Paula de Oliveira

Liquid chromatographic assay based on microextraction by packed sorbent for therapeutic drug monitoring of carbamazepine, lamotrigine, oxcarbazepine, phenobarbital, phenytoin and the active metabolites carbamazepine-10,11-epoxide and licarbazepine

A new, sensitive and fast high-performance liquid chromatography-diode-array detection assay based on microextraction by packed sorbent (MEPS/HPLC-DAD) is herein reported, for the first time, to simultaneously quantify carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), phenobarbital (PB), phenytoin (PHT), and the active metabolites carbamazepine-10,11-epoxide (CBZ-E) and licarbazepine (LIC) in human plasma. Chromatographic separation of analytes and ketoprofen, used as internal standard (IS), was achieved in less than 15min on a C18-column, at 35°C, using acetonitrile (6%) and a mixture (94%) of water-methanol-triethylamine (73.2:26.5:0.3, v/v/v; pH 6.5) pumped at 1mL/min. The analytes and IS were detected at 215, 237 or 280nm. The method showed to be selective, accurate [bias ±14.8% (or ±17.8% in the lower limit of quantification)], precise [coefficient variation ≤9.7% (or ≤17.7% in the lower limit of quantification)] and linear (r(2)≥0.9946) over the concentration ranges of 0.1-15μg/mL for CBZ; 0.1-20μg/mL for LTG; 0.1-5μg/mL for OXC and CBZ-E; 0.2-40μg/mL for PB; 0.3-30μg/mL for PHT; and 0.4-40μg/mL for LIC. The absolute extraction recovery of the analytes ranged from 57.8 to 98.1% and their stability was demonstrated in the studied conditions. This MEPS/HPLC-DAD assay was successfully applied to real plasma samples from patients, revealing to be a cost-effective tool for routine therapeutic drug monitoring of CBZ, LTG, OXC, PB and/or PHT.

A 3D Model for Mechanistic Control of Drug Release

A three-dimensional mathematical model for sorption/desorption by a cylindrical polymeric matrix with dispersed drug is proposed. The model is based on a system of partial differential equations coupled with boundary conditions over a moving boundary. We assume that the penetrant diffuses into a swelling matrix and causes a deformation, which induces a stress-driven diffusion and consequently a non-Fickian mass flux. A physically sound nonlinear dependence between strain and penetrant concentration is considered and introduced in a Boltzmann integral with a kernel computed from a Maxwell--Wiechert model. Numerical simulations show how the mechanistic behavior can have a role in drug delivery design.

Mathematical modeling of efficient protocols to control glioma growth

In this paper we propose a mathematical model to describe the evolution of glioma cells taking into account the viscoelastic properties of brain tissue. The mathematical model is established considering that the glioma cells are of two phenotypes: migratory and proliferative. The evolution of the migratory cells is described by a diffusion-reaction equation of non Fickian type deduced considering a mass conservation law with a non Fickian migratory mass flux. The evolution of the proliferative cells is described by a reaction equation. A stability analysis that leads to the design of efficient protocols is presented. Numerical simulations that illustrate the behavior of the mathematical model are included.

Analytical and numerical study of a coupled cardiovascular drug delivery model

A two dimensional coupled model of drug delivery in the cardiovascular tissue using biodegradable drug eluting stents is developed. Qualitative behavior, stability analysis as well as simulations of the model have been presented. Numerical results computed with an implicit-explicit finite element method show a complete agreement with the expected physical behavior.

Intranasal delivery of ciprofloxacin to rats: A topical approach using a thermoreversible in situ gel

&NA; Intranasal administration of antibiotics is an alternative and attractive delivery approach in the treatment of local infections such as chronic rhinosinusitis. This topical route has the advantage of delivering high drug concentrations directly to the site of infection when trying to eradicate the highly resistant bacterial biofilms. The purpose of this study was to assess and compare the pharmacokinetic parameters of ciprofloxacin following intranasal and intravenous administrations to rats in plasma, olfactory bulb and nasal mucosa of two different nasal regions. For intranasal administration a thermoreversible in situ gel was used to increase drug residence time in nasal cavity. Ciprofloxacin concentration time‐profile in nasal mucosa of the studied anterior region (at naso‐ and maxilloturbinates level) was markedly higher after intranasal administration (0.24 mg/kg) than that following intravenous administration (10 mg/kg), while in nasal mucosa of the more posterior region (at ethmoidal turbinates level) ciprofloxacin concentrations were found to be higher after intranasal administration when the different dose administered by both routes is taken into account. A plateau in ciprofloxacin concentration was observed in nasal mucosa of both studied regions after intranasal administration, suggesting a slow delivery of the drug over a period of time using the nasal gel formulation. In plasma and olfactory bulb, concentration of ciprofloxacin was residual after intranasal administration, which demonstrates this is a safe administration route by preventing systemic and particularly central nervous system adverse effects. Dose‐normalized pharmacokinetic parameters of ciprofloxacin exposure to nasal mucosa revealed higher values after intranasal delivery not only in the anterior region but also in the posterior nasal region. In conclusion, topical intranasal administration appears to be advantageous for delivering ciprofloxacin to the biophase, with negligible systemic and brain exposure using a 41.7‐fold lower dose than intravenous administration. Therefore, it may represent a promising approach in the drug management of chronic rhinosinusitis. Graphical abstract Figure. No caption available.

A coupled non-Fickian model of a cardiovascular drug delivery system

A coupled non-Fickian model of a cardiovascular drug delivery system using a biodegradable drug-eluting stent is proposed. The numerical results are obtained using an implicit-explicit finite-element method. The influence of vessel stiffness on the transport of drug eluted from the stent is analysed. The results presented in this paper suggest new perspectives to adapt the drug delivery profile to the needs of the patient.

Analytics and numerics of drug release tracking

The study of the dependence of fluxes, concentrations and response times, on the characteristic properties of drug delivery polymeric devices, plays an important role in the design of drug release platforms. The aim of this paper is to develop mathematical tools for an in-depth understanding of drug release tracking. The mathematical model presented takes into account the viscoelastic properties of the polymer and the state of the dispersed drug: free or chemically bound to the matrix. For nonlinear chemical bounds the process is described by a nonlinear integro-differential system and the drug release tracking is treated numerically. For linear chemical bounds closed formulas for the fluxes and response times are established in terms of the parameters that characterize the drug and the platform. These formulas provide a set of a priori estimations for the variables of the model. Numerical examples which show the effectiveness of the approach are included.

Diffusion, viscoelasticity and erosion

In this paper diffusion through a viscoelastic biodegradable material is studied. The phenomenon is described by a set of three coupled partial differential equations that take into account passive diffusion, stress driven diffusion and the degradation of the material. The stability properties of the model are studied.Erodible viscoelastic materials, as biodegradable polymers, have a huge range of applications in medicine to make drug eluting implants. Using the mathematical model the behavior of a particular ocular drug eluting implant which describes drug delivery into the vitreous chamber of the eye is presented. The model consists of coupled systems of partial differential equations linked by interface conditions. The chemical structure, the viscoelastic properties and the diffusion in the implant as well as the transport in the vitreous are taken into account to simulate the evolution in vivo of released drug. The dependence of the delivery profile on the properties of the material is addressed. Numerical simulations that illustrate the interplay between these phenomena are included.

A SECOND ORDER APPROXIMATION FOR QUASILINEAR NON-FICKIAN DIFFUSION MODELS

Abstract. In this paper initial boundary value problems, defined using quasilinear diffusion equations of Volterra type, are considered. These equations arise for instance to describe diffusion processes in viscoelastic media whose behavior is represented by a Voigt–Kelvin model or a Maxwell model. A finite difference discretization defined on a general non-uniform grid with second order convergence order in space is proposed. The analysis does not follow the usual splitting of the global error using the solution of an elliptic equation induced by the integro-differential equation. The new approach enables us to reduce the smoothness required to the theoretical solution when the usual split technique is used. Non-singular and singular kernels are considered. Numerical simulations which show the effectiveness of the method are included.

Mathematics of aging: Diseases of the posterior segment of the eye

Abstract The changes caused by aging affect all body tissues. The vitreous humor, which fills the space between the lens and the retina, progressively liquefies and shrinks, eventually causing a posterior vitreous detachment. Retinal disorders caused by the breakdown of the blood retinal barrier are also associated with physiological aging. In this work a mathematical model of the pharmacokinetics of a drug eluted from an intravitreal biodegradable implant in an aging eye is presented. The influences of vitreous liquefaction and retina diseases are analyzed. The model is represented by a set of P.D.E’s describing the evolution of the concentration in a drug eluting implant, coupled with two systems of partial differential equations, describing the transport of drug in the vitreous chamber and the retina. Different scenarios of the physiology of vitreous and of inflammation’s degrees of the retina are numerically compared. The numerical results suggest a dominating influence of retina permeability.