Swine as the Animal Model for Testing New Formulations of Anti-Inflammatory Drugs: Carprofen Pharmacokinetics and Bioavailability of the Intramuscular Route.

Carprofen (CP) is a non-steroidal anti-inflammatory drug (NSAID) frequently used to treat respiratory diseases in numerous small animals, but also in large species. CP is a formidable candidate for further therapeutic research of human inflammatory diseases using the pig as an animal model. However, CP administration in swine is very uncommon and respective pharmacokinetics/bioavailability studies are scarce. A simultaneous population pharmacokinetic analysis after CP intravenous and intramuscular administrations in pigs has shown high extent and rate of absorption and a similar distribution profile with respect to man and other mammals. However, clearance and half-life values found in swine suggest a slower elimination process than that observed in man and some other animal species. Although not reported in other species, liver and kidney concentrations achieved at 48 h post-intramuscular administration in pigs were ten times lower than those found in plasma. Simulations pointed to 4 mg/kg every 24 h as the best dosage regimen to achieve similar therapeutic levels to those observed in other animal species. All these findings support the use of pig as an animal model to study the anti-inflammatory effects of CP in humans.

Efficacy of hyperthermia pleurodesis: A comparative experimental study on serous membrane of abdominopelvic and thoracic cavities of rats.

BACKGROUND: Pleurodesis is a common technique for treating the accumulation of air or liquid in the pleural space caused by pneumothorax or pleural effusion, it is based on the bounding of pleural layers through induced inflammatory lesions. There are several pleurodesis procedures. OBJECTIVES: To test and describe the inflammatory effect of hyperthermia on the pleural and peritoneal mesothelia of rats, with the aim of testing the effectiveness of this process for inducing pleurodesis. METHODS: 35 Sprague-Dawley (male/female) rats were randomized into four treatment groups: Group A (Talc, 10 individuals); group B (control, 5 individuals); group C (hyperthermic isotonic saline, 10 individuals); and group D (filtrate air at 50°, 10 individuals). Inflammatory effect of hyperthermia was the primary outcome parameter. RESULTS: In the talc group, minimal adhesions between both pleural and peritoneal layers were observed in seven rats. Talc produced peritoneal mesothelium inflammation and fibrosis associated to foreign body giant cells in 80% (8/10) of the sample. Furthermore, clear evidence of a granulomatous foreign-body reaction was detected. No macroscopic and/or microscopic damage was registered in the remaining three groups (control, hyperthermic, and filtrate air). CONCLUSIONS: Talc is an excellent method for producing pleuro-peritoneal inflammatory lesions. On the contrary, hyperthermia apparently does not induce the macroscopic and microscopic damage that is required for efficient pleurodesis. Therefore, hyperthermia should not be used for pleurodesis procedures.

Efficacy of hyperthermia pleurodesis: A comparative experimental study on serous membrane of abdominopelvic and thoracic cavities of rats.

BACKGROUND: Pleurodesis is a common technique for treating the accumulation of air or liquid in the pleural space caused by pneumothorax or pleural effusion, it is based on the bounding of pleural layers through induced inflammatory lesions. There are several pleurodesis procedures. OBJECTIVES: To test and describe the inflammatory effect of hyperthermia on the pleural and peritoneal mesothelia of rats, with the aim of testing the effectiveness of this process for inducing pleurodesis. METHODS: 35 Sprague-Dawley (male/female) rats were randomized into four treatment groups: Group A (Talc, 10 individuals); group B (control, 5 individuals); group C (hyperthermic isotonic saline, 10 individuals); and group D (filtrate air at 50°, 10 individuals). Inflammatory effect of hyperthermia was the primary outcome parameter. RESULTS: In the talc group, minimal adhesions between both pleural and peritoneal layers were observed in seven rats. Talc produced peritoneal mesothelium inflammation and fibrosis associated to foreign body giant cells in 80% (8/10) of the sample. Furthermore, clear evidence of a granulomatous foreign-body reaction was detected. No macroscopic and/or microscopic damage was registered in the remaining three groups (control, hyperthermic, and filtrate air). CONCLUSIONS: Talc is an excellent method for producing pleuro-peritoneal inflammatory lesions. On the contrary, hyperthermia apparently does not induce the macroscopic and microscopic damage that is required for efficient pleurodesis. Therefore, hyperthermia should not be used for pleurodesis procedures.

Carprofen Permeation Test through Porcine Ex Vivo Mucous Membranes and Ophthalmic Tissues for Tolerability Assessments: Validation and Histological Study.

Carprofen (CP), a non-steroidal anti-inflammatory drug (NSAID), is profusely used in veterinary medicine for its analgesic and anti-inflammatory activity. Some undesirable effects are associated with its systemic administration. Alternative local routes are especially useful to facilitate its administration in animals. The main aim of this paper is to validate the suitability of ex vivo permeation experiments of CP with porcine mucous membranes (buccal, sublingual and vaginal) and ophthalmic tissues (cornea, sclera and conjunctiva) intended to be representative of naïve in vivo conditions. Chromatographic analysis of CP in membrane-permeated samples and drug-retained have been validated following standard bioanalytical guidelines. Then, recovery levels of drugs in tissue samples were assessed with aqueous phosphate buffered saline (PBS) buffer to preserve the histological integrity. Finally, as a proof of concept, a series of CP permeation tests in vertical Franz diffusion cells has been performed to evaluate permeation flux and permeability constants in all tissues, followed by a histological study for critical evaluation. Furthermore, synthetic tissue retention-like samples were prepared to verify the value of this experimental study. Results show linear relationships with good determination coefficient (R2 > 0.998 and R2 > 0.999) in the range of 0.78 to 6.25 mg/mL and 3.125 mg/mL to 100 mg/mL, respectively. Low limits of quantification around 0.40 µg/mL were allowed to follow permeation levels until a minimum of 0.40% of the locally-applied dose. This method showed a good accuracy and precision with values lower than 2%. After the recovery technique, reproducible values below 30% were achieved in all tissues, suggesting it is a non-damaging method with low efficiency that requires the use of further solvents to enhance the extraction percentages. After permeation and histology tests, no relevant peak interferences were detected, and no cell or tissue damage was found in any tissue. In conclusion, results demonstrate the suitability of this test to quantify the distribution of CP with good histological tolerability.

Ex Vivo Permeation of Carprofen Vehiculated by PLGA Nanoparticles through Porcine Mucous Membranes and Ophthalmic Tissues.

(1) Background: Carprofen (CP), 2-(6-chlorocarbazole) propionic acid, is used as an anti-inflammatory, analgesic and anti-pyretic agent and it belongs to the family of non-steroidal anti-inflammatory drugs (NSAIDs). CP has some adverse reactions in systemic administration; for this reason, topical administration with CP nanoparticles (CP-NPs) can be an optimal alternative. The main objective of this work is the investigation of ex vivo permeation of CP through different types of porcine mucous membranes (buccal, sublingual and vaginal) and ophthalmic tissues (cornea, sclera and conjunctiva) to compare the influence of CP-NPs formulation over a CP solution (CP-Solution). (2) Methods: The ex vivo permeation profiles were evaluated using Franz diffusion cells. Furthermore, in vivo studies were performed to verify that the formulations did not affect the cell structure and to establish the amount retained (Qr) in the tissues. (3) Results: Permeation of CP-NPs is more effective in terms of drug retention in almost all tissues (with the exception of sclera and sublingual). In vivo studies show that neither of the two formulations affects tissue structure, so both formulations are safe. (4) Conclusions: It was concluded that CP-NPs may be a useful tool for the topical treatment of local inflammation in veterinary and human medicine.

Optimization, Biopharmaceutical Profile and Therapeutic Efficacy of Pioglitazone-loaded PLGA-PEG Nanospheres as a Novel Strategy for Ocular Inflammatory Disorders.

PURPOSE: The main goal of this study was to encapsulate Pioglitazone (PGZ), in biodegradable polymeric nanoparticles as a new strategy for the treatment of ocular inflammatory processes. METHODS: To improve their biopharmaceutical profile for the treatment of ocular inflammatory disorders, nanospheres (NSs) of PGZ were formulated by factorial design with poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). Interactions drug-polymer have been carried out by spectroscopic (X-ray spectroscopy, FTIR) and thermal methods (DSC). The PGZ-NSs were tested for their in vitro release profile, cytotoxicity, and ocular tolerance (HET-CAM® test); ex vivo corneal permeation, and in vivo inflammatory prevention and bioavailability. RESULTS: The optimized system showed a negative surface charge of -13.9 mV, an average particle size (Zav) of around 160 nm, a polydispersity index (PI) below 0.1, and a high encapsulation efficiency (EE) of around 92%. According to the DSC results, the drug was incorporated into the NSs polymeric matrix. The drug release was sustained for up to 14 h. PGZ-NSs up to 10 µg/ml exhibited no retinoblastoma cell toxicity. The ex vivo corneal and scleral permeation profiles of PGZ-NSs showed that retention and permeation through the sclera were higher than through the cornea. Ocular tolerance in vitro and in vivo demonstrated the non-irritant character of the formulation. CONCLUSION: The in vivo anti-inflammatory efficacy of developed PGZ-NSs indicates this colloidal system could constitute a new approach to prevent ocular inflammation.

Development of a buccal doxepin platform for pain in oral mucositis derived from head and neck cancer treatment.

This study describes the development of semisolid formulations containing doxepin (DOX) for pain relief in oral mucositis, frequently related to chemotherapy and/or radiotherapy treatments in patients with head and neck cancer. Chemical permeation enhancers were evaluated and selected according to the results obtained from rheological studies, drug release, and drug permeation and retention through buccal mucosa. Finally, the selected formulation was compared in vivo, with a reference DOX mouthwash, whose clinical efficacy had been previously reported. The obtained findings showed that an orabase® platform loading transcutol® (10%) and menthol (5%) for the buccal vehiculization of DOX exhibited a decreased elastic and viscous behavior improving its application. The main drug release mechanism could be considered as diffusion according to Higuchi model. Obtained DOX permeation rates were considered optimal for an analgesic effect and far below to an antidepressant activity. Similar in vivo plasma concentrations were found for the semisolid formulation and the reference mouthwash. However, DOX amounts retained in the mucosa of animals for the semisolid formulation were higher than the reference, which let us hypostatize even stronger potential local therapeutic effect with additional advantages such as, mucoadhesive properties, absence of alcohol, some degree of freshness, as well as, drug palatability improvement.

Transbuccal delivery of doxepin: studies on permeation and histological investigation.

According to previous studies reporting the anesthetic/analgesic action of oral topical doxepin administration, this study evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells. Cumulative amounts of doxepin permeated were plotted as a function of time. Kinetic permeation parameters as flux (Js), lag time (Tl) and permeability coefficient (Kp) were calculated. Theoretical human plasmatic steady-state doxepin concentration and drug retained in the tissue were also determined in order to evaluate its potential therapeutic use, central or peripheral. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. Obtained results showed a poor aqueous doxepin permeation through buccal mucosa membrane (median parameters Js=34.79 µg/h, Kp=0.49×10(-3)cm/h and Tl=2.8h). Predicted doxepin plasma concentrations would reach 46 ng/mL, far from the required to have central nervous system activity as tricyclic agent. However, median doxepin amount remaining in the mucosa membrane was 0.24 µg/cm(2)/µg tissue, which evidenced a reservoir function of the buccal mucosa. Histologically, no structural damage was observed in the tissues. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice.

An improved cryopreservation method for porcine buccal mucosa in ex vivo drug permeation studies using Franz diffusion cells.

The use of isolated animal models to assess percutaneous absorption of molecules is frequently reported. The porcine buccal mucosa has been proposed as a substitute for the buccal mucosa barrier on ex vivo permeability studies avoiding unnecessary sacrifice of animals. But it is not always easy to obtain fresh buccal mucosa. Consequently, human and porcine buccal mucosa is sometimes frozen and stored in liquid nitrogen, but this procedure is not always feasible. One cheaper and simpler alternative is to freeze the buccal mucosa of freshly slaughtered pigs in a mechanical freezer, using DMSO and albumin as cryoprotective agents. This study compared the ex vivo permeability parameters of propranolol hydrochloride through porcine buccal mucosa using a Franz diffusion cell system and HPLC as detection method. The freezing effects on drug permeability parameters were evaluated. Equally histological studies were performed. Furthermore, the use of the parameter transmucosal water loss (TMWL) as an indicator of the buccal mucosa integrity was evaluated just as transepidermal water loss (TEWL) is utilized for skin integrity. The results showed no difference between fresh and frozen mucosal flux, permeability coefficient or lag time of propranolol. However, statistical significant difference in TMWL between fresh and frozen mucosa was observed.

A comparative ex vivo drug permeation study of beta-blockers through porcine buccal mucosa.

Apparent permeability coefficients (kp) of a series of beta-blockers: acebutolol, atenolol, labetalol, metoprolol, oxprenolol and propranolol, through porcine buccal mucosa were determined. The aim of the study was to determine the permeation parameters (apparent permeability coefficient, kp; flux, J; and lag time, TL) as a measure of the intrinsic permeability of porcine buccal mucosa to these drugs, in order to predict the efficacy of their possible administration through human buccal mucosa. A positive linear correlation was observed between the apparent permeability coefficient, kpand the partition coefficient, P. Oxprenolol and propranolol are the drugs that presented the highest values of kp: 0.3231×10(2) cm/h and 0.5666×10(2) cm/h, respectively. Multiple linear regression (MLR) using least square estimation was performed on the data set with logkpas dependent variable and the descriptors as predictor variables. The potential systemic capacity after a buccal administration was predicted by estimating the plasma concentrations at steady-stated (Css). Considering the entire process of permeation ex vivo, propranolol and oxprenolol would seem to be the best candidates for administration through the buccal mucosa.

Gestión de la calidad en el Sistema Sanitario Público de la Comunidad Foral de Navarra / Quality management in the public health system of the Autonomous Community of Navarre

La gestión de la calidad en el Sistema Sanitario Público Navarro tiene 3 ámbitos principales de actuación: la atención primaria, la atención especializada y la coordinación entre ambos niveles de atención. El pilar básico del Programa de Gestión de la Calidad de Atención Primaria es el desarrollo y potenciación de los Programas de Mejora Internos, para lo que se cuenta con la implicación de los profesionales. El Programa de Gestión de la Calidad es un apoyo para el desarrollo del Plan de Gestión cuyos componentes básicos están en relación con la cartera de servicios, los indicadores específicos de calidad, los planes de mejora internos y la utilización de recursos. Los contratos-programa, el modelo MAPPA-Horizonte y la estrategia corporativa de análisis de percepción de la calidad de los distintos actores constituyen el armazón que sustenta la política de calidad en el ámbito de atención especializada. El Plan de Coordinación y la Estructura de Coordinación, que incluye un equipo técnico de coordinación y 18 grupos de mejora, son los elementos clave para el desarrollo de las líneas estratégicas en el ámbito de actuación de la coordinación primaria-especializada (AU)

Action of blood serum from rats with turpentine sterile inflammation on the development of CFU erythrocyte colonies: possible role of erythropoietin

Los cultivos de CFUe de la médula ósea del ratón fueron preparados de acuerdo con el método de Iscove. Fueron consideradas colonias las agrupaciones de células eritroides en número de ocho que se observan a las 48 h de la siembra. Cada cultivo se realizó por triplicado y se repitieron los siete grupos cinco veces. El suero sanguíneo de las ratas con inflamación provocada por el absceso estéril de la trementina fue inactivado a 56-C y depositado a -70-C hasta ser usado; el suero normal de rata recibió igual tratamiento. Cada uno de los siete grupos contiene todos los elementos básicos del cultivo, variando únicamente en el agregado de EP exógena p en la adición del suero sanguíneo de inflamación o normal. Los siete grupos de cada experimento son: Grupo I que carece de EP exógena. Grupo II que contiene EP. Los grupos III y IV contienen EP y diferentes concentraciones de suero con inflamación. El Grupo V no tiene EP pero tiene suero con inflamación. El Grupo VI no tiene EP pero tiene suero normal de rata, y el Grupo VII que contiene EP y suero normal de rata. La disminución significativa del número de colonias CFUe en los grupos III y IV con respecto al grupo II y la disminución del número de colonias en los grupos I, V y VI que no contienen EP nos sugieren la posibilidad de que la EP exógena agregada a los grupos de cultivos III y IV es neutralizada totalmente o en parte por la acción del suero sanguíneo de ratas con inflamación. No se observan cambios en el grupo VII

Action of blood serum from rats with turpentine sterile inflammation on the development of CFU erythrocyte colonies: possible role of erythropoietin

Los cultivos de CFUe de la médula ósea del ratón fueron preparados de acuerdo con el método de Iscove. Fueron consideradas colonias las agrupaciones de células eritroides en número de ocho que se observan a las 48 h de la siembra. Cada cultivo se realizó por triplicado y se repitieron los siete grupos cinco veces. El suero sanguíneo de las ratas con inflamación provocada por el absceso estéril de la trementina fue inactivado a 56-C y depositado a -70-C hasta ser usado; el suero normal de rata recibió igual tratamiento. Cada uno de los siete grupos contiene todos los elementos básicos del cultivo, variando únicamente en el agregado de EP exógena p en la adición del suero sanguíneo de inflamación o normal. Los siete grupos de cada experimento son: Grupo I que carece de EP exógena. Grupo II que contiene EP. Los grupos III y IV contienen EP y diferentes concentraciones de suero con inflamación. El Grupo V no tiene EP pero tiene suero con inflamación. El Grupo VI no tiene EP pero tiene suero normal de rata, y el Grupo VII que contiene EP y suero normal de rata. La disminución significativa del número de colonias CFUe en los grupos III y IV con respecto al grupo II y la disminución del número de colonias en los grupos I, V y VI que no contienen EP nos sugieren la posibilidad de que la EP exógena agregada a los grupos de cultivos III y IV es neutralizada totalmente o en parte por la acción del suero sanguíneo de ratas con inflamación. No se observan cambios en el grupo VII (AU)