Nanocarriers for optimizing the balance between interfollicular permeation and follicular uptake of topically applied clobetasol to minimize adverse effects.

The treatment of various hair disorders has become a central focus of good dermatologic patient care as it affects men and women all over the world. For many inflammatory-based scalp diseases, glucocorticoids are an essential part of treatment, even though they are known to cause systemic as well as local adverse effects when applied topically. Therefore, efficient targeting and avoidance of these side effects are of utmost importance. Optimizing the balance between drug release, interfollicular permeation, and follicular uptake may allow minimizing these adverse events and simultaneously improve drug delivery, given that one succeeds in targeting a sustained release formulation to the hair follicle. To test this hypothesis, three types of polymeric nanocarriers (nanospheres, nanocapsules, lipid-core nanocapsules) for the potent glucocorticoid clobetasol propionate (CP) were prepared. They all exhibited a sustained release of drug, as was desired. The particles were formulated as a dispersion and hydrogel and (partially) labeled with Rhodamin B for quantification purposes. Follicular uptake was investigated using the Differential Stripping method and was found highest for nanocapsules in dispersion after application of massage. Moreover, the active ingredient (CP) as well as the nanocarrier (Rhodamin B labeled polymer) recovered in the hair follicle were measured simultaneously, revealing an equivalent uptake of both. In contrast, only negligible amounts of CP could be detected in the hair follicle when applied as free drug in solution or hydrogel, regardless of any massage. Skin permeation experiments using heat-separated human epidermis mounted in Franz Diffusion cells revealed equivalent reduced transdermal permeability for all nanocarriers in comparison to application of the free drug. Combining these results, nanocapsules formulated as an aqueous dispersion and applied by massage appeare to be a good candidate to maximize follicular targeting and minimize drug penetration into the interfollicular epidermis. We conclude that such nanotechnology-based formulations provide a viable strategy for more efficient drug delivery to the hair follicle. Moreover, they present a way to minimize adverse effects of potent glucocorticoids by releasing the drug in a controlled manner and simultaneously decreasing interfollicular permeation, offering an advantage over conventional formulations for inflammatory-based skin/scalp diseases.

QSPR in oral bioavailability: specificity or integrality?

During the last decade the technological advances in drug discovery changed the absorption, distribution, metabolism, excretion and toxicity (ADMET) profiles of New Chemical Entities (NCEs). Among ADMET processes, absorption plays an important role in the research and development of more effective orally administered drugs. Although significant progress has been made in in vitro, in situ and in vivo experimental determinations of absorption, the development of in silico methodologies has emerged as a cheaper and fast alternative to predict them. Even though several in silico models have been described in the literature to predict oral bioavailability and related properties, the prediction accuracy and their potential use is still limited. The low precision and high variability of data, the lack of a complete experimental and theoretical validation of in silico approach, and above all, the multi-factorial nature of the oral absorption term, make the development of predictive in silico models a thorny task. The present review discusses several important advances regarding the QSPR approaches used in the development of predictive oral bioavailability models. The importance of fixing the problem associated with data resource, as well as improving the reliability of in silico results is highlighted. Optimization of individual properties along the absorption process must be integrated in a multi-objective scenario for studying oral bioavailability behavior in the early drug discovery and development.

Potential impact of European decisions and reports in pharmacy planning in Spain

Currently there are several cases in the field of the European Union regarding Spanishlegislation on private pharmacy planning. The first of these cases was initiated by issuing areasoned opinion by the European Commission on 28 June 2006. The second approach hastaken place through the various preliminary questions raised before the Court of Justice ofthe European Communities by certain Spanish courts. Although not all of the aboveprocedures have been completed, certain European pronouncements do provide what mightbe the consequences that they may have on the Spanish legislation on the subject. It is verylikely that the binomial property-ownership in favor of pharmacists and planning criteriaestablished in the Spanish regulations is considered compatible with European law. On thecontrary, it is feasible that certain aspects of the merit scales applied by the AutonomousCommunities for awarding newly authorized community pharmacies must be changed(AU)

Adjudication of new community pharmacies: comparison of ranking criteria

This article studies the differences between the models of candidate classification for the adjudication of new pharmacies in the different Spanish self-governing regions. The objective of this study is to analyze the profile of the selected professional. Generally, the ranking takes into account the professional activity as pharmacist, the pre-graduate formation as well as the postgraduate, with different weights. Some of the 15 autonomies include as merits the cooficial languages, an optional written test and special situations as unemployment.In general, the criteria try to find out the best profile of pharmacist based on the professional experience and the postgraduate formation(AU)

Nortriptyline for smoking cessation: release and human skin diffusion from patches.

The objective of this work was to develop a simple and inexpensive transdermal formulation containing Nortriptyline Hydrochloride (NTH) for smoking cessation support therapy. Hydroxypropyl-methyl-cellulose was chosen as polymer and a mixture of transdermal enhancers (selected from previous research) was incorporated. The formulations were characterised in terms of appearance, thickness, uniformity of NTH content, release and skin permeation. Release studies demonstrated controlled release for four formulations. Diffusion studies were performed through human heat separated epidermis (HHSE) using Franz Diffusion Cells (FDC). Patches provided different fluxes varying from 20.39+/-7.09 microg/(cm(2) h) to 256.19+/-94.62 microg/(cm(2) h). The penetration profiles of NTH within the stratum corneum (SC) and deeper skin layers (DSL) were established after three administration periods (3 h, 6 h, and 24 h). Skin changes induced by the application of the patches were observed by confocal laser scanning microscopy (CLSM). The highest flux obtained would provide the recommended doses for smoke cessation support therapy (25-75 mg per day) with a 2 cm x 2 cm patch or a 3.5 cm x 3.5 cm patch, respectively, without skin damage evidence.

Adjudicación de farmacias: análisis comparativo de baremos / Adjudication of new community pharmacies: comparison of ranking criteria

Este trabajo estudia los diferentes modelos de baremación para la adjudicación de oficinas defarmacias en las distintas comunidades autónomas. El objetivo final es analizar el perfil deladjudicatario que se propicia con ellos. De forma general, el concurso contempla el ejercicioprofesional como farmacéutico, la formación de pregrado y la formación posgrado, condistintos matices y pesos. En algunas autonomías se valoran, asimismo, los idiomascooficiales, una prueba escrita voluntaria sobre conocimientos y determinadas situacionesespeciales (minusvalía y paro).En general se propicia un perfil de adjudicatario que suma la experiencia laboral con unacontinua formación y reciclaje(AU)

This article studies the differences between the models of candidate classification for the adjudication of new pharmacies in the different Spanish self-governing regions. The objective of this study is to analyze the profile of the selected professional. Generally, the ranking takes into account the professional activity as pharmacist, the pre-graduate formation as well as the postgraduate, with different weights. Some of the 15 autonomies include as merits the cooficial languages, an optional written test and special situations as unemployment. In general, the criteria try to find out the best profile of pharmacist based on the professional experience and the postgraduate formation(AU)

Nortriptyline hydrochloride skin absorption: development of a transdermal patch.

The influence of propylen glycol (PG), ethanol, and oleic acid (OA) on nortriptyline hydrochloride (NTH) penetration through human epidermis was studied in vitro at two different pH values (5.5 and 7.4). The influence of lactic acid and polysorbate 80 was studied for a pH of 5.5. Permeation studies through Heat Separated Epidermis, as well as the enhancing effect of the different vehicles, showed a pH dependency. A pH value of 5.5 in the donor solution decreases significantly the permeability coefficient (Kp) with respect to a pH value of 7.4 (0.011+/-0.004 x 10(-6) versus 0.36+/-0.04 x 10(-6)cm/s). The vehicles showed an increasing enhancement effect in the order: polysorbate 80>ethanol/PG/OA>PG>ethanol>ethanol/lactic acid>lactic acid at pH 5.5 while they reduced the permeation of NTH at pH 7.4. Considering the results obtained at pH 5.5, the maximum enhancement ratios were found for polysorbate 80 and the combination ethanol/PG/OA (10.72 and 3.90). Both vehicles were selected for designing a NTH transdermal delivery system (NTH-TDS) using (hydroxypropyl)methyl-cellulose as polymer. The NTH-TDS based on the combination of ethanol/PG/OA showed an enhancement ratio with respect to control of 2.09 and the addition of polysorbate 80 to the matrix, of 5.82.

Concursos de traslado y apertura: una opción peculiar en la Comunidad Autónoma Canaria / Move procedure of the pharmacies and new establishment in the Canary Island

El presente artículo describe la regulación del peculiar concurso de traslados de oficinas de farmacia en la Comunidad Autónoma de Canarias. Se comenta asimismo el concurso de aperturas, por su conexión con el anterior. Se investigan las razones justificativas de la normativa canaria y, se comparan las alternativas similares de otras comunidades, como el baremo para el concurso de aperturas de la Comunidad Valenciana. Finalmente se enumeran los principales inconvenientes de este sistema

The present paper describes in detail the peculiar move procedure of the chemist shops that takes place in the Canary Island. It can be performed in any place of the Community. The paper also comments the procedure for new establishment installation, as it is clearly related. The reasons justifying the regulation are investigated and some other possibilities used by different autonomic governments are compared, as the merit scale used by the Valenciana Community. The disadvantages of the move procedure are also pointed out

Labetalol absorption kinetics: rat small intestine and colon studies.

Labetalol is a widely used drug for the management of hypertension, which is preferably administered by the oral route despite its low bioavailability. The objective of this study is to ascertain the mechanisms underlying its absorption as an approach to help in predicting the influence of dosage changes, possible drug-drug and drug-fruit juice interactions. Perfusion experiments have been performed in rats in two sites of absorption: the intestine and the colon. The nonlinearity of the process has been established by means of the assay of a wide range of concentrations (2-2000 microM). Fitting of the concentration versus time data allows the estimation of passive diffusion constant in the intestine (1.42 +/- 0.05/h) and the colon (1.13 +/- 0.06/h), V(m) and K(m) of the input process (9.85 +/- 4.98 microM/h, and 10.44 +/- 26.16 microM, respectively) and K(m) of an efflux system (0.53 +/- 1.16 microM) and V(m) in both intestinal segments (2.60 +/- 11.37 microM . /h in the intestine and 0.66 +/- 1.38 microM . /h in the colon). The efflux carrier implicated is identified by means of several inhibition experiments, whose inhibition ability is mathematically estimated. Results suggest the p-glycoprotein as responsible for the efflux of labetalol.

El derecho de continuidad en la propiedad de las oficinas de farmacia / Continuity right on the pharmacy community property

En la Ley 16/1997, de 25 de abril, de Regulación de Servicios de las Oficinas de Farmacia, se establece el derecho de transmisión de dichas oficinas a favor únicamente de farmacéuticos. Por otra parte, la normativa define el derecho de continuidad que se erige como la única excepción prevista reglamentariamente a este precepto. Este derecho de continuidad puede contemplar también el concepto de reserva de titularidad que puede considerarse como una especificidad dentro del mismo. Se hace un breve resumen de los orígenes de este precepto y se analiza la situación actual, que presenta una amplia variabilidad debido a las discrepancias de la normativa autonómica en materia de ordenación farmacéutica

Community pharmacies can only be owned by pharmacists, as enforced in the Law 16/1997, 25th April (Regulation of Community Pharmacy Services). Nevertheless, the continuity right allows a unique exception, which can also comprise the titular reservation (a special situation). A concise summary of the origin and development of this rule is presented. The situation in Spain nowadays is characterized as highly variable mainly due to the fact that autonomic governments are responsible for the pharmacy ordinance

Mathematical modelling of in situ and in vitro efflux of ciprofloxacin and grepafloxacin.

The efflux process due to p-glycoprotein-like mechanisms of ciprofloxacin (CIP) and grepafloxacin (GRX) has been studied "in situ" in rats and "in vitro" in Caco-2 cells. The results were modelled by a curve fitting procedure which allowed the characterization of the passive (Pd) and carrier mediated parameters (Vm and Km) from the raw data without initial velocities estimation. CIP absorption in rat was characterized as a passive diffusion at the assayed concentrations. Although the involvement of an efflux transporter cannot be ruled out, its relevance in the transport of the fluoroquinolone is negligible. In GRX absorption, an efflux process is implicated and it is detected in both absorption models. GRX permeability depends on the intestinal segment, reflecting the previously reported different expression level of the efflux transporters along the gut in rat. A first attempt to correlate the "in vitro" and the "in situ" data has been done. The mathematical model has been constructed using very simplistic assumptions and it will require further refinement but, nevertheless, the results are promising and demonstrate that a good modelling approach helps to identify the system critical parameters and how the system behaviour change when the parameters are modified as it happens when we move from the "in vitro" to the "in situ" level. Predicted versus experimental permeability values show a good correlation, demonstrating that the relevance of the secretion process "in situ" in rat can be predicted from the "in vitro" cell results.

Consideraciones acerca de la propiedad de oficinas de farmacia: doble titularidad / Considerations about property of the pharmacy: double titularty

Se revisa la normativa relativa a la propiedadde las farmacias respecto a la disposición deque únicamente puede ostentar la propiedadde una farmacia (Reales Ordenanzas -derogadas-,leyes autonómicas de ordenación farmacéutica).Se alude asimismo a la normativa que contemplalos procedimientos de autorización (Ordende 21 de noviembre de 1979 y Orden de17 de enero de 1980 del Ministerio de Sanidady Seguridad Social) que representaron una garantíadel cumplimiento de este requisito. Secomentan algunas sentencias que ponen demanifiesto la problemática que ha surgido endeterminados momentos

The ruIes applying to the owners of the Spanishpharmacy establishments that restrict thepossibility to one establishment are reviewed.The procedures to obtain an authorization(Order of 21st November 1979 and Order of17th January 1980 from the Social Insuranceand Health Ministry) are also cited as theyconstituted a guarantee of requirement accomplishment.Some sentences considering illegalsituations are commented in order to point outthe importance of the rules

In vitro percutaneous penetration of acyclovir from solvent systems and Carbopol 971-P hydrogels: influence of propylene glycol.

The mechanism underlying propylene glycol (PG) effects on acyclovir (ACV) penetration through human epidermis were studied. Solvent systems and Carbopol gels containing increasing percentage of PG (from 0% to 70%, w/w) were used. Viscosity studies of both vehicles were carried out to characterise the influence of rheological behaviour. In solvent systems skin permeation values of ACV increase as the concentration of PG increase yielding a maximum enhancement ratio (ER = 10) for 70% PG. The release rate of ACV from gels was determined. Higuchi's model was used to estimate the apparent diffusion coefficient of the drug. These values show a decrease as the content of PG in the vehicle increases; this effect could be attributed to the increase of the viscosity in the diffusional pathway. When gels are used skin permeation values of ACV were smaller than those of the solvent systems. This could be attributed to the network structure created by the polymer that increases the length of the diffusional pathway. The maximum ER (= 6.8) was for Carbopol gel containing 50% PG. Therefore, these gels can be considered candidates for further research to confirm their usefulness as delivery systems for ACV topical formulations.

Kinetic modelling of passive transport and active efflux of a fluoroquinolone across Caco-2 cells using a compartmental approach in NONMEM.

The purpose was to develop a general mathematical model for estimating passive permeability and efflux transport parameters from in vitro cell culture experiments. The procedure is applicable for linear and non-linear transport of drug with time, <10 or >10% of drug transport, negligible or relevant back flow, and would allow the adequate correction in the case of relevant mass balance problems. A compartmental kinetic approach was used and the transport barriers were described quantitatively in terms of apical and basolateral clearances. The method can be applied when sink conditions are not achieved and it allows the evaluation of the location of the transporter and its binding site. In this work it was possible to demonstrate, from a functional point of view, the higher efflux capacity of the TC7 clone and to identify the apical membrane as the main resistance for the xenobiotic transport. This methodology can be extremely useful as a complementary tool for molecular biology approaches in order to establish meaningful hypotheses about transport mechanisms.

Formulación magistral: arte y calidad / Magistral formulation: art and quality

El artículo revisa la definición de formulación magistral y enuncia la normativa que le es de aplicación. Resume su actual función en relación al pasado. Comenta la oportunidad que genera la normativa, centrada en la mejora del servicio que oferta. También analiza la amenaza que puede derivarse para la profesión de la génesis de categorías entre las oficinas y de un coste social y económico muy elevado en relación al volumen de la formulación sobre la dispensación total (AU)

Kinetic modeling of triamterene intestinal absorption and its inhibition by folic acid and methotrexate.

The aim of this work was to study the intestinal absorption process of triamterene in situ in rats in order to gain insight on its absorption mechanism. The study shows an example of application of a pharmacokinetic model for drug disappearance from a compartment by simultaneous first order and Michaelis-Menten processes to the intestinal drug disappearance by absorption in a non-steady state system. The parameter used to quantify absorption was the absorption rate constant, determined in situ by means of a loop perfusion technique, performed in colon and in whole small intestine of rat at three pHs (5.00, 7.00 and 8.00) and in the presence of folic acid and methotrexate. Different concentrations of the drug were perfused in each condition. The concentrations versus time data were modeled with different kinetic absorption and inhibition differential equations to obtain the passive and active transport components and to elucidate the inhibition mechanisms. The results obtained confirm that triamterene is absorbed by means of passive diffusion and by a transporter or transporters related to folates. Folic acid and methotrexate are able to inhibit triamterene absorption. The results do not allow the selection of a competitive or non-competitive model for inhibition and this fact could be due to the presence of different carriers. The possibility of the existence of a secretion process sensitive to verapamil is also discussed.

Transintestinal secretion of ciprofloxacin, grepafloxacin and sparfloxacin: in vitro and in situ inhibition studies.

The influence of the secretion process on the absorption of ciprofloxacin, grepafloxacin and sparfloxacin has been evaluated by means of inhibition studies. Two well known P-glycoprotein inhibitors (cyclosporine, verapamil), a mixed inhibitor of P-glycoprotein and the organic cation transporter OCT1 (quinidine) and a well established MRP substrate (p-aminohipuric acid) have been selected in order to distinguish the possible carriers implicated. An in situ rat gut perfusion model and CACO-2 permeability studies are used. Both methods suggest the involvement of several types of efflux transporters for every fluoroquinolone. The relevance of the secretory pathway depends on the intrinsic permeability of the quinolone. The in vitro model seems to be more suitable for discriminating mechanisms underlying the absorption process, while in situ studies are less sensitive to inhibition studies.

Quinolonas y Streptococcus pneumoniae. Mecanismo de acción y resistencia / Quinolones and Streptococcus pneumoniae. Mechanisms of action and resistance

Streptococcus pneumoniae se considera el principal agente causal de la neumonía adquirida en la comunidad, además de estar implicado con frecuencia en exacerbaciones de bronquitis crónica, otitis media aguda, sinusitis, meningitis y otras infecciones. Durante los últimos años, en búsqueda de nuevas sustancias debido a la aparición de resistencias en este microorganismo, se han estudiado, entre otros agentes antibacterianos, las fluoroquinolonas. Asimismo, la biología molecular ha ayudado a estudiar y comprender casi todos los mecanismos bioquímicos de resistencia y las rutas para la diseminación de la información genética entre las bacterias. En esta revisión se repasa el mecanismo de acción de las quinolonas y los mecanismos causantes de la resistencia de S. pneumoniae a ellas, por su importancia clínica y epidemiológica. S. pneumoniae es un caso peculiar, puesto que en este microorganismo la actividad bactericida puede producirse a través de la girasa, la topoisomerasa IV o ambas, dependiendo de la estructura de la quinolona, lo cual implica una influencia de la estructura en el logro del éxito antimicrobiano. Es importante, pues, conocer el prototipo de resistencia para hacer una recomendación de la antibioticoterapia adecuada, cuando esté indicada. (AU)

Mecanismos de resistencia bacteriana a las quinolonas / Mechanisms of bacterial resistance to quinolones

Para ejercer su efecto citotóxico las quinolonas deben penetrar a través de la membrana bacteriana y alcanzar su diana celular, la DNA girasa o la topoisomerasa IV, e inducir la muerte de la célula. Por ello, los mecanismos de resistencia a las fluoroquinolonas incluyen mutaciones en los genes que codifican la DNA girasa y la topoisomerasa IV dando lugar a las QRDR, alteraciones en la permeabilidad de la membrana que disminuyen la penetración intracelular del fármaco y actividad de transportadores activos endógenos que provocan la expulsión de los antimicrobianos desde la membrana celular al medio exterior. Estos mecanismos de resistencia pueden manifestarse solos o en combinación, si bien parece que in vivo el aumento en el grado de resistencia a las quinolonas es producto de varios mecanismos simultáneos. En el presente trabajo se revisan estos mecanismos de resistencia y se establece, en la medida de lo posible, una relación con la estructura de la quinolona. (AU)

[Mechanisms of bacterial resistance to quinolones]. / Mecanismos de resistencia bacteriana a las quinolonas.

In order to produce their cytotoxic effect, quinolones must enter the cell through the bacterial membrane to reach their target, DNA-gyrase or topoisomerase IV, and induce cell death. The mechanisms of resistance to fluoroquinolones include: those mediated by gene mutations codifying for DNA gyrase and topoisomerase IV and leading to QRDR; those characterized by changes in the permeability of the outer membrane which decrease intracellular penetration of the drug; and those caused by active endogenous carriers responsible for drug efflux. These resistance mechanisms can occur alone or in combination; in fact, it is believed that high resistance levels to quinolones in vivo are associated with simultaneous mechanisms. This article reviews such resistance mechanisms and establishes, when possible, their relation to the structure of quinolones.