with the important case in which the predictor variable is a drug infusion scheme; (3) the approach is noncompartmental in contrast to the effect-compartment approaches and it does not require a specific structured modeling of the cb(t)-r(t) relationship when dealing with drugs with linear PKs in a general operational sense; and (4) the method makes use of a dimensionless transformation of the hysteresis variable that eliminates numerical scaling problems so that a complex penalty function optimization approach can be avoided. The TF is determined by a cross validation procedure in conjunction with the BLP determined by HM. The method is demonstrated using pharmacodynamic data for several drugs, considering both concentration-based and drug input-based r(t) values. The significance of the information obtained from the determined BLP and TF is discussed, including the concepts of equilibration dynamics and overloading. The limitations and potential problems of the methodology are discussed.

Alfentanil↗
PubMed1992

Neural networks in pharmacodynamic modeling. Is current modeling practice of complex kinetic systems at a dead end?

Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems, in particular the brain. Computational NN are classified as parallel distributed processing systems that for many tasks are recognized to have superior processing capability to the classical sequential Von Neuman computer model. NN are recognized mainly in terms of their adaptive learning and self-organization features and their nonlinear processing capability and are considered most suitable to deal with complex multivariate systems that are poorly understood and difficult to model by classical inductive, logically structured modeling techniques. A NN is applied to demonstrate one of the potentially many applications of NN for modeling complex kinetic systems. The NN was used to predict the effect of alfentanil on the heart rate resulting from a complex infusion scheme applied to six rabbits. Drug input-drug effect data resulting from a repeated, triple infusion rate scheme lasting from 30 to 180 min was used to train the NN to recognize and emulate the input-effect behavior of the system. With the NN memory fixed from the 30- to 180-min learning phase the NN was then tested for its ability to predict the effect resulting from a multiple infusion rate scheme applied in the subsequent 180 to 300 min of the experiment. The NN's ability to emulate the system (30-180 min) was excellent and its predictive extrapolation capability (180-300 min) was very good (mean relative prediction accuracy of 78%). The NN was best in predicting the higher intensity effect and was able to identify and predict an overshoot phenomenon likely caused by a withdrawal effect from acute tolerance. Current modeling philosophy and practice is discussed on the basis of the alternative offered by NN in the modeling of complex kinetic systems. In modeling such systems it is questioned whether traditional modeling practice that insists on structure relevance and conceptually pleasing structures has any practical advantages over the empirical NN approach that largely ignores structure relevance but concentrates on the emulation of the behavior of the kinetic system. The traditional searching for appropriate models of complex kinetic systems is a painstakingly slow process. In contrast, the search for empirical models using NN will continue to improve, limited only by technological advances supporting the very promising NN developments.

Alfentanil↗