Biomedical subjects

M Llabrés

Publications and source records attributed to M Llabrés.

At least 19 recordsLinked to original sources

PubMed2006

A mathematical model for interpreting in vitro rhGH release from laminar implants.

Recombinant human growth hormone (rhGH), used mainly for the treatment of growth hormone deficiency in children, requires daily subcutaneous injections. The use of controlled release formulations with appropriate rhGH release kinetics reduces the frequency of medication, improving patient compliance and quality of life. Biodegradable implants are a valid alternative, offering the feasibility of a regular release rate after administering a single dose, though it exists the slight disadvantage of a very minor surgical operation. Three laminar implant formulations (F(1), F(2) and F(3)) were produced by different manufacture procedures using solvent-casting techniques with the same copoly(D,L-lactic) glycolic acid (PLGA) polymer (Mw=48 kDa). A correlation in vitro between polymer matrix degradation and drug release rate from these formulations was found and a mathematical model was developed to interpret this. This model was applied to each formulation. The obtained results where explained in terms of manufacture parameters with the aim of elucidate whether drug release only occurs by diffusion or erosion, or by a combination of both mechanisms. Controlling the manufacture method and the resultant changes in polymer structure facilitates a suitable rhGH release profile for different rhGH deficiency treatments.

Biocompatible Materials↗

PubMed2006

Evaluation of cholecystokinin (CCK-8) peptide thermal stability for use as radiopharmaceutical by means isothermal and nonisothermal approaches.

The purpose of this research was to study the thermal stability of cholecystokinin octapeptide (CCK-8) in aqueous solution at pH 12 and ionic strength 0.01 M, which were kept as constants, by using isothermal and nonisothermal methods. The isothermal decomposition of CCK-8 was investigated as a function of temperature (40 degrees C to 70 degrees C). Nonisothermal stability studies were performed using a linear increasing temperature program. Two different nonisothermal studies were carried out at 0.25 degrees K and 0.5 degrees K per hour, and the temperature interval varied from 40 degrees C to 82 degrees C. The degradation of CCK-8 followed first-order kinetics, obeying the Arrhenius equation in the experimental temperature range. This indicated that the degradation mechanism of CCK-8 could be the equal within the temperature range studied. The nonisothermal approach resulted in activation energy (Ea) and shelf-life (t90%) values that agree well with those obtained by the isothermal method. The level of uncertainty in the estimates of t90% and Ea values is determined mainly by the extent of drug degradation and temperature change during the experiment. Therefore, nonisothermal experiments save time, labor and materials (i.e. the amount of drugs necessary to conduct the experiment) compared to the classic isothermal experiments, if they are performed using a suitable experimental design and a precise analytical method.

Chromatography, High Pressure Liquid↗

PubMed2005

A family of metrics for biopolymers based on counting independent sets.

We introduce a new family of metrics for graphs of fixed size, based on counting-independent sets. Our definition is simpler and easier to calculate than the edge ideal metric family defined by Llabrés and Rosselló without loosing any of its abstract properties. We contrast them on some examples with graphs that represent protein secondary and three-dimensional (3D) structures. We conclude that although the edge ideal metrics are faster to calculate on some sparse graphs, in general, the independent set metrics are more tractable.

Algorithms↗

PubMed2005

Dysphagia as the sole manifestation of myasthenia gravis.

Three patients are described who had dysphagia as the sole manifestation of myasthenia gravis. Severity ranged from the need to be fed by nasogastric tube to moderate dysphagia requiring only diet change. Oesophageal manometry was carried out in two patients and showed generalised weakness of peristaltic contractions which included the smooth muscle part of the oesophagus. These disturbances worsened with repeated swallows. They were partly reversed by intravenous edrophonium and by rest. Repetitive nerve stimulation was normal in all three patients, but stimulated single fibre EMG of the frontalis muscle showed that all had impairment of neuromuscular transmission. Anti-AChR antibodies were found in only one patient. The most affected patient was treated with pyridostigmine, plasmapheresis, and high dose prednisone. The remaining two patients received only oral anticholinesterases.

Adult↗

PubMed2005

Structural properties of biodegradable polyesters and rheological behaviour of their dispersions and films.

This paper focuses on the dependence of the rheological properties of PLA-PEG and PLGA dispersions and films on the polymer structural properties, in order to obtain useful information to predict and explain the performance of polyester films as drug-delivery systems. In this study, one PLA-PEG and three PLGA polymers of different molecular mass were synthesized and characterized by NMR, GPC, DSC and TGA-FT-IR. To characterize the viscoelastic behaviour of concentrated solutions in dichloromethane and of the films obtained by a solvent-casting technique, oscillatory shear rheometry was used. The polymer dispersions showed a characteristic Newtonian viscous behaviour, but with different consistency index depending on the nature of the polymer. Freshly prepared, PLGA and PLA-PEG films had elastic modulus (G') greater than viscous modulus (G"). The decrease in both moduli caused by an increase in temperature from 25 to 37 degrees C was especially marked for the polymers with T(g) below or around 25 degrees C (PLGA 27 kDa and PLA-PEG 27 kDa). After being immersed in pH 7.4 aqueous solution for one week, PLGA films showed a significant increase in both G' and G", due to the promotion of polymer-polymer interactions in a non-solvent medium. In contrast, the PLA-PEG film became softer and more hydrated, due to the amphiphilic character of the polymer. The water taken up by the film acted as a plasticizer and induced the softening of the system. These results suggest that the presence of PEG chains exerts a strong influence on the mechanical properties of polyesters films and, possibly, the performance as coating or matrices of drug-delivery systems.

Biodegradation, Environmental↗

PubMed2004

Methadone implants for methadone maintenance treatment. In vitro and in vivo animal studies.

Methadone implant formulations elaborated with polylactide-co-glycolide (PLGA) and polylactic acid (PLA) for 1 week and 1 month release duration, respectively, were evaluated in vitro and in vivo. One-week implants prepared with methadone clorhydrate, methadone clorhydrate/methadone base blend or methadone base were tested in vitro. Results showed that the methadone release rate decreased as the methadone base increased. The best release profile was achieve when the methadone base implants, made by compression of a 50:50 PLGA (12 kDa) and methadone base mix, were coated with PLA (30 kDa). For 1-month implants, the methadone base load was increased to 65% and PLA of 30 kDa was used as a matrix component. In this case the implants were coated with the same polymer. Deconvolution methods could not be used for in vivo release estimation because an increase in methadone clearance was observed with methadone clorhydrate solution multiple-dose treatment. Therefore the amount of drug remaining within the implants was evaluated and the deconvolution was only used to establish the release profile range. The upper limit was estimated applying the absorption-disposition function obtained after multiple-dose administrations while the lower curve was estimated using the single-dose function. Methadone serum levels were maintained around 200 ng/ml during 1 week and approximately 5 weeks with the optimised implants. In vivo-in vitro correlations were always very good with slopes near 1.

Animals↗

PubMed2004

A new family of metrics for biopolymer contact structures.

Contact structures are simplified representations of biopolymers' three-dimensional structures. In this paper we introduce a new family of metrics (dm)m >/=3 for contact structures of a fixed length, based on their representation by means of edge ideals of a polynomial ring, that generalize Reidys and Stadler's subgroup metric for RNA secondary structures. We study some abstract properties of these metrics, and we obtain explicit descriptions of them for some values of m.

Algorithms↗

PubMed2004

Rheological properties of PLGA film-based implants: correlation with polymer degradation and SPf66 antimalaric synthetic peptide release.

This paper reports on the rheological properties of poly(D,L-lactic-co-glycolic acid) polymers (PLGA) dispersions used to form films and of the implants prepared by compression of SPf66 antimalaric peptide between several films, before application and during drug release. 25% PLGA (M(w)=48,000Da) dispersions in dichloromethane showed viscous Newtonian behaviour, being easy flowing and adaptable to the moulds. Evolution of viscoelastic properties, polymer molecular weight, and SPf66 release pattern from the implants immersed in various media was evaluated. Oscillatory shear test showed that freshly prepared implants have an elastic modulus, G', greater than the viscous modulus, G", being both practically independent of angular frequency. After 6 weeks immersion in a pH 7.4 phosphate buffer, G' and G" increased in almost one order of magnitude, despite of a significant polymer degradation. Polymer molecular weight decreased slowly during the first 10 days of immersion (a similar pattern was obtained at pHs 2 and 7.4) and then the degradation process accelerated (degradation index on day 7 equals to 0.89, and on day 14 equals to 16.5). SPf66 release profile followed a pattern similar to that of the polymer degradation index. These observations are explained in terms of changes in polymer structure and conformation that happen in the implant.

Absorbable Implants↗

PubMed2004

Stability indicating method for SPf66 antimalarial peptide in solution.

Stability studies on the SPf66 antimalarial peptide with different pH and temperature conditions were carried out. The degradation mechanism was elucidated by the size-exclusion chromatography (SEC) technique and the experimental data obtained at 37 degrees C and different pH were fitted to a kinetic degradation model that could explain the loss of its immunogenic capacity. At 5, 25, 37, and 70 degrees C and pH 2, changes were detected in the areas of the different species, although the values obtained could not be fitted to any known degradation kinetics.

Chromatography, Gel↗

PubMed2001

In vivo-in vitro study of biodegradable methadone delivery systems.

Three one-week controlled-release methadone formulations: polylactic acid microspheres (F-PLA) and poly(lactide-co-glycolide) microspheres (F-PLGA) with 24 and 30% methadone content, respectively, and an implant of 50:50 poly(lactide-co-glycolide): methadone, were evaluated in vitro and in vivo. The implant released the total amount of methadone in vitro while microsphere formulations released the methadone incompletely, 63% from F-PLA and 85% from F-PLGA in a week. Methadone release in vivo was estimated by deconvolution, F-PLGA giving a bioavailability >99% (methadone was totally released in 48h), while the estimated bioavailability of F-PLA was lower than expected. The bioavailability of the implant by deconvolution was around 60%, but absence of methadone in the implant indicated its complete release. These differences are due to an increase in methadone clearance after 72 h of the in vivo experimental period had passed, disturbing a good in vivo-in vitro correlation. A linear correlation between in vitro methadone release and in vivo release calculated from the amount of drug remaining within the implant, was found until the drug was completely released.

Animals↗

PubMed2001

Comparative study of protein molecular weights by size-exclusion chromatography and laser-light scattering.

High-performance size-exclusion chromatography (SEC) based on UV-Vis detection is a relative technique for molecular weight determination whereas procedure based on multi-angle laser light scattering (MALLS) is both rapid and absolute. The two methods using recombinant human growth hormone (rHGH) and beta-lactoglobulin samples were compared. A calibration curve for the chromatographic system was generated based on standard proteins and the data were fitted by least squares to a third order polynomial model. The molecular weight from the conventional SEC method for both proteins was higher than the reported values. The molecular weight of rHGH from MALLS was 23.1+/-0.57 and 21.2+/-0.80 kDa using differential refractive index (SEC-MALLS/RI) and UV (SEC-MALLS/UV-Vis) detectors as mass detectors. Both values agree, within experimental error with the molecular weight sequence of rHGH, 22.1 kDa. In contrast, the molecular weight from LS for beta-lactoglobulin was 22.5+/-0.55 kDa by SEC-MALLS/RI and 23.0+/-1.22 kDa by SEC-MALLS/UV-Vis, respectively, values always higher than those supplied by the manufacturer, 18.4 kDa. The reproducibility of the SEC-MALLS/UV-Vis method versus the SEC-MALLS/RI method was performed using the concordance correlation coefficient. The method's reproducibility was accepted by assuming a precision of 98% and a 1% loss in precision.

Chromatography, Gel↗

PubMed2000

Development of two high-performance liquid chromatographic methods for the analysis and characterization of insulin and its degradation products in pharmaceutical preparations.

Two high-performance liquid chromatography methods either in reversed-phase or as size exclusion separation mode were developed and validated for the analysis of insulin and its degradation products in pharmaceutical preparations. The results show the reliability of the analytical methods for the intended used. The static and dynamic light scattering were used to characterize the insulin and its derivatives. The absolute molecular weight of human insulin monomer and dimer were 5800 and 12400 Da respectively whereas its z-average root mean square radius were 21.6+/-0.4 and 40.5+/-0.7 nm, respectively. In contrast, the hydrodynamic diameter varied between 2.69 and 5.50 nm, depending of the association behavior of insulin.

Chromatography, High Pressure Liquid↗

PubMed2000

Statistical assessment of between batch stability equivalence.

A statistical method for testing the equivalence between batches regarding their stability is proposed. This method is based on the statistical linear model making use of a set of dummy variables to code the different batches. The method gives us the point estimates of the slope and zero intercept of one batch, and the differences and the corresponding confidence intervals with the remaining batches. In a second step, zero intercepts and slopes are estimated for all the batches. Stability equivalence assessment is based on the comparison of the confidence intervals for the differences between batches with the maximum difference allowable. The main advantages of this method are the possibility to compare several batches, to disclose the equivalence stability criteria from the statistical hypothesis about the equality between slopes, and the joint estimated of the residual variance whatever the decision to pool or not the data from different batches. This method is illustrated with two data set; the first one, previously published by other authors, involved six batches; the second data set include two batches and arose in a stability study of a commercial human insulin conducted in our laboratory.

Confidence Intervals↗

PubMed2000

Kinetic model for 5-fluorouridine degradation. Catalytic effect of 5-fluorouracil.

The effects of 5-fluorouridine (5-FUR, CAS 316-46-1) degradation products, 5-fluorouracil (5-FU, CAS 51-21-8) and D-ribose (CAS 50-69-1), on its degradation rate was investigated following a 2(3) factorial design. The experimental data fitted to the proposed mathematical model which includes two parallel degradation mechanisms: the first one, a second order bimolecular reaction involving both 5-FUR and 5-FU, and the second, a first order one. Experimental data obtained show a high variability. Both graphic and statistical analysis of the experiments for which a full kinetic model was applied manifested that the degradation mechanism included an autocatalytic route and confirmed the role of the 5-FU on the hydrolysis of 5-FUR.

Algorithms↗

PubMed1999

One-month sustained release microspheres of 125I-bovine calcitonin. In vitro-in vivo studies.

To obtain a 1-month release formulation of 125I-bovine calcitonin, microspheres were prepared with three different PLA copolymers, PLGA I (mol. wt. [MW]=30000), polyethyleneglycol (PEG)-PLGA (MW=34000) and PLGA II (MW=12000) using the double emulsion method. The release of 125I-bovine calcitonin was assayed in vitro using dialysis bags at 37 degrees C in isotonic phosphate buffer (pH 7.4). The in vitro release results indicated a very slow release rate for an optimal 1-month sustained release formulation. 125I-bovine calcitonin microspheres were administered under the skin on the back of Wistar rats and the radioactivity at the injection site was subsequently measured over a 4-week period. The in vitro and in vivo profiles were affected by the weight average molecular weight of the copolymers. The 125I-bovine calcitonin release rate was faster from microspheres prepared with PLGA II (MW=12000) than from microspheres prepared with higher molecular weight copolymers (PLGA I and PEG-PLGA). Microspheres prepared with PLGA II (MW=12000) release 100% of the dose in 1 month, in vivo release profiles presented two phases, during the first 2 weeks approximately 70% of the 125I-bovine calcitonin injected was released, followed by a second slower phase.

Animals↗

PubMed1997

Stability indicating high performance liquid chromatography methods for 5-fluorouridine in aqueous solution.

Two methods of reversed-phase high performance liquid chromatography (RP-HPLC) were used to detect and quantify the degradation of 5-fluorouridine (CAS 316-46-1, 5-FUR) in aqueous solution. The 1H-NMR technique was used for identifying the degradation products. Several assays were performed from different aqueous solutions of 5-FUR. The best results (optimal resolution, reproducibility and rapidity) were achieved by using Resolve C-18 as stationary phase and a mix (96:4) of 50 mmol/l ammonium dihydrogen phosphate (adjusted to pH 3.5 with phosphoric acid) and acetonitrile as mobile phase. Despite the 5-FUR hydrolysis to 5-fluorouracil (5-FU) and D-ribose under moderate conditions in unlikely, due to high stability of the nucleoside, these were the identified degradation products in assays carried out.

Chromatography, High Pressure Liquid↗

PubMed1991

Design and evaluation of sustained-release tablets of lithium in a fat matrix and its bioavailability in humans.

The development of sustained-release lithium (Li) tablets, intended to release the active principle at a rate of 1.0 mM/h for 10 h, was undertaken. The parameters used for the control of the release were the glyceril palmite-stearate content, the carboxypolymethylene content, and the compression force. The experimental design is based on Hadamard's matrices and is of the adaption by stages type. The formulation seen as optimal from in vitro assays was later assessed in vivo by a crossover study of six subjects. The parameters used to measure the bioavailability were the total amount of Li excreted in the urine in the 96 h following ingestion, the maximum urinary excretion rate, and the time at which this rate was reached. The acceptability interval for the first two parameters was established from the theoretical curve of urinary excretion, which was calculated by convolution of the desired in vivo release variable (1.0 mM/h for 10 h) by the absorption-disposition variable obtained after administering the preparation in Li carbonate capsules. The results obtained show that the bioavailability of the formulation is 75% of the immediate-release formulation used as control and that the release rate, although close to the desired value, lasts only 7 or 8 h; these results agree with those given by numerical deconvolution using the mean urinary excretion curves.

Acrylic Resins↗

PubMed1990

A new approach to pharmacokinetic parameters: estimation of cefuroxime during haemodialysis.

A linear three-compartment model is proposed as a means of estimating disposition and extracorporeal elimination pharmacokinetic parameters during haemodialysis. It was created by connecting a compartment, corresponding to the amount of drug present in the dialysis cell, to the central compartment of the standard two-compartment model from which elimination would normally take place. The transfer rate constants between the central compartment and the 'dialysis cell' and vice versa were given in terms of the plasma flow, central compartment volume, and volume of plasma contained in the dialysis cell, and thus cannot be considered to be independent parameters. The product of the rate constant for elimination from the dialysis cell, k30, and the plasma volume within the cell was used to quantify the extracorporeal elimination and termed intrinsic dialyser clearance, CLint,D. The model was used to interpret the plasma level curves obtained after administering 750 mg cefuroxime by IV bolus to a group of patients undergoing haemodialysis. The distribution parameters estimated by non-linear regression were similar to those given in the literature; however, in five of the twelve cases, no estimate of cefuroxime elimination from the central compartment (k10) could be derived. On the other hand, the estimates of the elimination rate constant (k30) from the deep peripheral compartment were greater than the values given in the literature, ranging from 50.6 h-1 to 151.0 h-1 and CLint,D ranging from 3.1 h-1 to 8.90 l h-1. The error in measuring the flow of plasma which reaches the dialyser, its influence upon the estimation of the model parameters and the relationship between the parameters themselves and those customarily used in the study of drug haemodialysis are all discussed.

Cefuroxime↗