Adsorption, desorption, and diffusion of k-mers on a one-dimensional lattice.

Kinetics of the deposition process of k -mers in the presence of desorption or/and diffusional relaxation of particles is studied by Monte Carlo method on a one-dimensional lattice. For reversible deposition of k-mers, we find that after the initial "jamming," a stretched exponential growth of the coverage theta(t) toward the steady-state value theta(eq) occurs, i.e., theta(eq)-theta(t) is proportional to exp[-(t/tau)(beta)]. The characteristic time scale tau is found to decrease with desorption probability P(des) according to a power law, tau is proportional to P(des)(-gamma), with the same exponent gamma=1.22+/-0.04 for all k-mers. For irreversible deposition with diffusional relaxation, the growth of the coverage theta(t) above the jamming limit to the closest packing limit (CPL) theta(CPL) is described by the pattern theta(CPL)-theta(t) is proportional to E(beta)[-(t/tau)(beta)], where E(beta) denotes the Mittag-Leffler function of order beta(0,1) . Similarly to the reversible case, we found that the dependence of the relaxation time tau on the diffusion probability P(dif) is consistent again with a simple power-law, i.e., tau is proportional to P(dif)(-delta). When adsorption, desorption, and diffusion occur simultaneously, coverage always reaches an equilibrium value theta(eq), which depends only on the desorption/adsorption probability ratio. The presence of diffusion only hastens the approach to the equilibrium state, so that the stretched exponential function gives a very accurate description of the deposition kinetics of these processes in the whole range above the jamming limit.

Kinetic model of drug distribution in the urinary bladder wall following intravesical instillation.

Intravesical administration of cytotoxic agents is commonly used in urological practice for treatment of superficial bladder cancer. The leading motive is optimisation of drug delivery near the site of action and reduction of systemic toxicity. Bladder pharmacokinetics is complicated by several mechanisms. The objectives of this work were to develop a kinetic model of drug distribution in the bladder wall following intravesical instillation and to study the effect of various parameters on tissue and systemic drug exposure and explore the potential benefits of permeability enhancing effects of chitosan (CH) and polycarbophil (PC) through simulation. Key elements of the model are variable urinary drug concentration due to urine formation and voiding, biphasic diffusion in the bladder tissue and systemic absorption. Model parameters were estimated from bladder-tissue concentration profiles obtained in previous in vitro experiments with pipemidic acid (PPA) as a model drug. The results support further investigations on application of CH and PC in intravesical drug delivery. Both polymers increase permeability of the bladder wall by diffusion enhancement in the urothelium and presumably by improving the contact with the bladder surface. The developed mathematical model could serve for optimisation of intravesical drug delivery and future development of intravesical drug delivery systems.

Simulation study of granular compaction dynamics under vertical tapping.

We study, by numerical simulation, the compaction dynamics of frictional hard disks in two dimensions, subjected to vertical shaking. Shaking is modeled by a series of vertical expansion of the disk packing, followed by dynamical recompression of the assembly under the action of gravity. The second phase of the shake cycle is based on an efficient event-driven molecular-dynamics algorithm. We analyze the compaction dynamics for various values of friction coefficient and coefficient of normal restitution. We find that the time evolution of the density is described by rho(t)=rho{infinity}-DeltarhoE{alpha}[-(ttau){alpha}], where E{alpha} denotes the Mittag-Leffler function of order 0

Asymptotic properties of path integral ideals.

We introduce and analyze an interesting quantity, the path integral ideal, governing the flow of generic discrete theories to the continuum limit and greatly increasing their convergence. The said flow is classified according to the degree of divergence of the potential at spatial infinity. Studying the asymptotic behavior of path integral ideals we isolate the dominant terms in the effective potential that determine the behavior of a generic theory for large discrete time steps.

Predicting the anti-hypertensive effect of nitrendipine from plasma concentration profiles using artificial neural networks.

Nitrendipine is an effective and safe calcium-channel blocker for the treatment of mild to moderate hypertension. The aim of this study is to show that an artificial neural network (ANN) model of the relationship between nitrendipine plasma levels and pharmacodynamic effects can be built and used for pressure-drop prediction after oral administration of the drug in spite of the poor correlation between plasma concentrations and the effect. To achieve the goal, the following steps were taken: evaluation of the quality of the database for training the ANN, definition of the optimal input set for the ANN, and prediction of the diastolic pressure drop using the ANN. The possible consequences of successful ANN modelling are an optimisation of the drug administration regimen, to achieve the best possible effect, as well as optimal drug formulation for drugs with complicated pharmacokinetic/pharmacodynamic relationships.

Influence of fever on the pharmacokinetics of ciprofloxacin.

The influence of fever on the pharmacokinetics of ciprofloxacin was investigated in seven patients with acute febrile diseases. Antibiotic serum concentrations were determined using high-performance liquid chromatograpy (HPLC). The analog computer and the Simulink software package were used to identify the pharmacokinetic model and Penoclin software package to obtain the secondary parameters. During fever, higher maximum serum concentrations (Cmax) of ciprofloxacin were observed in six out of seven patients. The result suggests that the influence of fever on the pharmacodynamics of ciprofloxacin is favorable.

Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories.

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.

Transport theory of granular swarms.

The transport of trace granular gas (swarm) in a carrier granular fluid is studied by means of the Boltzmann-Lorentz kinetic equation. Time-dependent perturbation theory is used to follow the evolution of the granular swarm from an arbitrary initial distribution. A nonhydrodynamic extension of the diffusion equation is derived, with transport coefficients that are time dependent and implicitly depend on the wave vector. Transport coefficients of any order are obtained as velocity moments of the solutions of the corresponding kinetic equations derived from the Boltzmann-Lorentz equation. For the special case of the initial distribution of swarm particles, transport coefficients are identified as time derivatives of the moments of the number density. Finally the granular particle transport theory is extended by the introduction of the concept of non-particle-conserving collisions.

Influence of fever on cefazolin pharmacokinetics.

The influence of fever on the pharmacokinetics of cefazolin was investigated in patients with acute febrile diseases. Nine patients were included in the study. Antibiotic serum concentrations were determined using high performance liquid chromatograpy (HPLC). An analog computer and the SIMULINK software package were used to identify the pharmacokinetic model and PCNONLIN software package to obtain the secondary parameters. In 6 patients a two-compartment pharmacokinetic model of cefazolin was observed during fever and after defervescence. In 2 patients a two-compartment model changed to a one-compartment after defervescence, and a one-compartment model was observed in one patient during both periods. Cefazolin-treated patients with a two-compartment model (6/9) had higher Cmax, mean steady state serum concentrations (Css), and area under the plasma concentration-time curve (AUC(0-->infinity)), smaller central compartment volume (V1), and lower clearance (Cl) during fever. The varying distribution of antibiotics during fever probably reflects different hemodynamic responses to fever.

The role of pharmacokinetic modelling and computer simulation in drug formulation design.

The purpose of this study is to develop a formulation for a once-a-day peroral application with controlled release of nitrendipine. The second aim of the study is to define by the use of modelling and computer simulation those critical points in the development of the formulation, the knowledge and controlling of which brings a rationalisation in the sense of time and material.

Interdependence of histamine and methylhistamine kinetics: modelling and simulation approach.

In the article a model of histamine kinetics is described. A motivation of this project was to investigate the hypothesis that methylhistamine may be a marker of histamine appearance in plasma. A model has been made to support the hypothesis. Since metabolic and transport pathways of histamine and methylhistamine are complex and not very well known, the relationship between histamine and methylhistamine should be elucidated by mathematical modelling. From experimental data and the information in the literature, a nonlinear and time-varying four-compartment model is proposed. Extensive release of histamine from mast cells when methylhistamine is injected, is modelled as histamine to methylhistamine ratio control loop.

Pathways of paracetamol absorption from layered excipient suppositories: artificial intelligence approach.

When studying paracetamol availability after rectal administration, the differences between slower and faster release suppositories were discovered. Approach with modelling and simulation of compartment-based models was used to explore the differences. A study of paracetamol from layered excipient suppositories shows that many different mechanisms are involved in the drug pharmacokinetics. There is also a large number of articles, each dealing with only one or with a few of the mechanisms. However, there is little information available on how the mechanisms interact in the organism and thus govern the pharmacokinetics of the drug, which means that systemic view in the expert knowledge is missing. In the case of paracetamol rectal availability the use of partially fuzzyfied model allowed systemic combination of all described mechanisms found in the literature and measured data. In spite of non-identifiability, the model showed that patterns that explained differences in bioavailabilities of the two formulations of suppositories could be found. Results of modelling and simulation show that "in vivo" there is practically no difference in cumulative release profiles between the two formulations. However, due to higher content of mono-di-glycerides in a slower release formulation, the extent of absorption is augmented both by absorption-enhancing effect of mono-di-glycerides and the liver bypass mechanism via diminished viscosity.

Structural characterization of submerged granular packings.

We consider the impact of the effective gravitational acceleration on microstructural properties of granular packings through experimental studies of spherical granular materials saturated within fluids of varying density. We characterize the local organization of spheres in terms of contact connectivity, distribution of the Delaunay free volumes, and the shape factor (parameter of nonsphericity) of the Voronoï polygons. The shape factor gives a clear physical picture of the competition between less and more ordered domains of particles in experimentally obtained packings. As the effective gravity increases, the probability distribution of the shape factor becomes narrower and more localized around the lowest values of the shape factor corresponding to regular hexagon. It is found that curves of the pore distributions are asymmetric with a long tail on the right-hand side, which progressively reduces while the effective gravity gets stronger for lower densities of interstitial fluid. We show that the distribution of local areas (Voronoï cells) broadens with decreasing value of the effective gravity due to the formation of lose structures such as large pores and chainlike structures (arches or bridges). Our results should be particularly helpful in testing the newly developed simulation techniques involving liquid-related forces associated with immersed granular particles.

Optimization of the monolayer growth in adsorption-desorption processes.

Kinetics of the deposition process of dimers in the presence of desorption is studied by Monte Carlo method on a one-dimensional lattice. The aim of this work is to investigate how do various temporal dependencies of the desorption rate hasten or slow down the deposition process. The growth of the coverage θ(t) above the jamming limit to its steady-state value θ(∞) is analyzed when the desorption probability P(des) decreases both stepwise and linearly (continuously) over a certain time domain. We report a numerical evidence that the time needed for a system to reach the given coverage θ can be significantly reduced if P(des) decreases in time. Finally, a self-consistent optimization procedure, when the probability P(des) depends on the current coverage density θ(t), is formulated and tested. The present model reproduces qualitatively the densification kinetics and the memory effects of vibrated granular materials. Our results suggest that the process of vibratory compaction of granular materials can be optimized by using a time dependent intensity of external excitations.

Systematically accelerated convergence of path integrals.

We present a new analytical method that systematically improves the convergence of path integrals of a generic N-fold discretized theory. Using it we calculate the effective actions S(p) for p< or =9, which lead to the same continuum amplitudes as the starting action, but that converge to that continuum limit as 1/N(p). We checked this derived speedup in convergence by performing Monte Carlo simulations on several different models.

[Present possibilities of treatment of chronic B-cell lymphocytic leukemia]. / Savremene mogucnosti lecenja B-hronicne limfocitne leukemije.

Chronic lymphocytic leukemia (CLL) belongs to the group of diseases with a malignant course and bad outcome. Clinically, the course of CLL exceptionally varies, survival ranges from one to twenty years. The choice of treatment for those affected with CLL is not simple because of the different course of the disease in individual patients and because of the different attitudes in the application of available means of therapy. By introducing antitumor drugs (Interferon alpha-2, Interleukin 2b), new chemotherapeutics (Fludarabin, Pentostatin), monoclonal antibodies and especially by introducing allogenic bone marrow transplantation into therapy, new possibilities are attained for the more efficient treatment of these patients.

[Prognostic significance of cytologic and histomorphologic changes in bone marrow in the treatment of patients with chronic lymphocytic leukemia]. / Prognozni znacaj citoloskih i histomorfoloskih promena kosne srzi u lecenih bolesnika obolelih od hronicne limfocitne leukemije.

In the aim of establishing the prognosis of chronic lymphocytic leukemia (HLL) in relation to the severeness and course of the disease, during the course of treatment of the patients, two parameters were followed prior to therapy and one year following conducted therapy regarding the morphological changes of lymphocytes in bone marrow specimens and peripheral blood samples and the type of cell infiltration in the bone marrow by means of histomorphological examination. The obtained results point to the fact that progression of illness can be expected also in those patients who are in a milder clinical stadium (stadium A), in the cases when we find more than 20% of atypical lymphocyte forms (prolymphocytes and forms with nucleus aberrations) in the peripheral blood and in the bone marrow, as well as in the cases with a diffuse type of bone marrow infiltration. Such forms should be checked more often. At the same time application of therapy is suggested right after the diagnosis is set, even though the patient may be in the early clinical stadium of the disease, as well as the decision about aggressive treatment.