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P Macheras

Publications and source records attributed to P Macheras.

At least 19 recordsLinked to original sources
PubMed2006

In-vitro study on the competitive binding of diflunisal and uraemic toxins to serum albumin and human plasma using a potentiometric ion-probe technique.

The competitive binding of diflunisal and three well-known uraemic toxins (3-indoxyl sulfate, indole-3-acetic acid and hippuric acid) to bovine serum albumin (BSA), human serum albumin (HSA) and human plasma was studied by direct potentiometry. The method used the potentiometric drug ion-probe technique with a home-made ion sensor (electrode) selective to the drug anion. The site-oriented Scatchard model was used to describe the binding of diflunisal to BSA, HSA and human plasma, while the general competitive binding model was used to calculate the binding parameters of the three uraemic toxins to BSA. Diflunisal binding parameters, number of binding sites, n(i) and association constants for each class of binding site, K(i), were calculated in the absence and presence of uraemic toxins. Although diflunisal exhibits high binding affinity for site I of HSA and the three uraemic toxins bind primarily to site II, strong interaction was observed between the drug and the three toxins, which were found to affect the binding of diflunisal on its primary class of binding sites on both BSA and HSA molecules and on human plasma. These results are strong evidence that the decreased binding of diflunisal that occurs in uraemic plasma may not be solely attributed to the lower albumin concentration observed in many patients with renal failure. The uraemic toxins that accumulate in uraemic plasma may displace the drug from its specific binding sites on plasma proteins, resulting in increased free drug plasma concentration in uraemic patients.

Algorithms↗
PubMed2003

The power law can describe the 'entire' drug release curve from HPMC-based matrix tablets: a hypothesis.

The purposes of this study were to (i) re-examine the relevance of Higuchi equation and the power law using both simulated and experimental release data in conjunction with the linearized, in terms of t(1/2), percent of drug release plots, (ii) demonstrate that the power law describes the entire drug release profile of several experimental data, and (iii) point out a physically based hypothesis for the successful use of power law in describing the entire drug release profile. Simulated data generated from the equation of power law were further analyzed using linear regression analysis in accord with the Higuchi equation. The analysis revealed that data generated from the equation of power law can be misinterpreted as obeying the Higuchi equation. The use of power law in describing the entire drug release curve from HPMC-based matrix tablets is validated by direct fit of power law equation to published data of other authors. A hypothesis based on the nonclassical diffusion of the solutes in the HPMC matrices is used to interpret the successful use of the power law in describing the entire release profile.

Algorithms↗
PubMed2001

Fractal volume of drug distribution: it scales proportionally to body mass.

PURPOSE: To develop the physiologically sound concept of fractal volume of drug distribution, vf, and evaluate its utility and applicability in interspecies pharmacokinetic scaling. METHODS: Estimates for vf of various drugs in different species were obtained from the relationship: vf = (v - Vpl)(Vap - Vpl)/V + Vpl where v is the total volume of the species (equivalent to its total mass assuming a uniform density Ig/mL), Vpl is the plasma volume of the species and Vap is the conventional volume of drug distribution. This equation was also used to calculate the fractal analogs of various volume terms of drug distribution (the volume of central compartment, Vc, the steady state volume of distribution, Vss, and the volume of distribution following pseudodistribution equilibrium, Vz). The calculated fractal volumes of drug distribution were correlated with body mass of different mammalian species and allometric exponents and coefficients were determined. RESULTS: The calculated values of vf for selected drugs in humans provided meaningful and physiologically sound estimates for the distribution of drugs in the human body. For all fractal volume terms utilized, the allometric exponents were found to be either one or close to unity. The estimates of the allometric coefficients were found to be in the interval (0,1). These decimal values correspond to a fixed fraction of the fractal volume term relative to body mass in each one of the species. CONCLUSIONS: Fractal volumes of drug distribution scale proportionally to mass. This confirms the theoretically expected relationship between volume and mass in mammalian species.

Animals↗
PubMed2001

Nonlinear dynamics and chaos theory: concepts and applications relevant to pharmacodynamics.

The theory of nonlinear dynamical systems (chaos theory), which deals with deterministic systems that exhibit a complicated, apparently random-looking behavior, has formed an interdisciplinary area of research and has affected almost every field of science in the last 20 years. Life sciences are one of the most applicable areas for the ideas of chaos because of the complexity of biological systems. It is widely appreciated that chaotic behavior dominates physiological systems. This is suggested by experimental studies and has also been encouraged by very successful modeling. Pharmacodynamics are very tightly associated with complex physiological processes, and the implications of this relation demand that the new approach of nonlinear dynamics should be adopted in greater extent in pharmacodynamic studies. This is necessary not only for the sake of more detailed study, but mainly because nonlinear dynamics suggest a whole new rationale, fundamentally different from the classic approach. In this work the basic principles of dynamical systems are presented and applications of nonlinear dynamics in topics relevant to drug research and especially to pharmacodynamics are reviewed. Special attention is focused on three major fields of physiological systems with great importance in pharmacotherapy, namely cardiovascular, central nervous, and endocrine systems, where tools and concepts from nonlinear dynamics have been applied.

Biopharmaceutics↗
PubMed2001

A stochastic model describes the heterogeneous pharmacokinetics of cyclosporin.

The pharmacokinetics of cyclosporin (CsA) are unusual because of several heterogeneous features which include the presence of more than one conformer, considerable accumulation in erythrocytes and lipoproteins, extensive plasma protein binding, distribution into deep tissues, biliary secretion and hepatic clearance involving a large number of metabolites. In this study, a stochastic compartmental model was developed to describe the heterogeneous elimination kinetics of CsA. This new approach relies on a probabilistic transfer model with a gamma distributed probability intensity coefficient for drug elimination. For comparative purposes both the stochastic model and compartmental deterministic models were fitted to real post infusion data from patients receiving CsA as a 2-hr intravenous infusion. The criteria for selecting the best model showed that the stochastic model, although simpler than the compartmental deterministic models, is more flexible and gives a better fit to the kinetic data of CsA than the compartmental deterministic models. The stochastic model with a random rate intensity coefficient adequately describes the heterogeneous pharmacokinetics of CsA.

Cyclosporine↗
PubMed2000

Non-linear regression analysis with errors in both variables: estimation of co-operative binding parameters.

Four different parameter estimation criteria, the geometric mean functional relationship (GMFR), the maximum likelihood (ML), the perpendicular least-squares (PLS) and the non-linear weighted least squares (WLS), were used to fit a model to the observed data when both regression variables were subject to error. Performances of these criteria were evaluated by fitting the co-operative drug-protein binding Hill model on simulated data containing errors in both variables. Six types of data were simulated with known variances. Comparison of the criteria was done by evaluating the bias, the relative standard deviation (S.D.) and the root-mean-squared error (RMSE), between estimated and true parameter values. Results show that (1) for data with correlated errors, all criteria perform poorly; in particular, the GMFR and ML criteria. For data with uncorrelated errors, all criteria perform equally well with regard to the RMSE. (2) Use of GMFR and ML lead to lower values for S.D. but higher biases compared with WLS and PLS. (3) WLS performs less well when equal dispersion is applied to the two observed variables.

Binding Sites↗
PubMed1999

Modeling of supersaturated dissolution data.

A recursion equation which relies on the population growth model of dissolution is used for the analysis of supersaturated dissolution data. The concentration-time data of dissolution experiments are initially transformed to fractions of dose dissolved-generations by adopting an appropriate time interval as the time step of the recursion equation. A computer program is used to derive estimates for the maximum fraction of dose dissolved and the fraction of dose remaining in solution at steady state. Good fittings were observed when this equation was applied to phenytoin and nifedipine supersaturated dissolution data obtained from literature.

Chemistry, Pharmaceutical↗
PubMed1999

Quantitative determination of cefepime in plasma and vitreous fluid by high-performance liquid chromatography.

An isocratic reversed-phase HPLC method was developed to determine cefepime levels in plasma and vitreous fluid. Cefepime and the internal standard cefadroxil were separated on a Shandon Hypersil BDS C18 column by using a mobile phase of 25 mM sodium dihydrogen phosphate monohydrate (pH 3) and methanol (87:13, v/v). Ultraviolet detection was carried out at 270 nm. The retention times were 4.80 min for cefepime and 7.70 min for cefadroxil. This fast procedure which involves an efficient protein precipitation step (addition of HClO4), allows a quantification limit of 2.52 microg ml(-1) and a detection limit of 0.83 microg ml(-1). Recoveries and absolute recoveries of cefepime from plasma were 96.13-99.44% and 94-102.5% respectively. The intra-day and inter-day reproducibilities were less than 2% for cefepime at 10, 30, 50 microg ml(-1) (n=10). The method was proved to be suitable for determining cefepime levels in human plasma and was modified to measure vitreous fluid samples.

Aged↗
PubMed1999

A displacement approach for competitive drug-protein binding studies using the potentiometric 1-anilino-8-naphthalene-sulfonate probe technique.

A displacement approach for competitive binding studies was developed. The method utilizes the potentiometric 1-anilino-8-naphthalene-sulfonate (ANS) probe technique and is applied to the binding study of several non-steroidal anti-inflammatory drugs (NSADs) to bovine serum albumin (BSA). A home-made ANS electrode was used to monitor the displaced free ANS probe from its binding sites on the protein molecule by the stepwise addition of the studied drug. To assess and compare quantitatively the displacing ability of the various drugs, the 'ANS Displacement Index' is used. The possible interference of 19 ionizable drugs (NSADs, sulfonamides, etc.) to the ANS selective electrode at pH 7.4 was studied and their potentiometric selectivity coefficients (K(pot)(ANS,D)) were determined. Correction procedures for the determination of the free ANS concentration are proposed in the case of interfering ionic drugs. A blank binding experiment in conjunction with the incorporation of K(pot)(ANS,D) values in the 'general competitive site oriented model' allows one to derive estimates for the drug binding parameters, i.e. the number of binding sites and association constants.

Anilino Naphthalenesulfonates↗
PubMed1999

An alternative method for the estimation of the terminal slope when a few data points are available.

Phase plane plots are graphical expressions for differential equations plotting the state derivative dc/dt versus the state c. Using these plots, we developed a novel method for the estimation of the terminal slope from time-concentration data. The values of the derivatives used for the construction of the phase plane plots were calculated by two different methods of numerical differentiation. The first method (D1) is based on the classical calculation of slope of the line connecting two successive data points. The alternative method (D2) relies on an initial second-order polynomial interpolation utilizing three successive data points followed by the calculation of the derivative at each one of the concentration values. A forced-through-zero linear regression of the phase plane plot data is used to derive an estimate for the slope. For comparative purposes, the standard approach based on the semilogarithmic plot was also applied. For a hypothetical drug absorbed by first-order process into a one-compartment model, simulated time-concentration data disturbed by a Gaussian zero mean random error with various coefficients of variation were generated. Various sampling schedules, with two, three, four, or five data points, were utilized for the estimation of the terminal slope. Performances of the proposed methods on simulated data were expressed by means of root-mean-squared error, bias, and standard deviation. In all cases, D2 was superior to D1. The D2 method outperforms the standard method in that it furnishes estimates closer to the real values in all cases when two data points and in most cases when three data points were used. All methods behave similarly when four or five data points were used.

Pharmacokinetics↗
PubMed1999

Heterogeneous tube model for the study of small intestinal transit flow.

PURPOSE: A Monte-Carlo computer simulation technique was employed to study the details of the small intestinal transit flow in the gastrointestinal (GI) tract. METHODS: A heterogeneous tube model was constructed using a numerical computer simulation technique. The model was built from first principles and included several heterogeneous characteristics of the GI tract structure. We used a random, dendritic-type internal structure representing the villi of the GI tract. The small intestinal transit flow was simulated using two diffusion models, namely, the blind ant and the myopic ant models, which are different models to account the elapse of time, and which are both based on statistical properties of random walks. For each one of the models we utilize two types of biased random walk, placing different emphasis in the motion towards the output of the tube. We monitored the flow of the drug in terms of Monte-Carlo time steps (MCS) through the tube walls and dendritic villi present. RESULTS: The frequency of the transit times was dependent on the structure of the dendritic villi and on the type of biased random walk. The small intestinal flow profile of literature data for a large number of drugs was well characterized by the heterogeneous model using, as parameters, a certain number of villi per unit length of the tube and specific characteristics for both types of the biased random walk. A correspondence between the MCS and real time units was achieved. CONCLUSIONS: The transit process of the oral dosage forms in the GI tract can be reproduced with the heterogeneous model developed. This model can be used to study GI absorption phenomena.

Computer Simulation↗
PubMed1999

A heterogeneous tube model of intestinal drug absorption based on probabilistic concepts.

PURPOSE: To develop an approach based on computer simulations for the study of intestinal drug absorption. METHODS: The drug flow in the gastrointestinal tract was simulated with a biased random walk model in the heterogeneous tube model (Pharm. Res. 16, 87-91, 1999), while probability concepts were used to describe the dissolution and absorption processes. An amount of drug was placed into the input end of the tube and allowed to flow, dissolve and absorb along the tube. Various drugs with a diversity in dissolution and permeability characteristics were considered. The fraction of dose absorbed (Fabs) was monitored as a function of time measured in Monte Carlo steps (MCS). The absorption number An was calculated from the mean intestinal transit time and the absorption rate constant adhering to each of the drugs examined. RESULTS: A correspondence between the probability factor used to simulate drug absorption and the conventional absorption rate constant derived from the analysis of data was established. For freely soluble drugs, the estimates for Fabs derived from simulations using as an intestinal transit time 24500 MCS (equivalent to 4.5 h) were in accord with the corresponding data obtained from literature. For sparingly soluble drugs, a comparison of the normalized concentration profiles in the tube derived from the heterogeneous tube model and the classical macroscopic mass balance approach enabled the estimation of the dissolution probability factor for five drugs examined. The prediction of Fabs can be accomplished using estimates for the absorption and the dissolution probability factors. CONCLUSIONS: A fully computerized approach which describes the flow, dissolution and absorption of drug in the gastrointestinal tract in terms of probability concepts was developed. This approach can be used to predict Fabs for drugs with various solubility and permeability characteristics provided that probability factors for dissolution and absorption are available.

Computer Simulation↗
PubMed1998

The effect of HPMC--a cholesterol-lowering agent--on oral drug absorption in dogs.

The objective of this study was to evaluate the effects which hydroxypropylmethylcellulose (HPMC) may exert on oral drug absorption, in cases where this soluble fiber is administered to regulate blood lipid levels. Studies were conducted in vitro and in healthy female mongrel dogs using two different grades of HPMC, i.e. K8515 HPMC and ultra high molecular weight (UHMW) HPMC. The maximum plasma concentration, Cmax, of paracetamol and both the Cmax and the area under the concentration-time curve, AUC, of cimetidine were significantly decreased by the coadministration of 10 g of K8515 HPMC or 7.5 g of UHMW HPMC dissolved in 500 mL normal saline under fasting conditions. No statistically significant effects were observed on hydrochlorothiazide or mefenamic acid absorption. Based on in vitro data and previous studies it appears that reductions in gastric emptying and dissolution rate of paracetamol account for the effect observed in vivo. For cimetidine, a drug which can be absorbed from both the small and the large intestine, the indigestibility of HPMC in the colon in addition to the great reduction of dissolution rate led to reductions of both the Cmax and AUC values. The long Tmax values, even in the absence of HPMCs and the more modest reduction of the dissolution rate of hydrochlorothiazide by the HPMCs are thought to have precluded the observation of any significant alterations in the in vivo absorption profile. Owing to its erratic absorption, no statistically based conclusion could be drawn about the effects of coadministered HPMC on the oral absorption of the poorly soluble mefenamic acid. It is concluded that the effects of HPMCs on drug absorption in dogs are most pronounced for compounds with absorption profiles that are dependent on gastric emptying, i.e. compounds that are highly water soluble and that exhibit short Tmax values. Compounds with long absorption profiles appear to be less susceptible to changes in absorption behavior due to coadministration of HPMCs.

Animals↗
PubMed1998

Effect of elevated viscosity in the upper gastrointestinal tract on drug absorption in dogs.

The objectives of these studies were, first, to determine the effect of elevated luminal viscosity on the gastrointestinal absorption of four model drugs and, second, to identify the key processes influencing drug absorption under elevated viscosity conditions. Studies were conducted in vitro and in healthy female mongrel dogs under fasting conditions. In the canine model, both the rate and extent of paracetamol and hydrochlorothiazide absorption were significantly decreased by the coadministration of 15 g guar gum dissolved in 500 ml normal saline. In the case of cimetidine, the rate but not extent of absorption was decreased. Owing to the high variability in the data, no statistically based conclusion could be drawn about the effects of coadministered guar gum on the oral absorption of the poorly soluble mefenamic acid. Based on the in vitro data, it appears that substantial reductions in the dissolution rate of paracetamol, hydrochlorothiazide and cimetidine account for the effects observed in vivo. It is concluded that the effect of an elevation in the intraluminal viscosity on drug absorption is greatest for highly soluble drugs, and results from a combination of a decrease in dissolution rate and gastric emptying rate.

Acetaminophen↗
PubMed1998

Investigation of absorption kinetics by the phase plane method.

PURPOSE: To develop a simple approach for investigating absorption kinetics, which does not require modeling assumption or intravenous data. METHODS: The concentration (C) -time (t) data are plotted as a phase plane plot (dCldt versus C). Errorless C,t data were generated from one and two compartment models employing first-order, zero-order and Michaelis-menten input kinetics, and the phase plane plots were constructed. A simple test based on the ratio of slopes of the separate linear regression analyses of absorption and elimination data of the phase plane plot is proposed to justify or not the presence of zero order input kinetics. Errant data were used to assess the performance of the test developed. Literature data of theophylline and nitroglycerin formulations were analyzed using the phase plane plot. Input rate-time profiles were constructed for one compartment model drugs utilizing the data of the phase plane plot. RESULTS: The geometric forms of the phase plane plots derived form the errorless data of the various pharmacokinetic models were found to be indicative of the absorption kinetics. Very good resulted were obtained when the test for he discernment of absorption kinetics was applied to errant data. Zero-order absorption kinetics were justified (i) for the transdermal absorption of nitroglycerin and (ii) only for a certain period of time, for the gastrointestinal absorption of theophylline. CONCLUSIONS: Investigation of absorption kinetics can be accomplished with the phase plane method. The cumulative character of the classical percent absorbed versus time plots can be misleading in justifying the presence of zero-order input kinetics.

Absorption↗
PubMed1997

A population growth model of dissolution.

PURPOSE: To develop a new approach for describing drug dissolution which does not require the presuppositions of time continuity and Fick's law of diffusion and which can be applied to both homogeneous and heterogeneous media. METHODS: The mass dissolved is considered to be a function of a discrete time index specifying successive "generations" (n). The recurrence equation: phi n + 1 = phi n + r(1 - phi n)(1 - phi n X0/theta) was derived for the fractions of dose dissolved phi n and phi n+1, between generations n and n + 1, where r is a dimensionless proportionality constant, X0 is the dose and theta is the amount of drug corresponding to the drug's solubility in the dissolution medium. RESULTS: The equation has two steady state solutions, phi ss = 1 when (X0/theta) < or = 1 and phi ss = theta/X0 when (X0/theta) > 1 and the usual behavior encountered in dissolution studies, i.e, a monotonic exponential increase of phi n reaching asymptotically the steady state when either r < theta/X0 < 1 or r < 1 < theta/X0. Good fits were obtained when the model equation was applied to danazol data after appropriate transformation of the time scale to "generations". The dissolution process is controlled by the two dimensionless parameters theta/X0 and r, which were found to be analogous to the fundamental parameters dose and dissolution number, respectively. The model was also used for the prediction of fraction of dose absorbed for highly permeable drugs. CONCLUSIONS: The model does not rely on diffusion principles and therefore it can be applied under both homogeneous and non-homogeneous conditions. This feature will facilitate the correlation of in vitro dissolution data obtained under homogeneous conditions and in vivo observations adhering to the heterogeneous milieu of the GI tract.

Drug Delivery Systems↗