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)

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

Desabastecimiento y suministro irregular de medicamentos: problemas urgentes / Shortages and irregular supply of medicines: an urgent problem

Actualmente en el Estado español se están produciendo problemas en el suministro de medicamentos a los serviciosfarmacéuticos. En el presente artículo se revisa la normativa vigente acerca de la distribución de medicamentos.Se comentan además las posibles causas del problema. También se analizan los medios que desarrolla el Estadopara evitar esta problemática y la postura de la Comunidad Valenciana que, de manera pionera, quiere regular enmateria de distribución farmacéutica, mediante una normativa con rango de Ley, para evitar los problemas quese suscitan

In this paper, we discuss the problems arising from the current supply problems of medicines to pharmacy outlets inSpain, as well as a revision of present regulations governing their distribution. In addition to the possible causes, ananalysis of the measures developed by the state to combat these problems has been made, as well as an assessment ofthe impact of new pioneering legislation passed by the regional government of Valencia, aimed at finding a solution

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.

Modelling intestinal absorption of salbutamol sulphate in rats.

The objective was to develop a semiphysiological population pharmacokinetic model that describes the complex salbutamol sulphate absorption in rat small intestine. In situ techniques were used to characterize the salbutamol sulphate absorption at different concentrations (range: 0.15-18 mM). Salbutamol sulphate at concentration of 0.29 mM was administered in presence of verapamil (10 and 20 mM), grapefruit juice and sodium azide (NaN3) (0.3, 3 and 6 mM). Different pharmacokinetic models were fitted to the dataset using NONMEM. Parametric and non-parametric bootstrap analyses were employed as internal model evaluation techniques. The validated model suggested instantaneous equilibrium between salbutamol sulphate concentrations in lumen and enterocyte, and the salbutamol sulphate absorption was best described by a simultaneous passive diffusion (ka = 0.636 h(-1)) and active absorption (VMax = 0.726 mM/h, Km = 0.540 mM) processes from intestinal lumen to enterocyte, together with an active capacity-limited P-gp efflux (V'max = 0.678 mM/h, K'm = 0.357 mM) from enterocyte to intestinal lumen. The extent of salbutamol sulphate absorption in rat small intestine can be improved by NaN3, grapefruit juice and verapamil.

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

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

Modelos celulares para la caracterización del transporte intestinal de fármacos / Cell culture models for characterize the intestinal drug transport

Numerosos grupos de investigación de distintos países abogan por la inclusión, en el proceso de desarrollo de nuevos medicamentos, de ensayos in vitro en los que se evalúa la capacidad de transporte y difusión de los fármacos a través de monocapas de células epiteliales de diferentes tejidos, con el fin de reducir el número de ensayos en animales de experimentación y conseguir una selección orientada de las moléculas candidatas. En el presente trabajo se exponen las características y metodologías de trabajo destinadas a facilitar la manipulación y uso de dos líneas celulares: las Caco- 2, células de carcinoma de colon humano, que reproducen las características del intestino y las MDCK, células renales de perro (Madin- Darby Canine Kidney), útiles para cuantificar la excreción renal de fármacos, fundamentalmente mediada por la glicoproteína P, además de representar una alternativa a las células Caco- 2 en ensayos de permeabilidad, para fármacos que se absorben pasivamente

Numerous research groups of different countries defend the inclusion, in the process of development of new drugs, of in vitro test in which it can evaluates drug permeability and diffusion across epithelial cell monolayers of different tissues. The aims of these studies are to reduce the number of tests in animal models and to obtain an oriented selection of molecules candidates. In the present paper, characteristics and methodologies of work are exposed destined to facilitate the manipulation and use of two cellular lines: intestinal epithelial cell line (Caco-2) derived from a human colon adenocarcinoma, that reproduce the characteristics of the enterocytes, and a renal epithelial cell line MDCK (Madin-Darby Canine Kidney), useful to quantify renal excretion of drugs, fundamentally mediated by the P-glycoprotein, besides to represent an alternative to the cells Caco-2 in tests of drug permeability that is absorbed passively

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.

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)

Tribunal Constitucional: transmisibilidad vs concesiones. Más vale tarde que nunca / Constitutional Court: transmission vs concession. Better late than never

No disponible

Consistency of Carbopol 971-P NF gels and influence of soluble and cross-linked PVP.

A study is made of the polymerization process of polyacrylic acid, commercially known as Carbopol 971 NF, assessing its consistency as a function of the degree of neutralization at pH values from 3 to 12, approximately. Percentage concentrations ranging from 0.1 to 1.4% (w/w) were studied. The gels obtained were non-Newtonian, and pseudoplastic. As concentration and pH rise, the consistency of the gels increase to a maximum, which appears between pH 6 and 8, allowing their use as vehicles in bioadhesive formulations for mucosal application. Over the increasing viscosity interval, functions were obtained to indicate the consistency of the gel as a function of pH and concentration. Since the correlation between the theoretical and experimental results is excellent, the equation found can be used to theoretically calculate the working concentration and pH required to secure the necessary consistency for a given vehicle. The addition of soluble polyvinylpyrrolidone (PVP), and cross-linked PVP (PVPP) does not substantially modify the rheological behavior of the gels, thus permitting their addition to usual vehicles.

The influence of active secretion processes on intestinal absorption of salbutamol in the rat.

Salbutamol was perfused in the small intestine of rat using a standard rat gut "in situ" preparation: (1) in inhibitor-free solution at seven different concentrations (0.15, 0.29, 1.20, 5.0, 9.0, 13.0 and 18.0mM); (2) at a 0.29mM concentration - thought to be close to the allometric dose in man - in the presence of a non-specific enzyme inhibitor, sodium azide (0.3, 3.0 and 6.0mM); and (3) at 0.29mM in the presence of a selective secretion inhibitor, verapamil (10.0 and 20.0mM). In free solution, the mixed-order rate constants, k'(a), of salbutamol increase as the solute concentration increases until an apparent asymptotic value is reached. This could be due to the saturation of enzymatic systems responsible for the secretion of the drug from the enterocyte to the luminal fluid, a process that could explain the poor absorption of salbutamol. In the presence of sodium azide, the k(a) values increased about 1.5-fold, whereas in the presence of verapamil they increased two- to three-fold. These results indicate that salbutamol can act as a substrate of an intestinal secretory transport, which probably includes--at least in part--the enzyme P-glycoprotein, since verapamil has been shown to inhibit this enzyme by dose-dependent competition. This leads to a secretion-limited peroral absorption of salbutamol, which contributes to the poor oral bioavailability of the drug. The possible options for improving salbutamol absorption are discussed.

Experimental studies on the influence of surfactants on intestinal absorption of drugs. Cefadroxil as model drug and sodium taurocholate as natural model surfactant: studies in rat colon and in rat duodenum.

The influence of the natural bile acid surfactant sodium taurocholate (CAS 81-24-3) on colic and duodenal (i.e. the proximal third of the small intestine) absorption of cefadroxil (CAS 50370-12-2) was studied using the in situ rat gut technique, and compared with the effect of sodium lauryl sulfate (CAS 151-21-3), the most widely used synthetic anionic surfactant. Previously, the stability, compatibility, and micelle-solubilization characteristics of taurocholate were assessed in order to correct, when necessary, the absorption results. White the passive absorption rate constants (kf, h-1) determined in colon in the presence of increasing lauryl sulfate concentrations showed an asymptotic value about 7-fold higher than that of cefadroxil alone, only a 2-fold higher value was obtained in the presence of taurocholate at similar concentrations. Therefore the natural surfactant would increase the polarity of the colic absorbent membrane much less than lauryl sulfate does (about 3.5 times). The effects of taurocholate on the duodenal absorption of cefadroxil, which is the sum of a single passive process and a simultaneous carrier-mediated transport, can be summarized as follows: 1. When the working concentration of cefadroxil is far from carrier saturation (0.1 mg/ml) a slight but clear net decrease in the apparent kf value is observed in the presence of increasing concentrations of the natural surfactant (from 3.0 to 2.3 h-1) 2. When the concentration of the antibiotic in the working fluid is above carrier saturation (10 mg/ml) the picture is reversed, and a slight net increase in kf in the presence of increasing concentrations of taurocholate (from 0.8 to 1.2 h-1) is found. This means that the effect of taurocholate as a noncompetitive inhibitor of active cefadroxil transport is very much smaller than that observed with lauryl sulfate. Moreover, the increase in passive absorption relative to the synthetic surfactant is also much smaller. On the basis of allometric considerations it could be concluded that for practical purposes taurocholate does not act as a substantial absorption modifier for cefadroxil, at least in the small intestine, the main absorption site of the antibiotic. It can, however, not be considered an inert ingredient, and therefore oral administration of cefadroxil far from that of taurocholate-containing preparations, and even from lipid-rich meals should be strongly recommended.

Experimental studies on the influence of surfactants on intestinal absorption of drugs. Cefadroxil as model drug and sodium lauryl sulfate as model surfactant: studies in rat duodenum.

The effect of sodium lauryl sulfate (CAS 151-21-3) on the duodenal absorption of cefadroxil (CAS 50370-12-2) has been investigated with the aid of a classical rat gut in situ preparation. Both compounds were entirely compatible in working solutions. Cefadroxil was found to be very stable and only slightly solubilized in the micellar phase. The apparent first-order absorption rate constants for the free antibiotic fraction were determined in free solution, and in the presence of variable surfactant concentration in luminal fluid. A functional interpretation of these data, based both on the law of mass action and the complete noncompetitive transport inhibition equations, showed that the surfactant acts as a nonspecific inhibitor of the carrier-mediated absorption of the antibiotic, but also as an enhancer of its passive absorption component. The net result was an outstanding reduction in the absorption capacity of cefadroxil when it was perfused at 0.1 mg/ml, i.e. far from its carrier saturation (from 3.0 h-1 in free solution to 2.0(-1) at high surfactant concentration, with a minimum of about 1.4 h-1 in the presence of the surfactant at 0.5 mg/mg in duodenal fluid). When cefadroxil was perfused at 10.0 mg/ml, i.e. with its carrier-mediated transport beyond the saturation, the net result was a progressively enhanced absorption (ranging from about 0.9 h-1 in free solution to 2.0 h-1 at high surfactant concentration).(ABSTRACT TRUNCATED AT 250 WORDS)

Experimental studies on the influence of surfactants on intestinal absorption of drugs. Cefadroxil as model drug and sodium lauryl sulfate as model surfactant: studies in rat colon.

The effect of the anionic surfactant, sodium lauryl sulfate (CAS 151-21-3), on the absorption of cefadroxil (CAS 50370-12-2) as model antibiotic in colon has been studied by means of an in situ rat gut technique, as a previous step to investigate the influence of the surfactant on the intestinal, carrier-mediated absorption of the antibiotic. Microbial degradation tests were initially performed, which demonstrated that cefadroxil disappearance from luminal content was only due to absorption. Micelle solubilization of cefadroxil was also previously assessed through dialysis tests in order to adequately correct absorption rate constant values found in the presence of the surfactant at supramicellar concentration. Micelle solubilization was minimal, although statistically significant. Apparent passive absorption rate constants, ka(h-1), were determined in the presence of variable concentrations of lauryl sulfate in perfusion fluids. Results showed that ka values greatly increased as surfactant luminal concentration increased until an asymptotic value (about 7-fold higher than cefadroxil alone) was obtained; this was assumed to be due to a direct effect of the surfactant on membrane polarity. Moreover, the results were satisfactorily adjusted using a functional hyperbolic-type equation, as occurs with many other saturable processes. This was supposed to be indicative that the surfactant effect is due to an adsorption process of the surfactant ions or molecules to the intestinal absorbent membrane.

Partition behavior of anilines in bulk-phase and high-performance liquid chromatographic systems: influence on correlation with biological constants.

The partition behavior of a mixed series of ring-substituted anilines in reversed-phase high-performance liquid chromatographic systems is substantially different from that observed in a classical bulk-phase partition system with n-heptane as the aprotic reference solvent. On the basis of the equivalence of each ring substituent in the p-straight-chain methylene groups (v value) as a function of the fraction of organic solvent (acetonitrile or methanol) in the mobile phase, the biased partition behavior for imperfect homologues and heterologues is verified relative to that of perfect homologues. This behavior was tentatively attributed, mainly, to differences in the hydrogen bonding capacity of the compounds, which is associated with the electronic character of the working solvent. These differences cannot be normalized through the use of extrapolated initial partition coefficient (K'o) values because of carryover effects of the solvent. When the chromatographic partition constants (K') and K'o are used, correlations with previously determined intestinal absorption rate constants are definitely worse than the correlations with the reference n-heptane partition coefficients. Possible implications of these observations on lipophilicity-biological activity correlations are briefly discussed.

Absorption mechanisms of secondary aliphatic amines in rat colon and small intestine.

This study is intended to be a further and conclusive validation of the bihyperbolic model equation proposed by Plá-Delfina and Moreno to describe passive intestinal absorption mechanisms through the analysis of absorption-lipophilicity correlations for homologous series of xenobiotics and drugs. Secondary aliphatic amines, largely differing from previously tested substances, were selected as model compounds. Evidence is given which demonstrates that a minimum lipophilicity value exists for absorption in small intestine, instead of a maximum, as probabilistic theories predict. Moreover, bihyperbolic equation provides an excellent fit, with AIC figures up to -29. Aqueous pore absorption was small, presumably due to ionic interactions with pore charges (kp approximately 1.0 h-1), whereas membrane penetration was highly lucrative (km approximately 7.4 h-1), thus indicating that some part of the lipophilic ionic species is capable of penetrating "per se" the lipoidal membrane. As model predicts, bihyperbolic equation collapses to monohyperbolic for colonic absorption, where AIC figures up to -39 were found, with a km value of about 4.0 h-1. Membrane absorption efficiency was, surprisingly, similar in colon and small intestine for the tested solutes; it was attributed to the basic character of the compounds associated with working pH and ion absorption. This latter effect would deserve further investigation in oral sustained-release medication with basic drugs having similar pKa values.

Evidence of a specialized transport mechanism for the intestinal absorption of baclofen.

Absorption of the spasmolytic drug baclofen in three selected intestinal segments of living anaesthetized rats in situ, is shown to be a specialized transport mechanism obeying Michaelis-Menten kinetics. Equation parameters were calculated through different procedures, whose features are discussed. A computer method based on the integrated form of Michaelis-Menten equation which reproduces the entire time course of drug absorption from the data found in three intestinal perfusion series at different initial concentrations, yielded Vm and Km values of 12.0 mg h-1 and 8.0 mg, respectively, in the mean segment of the small intestine, a rather selective absorption site for baclofen. Lesser but comparable absorption rates were found in the proximal and distal segments of the small intestine, whereas in colon, drug absorption was negligible. Baclofen transport was significantly reduced in the presence of the enzymatic inhibitor sodium azide. If these results were extrapolated to humans, they would explain the excellent bioavailability profiles reported for baclofen at normal doses in spite of its physicochemical properties, which do not favour passive diffusion. Based on the same principle, the administration of usual doses at shorter time intervals could be recommended, instead of high, when higher plasma levels at steady-state are needed. On the other hand, more than 8-h sustained-release preparations of baclofen should, probably, be avoided.

Non-linear intestinal absorption kinetics of cefadroxil in the rat.

Absorption of cefadroxil in a selective intestinal absorption area (the proximal third of the small intestine) of the anaesthetized rat, at seven initial perfusion concentrations, ranging from 0.01 to 10.0 mg mL-1, is shown to be a non-linear transport mechanism. With the aid of computer-fitting procedures based on differential and integrated forms of Michaelis-Menten equation, Vm and Km values of 36.7-37.3 mg h-1 and 12.0-13.0 mg, respectively, were found. The statistical parameters were better than those obtained both for first-order and for combined Michaelis-Menten and first-order kinetics. There is no evidence for substantial passive diffusion processes. The results reported here, together with allometric considerations and literature data analysis, may help to explain some particular non-linear features of plasma level curves associated with the administration of fairly high oral doses of cefadroxil to humans.