The ability of a host plant to associate with different symbiotic partners affects ectomycorrhizal functioning.

Some plants that associate with ectomycorrhizal (ECM) fungi are also able to simultaneously establish symbiosis with other types of partners. The presence of alternative partners that may provide similar benefits may affect ECM functioning. Here we compared potential leucine-aminopeptidase (LA) and acid phosphatase (AP) enzyme activity (involved in N and P cycling, respectively) in ECM fungi of three hosts planted under the same conditions but differing in the type of partners: Pinus (ECM fungi only), Eucalyptus (ECM and arbuscular mycorrhizal -AM- fungi) and Acacia (ECM, AM fungi and rhizobial bacteria). We found that the ECM community on Acacia and Eucalyptus had higher potential AP activity than the Pinus community. The ECM community in Acacia also showed increased potential LA activity compared to Pinus. Morphotypes present in more than one host showed higher potential AP and LA activity when colonizing Acacia than when colonizing another host. Our results suggest that competition with AM fungi and rhizobial bacteria could promote increased ECM activity in Eucalyptus and Acacia. Alternatively, other host-related differences such as ECM community composition could also play a role. We found evidence for ECM physiological plasticity when colonizing different hosts, which might be key for adaptation to future climate scenarios.

[Blood-saving strategies in total primary knee replacement]. / Estrategias de ahorro de sangre en artroplastía total de rodilla primaria.

INTRODUCTION: The objective of this study was to make an update on the different strategies in the blood saving in prosthetic primary knee surgery, through a bibliographical review; As well as to know what strategies are followed in different hospitals in our field, through a survey. MATERIAL AND METHODS: We carried out a descriptive transversal observational study based on a survey of 64 surgeons and a bibliographical research on the different aspects included in the survey. RESULTS: Surgeons refer that they have presurgical blood-saving protocols implanted in their Hospital at 48.4%. The use of tranexamic acid (ATX) is quite widespread 71.9% of respondents (46/64). It is administered intravenously prior to surgery in 26.6% of cases, intraarticularly by 21.9% and in a combination of both in 23.4%. The preferred time for the placement of ischemia by surgeons is 57.8% prior to painting the field, while a 39.1% prefer to place it in sterile conditions. 3.1% of surgeons claim to implant the prosthesis without using ischemia in surgery. DISCUSSION: The use of ATX as the primary blood-saving strategy in TKR is being imposed. There is No consensus as to the optimal dose or its route of administration. The efficacy of the ATX is influencing the elimination of post-surgical drainage and the implementation of early rehabilitation programs.

INTRODUCCIÓN: El objetivo del presente estudio fue realizar una actualización sobre las diferentes estrategias en el ahorro de sangre en cirugía protésica de rodilla primaria, a través de una revisión bibliográfica; así como conocer qué estrategias se siguen en diferentes centros hospitalarios de nuestro ámbito, mediante un estudio multicéntrico. MATERIAL Y MÉTODOS: Se realizó un estudio observacional, transversal, descriptivo, basado en una encuesta hecha a 64 cirujanos y una búsqueda bibliográfica sobre los distintos aspectos incluidos en la encuesta. RESULTADOS: Los cirujanos refieren que cuentan con protocolos de ahorro sanguíneo prequirúrgicos implantados en su hospital en 48.4% (31/64). La utilización del ácido tranexámico (ATX) es bastante generalizada en 71.9% de los encuestados (46/64). Éste se administra vía endovenosa previa a la cirugía en 26.6% (17/64) de los casos, de manera intraarticular en 21.9% (14/64) y en una combinación de ambas en 23.4% (15/64). El momento preferido para la colocación de la isquemia por los cirujanos es en 57.8% (37/64) previo a preparar el campo, mientras que 39.1% (25/64) prefiere colocarla en estéril. En 3.1% (2/64) de cirujanos afirma implantar las prótesis sin utilizar isquemia en la cirugía. DISCUSIÓN: Se está imponiendo la aplicación de ATX como principal estrategia de ahorro de sangre en la artroplastía total de rodilla (ATR). No existe consenso en cuanto a la dosis óptima ni a su vía de administración. La eficacia del ATX está influyendo en la eliminación de los drenajes postquirúrgicos y en la implementación de programas de rehabilitación precoz.

[Evolution of open versus laparoscopic/robotic surgery: 10 years of changes in urology]. / Evolución de la cirugía abierta versus laparoscópica/robótica: 10 años de cambios en Urología.

INTRODUCTION: Laparoscopic surgery has been increasingly used in urology in recent years. Laparoscopy has been performed at our center since 2001. Changes over time in the indication of open versus laparoscopic/robotic surgery, hospital stay, and learning curve are reviewed. MATERIALS AND METHODS: A retrospective review of our database from 1997 to the end of 2007. A total of 3622 procedures were performed during this time (endoscopic procedures were excluded): 67.75% open, 26.17% laparoscopic, 2.29% perineal, and 3.78% robotic surgeries. Of these, 83.79% were performed in males and 16.20% in females. Mean patient age was 58.8 years. Data from the study period, including mean hospital stay and changes over time in operating time as a function of the learning curve, were analyzed and compared to data for the last 12 months of the study period. RESULTS: The percentages of all surgical procedures performed using a laparoscopic approach in the 1997-2006 versus the last 12 study months were as follows: nephrectomy, 31.8% versus 74.7%; living donor nephrectomy, 93% versus 100%; nephroureterectomy, 28.1% vs. 93.4%; partial nephrectomy, 31.3% vs 87%; and radical prostatectomy, 17.6% versus 73.5% including laparoscopic and robotic approaches. Shorter mean hospital stays and operating times were also seen. CONCLUSIONS: Use of the laparoscopic approach has greatly increased in the 10-year period studied. In renal surgery, few indications remain for open surgery. In prostate surgery, introduction of robotic surgery in 2005 and learning of laparoscopy by several of our urologists have dramatically changed the therapeutic approach. Gradual incorporation of laparoscopic surgery has led to a decreased hospital stay and to a shortening of the learning curve.

Evolución de la cirugía abierta versus laparoscópica/robótica: 10 años de cambios en Urología / Evolution of open versus laparoscopic/robotic surgery: 10 years of changes in urology

Introducción: Durante los últimos años se ha producido un incremento en la cirugía laparoscópica en urología. Nuestra institución realiza laparoscopia de forma continuada desde 2001. Revisamos la evolución de la indicación de cirugía abierta vs. laparoscópica/robótica, la estancia hospitalaria y la curva de aprendizaje. Material y métodos: Retrospectivamente revisamos nuestra base de datos desde 1997 hasta finales del 2007. Son 3,622 cirugías (excluyendo todas las de abordaje endoscópico): 67,75% abiertas, 26,17% laparoscópicas, 2,29% perineales y 3,78% robóticas. El 83,79% en hombres y el 16,20% en mujeres. La edad media es de 58,8 años. Se analizan los datos de la década estudiada incluyendo estancia media hospitalaria y evolución del tiempo quirúrgico en función de la curva de aprendizaje y se comparan con los de los últimos doce meses de la misma. Resultados: El porcentaje de cirugías laparoscópicas respecto de las totales, realizadas en los 9 primeros años frente a las de los 12 últimos meses del estudio son: nefrectomías: 31,8 y 74,7%; nefrectomías de donante vivo: 93 y 100%; nefroureterectomías: 28,1 y 93,4%; nefrectomías parciales: 31,3 y 87%, y prostatectomías radicales: 17,6 y 73,5% sumando laparoscópicas y robóticas. Se observa disminución de la estancia media y disminución del tiempo quirúrgico. Conclusiones: En los 10 años estudiados se ha producido un gran incremento en el abordaje laparoscópico. En la cirugía renal, son escasas las indicaciones de cirugía abierta. En cirugía prostática, la introducción de la cirugía robótica así como el aprendizaje laparoscópico por varios urólogos de nuestro centro ha cambiado radicalmente el enfoque terapéutico. La incorporación de la cirugía laparoscópica ha supuesto una disminución de la estancia hospitalaria y un acortamiento de la curva de aprendizaje (AU)

Introduction: Laparoscopic surgery has been increasingly used in urology in recent years. Laparoscopy has been performed at our center since 2001. Changes over time in the indication of open versus laparoscopic/robotic surgery, hospital stay, and learning curve are reviewed. Materials and methods: A retrospective review of our database from 1997 to the end of 2007. A total of 3622 procedures were performed during this time (endoscopic procedures were excluded): 67,75% open, 26,17% laparoscopic, 2,29% perineal, and 3,78% robotic surgeries. Of these, 83,79% were performed in males and 16,20% in females. Mean patient age was 58,8 years. Data from the study period, including mean hospital stay and changes over time in operating time as a function of the learning curve, were analyzed and compared to data for the last 12 months of the study period. Results: The percentages of all surgical procedures performed using a laparoscopic approach in the 1997–2006 versus the last 12 study months were as follows: nephrectomy, 31,8% versus 74,7%; living donor nephrectomy, 93% versus 100%; nephroureterectomy, 28,1% vs. 93,4%; partial nephrectomy, 31,3% vs 87%; and radical prostatectomy, 17,6% versus 73,5% including laparoscopic and robotic approaches. Shorter mean hospital stays and operating times were also seen. Conclusions: Use of the laparoscopic approach has greatly increased in the 10-year period studied. In renal surgery, few indications remain for open surgery. In prostate surgery, introduction of robotic surgery in 2005 and learning of laparoscopy by several of our urologists have dramatically changed the therapeutic approach. Gradual incorporation of laparoscopic surgery has led to a decreased hospital stay and to a shortening of the learning curve (AU)

[Metastasic urethral squamous-cell a cancer]. / Carcinoma escamoso de uretra metastático.

Urethral cancer is an infrequent pathology, less than 1% of the genitourinary tumors. It is more frequent in women (4:1), in the sixth or seventh decade of life. The most frequent histology being squamous cell carcinoma. First signs and symptoms usually are more attributable to benign stricture disease, rather than malignicy. The interval between the onset of symptoms and diagnosis may be as long as three years. Therefore most of these tumors are locally advanced at the time of diagnosis with generally poor prognosis despite aggressive treatment. Therapeutic management varies with the stage and location of the lesion. Because of the rarity of this pathology, no consensus has been reached on treatment modalities, but seems to be that must be a multimodal one, including surgery, radiotherapy and chemotherapy. We present the case of an 80 year-old male, with a diagnosis of urethral squamous-cell cancer, locally advanced at the time of diagnosis. Surgery was not feasible. The patient underwent chemotherapy and radiotherapy with evidence of quick progression thereafter.

Carcinoma escamoso de uretra metastático / Metastasic urethral squamous-cell a cancer

El carcinoma primario de uretra es una neoplasia poco común, constituyendo menos del 1% de los tumores genitourinarios. Éste es más habitual en el sexo femenino, en una proporción 4:1, apareciendo en la sexta o séptima década de la vida, siendo el tipo histológico más frecuente el carcinoma de células escamosas. Los primeros signos y síntomas son más propios de estenosis benigna de uretra que de malignidad. El periodo entre los primeros síntomas y el diagnóstico suele ser de alrededor de tres años. Por consiguiente la mayoría de estos tumores son localmente avanzados en el momento del diagnóstico y a pesar de ser sometidos a tratamientos agresivos tiene mal pronóstico. El tratamiento depende del estadio y la localización de la lesión. Debido a la rareza de esta neoplasia no existe un consenso de tratamiento, pero parece ser que éste debe ser multimodal, con cirugía, radioterapia y quimioterapia. Presentamos el caso de un varón de 80 años afecto de un carcinoma escamoso de uretra, localmente avanzado en el momento del diagnóstico. Ante la imposibilidad de recibir tratamiento quirúrgico fue tratado con quimioterapia más radioterapia, presentando al poco tiempo progresión precoz de la enfermedad (AU)

Urethral cancer is an infrequent pathology, less than 1% of the genitourinary tumors. It is more frequent in women (4:1), in the sixth or seventh decade of life. The most frequent histology being squamous cell carcinoma. First signs and symptoms usually are more attributable to benign stricture disease, rather than malignicy. The interval between the onset of symptoms and diagnosis may be as long as three years. Therefore most of these tumors are locally advanced at the time of diagnosis with generally poor prognosis despite aggressive treatment. Therapeutic management varies with the stage and location of the lesion. Because of the rarity of this pathology, no consensus has been reached on treatment modalities, but seems to be that must be a multimodal one, including surgery, radiotherapy and chemotherapy. We present the case of an 80 year-old male, with a diagnosis of urethral squamous-cell cancer, locally advanced at the time of diagnosis. Surgery was not feasible. The patient underwent chemotherapy and radiotherapy with evidence of quick progression thereafter (AU)

Total organic carbon (VCSN and VWP) and HPLC analysis for cleaning validation in a pharmaceutical pilot plant.

This paper presents a useful method using total organic carbon analyzers employing both combustion and wet oxidation for validating equipment cleaning procedures and verifying cleaning in a pharmaceutical pilot plant. The results are compared with those obtained using high-performance liquid chromatography. The study summarizes the initial steps that should be taken into account and focuses particularly on the solutions to some of the most critical considerations (e.g., glass material, detection and quantification limits, recovery). Also described are the calculation of control limits and the good results obtained.

[The cystic component in the renal cancer: conceptual overiew]. / Componente quístico del cáncer renal: Revisión conceptual.

The renal cancer (RC) cystic component is on the radiological tests and could be consolidate with pathological analysis. The concepts "cystic renal cancer" or "cystic renal tumor" contain a group of entities range from cystic grown pattern RCs to pseudocystic tumors as well as cystic renal diseases coinciding with the RC. The CR and the cystic renal diseases have a great variety to sorts of presentations, giving different ways of radiological images, blending solid and cystic areas. Some papers use indiscriminately expression "cystic" without pathologic proof. Just cystic grown pattern RCs and multilocular cystic carcinoma could be named "cystic renal tumors". For de rest, especially over image study, is more suitable to use expressions as "renal tumor of cystic configuration", while pathologic report are available.

Componente quístico del cáncer renal: revisión conceptual / The cystic component in the renal cancer: conceptual overview

El componente quístico del cáncer renal (CR) aparece en el estudio radiológico y queda consolidado con el examen anatomopatológico. El concepto 'cáncer renal quístico' o 'tumor renal quístico' es de uso habitual y comprende una serie de entidades que van desde los CR con patrón de crecimiento quístico a aquellos que poseen cavidades pseudoquísticas o se hallan imbricados en cualquiera de las enfermedades renales que presentan quistes renales. Diversas publicaciones utilizan de forma indistinta el calificativo 'quístico' sin esperar al estudio anatomopatológico, provocando confusión en la terminología. La gran variabilidad en la forma de presentación tanto del CR como de las enfermedades quísticas renales produce distintas formas de presentación radiológica en que se mezclan áreas sólidas y otras de contenido líquido, aunque sólo el examen patológico podrá afirmar que se trata de un CR quístico genuino. Sólo el CR con patrón de crecimiento quístico y el carcinoma multilocular quístico pueden ser llamados con propiedad tumores renales quísticos. Para el resto de entidades, en especial durante el estudio iconográfico, es más adecuado utilizar expresiones no concluyentes como 'masa renal de configuración quística' o 'tumor renal de aspecto quístico' (AU)

The renal cancer (RC) cystic component is on the radiological tests and could be consolidate with pathological analysis. The concepts 'cystic renal cancer' or 'cystic renal tumor' contain a group of entities range from cystic grown pattern RCs to pseudocystic tumors as well as cystic renal diseases coinciding with the RC. The CR and the cystic renal diseases have a great variety to sorts of presentations, giving different ways of radiological images, blending solid and cystic areas. Some papers use indiscriminately expression 'cystic' without pathologic proof. Just cystic grown pattern RCs and multilocular cystic carcinoma could be named 'cystic renal tumors'. Forde rest, especially over image study, is more suitable to use expressions as 'renal tumor of cystic configuration', while pathologic report are available (AU)

Exéresis laparoscópica de divertículo vesical gigante / Laparoscopic exeresis of a giant vesical diverticle

Las divertículos vesicales en adultos son causados principalmente por obstrucción infravesical. Su tratamiento está indicado en casos de presencia de síntomas del tracto urinario inferior resistentes a tratamiento médico, infecciones de vías urinarias, litiasis intradiverticulares, obstrucción ureteral y cáncer intradiverticular. Las vías de abordaje quirúrgico son: abierta (intravesical, extravesical o combinada), endoscópica (resección del cuellos diverticular, fulguración de mucosa diverticular ó ambas), laparoscópica (transperitoneas o extraperitoneal) y robótica. Les presentamos el caso de un divertículo vesical de gran tamaño acompañado de importantes síntomas de tracto urinario inferior, tratado mediante diverticulectomía laparoscópica (AU)

Bladder diverticula mainly are secondary to infrabladder obstruction. Its treatment is indicated in case of low urinary tract obstruction resistant to medical treatment, urinary infections, intradiverticular stones, uretheral obstruction and intradiverticular carcinoma. Their surgical approach are: open surgery, endoscopic, laparoscopic and robotic. We show a patient with an important low urinary tract sintomatology treated with laparoscopic diverticulectomey (AU)

In vitro inhibitory effect of rupatadine on histamine and TNF-alpha release from dispersed canine skin mast cells and the human mast cell line HMC-1.

OBJECTIVE AND DESIGN: To examine the inhibitory potential of rupatadine, a new H1-antihistamine and anti-PAF agent, on histamine and TNF-alpha release. Comparison with an H1-antihistamine (loratadine) and a PAF-antagonist (SR-27417A). MATERIAL: Dispersed canine skin mast cells were used to assess the effect of the drugs tested on FcepsilonRI-dependent and -independent histamine release; the human HMC-1 cell line was used to study TNF-alpha release. TREATMENT AND METHODS: Before stimulation mast cell populations were treated with increasing concentrations of rupatadine, loratadine and SR-27417A. Histamine and TNF-alpha release were measured following 15-30 min and 3 h activation, respectively. RESULTS: The IC50 for rupatadine in A23187, concanavalin A and anti-IgE induced histamine release was 0.7+/-0.4 microM, 3.2+/-0.7 microM and 1.5+/-0.4 microM, respectively whereas for loratadine the IC50 was 2.1+/-0.9 microM, 4.0+/-1.3 M and 1.7+/-0.5 microM. SR-27417A exhibited no inhibitory effect. Rupatadine, loratadine and SR-27417A inhibited TNF-alpha release with IC50 2.0+/-0.9 microM, 2.1+/-1.1 M and 4.3+/-0.6 microM, respectively. CONCLUSIONS: Rupatadine and loratadine showed similar inhibitory effect on histamine and TNF-alpha release, whereas SR-27417A only exhibited inhibitory effect against TNF-alpha.

Stem cell factor enhances IgE-mediated histamine and TNF-alpha release from dispersed canine cutaneous mast cells.

Stem cell factor (SCF), the c-kit receptor ligand, plays a critical role in mast cell (MC) development and differentiation. In addition, SCF has recently been found to both modulate and induce MC activation. To investigate the effect of SCF on canine cutaneous MC function, we have characterized the ability of SCF to modulate the release by mature canine MC of preformed (histamine) and newly generated (TNF-alpha) mediators. Mature MC were isolated from skin and cultured in the absence or presence of exogenous SCF (6 ng/ml) for up to 5 days and then challenged with anti-IgE (1 microg/ml) alone for 30 min or with a combination of SCF (50 ng/ml) and anti-IgE. SCF alone failed to trigger either histamine or TNF-alpha release at any time. However, we observed that SCF used as a co-stimulus significantly potentiated histamine and TNF-alpha release in canine MC activated through Fc epsilon RI regardless of whether or not SCF was added to the medium during culturing. Thus, the mean histamine release (%) and TNF-alpha production (pg/ml) were found to be significantly higher if cells were maintained in culture in SCF-supplemented medium compared with cells cultured in the absence of exogenous SCF. We also observed that MC responsiveness to immunological stimulation increased with culture time, the percentage of histamine released being higher in cells cultured for at least 3 days when compared to freshly isolated MC. Taken together these findings suggest that canine skin MC releasability can be enhanced independently either through prolonged incubation with SCF and/or through anti-IgE and SCF co-stimulation.

Clinical anti-inflammatory efficacy of arofylline, a new selective phosphodiesterase-4 inhibitor, in dogs with atopic dermatitis.

Forty atopic dogs were studied for 28 days after the oral administration of four randomised treatments: (A) arofylline (1 mg/kg) twice daily for four weeks; (B) prednisone (0.5 mg/kg) twice daily for the first week, once a day during the second week and every 48 hours for the remaining two weeks; (C) prednisone following the same protocol but at a dose of 0.25 mg/kg; or (D) arofylline (1 mg/kg) twice daily for four weeks plus prednisone (0.25 mg/kg) following the same protocol as in (B) and (C). The degree of pruritus and skin lesions and the side effects were evaluated and graded from 0 to 3 before and weekly during the treatments. In all cases there was a progressive clinical improvement in the clinical signs, with no statistical differences among the four treatments. However, many of the dogs treated with arofylline vomited and had adverse gastrointestinal signs.

Comparative study of histamine release from skin mast cells dispersed from atopic, ascaris-sensitive and healthy dogs.

Atopic dermatitis results from the interaction between allergen and allergen-specific IgE bound to the mast cell surface receptors. This process triggers mast cell degranulation and accounts at least for early phase reaction. Furthermore, there is increasing in vitro and in vivo evidence that IgE has the ability to induce overexpression of the Fc epsilonRI receptor on the mast cell plasma membrane. In order to study the potential effect of an increase in serum IgE on mast cell activity, the histamine releasability of mature mast cells isolated from the skin of atopic, ascaris-sensitive and healthy dogs was analyzed. No histamine release was detected upon the immunological stimulation of cells that were not previously sensitized with atopic or ascaris-sensitive dog serum. However, when passively sensitized, skin mast cells were challenged with either Asc SI antigen or anti-IgE, the mast cell histamine release increased in a stimulus concentration-dependent manner. The amount of histamine released was significantly higher in response to anti-IgE than in response to Asc SI antigen. However. the difference in the percentage of mast cell histamine release between atopic (26.3+/-2.8%) and non-atopic (30.9+/-1.7%) dogs was not statistically significant, similar to what occurred when ascaris-sensitive (12.8+/-1.6%) and non-sensitive (13.2+/-1.7%) dogs were compared. Although these results could suggest that there is either little or no increase in the density of IgE receptors in atopic or ascaris-hypersensitive dogs versus controls, we strongly consider either the possibility that the digestion procedure might affect cell behaviour in vitro or that an underlying increase of receptors poorly affects the release of granule-stored mediators but influences mast cell activity in a different manner.

Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF).

Rupatadine (UR-12592, 8-chloro-6, 11-dihydro-11-[1-[(5-methyl3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]-cyclohepta[1,2b]pyridine ) is a novel compound that inhibits both platelet-activating factor (PAF) and histamine (H1) effects through its interaction with specific receptors (Ki(app) values against [3H]WEB-2086 binding to rabbit platelet membranes and [3H]-pyrilamine binding to guinea pig cerebellum membranes were 0.55 and 0.10 microM, respectively). Rupatadine competitively inhibited histamine-induced guinea pig ileum contraction (pA2 = 9.29 +/- 0.06) without affecting contraction induced by ACh, serotonin or leukotriene D4 (LTD4). It also competitively inhibited PAF-induced platelet aggregation in washed rabbit platelets (WRP) (pA2 = 6.68 +/- 0.08) and in human platelet-rich plasma (HPRP) (IC50 = 0.68 microM), while not affecting ADP- or arachidonic acid-induced platelet aggregation. Rupatadine blocked histamine- and PAF-induced effects in vivo, such as hypotension in rats (ID50 = 1.4 and 0.44 mg/kg i.v., respectively) and bronchoconstriction in guinea pigs (ID50 = 113 and 9.6 micrograms/kg i.v.). Moreover, it potently inhibited PAF-induced mortality in mice (ID50 = 0.31 and 3.0 mg/kg i.v. and p.o., respectively) and endotoxin-induced mortality in mice and rats (ID50 = 1.6 and 0.66 mg/kg i.v.). Rupatadine's duration of action was long, as assessed by the histamine- and PAF-induced increase in vascular permeability test in dogs (42 and 34% inhibition at 26 h after 1 mg/kg p.o.). Rupatadine at a dose of 100 mg/kg p.o. neither modified spontaneous motor activity nor prolonged barbiturate-sleeping time in mice, which indicates a lack of sedative effects. Overall, rupatadine combines histamine and PAF antagonist activities in vivo with high potency, the antihistamine properties being similar to or higher than those of loratadine, whereas rupatadine's PAF antagonist effects were near those of WEB-2066. Rupatadine is therefore a good candidate for further development in the treatment of allergic and inflammatory conditions in which both PAF and histamine are implicated.

Pharmacokinetic and pharmacodynamic studies of the histamine H1-receptor antagonist ebastine in dogs.

The pharmacokinetics and pharmacodynamics of ebastine at single oral doses of 10 and 20 mg were studied in six healthy beagle dogs. Plasma concentrations of the active metabolite of ebastine were measured at predetermined times after the dose. At these times an intradermal injection of 0.01 mL of a 0.2 mg mL-1 histamine diphosphate solution was given, and wheal areas were computed. The plasma elimination half-life of ebastine was 4.38 +/- 1.01 h after 10 mg ebastine and 4.09 +/- 0.74 h after 20 mg ebastine; the distribution volume was 3.99 +/- 0.88 and 3.65 +/- 0.75 L kg-1 after 10 and 20 mg of ebastine, respectively; the clearance after the 10 mg dose of ebastine was 0.67 +/- 0.24 L h-1 kg-1 and after 20 mg ebastine was 0.63 +/- 0.17 L h-1 kg-1. The mean histamine-induced wheal areas were significantly suppressed from 1 to 25 h after the 10 mg dose ebastine and from 1 to 32 h after the 20 mg dose ebastine, compared with the mean predose wheal areas (P < 0.001). Maximum suppression of the wheals was 75 and 82% from 10 and 20 mg ebastine, respectively. A combined pharmacokinetic-pharmacodynamic model was used to analyse the relationship between inhibition of wheal skin reaction and changes in the active metabolite of plasma concentration after ebastine administration. A significant delay of 3-4 h was present between the maximum effect and the peak plasma concentration. Calculated from mean data, the rate constant for equilibration of the drug between plasma and effect site was 0.17 and 0.22 h-1 after 10 and 20 mg ebastine with a half-life of 4.13 and 3.56 h, respectively, and the steady-state plasma concentration resulting in 50% of maximal effect was 18.9 +/- 4.8 ng mL-1 after 10 mg and 18.2 +/- 5.7 ng mL-1 after 20 mg ebastine.