Virginia Merino
Universitat de València, Farmacia Y Tecnología Farmaceutica, Faculty Member
RESUMEN Predecir la magnitud y la velocidad de absorcion de una sustancia es crucial en el diseno de medicamentos. En este campo se han empleado distintas metodologias, como modelos in vitro o ensayos in situ o in vivo en animales. Este... more
RESUMEN Predecir la magnitud y la velocidad de absorcion de una sustancia es crucial en el diseno de medicamentos. En este campo se han empleado distintas metodologias, como modelos in vitro o ensayos in situ o in vivo en animales. Este trabajo analiza modelos matematicos empleados para estudiar la absorcion intestinal y analizar la influencia de tensioactivos en la permeabilidad intestinal; predecir la fraccion de dosis absorbida; caracterizar parametros de absorcion pasiva y activa; y establecer correlaciones entre parametros obtenidos in vitro e in situ. Cuanto mas complejo es el modelo tanto mejor se correlaciona con los valores en humanos, pero resultan mas dificiles de implementar. Los modelos in vitro resultan bastante adecuados para predecir la absorcion cuando se produce por difusion pasiva, pero deficitarios cuando se produce por transporte activo. Se pone de manifiesto la necesidad de continuar desarrollando modelos que permitan el escalado a humanos. Palabras clave: Modelado matematico de la absorcion. Prediccion de la absorcion. Modelos experimentales para la absorcion. Correlaciones in vitro-in vivo.
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La inclusion de antibioticos en el cemento oseo destinado a la fijacion mecanica de las protesis constituye un sistema de liberacion local de antibiotico que permite minimizar la prevalencia y la gravedad de las reacciones adversas que... more
La inclusion de antibioticos en el cemento oseo destinado a la fijacion mecanica de las protesis constituye un sistema de liberacion local de antibiotico que permite minimizar la prevalencia y la gravedad de las reacciones adversas que pueden desencadenar los farmacos cuando estos se administran por via sistemica. El objetivo del trabajo es estudiar el mecanismo y cinetica de liberacion in vitro de ciprofloxacino y vancomicina incorporados en diferentes cementos oseos comerciales y evaluar la bioactividad mediante un ejercicio de simulacion farmacocinetica. Se prepararon mezclas de los cementos de estudio con ciprofloxacino clorhidrato y vancomicina (40:0,5:0,5). Los estudios de liberacion se realizaron en agitacion continua en solucion salina de tampon fosfatos, pH=7,4, durante dos meses. Las cantidades liberadas acumuladas y las velocidades de elucion se evaluaron mediante ANOVA. Con el fin estudiar la bioactividad, se realizo una simulacion de Monte Carlo. La cantidad total liberada de ciprofloxacino en un periodo de 8 semanas fue de 0,29±0,06mg desde los cementos Palacos®, 0,44±0,06mg Lima® y 0,18±0,04mg Simplex®. La cantidad total de vancomicina liberada en 24 horas fue de 0,34±0,17mg desde el cemento Palacos®, 0,68±0,16mg Lima® y 0,17±0,02mg Simplex®. Transcurrido este tiempo la liberacion ceso. El estudio de simulacion, muestra que durante las primeras 72 horas, la cobertura antibiotica dependeria tanto del cemento elegido, como de la sensibilidad del microorganismo y el dia postquirurgico. Teniendo en cuenta el drenaje externo, es de prever que tras estas primeras 72 horas, una vez retirado, la bioactividad aumente.
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Determination of bioequivalence remains a challenge in generic topical drug development. To support pharmacokinetic studies, strategies to demonstrate microstructure sameness of the products being compared include in vitro evaluations,... more
Determination of bioequivalence remains a challenge in generic topical drug development. To support pharmacokinetic studies, strategies to demonstrate microstructure sameness of the products being compared include in vitro evaluations, such as the comparison of rheological properties, droplet size and in vitro release rates. Nevertheless, defining the appropriate acceptance range to consider equivalence between test and reference formulation is complex. To shed more light into this issue, in vitro release and rheological properties were compared to in vivo bioequivalence data (systemic blood measurements within a clinical trial) after topical application of a single dose. Test and reference formulations of diclofenac diethylamine emulgels were evaluated. While the test formulation met the requirements for equivalence in both the in vivo bioequivalence and in vitro release study, the rheological properties were considered equivalent depending on the criteria used. The 90% confidence interval of the ratios between geometric mean values of both formulations were within the limits of 75-133%, but outside the 90-111% limit under discussion in the scientific community. Altogether these data indicate that differences beyond ±10% between rheological parameters of test and reference formulation might not translate into meaningful release nor bioavailability divergence.
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Abstract This chapter reviews alternative methods recommended for animal testing in various toxicological areas. An alternative model to achieve complete animal replacement for acute toxicity testing is not possible. Skin... more
Abstract This chapter reviews alternative methods recommended for animal testing in various toxicological areas. An alternative model to achieve complete animal replacement for acute toxicity testing is not possible. Skin corrosion/irritation alternative methods have been validated and accepted. For eye irritation testing, no single method is able to replace the Draize rabbit eye test. Skin sensitization methods imply refinement and reduction of numbers of animals. An in vitro dermal absorption test could be an alternative to in vivo testing. There are no generally accepted alternative methods to replace the usual repeated-dose toxicity in vivo assays. To determine the genotoxic and mutagenic potential of a compound a battery of in vitro tests may be used. Two alternative methods may provide information on possible carcinogenic effects. Acute phototoxicity can be assayed with in vitro tests, and for reproductive and developmental toxicity three embryotoxicity tests have been formally validated (by ECVAM). Complete animal replacement will represent a scientific and technical challenge.
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Progesterone (PG) affords neuroprotection in degenerative diseases associated to oxidative stress, such as cataracts, age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa. The aim of this project was... more
Progesterone (PG) affords neuroprotection in degenerative diseases associated to oxidative stress, such as cataracts, age-related macular degeneration, glaucoma, diabetic retinopathy and retinitis pigmentosa. The aim of this project was to develop ocular inserts for delivery of PG to the eye. Different inserts with PG in its composition were formulated and the insert with the best characteristics (59% polyvinyl alcohol, 39% polyvinylpyrrolidone K30 and 2% propylene glycol) was selected for ex vivo studies. Physical characteristics and drug release patterns of the insert were analysed. In vitro diffusion studies revealed a controlled diffusion of progesterone. Ex vivo experiments demonstrated similar trans-corneal and trans-scleral PG diffusion (corneal apparent permeability coefficient 6.46 ± 0.38 × 10-7 cm/s and scleral apparent permeability coefficient 5.87 ± 1.18 × 10-7 cm/s; mean ± SD; n = 5). However, the amount of PG accumulated in scleras was statistically higher than in corneas (30.07 ± 9.09 μg/cm2 and 15.56 ± 4.36 μg/cm2 respectively). The PG-loaded inserts (55.6 μg/cm2) were thin, translucent, showed no irritancy (HET-CAM test) and were elastic and robust, all suitable properties for its potential use in the treatment of several ocular diseases.
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The WHO Biopharmaceutical Classification System (BCS) is a practical tool to identify active pharmaceutical ingredients (APIs) that scientifically qualify for a waiver of in vivo bioequivalence studies. The focus of this study was to... more
The WHO Biopharmaceutical Classification System (BCS) is a practical tool to identify active pharmaceutical ingredients (APIs) that scientifically qualify for a waiver of in vivo bioequivalence studies. The focus of this study was to engage a global network of laboratories to experimentally quantify the pH-dependent solubility of the highest therapeutic dose of 16 APIs using a harmonized protocol. Intra-laboratory variability was ≤5 %, and no apparent association of inter-laboratory variability with API solubility was discovered. Final classification “low solubility” vs “high solubility” was consistent among laboratories. In comparison to the literature-based provisional 2006 WHO BCS classification, three compounds were re-classified from “high” to “low-solubility”. To estimate the consequences of these experimental solubility results on BCS classification, dose-adjusted in silico predictions of the fraction absorbed in humans were performed using GastroPlus®. Further expansion of t...
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Mesoporous silica microparticles were prepared, loaded with the dye safranin O (<b>M-Saf</b>) or with the drug budesonide (<b>M-Bud</b>) and capped by the grafting of a bulky azo derivative. Cargo release from... more
Mesoporous silica microparticles were prepared, loaded with the dye safranin O (<b>M-Saf</b>) or with the drug budesonide (<b>M-Bud</b>) and capped by the grafting of a bulky azo derivative. Cargo release from <b>M-Saf</b> at different pH values (mimicking those found in the gastrointestinal tract (GIT)) in the absence or presence of sodium dithionite (a reducing agent mimicking azoreductase enzyme present in the colon) was tested. Negligible safranin O release was observed at pH 6.8 and 4.5, whereas a moderate delivery at pH 1.2 was noted and attributed to the hydrolysis of the urea bond that linked the azo derivative onto the external surface of the inorganic scaffold. Moreover, a marked release was observed when sodium dithionite was present and was ascribed to the rupture of the azo bond in the molecular gate. Budesonide release from <b>M-Bud</b> in the presence of sodium dithionite was also assessed by UV–vis and HPLC measurements...
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The objective was to evaluate the influence of the formulation in the in vitro transdermal absorption through pig ear skin of three preservatives, bronopol, bronidox and formaldehyde as well as the absorption of formaldehyde from bronopol... more
The objective was to evaluate the influence of the formulation in the in vitro transdermal absorption through pig ear skin of three preservatives, bronopol, bronidox and formaldehyde as well as the absorption of formaldehyde from bronopol and dimethyloldimethyl hydantoin (DMDM hydantoin). An aqueous solution, an O/W emulsion and a hydrogel were assayed. Bronidox and bronopol absorption depends on the formulation. The O/W emulsion was the system that least promoted absorption of bronidox while the absorption of bronopol was lower from the hydrogel. The aqueous solution provided maximal transdermal absorption of both preservatives. Moreover, the transdermal absorption of formaldehyde released from bronopol also depends on the formulation, being the aqueous solution the system that allowed greater absorption. Transdermal absorption of formaldehyde, applied directly or released from DMDM hydantoin, is not conditioned by the excipients. The degree of transdermal absorption of all the preservatives tested is low and therefore the concentrations allowed by regulations are safely used. Nonetheless, since formaldehyde was detected in the receptor compartment after a long time exposure to bronopol and DMDM hydantoin it would be important to consider the possibility of limiting the use of these two preservatives to rinse off products as is the case of bronidox.
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In recent years, the use of 3D printing technologies in orthopedic surgery has markedly increased, as they offer the possibility of printing personalized prostheses. The work presented in this article is a preliminary study of a research... more
In recent years, the use of 3D printing technologies in orthopedic surgery has markedly increased, as they offer the possibility of printing personalized prostheses. The work presented in this article is a preliminary study of a research project which aims to manufacture customized spacers containing antibiotics for use in joint replacement surgery. The objective of this work was to design and print different 3D constructs to evaluate the use of different materials, their properties after the process of 3D printing, such as resistance, and the release kinetics of drugs from the constructs. Different designs and different materials were analyzed to obtain a 3D construct with suitable properties. Our design takes advantage of the micropores created between the layers of the 3D printed filaments to release the contained drug. Using polylactic acid (PLA) we were able to print cylindrical structures with interconnected micropores and a hollow chamber capable of releasing methylene blue, ...
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Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work,... more
Nanohydrogels based on natural polymers, such as polysaccharides, are gaining interest as vehicles for therapeutic agents, as they can modify the pharmacokinetics and pharmacodynamics of the carried drugs. In this work, hyaluronan-riboflavin nanohydrogels were tested in vivo in healthy rats highlighting their lack of toxicity, even at high doses, and their different biodistribution with respect to that of native hyaluronan. They were also exploited as carriers of a hydrophobic model drug, the anti-inflammatory piroxicam, that was physically embedded within the nanohydrogels by an autoclave treatment. The nanoformulation was tested by intravenous administration showing an improvement of the pharmacokinetic parameters of the molecule. The obtained results indicate that hyaluronan-based self-assembled nanohydrogels are suitable systems for low-soluble drug administration, by increasing the dose as well as the circulation time of poorly available therapeutic agents.
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Research Interests: Biomedical Engineering, Kinetics, Medicine, Vancomycin, Humans, and 15 moreBone Cement, Temperature, Drug Delivery Systems, Solubility, Arthroplasty, Clinical Sciences, Antibiotics, Anti-Bacterial Agents, Implant, Bone Cements, Ciprofloxacin, Ciprofloxacin Hydrochloride, Polystyrenes, Elution, and Drug combinations
N-substituted benztropine analogs are potent dopamine uptake inhibitors that display pharmacokinetic/dynamic properties consistent with the profile of a substitute medication for cocaine addiction. The purpose of the present experiments... more
N-substituted benztropine analogs are potent dopamine uptake inhibitors that display pharmacokinetic/dynamic properties consistent with the profile of a substitute medication for cocaine addiction. The purpose of the present experiments was to characterize in rats the addictive-like properties of one such analog, 3 alpha-[bis(4&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-fluorophenyl)methoxy]-tropane (AHN-1055), incorporating probes of its stimulant and incentive/motivational effects and of its ability to influence cocaine self-administration. We used open field activity and drug self-administration assays. To examine the effects of AHN-1055 on locomotor behavior, the analog was administered alone (0, 1, 3, and 10 mg/kg intraperitoneally) and in combination with cocaine (15 mg/kg i.p.). The influence of AHN-1055 on cocaine&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s intake was studied by administering the analog (0, 3, and 10 mg/kg i.p.) before the start of the self-administration sessions. To compare the addictive-like properties of AHN-1055 and cocaine, progressive ratio performance and abstinence-induced context-conditioned relapse were evaluated. AHN-1055 evoked robust and sustained locomotor activity when administered alone and increased cocaine-induced locomotor stimulation. Notably, the analog showed by comparison to cocaine weak reinforcing efficacy in a modified progressive ratio schedule of drug reinforcement, and contrary to cocaine, it showed no ability to promote context-conditioned relapse to drug seeking following stable self-administration and abstinence. Further, AHN-1055 treatment blocked cocaine intake dose-dependently in rats with a steady history of cocaine self-administration without reducing responding for sucrose, a natural reward. These findings demonstrate essential psychopharmacological differences between AHN-1055 and cocaine and highlight important properties of the analog as a possible pharmacotherapy in cocaine addiction.
Research Interests: Pharmacology, Psychology, Addiction, Animal Behavior, Medicine, and 15 moreDopamine, Animals, Cocaine, Male, Open Field, Dopamine Transporter, Cholinergic Receptor, Locomotor Activity, AHN, Muscarinic Receptor, Dynamic Properties, Motor activity, Psychology and Cognitive Sciences, Progressive Ratio, and Medical and Health Sciences
Research Interests: Chemistry, Depression, Neuropsychopharmacology, Medicine, Gene expression, and 15 moreDopamine, Classical Conditioning, Brain, Low Dose, Mice, Animals, Cocaine, Male, Amphetamine, Dopamine Transporter, Locomotor Activity, AHN, Motor activity, Conditioned place preference, and Medical and Health Sciences
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Research Interests: Pharmacology, Pharmacokinetics, Medicine, Population, Mixed Effects Models, and 15 moreAnimals, Male, European, Rats, Time Factors, Depot, Wistar Rats, Area Under Curve, Amiodarone, Blood Proteins, NONMEM, Tissue distribution, Compartment Model, plasma proteins, and Pharmacology and pharmaceutical sciences
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Objective: To describe, in patients undergoing colorectal surgery (CRS), the pharmacokinetics of a single, prophylactic preoperative dose of 1500 mg of metronidazole plus 240 mg gentamicin and measure its efficacy in accordance with the... more
Objective: To describe, in patients undergoing colorectal surgery (CRS), the pharmacokinetics of a single, prophylactic preoperative dose of 1500 mg of metronidazole plus 240 mg gentamicin and measure its efficacy in accordance with the accepted ...
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Inter- and intra-batch variability of the quality attributes contribute to the uncertainty for demonstrating equivalent microstructure of post-approval changes and generic/hybrids of semisolid topical products. Selecting a representative... more
Inter- and intra-batch variability of the quality attributes contribute to the uncertainty for demonstrating equivalent microstructure of post-approval changes and generic/hybrids of semisolid topical products. Selecting a representative sample size to describe accurately the in vitro properties of semisolids and to reach enough statistical power to demonstrate similarity between two semisolid topical products is currently challenging. The objective of this work is to establish the number of batches and units per batch to be compared based on different inter-batch and intra-batch variability to demonstrate equivalence in the physical characteristics of the products that ensure a similar microstructure of the semisolid. This investigation shows that the minimum number of batches to be compared of each product is 3 and the minimum number of units per batch could be 6 in the case of low intra- and inter-batch variability. If the products are not identical, i.e., 2.5–5% differences that...
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This study examines the statistical implications, and their possible implementation, of the “Draft guideline on quality and equivalence of topical products” issued by the European Medicines Agency in 2018, with particular focus on the... more
This study examines the statistical implications, and their possible implementation, of the “Draft guideline on quality and equivalence of topical products” issued by the European Medicines Agency in 2018, with particular focus on the section devoted to quality equivalence of physical properties. A new confidence interval to conduct the quality equivalence test and a way to cope with the multiplicity of quality parameters are presented and discussed. As an example, the results and the statistical analysis of a study on betamethasone 0.5 mg/g ointment are presented. It is suggested that the equivalence limits proposed in the draft guideline are overly strict: It is as difficult to declare quality equivalence between two packaging formats of the same reference product as to declare quality equivalence between the reference and the test product.
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The main objective of this investigation was to develop an in vitro–in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC... more
The main objective of this investigation was to develop an in vitro–in vivo correlation (IVIVC) for immediate release candesartan cilexetil formulations by designing an in vitro dissolution test to be used as development tool. The IVIVC could be used to reduce failures in future bioequivalence studies. Data from two bioequivalence studies were scaled and combined to obtain the dataset for the IVIVC. Two-step and one-step approaches were used to develop the IVIVC. Experimental solubility and permeability data confirmed candesartan cilexetil. Biopharmaceutic Classification System (BCS) class II candesartan average plasma profiles were deconvoluted by the Loo-Riegelman method to obtain the oral fractions absorbed. Fractions dissolved were obtained in several conditions in USP II and IV apparatus and the results were compared calculating the f2 similarity factor. Levy plot was constructed to estimate the time scaling factor and to make both processes, dissolution and absorption, superim...
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Colonic Drug Delivery Systems (CDDS) are especially advantageous for local treatment of inflammatory bowel diseases (IBD). Site-targeted drug release allows to obtain a high drug concentration in injured tissues and less systemic adverse... more
Colonic Drug Delivery Systems (CDDS) are especially advantageous for local treatment of inflammatory bowel diseases (IBD). Site-targeted drug release allows to obtain a high drug concentration in injured tissues and less systemic adverse effects, as consequence of less/null drug absorption in small intestine. This review focused on the reported contributions in the last four years to improve the effectiveness of treatments of inflammatory bowel diseases. The work concludes that there has been an increase in the development of CDDS in which pH, specific enzymes, reactive oxygen species (ROS), or a combination of all of these triggers the release. These delivery systems demonstrated a therapeutic improvement with fewer adverse effects. Future perspectives to the treatment of this disease include the elucidation of molecular basis of IBD diseases in order to design more specific treatments, and the performance of more in vivo assays to validate the specificity and stability of the obta...
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The authors wish to make the following corrections to this paper [...]
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Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the... more
Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µg/0.5 mg/g) in order to define the acceptance range that allows concluding equivalence between these batches. Being batches of the same reference product, they are expected to be clinically equivalent and possess similar microstructure. The 90% confidence intervals for the test/reference ratio of these physical parameters were calculated with parametric and non-parametric approaches. Both methods conclude that equivalent microstructure between batches cannot be demonstrated with a reasonable sample size when the acceptance range was set at ±10%, since several physical parameters exhibit inter-batch variability >...
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This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties... more
This study aimed at investigating the effect of electrical current profile upon the iontophoretic transport of (i) ascorbic acid (AA) and (ii) ellagic acid (EA), into porcine skin in vitro, and the impact of the physicochemical properties of both actives on their mechanism of transport when formulated in cosmetic compositions. The experiments were performed using a proprietary iontophoretic device containing a roller to apply the formulation. Three current profiles were tested: (i) galvanic direct current (DC), (ii) square unipolar pulse current (SPC), and (iii) galvanic direct current (DC) + pulse current (PC). The skin samples were collected at different sampling points, extracted and analyzed by HPLC. Results suggested that the DC + PC mode for only 5 min was able to significantly increase the delivery of AA from o/w cosmetic compositions. The use of this current profile might improve the skin penetration of AA due to electromigration and passive diffusion, the latter being facil...
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The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum... more
The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical enhancers (decenoic and oleic acid, laurocapram, and R-(+)-limonene) and iontophoresis at two current densities, 0.25 and 0.5 mA/cm2 were tested. R-(+)-limonene, and iontophoresis at 0.5 mA/cm2 were proven to be the most efficient in increasing propranolol transdermal flux, both doubled the original propranolol transdermal flux. Iontophoresis was demonstrated to be superior than the chemical enhancer because it allowed faster delivery of the drug. The DPK method was sufficiently sensitive to detect subtle vehicle-induced effects on the skin permeation of propranolol. The shorter duration of these experiments and their ability to provide mechanistic information about partition between vehicle ...
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Mesoporous silica microparticles were prepared, loaded with the dye safranin O () or with the drug budesonide () and capped by the grafting of a bulky azo derivative. Cargo release from at different pH values (mimicking those found in the... more
Mesoporous silica microparticles were prepared, loaded with the dye safranin O () or with the drug budesonide () and capped by the grafting of a bulky azo derivative. Cargo release from at different pH values (mimicking those found in the gastrointestinal tract) in the absence or presence of sodium dithionite (a reducing agent mimicking azoreductase enzyme present in the colon) was tested. Negligible safranin O release was observed at pH 6.8 and 4.5, whereas a moderate delivery at pH 1.2 was noted and attributed to the hydrolysis of the urea bond that linked the azo derivative onto the external surface of the inorganic scaffold. Moreover, a marked release was observed when sodium dithionite was present and was ascribed to the rupture of the azo bond in the molecular gate. Budesonide release from in the presence of sodium dithionite was also assessed by ultraviolet-visible spectroscopy and high performance liquid chromatography measurements. In addition, preliminary experiments with ...
Magnetic mesoporous silica microparticles were loaded with safranin O (S1) and with hydrocortisone (S2) and the outer surface functionalized with a bulky azo derivative bearing urea moieties. Aqueous suspensions of both solids at pH 7.4... more
Magnetic mesoporous silica microparticles were loaded with safranin O (S1) and with hydrocortisone (S2) and the outer surface functionalized with a bulky azo derivative bearing urea moieties. Aqueous suspensions of both solids at pH 7.4 showed negligible payload release whereas a marked delivery was observed in the presence of sodium dithionite due to the rupture of the azo bonds. Besides, a moderate cargo release was observed at acidic pH due to the hydrolysis of the urea bonds that linked the azo derivative onto the external surface of the inorganic scaffolds. In vitro digestion models showed that S1 and S2 microparticles could be used for the controlled release of payload in the reducing colon environment (in which azoreductase enzymes are present). On the other hand, in vivo pharmacokinetic studies in rats showed that safranine O release from S1 microparticles was concentrated in colon. The performance of S2 microparticles for the treatment of colitis in rats (induced by oral ad...
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Effective treatment of Parkinson's disease (PD) involves administration of therapeutic agents with complementary mechanisms of action in order to replenish, sustain or substitute endogenous dopamine. The objective of this study was to... more
Effective treatment of Parkinson's disease (PD) involves administration of therapeutic agents with complementary mechanisms of action in order to replenish, sustain or substitute endogenous dopamine. The objective of this study was to investigate anodal co-iontophoresis of pramipexole (PRAM; dopamine agonist) and rasagiline (RAS; MAO-B inhibitor) in vitro and in vivo. Passive permeation of PRAM and RAS (20 mM each) across porcine skin after 6 h was 15.7 ± 1.9 and 16.0 ± 2.9 µg/cm, respectively. Co-iontophoresis at 0.15, 0.3 and 0.5 mA/cm resulted in statistically significant increases in delivery of PRAM and RAS; at 0.5 mA/cm, cumulative permeation of PRAM and RAS was 613.5 ± 114.6 and 441.1 ± 169.2 µg/cm, respectively - corresponding to 38- and 27-fold increases over passive diffusion. Electromigration was the dominant mechanism for both molecules (>80%) and there was no effect on convective solvent flow. Statistically equivalent delivery was observed with human skin. The co...
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In this work, 6-phosphogluconic trisodium salt (6-PG-Na+) is introduced as a new aqueous and non-toxic crosslinker agent to obtain ionic hydrogels. Here, it is shown the formation of hydrogels based on chitosan crosslinked with 6-PG-Na+.... more
In this work, 6-phosphogluconic trisodium salt (6-PG-Na+) is introduced as a new aqueous and non-toxic crosslinker agent to obtain ionic hydrogels. Here, it is shown the formation of hydrogels based on chitosan crosslinked with 6-PG-Na+. This formulation is obtained by ionic interaction of cationic groups of polymer with anionic groups of crosslinker. These hydrogels are non-toxic, do not cause dermal irritation, are easy to extend and have an adequate adhesion force to be applied as polymeric film over the skin. This formulation exhibits a first order release kinetic and can be applied as drug vehicle for topical administration or as wound dressing for wound healing. The primary goal of this communication is to report the identification and utility of 6-phosphogluconic trisodium salt (6-PG-Na+) as a non toxic crosslinker applicable for cationic polymers.
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Magnetic micro-sized mesoporous silica particles were used for the preparation of a gated material able to release an entrapped cargo in the presence of an azo-reducing agent and, to some extent, at acidic pH. The magnetic mesoporous... more
Magnetic micro-sized mesoporous silica particles were used for the preparation of a gated material able to release an entrapped cargo in the presence of an azo-reducing agent and, to some extent, at acidic pH. The magnetic mesoporous microparticles were loaded with safranin O and the external surface was functionalized with an azo derivative(bearing a carbamate linkage) yielding solid. Aqueous suspensions ofat pH 7.4 showed negligible safranin O release due to the presence of the bulky azo derivative attached onto the external surface of the inorganic scaffold. However, in the presence of sodium dithionite (azoreductive agent), a remarkable safranin O delivery was observed. At acidic pH, a certain safranin O release fromwas also found. The pH-triggered safranin O delivery was ascribed to the acid-induced hydrolysis of the carbamate moiety that linked the bulky azo derivatives onto the mesoporous inorganic magnetic support. The controlled release behavior ofwas also tested using a mo...
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One of its most serious complications associated with arthroplasty is the development of infections. Although its prevalence is only between 0.5% and 3%, in some cases it can lead to death. Therefore, an important challenge in joint... more
One of its most serious complications associated with arthroplasty is the development of infections. Although its prevalence is only between 0.5% and 3%, in some cases it can lead to death. Therefore, an important challenge in joint surgery is the prevention of infections when an arthroplasty is performed. The use of antibiotic-loaded cements could be a suitable tool due to numerous advantages. The main advantage of the use of antibiotic loading into bone cement derives directly from antibiotic release in the effect site, allowing achievement of high concentrations at the site of action, and minimal or no systemic toxicity. This route of administration was first described by Buchholz and Engelbrecht. In the case of infection treatment, this is an established method and its good results have been confirmed. However, its role in infection prevention, and, therefore, the use of these systems in clinical practice, has proved controversial because of the uncertainty about the development...
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Background: The application of therapeutic agents to the skin addresses three general objectives: (a) the treatment of a variety of dermatologic diseases; (b) the “targeted” delivery of drugs to deeper subcutaneous tissues, with a... more
Background: The application of therapeutic agents to the skin addresses three general objectives: (a) the treatment of a variety of dermatologic diseases; (b) the “targeted” delivery of drugs to deeper subcutaneous tissues, with a concomitant reduction in systemic exposure; and (c) socalled transdermal administration to elicit a systemic pharmacologic effect. Objective: Recently, significant progress towards all three goals has been recorded and the level of research and development activity remains high. We aim to discuss these advances from mechanistic and clinical standpoints. Results: For the topical treatment of skin disease, novel vehicles (e.g., stabilized, supersaturated systems and liposomal formulations) have led to dramatic improvements in local drug bioavailability. Transdermal delivery of drugs for systemic effect, though limited in terms of the number of compounds, is perhaps the most commercially successful (in terms of the number of products) of the controlled releas...
The etiology of undernourishment in cancer patients is multifactorial: tumor-related mechanisms (such as obstruction, metabolic abnormalities, and functionality changes) in addition to the influence of anticancer therapies, which can... more
The etiology of undernourishment in cancer patients is multifactorial: tumor-related mechanisms (such as obstruction, metabolic abnormalities, and functionality changes) in addition to the influence of anticancer therapies, which can induce or worsen undernutrition. The evident role of undernutrition in cancer treatment outcomes suggests the need of considering nutritional status when evaluating anticancer drugs. In order to merge the available data and offer researchers and clinicians a global view of this phenomenon, the present manuscript reviews on a drug-by-drug basis the undernutrition-related pharmacokinetic and pharmacodynamic aspects of anticancer treatments. This review notes interesting trends in the relationship between undernourishment and pharmacokinetics across studies, and indicates that dosing modifications of these drugs may be necessary to optimize chemotherapeutic treatments. Furthermore, this review has compiled evidence regarding undernourishment&#39;s capacity of enhancing treatment-related myelosuppression, cardiotoxicity, ototoxicity, neurotoxicity, and malignancies.