Climate change and industrialization as the main drivers of Spanish agriculture water stress.

In recent decades, there has been growing concern regarding worsening global climate conditions for agricultural production, especially in Mediterranean climate and other semi-arid areas where the scarcity of water is a major problem. The objective of the study was to estimate the long-term evolution (in Spain, over 1922-2016) of the decoupling between crop's water requirements and the green water available, and to analyze the causes of the changes. The FA0-56 methodology was followed to estimate the green water, blue water and water stress of crops, via an explicit territorial distribution, using 0.5o grid cells. We propose a new indicator called Violet Water. This indicator groups together the water stress of the rainfed croplands and the blue water of the irrigated croplands, representing the components of this decoupling. Our results show that crops´ water requirements increased by 21% and violet water by 30% over the study period. The decomposition analysis used to study the drivers of these changes suggests that increasing reference evapotranspiration, caused by global warming, was the major driver triggering the growth of crop water requirements. Meanwhile, the changes in violet water values were mainly driven by the coupling of the cropland's spatiotemporal structure and climate change. The sensitivity analysis performed showed that the increasing trends in water stress, blue water and violet water were consistent for almost all the tested scenarios, but significant differences on the scale aroused depending on the climate data used (climate normal or each year climate) and specially on the geographical and historical Kc adjustment (crop-fixed Kc versus adjusted Kc). This highlights the importance of considering simultaneously the effect of the different factors, but also the need for refining this type of adjustment in future research.

In situ experiment to evaluate biochemical responses in the freshwater mussel Diplodon chilensis under anthropogenic eutrophication conditions.

An in-situ experiment was performed to study metabolic responses of the freshwater mussel Diplodon chilensis to water contaminated by leachates from an open dump and cattle activity, in order to analyze both the effects of those contaminants on aquatic environments and the potential use of a native bivalve to evaluate the effects of anthropic influence and eutrophication. Bivalves from a reference site were cage-transplanted to a control site (site A) and to a temporal water pond (site B) over 30 and 60 periods. Water quality analyses revealed that the site B was affected by anthropogenic influence. Mussel's hemocytes from site B showed 50% lower reactive oxygen species production and 130% higher lysosomal membrane stability in the site B mussels. In addition, no oxidative stress was evident in gills, despite the elevated copper and iron concentrations recorded in the site B water samples (CuB = 0.3350 ± 0.0636 mg. L-1vs. CuA = 0.0045 ± 0.0007 mg. L-1; FeB = 3.8650 ± 0.4031 mg. L-1vs. FeA = 0.0365 ± 0.0049 mg. L-1). In contrast, the adductor muscle accumulated more Fe (~10-20-fold) than the gills and showed signs of oxidative stress, e.g. superoxide dismutase activity and TBARS levels were increased by 10% were 34%, respectively, in the site B compared with the site A after 60 days of exposure. Additionally, the adductor muscle showed signs of anaerobic metabolism activation. Cu is accumulated in gills from both sites' individuals, at 60 days, in concordance with the increase in the activity of the cu-containing enzyme cytochrome-c-oxidase. There was a reduction in the overall condition and digestive gland index in bivalves exposed at site B, associated with diminished levels of lipid and protein contents. Metal-pollution and eutrophication affects D. chilensis metabolism and is associated to tissue-specific exposure, anaerobic metabolism and general energetic condition depletion.

Improved robustness of an ethanologenic yeast strain through adaptive evolution in acetic acid is associated with its enzymatic antioxidant ability.

AIMS: To investigate multiple tolerance of Saccharomyces cerevisiae obtained through a laboratory strategy of adaptive evolution in acetic acid, its relation with enzymatic ROS detoxification and bioethanol 2G production. METHODS AND RESULTS: After adaptive evolution in acetic acid, a clone (Y8A) was selected for its tolerance to high acetic acid concentrations (13 g l-1 ) in batch cultures. Y8A was resistant to multiple stresses: osmotic, thermic, oxidative, saline, ethanol, organic acid, phenolic compounds and slow freeze-thawing cycles. Also, Y8A was able to maintain redox homeostasis under oxidative stress, whereas the isogenic parental strain (Y8) could not, indicating higher basal activity levels of antioxidative enzyme Catalase (CAT) and Gluthatione S-transferase (GST) in Y8A. Y8A reached higher bioethanol levels in a fermentation medium containing up to 8 g l-1 of acetic acid when compared to parental strain Y8. CONCLUSIONS: A multiple-stress-tolerant clone was obtained using adaptive evolution in acetic acid. Stress cross-tolerance could be explained by its enzymatic antioxidative capacity, namely CAT and GST. SIGNIFICANCE AND IMPACT OF THE STUDY: We demonstrate that adaptive evolution used in S. cerevisiae was a useful strategy to obtain a yeast clone tolerant to multiple stresses. At the same time, our findings support the idea that tolerance to oxidative stress is the common basis for stress cotolerance, which is related to an increase in the specific enzymes CAT and GST but not in Superoxide dismutase, emphasizing the fact that detoxification of H2 O2 and not O2 ˙ is a key condition for multiple stress tolerance in S. cerevisiae.

Trace metals and oxidative status in soft tissues of caged mussels (Aulacomya atra) on the North Patagonian coastline.

This study investigated metal accumulation and oxidative effects in mantle, gill and digestive gland of the ribbed mussel Aulacomya atra from the Argentinean North Patagonian coastline. Mussels were transplanted over an 18-month period from a site with low anthropogenic impact to a harbor site with higher seawater concentration of aluminum, chromium, copper, manganese, nickel and zinc. Total trace metal concentration in seawater did not change throughout the 18-month transplant in either site. A. atra bioaccumulated metals in digestive gland, gills and mantle at different levels. Digestive gland had the highest concentration of metals, especially towards the end of the transplant experiment in the harbor area. Mussels transplanted to the harbor site experienced an upregulation in their antioxidant system, which likely explains the lack of oxidative damage to lipids despite higher metal accumulation. These results demonstrate that A. atra selectively accumulates metals from the water column and their prooxidant effects depend on the tissue antioxidant defenses and the exposure time.

Histopathological factors predicting response to neoadjuvant therapy in gastric carcinoma.

BACKGROUND: Neoadjuvant therapy (NAT) is a useful therapeutic option. However, some patients respond poorly to it and can even show tumor progression. It is important to define factors that can predict response to NAT. MATERIALS AND METHODS: This is a retrospective cohort study to define histopathological factors predicting response to NAT in gastric tubular carcinoma. This study has enrolled 80 patients receiving chemotherapy for locally advanced gastric carcinoma. RESULTS: 44.5% of the patients were men; mean age was 64.49 years. Only 5.7% of the patients showed a complete response to therapy, 10% had grade 1, 21.4% grade 2, and 62.9% grade 3 regression. On follow-up, 43.8% of the patients showed recurrence of disease (57.1% distant metastasis) and 33.8% eventually died of it. We found a statistically significant association between response and prognosis. We found a statistically significant association between regression and perineural, vascular, and lymph vessel invasion. Logistic regression model showed that only lymph vessel invasion had independent influence. Lymph vessel invasion not only indicated lack of response to therapy, but also higher incidence of lymph node involvement in the gastrectomy specimen. DISCUSSION: Our study indicates that the presence of vascular or perineural invasion in the endoscopic biopsies and high histopathological grade predict poor response to therapy. This seems peculiar, for undifferentiated tumors are supposed to have better response to therapy. CONCLUSION: Our study indicates that undifferentiated tumors respond worse to therapy. Furthermore, studies are necessary to define lack of response, to help avoid neoadjuvant therapy in unfavorable cases.

HEp-2 cell line as an experimental model to evaluate genotoxic effects of pentavalent inorganic arsenic / HEp-2 como modelo experimental para evaluar los efectos genotóxicos del arsénico inorgánico pentavalente

Early detection of toxic events induced by xenobiotics is necessary for a proper assessment of human risk after the exposure to those agents. The aim of this work was to evaluate the cell line HEp-2 as an experimental model to determine the genotoxic effects of sodium arsenate. To this end, we determined the metabolic activity cells by the MTT test on seven concentrations of arsenate that range from 27 to 135,000 μM, obtaining the median lethal concentration (LC50), the lowest observed effect concentration (LOEC), and the not observed effect concentration (NOEC) of sodium arsenate at 24 h of exposition. According to the cytotoxic response obtained, we evaluated the genotoxic effect of the 27 and 270 μM concentrations by using the micronucleus assay and chromosomal aberrations test. We found a statistically significant increase (p<0.05) in the frequency of micronuclei between control cultures and those exposed to the highest concentration of sodium arsenate. Furthermore, the frequencies of nucleoplasmic bridges and tripolar mitosis were significantly higher in cell cultures exposed to the above concentrations compared to the control cultures (p<0.05). The participation of the glutathione system as response to the arsenate exposition was also analyzed, and a statistically significant increase in the glutathione content was found in those cells exposed to 27 μM of arsenate. The Glutathione S-transferase activity did not increase in the exposed cells compared to control cells, suggesting that the arsenate reduction involved other metabolic pathways in the HEp-2 cells. These results confirm that, under the conditions carried out in this study, sodium arsenate is genotoxic for HEp-2 cells. Therefore, we suggest that this cell line would be a good model for the assessment of the cytotoxic and genotoxic effects of xenobiotics on human cells.

La detección temprana de eventos tóxicos inducidos por xenobióticos es necesaria para una adecuada evaluación del riesgo humano ante la exposición a dichos agentes. El objetivo de este trabajo fue evaluar a la línea celular HEp-2 como modelo experimental para determinar los efectos genotóxicos del arseniato de sodio. Para ello, se determinó la actividad metabólica de las células mediante el ensayo de MTT, en siete concentraciones de arseniato de sodio en el rango 27-135.000 μM, determinando la concentración letal media (LC50), la menor concentración de efecto observado (LOEC) y la mayor concentración de efecto no observado (NOEC) de arseniato de sodio para una exposición de 24 h. Teniendo en cuenta los datos de citotoxicidad, se evaluó el efecto genotóxico a las concentraciones 27 y 270 μM por medio del ensayo de micronúcleos y aberraciones cromosómicas, encontrando un aumento estadísticamente significativo en la frecuencia de micronúcleos entre el control y la mayor concentración arseniato de sodio ensayada. Además, la presencia de puentes nucleoplasmáticos y mitosis tripolar fue significativamente mayor en ambas concentraciones estudiadas con respecto al control. Se analizó la participación del sistema de glutatión como respuesta a la exposición al arseniato, encontrándose un aumento estadísticamente significativo en el contenido de glutatión en la concentración de arseniato de 27 μM. La actividad de la glutatión S-transferasa no aumentó, lo que sugiere que la reducción del arseniato implicó otra vía metabólica en las células HEp-2. Estos resultados confirman que el arseniato de sodio induce genotoxicidad en células HEp-2 en las condiciones realizadas en este estudio y por lo tanto este tipo de línea celular es un buen modelo para ensayos de citotoxicidad y genotoxicidad en los cuales se quiere evaluar el riesgo humano.

Food allergy in Catalonia: Clinical manifestations and its association with airborne allergens.

BACKGROUND: Food allergy affects around 6% of the European population and its prevalence worldwide has been increasing in the last decades, but studies focused on investigating food allergy epidemiology in Europe are lacking. OBJECTIVE: The Cibus project was created to register the main culprit foods and their clinical manifestations in food allergic patients in Catalonia. METHODS: A specific online database was designed. Allergists from eight different Catalan hospitals registered the new diagnoses of food allergy. RESULTS: 618 food allergic patients were included. Egg and milk were the main elicitors in the early ages, while fruits and nuts were the most frequent in patients >14 years old. Fish was more frequent in children, while seafood and Anisakis allergy were more frequent in the >14-year-old group. Overall, peach was the most prevalent food eliciting an allergic reaction (10%). Food allergy diagnosis was reached using compatible clinical history and positive skin prick test to the involved food in 98% of cases. Globally, urticaria was the most frequently reported manifestation in our population (48.2%), followed by oral allergy syndrome (25.6%) and anaphylaxis (24.8%). CONCLUSIONS: The Cibus project gives a full overview of the profile of food allergic patients in Catalonia and reinforces the predominance of plant food allergies in the Mediterranean area.

Multibiomarker responses in aquatic insect Belostoma elegans (Hemiptera) to organic pollution in freshwater system.

The present study analyzes a battery of biomarkers in the water bug Belostoma elegans from a stream polluted with organic matter (OMS), and another one considered as reference site (RS) during spring-summer season (December to March). Biochemical parameters of glucidic, lipidic and oxidative metabolic pathways were analyzed in males and females of this insect. In general, no significant differences were observed in all biomarkers assayed between both sexes, except lactate concentration which was higher in males than in females (p < 0.0006) in the first three months. About carbohydrate metabolism parameters, only pyruvate-kinase showed significant differences between insects collected in both streams (p < 0.05) during December. However, the total lipid content, saturated fatty acid, and mainly triacylglycerol were higher in insects from RS compared to those from OMS (p < 0.002) in all sampled months. Levels of lipoperoxidation, protein oxidation, reduced glutathione and glutathione-S-transferase activity showed no differences between insects collected from both streams. Nevertheless, the significant increase observed in superoxide dismutase and catalase activities (p < 0.004) could be due to the elevated oxidative metabolism in insects from RS compared to those from OMS with lower dissolved oxygen. Regarding those responding parameters, males accounted for the differences between the two sites during the study period. In conclusion, our results support that lipidic energetic reserves and antioxidant enzyme activities in B. elegans could be used as biomarkers of environmental pollution by organic matter.

Use of an experimental model to evaluate infection resistance of meshes in abdominal wall surgery.

BACKGROUND: Staphylococcal species are the most common organisms causing prosthetic mesh infections, however, infections due to rapidly growing mycobacteria are increasing. This study evaluates the resistance of biomaterial for abdominal wall prostheses against the development of postoperative infection in a rat model. MATERIAL AND METHODS: In 75 rats, we intramuscularly implanted three different types of prostheses: (1) low-density polypropylene monofilament mesh (PMM), (2) high-density PMM, and (3) a composite prosthesis composed of low-density PMM and a nonporous hydrophilic film. Meshes were inoculated with a suspension containing 108 colony-forming units of Staphylococcus aureus, Staphylococcus epidermidis, Mycobacterium fortuitum, or Mycobacterium abscessus before wound closure. Animals were sacrificed on the eighth day postoperatively for clinical evaluation, and the implants were removed for bacteriologic analyses. RESULTS: Prostheses infected with S aureus showed a higher bacterial viability, worse integration, and clinical outcome compared with infection by other bacteria. Composite prostheses showed a higher number of viable colonies of both M fortuitum and Staphylococcus spp., with poorer integration in host tissue. However, when the composite prosthesis was infected with M abscessus, a lower number of viable bacteria were isolated and a better integration was observed compared with infection by other bacteria. CONCLUSIONS: Considering M abscessus, a smaller collagen-free contact surface shows better resistance to infection, however, depending on the type of bacteria, prostheses with a large surface, and covered with collagen shows reduced resistance to infection, worse integration, and worse clinical outcome.

Effects of glyphosate on growth rate, metabolic rate and energy reserves of early juvenile crayfish, Cherax quadricarinatus M.

Early juveniles of the crayfish Cherax quadricarinatus were exposed for 60 days to 10 and 40 mg/L of pure glyphosate (acid form) in freshwater. Mortality was 33 % at the highest concentration, while no differences in molting were noted among treatments. After the first month of exposure, weight gain was significantly (p < 0.05) reduced in the 40 mg/L group. At the end of the assay, lipid levels in muscle, as well as protein level in both hepatopancreas and muscle were significantly (p < 0.05) reduced. These results suggest long-term utilization of both lipid and protein as main energetic reserves, likely in response to the chronic stress associated with herbicide exposure. Besides, the lower pyruvate kinase activity in muscle suggests a possible metabolic depression in this tissue. The hemolymphatic ASAT:ALAT ratio showed higher levels than the control at the highest glyphosate concentration, indicating possible damage to several tissues.

Validación farmacéutica y detección de errores de prescripción de antineoplásicos en pacientes oncohematológicos / Pharmaceutical validation and error detection in the prescription of antineoplastics in oncohematological patients

Objetivo: Identificar los distintos tipos de error de prescripción de citostáticos en pacientes oncohematológicos adultos y pediátricos de nuestro hospital y proponer estrategias de mejora. Métodos: Estudio observacional longitudinal prospectivo en el que se validaron las prescripciones médicas de antineoplásicos procedentes de Hematología y Oncohematología Pediátrica durante 15 me ses. Se clasificaron los tipos de error atendiendo a la terminología y taxonomía publicadas por Otero et al en el documento "Errores de medicación: estandarización de la terminología y clasificación", recogiéndose 11 variables. Entre otros parámetros se determinaron: porcentaje de error global, por tipo de prescripción y servicios, así como de intervención farmacéutica y grado de aceptación. Resultados: Se detectaron un total de 92 errores correspondientes al 1,4% del total de prescripciones, y los de mayor frecuencia fueron: dosificación incorrecta (28,2%), duración incorrecta (21,7%) y volumen y/o vehículo inadecuados (16,3%). Además se detectó una orden de tratamiento de un paciente pediátrico alérgico al citostático prescrito. El 81,8% de órdenes con error se prescribieron de forma manual. En Hematología se obtuvo un 0,9% de error y en Oncohematología Pediátrica un 3,5%. Tanto el índice de intervención farmacéutica como su grado aceptación fueron del 100% (AU)

Objective: To identify the different types of cytostatic prescription errors in adult and paediatric oncohematological patients in our hospital and to propose strategies for improvement. Methods: Longitudinal, prospective, observational study in which prescriptions for antineoplastics from the haematology and paediatric oncohaematology departments were validated over a 15-monthperiod. The types of error were classified in accordance with the terminology and taxonomy published by Otero and cols in the document “Medication errors: standardisation of terminology and classification”. Eleven variables were recorded. Amongst other parameters, the following were determined: percentage of overall error, percentage of error in type of prescription, percentage of service error, percentage of pharmaceutical intervention and level of acceptance. Results: A total of 92 errors were recorded which corresponded to1.4% of the total prescriptions. The most significant errors were: incorrect dose (28.2%), incorrect duration (21.7%), incorrect volume and/or inadequate vehicle (16.3%), and in one case a prescription was made up where the patient was allergic to the specific cytostatic drug prescribed. 81.8% of prescription errors were made manually. In the haematology department a 0.9% error was recorded, as was a3.5% error in paediatric oncohaematology. Both the rate of pharmaceutical intervention and its level of acceptance were 100% (AU)

[Pharmaceutical validation and error detection in the prescription of antineoplastics in oncohematological patients]. / Validación farmacéutica y detección de errores de prescripción de antineoplásicos en pacientes oncohematológicos.

OBJECTIVE: To identify the different types of cytostatic prescription errors in adult and paediatric oncohematological patients in our hospital and to propose strategies for improvement. METHODS: Longitudinal, prospective, observational study in which prescriptions for antineoplastics from the haematology and paediatric oncohaematology departments were validated over a 15-month period. The types of error were classified in accordance with the terminology and taxonomy published by Otero and cols in the document "Medication errors: standardisation of terminology and classification". Eleven variables were recorded. Amongst other parameters, the following were determined: percentage of overall error, percentage of error in type of prescription, percentage of service error, percentage of pharmaceutical intervention and level of acceptance. RESULTS: A total of 92 errors were recorded which corresponded to 1.4% of the total prescriptions. The most significant errors were: incorrect dose (28.2%), incorrect duration (21.7%), incorrect volume and/or inadequate vehicle (16.3%), and in one case a prescription was made up where the patient was allergic to the specific cytostatic drug prescribed. 81.8% of prescription errors were made manually. In the haematology department a 0.9% error was recorded, as was a 3.5% error in paediatric oncohaematology. Both the rate of pharmaceutical intervention and its level of acceptance were 100%.

[Tacrolimus blood levels and incidence of graft rejection in heart transplantation]. / Relación entre los niveles de tacrolimus en sangre y la incidencia de rechazo en enfermos trasplantados de corazón.

OBJECTIVE: To determine the relationship between pharmacokinetic parameters and clinical outcomes after heart transplantation and to determine the range of tacrolimus blood levels which provides the most effective protection against graft rejection. To study other factors that predict graft rejection. METHOD: We retrospectively analyzed the clinical outcomes of all adult patients who received a heart transplant between January 2000 and October 2003 and had routine monitoring of tacrolimus trough levels at the time of scheduled endomyocardial biopsy. Rejection was defined as Grade = 3, based on the International Society for Heart and Lung Transplantation (ISHLT) criteria. The follow-up period was 1 year. All patients were on a triple therapy regimen of Tacrolimus (TAC), Corticosteroids and Azatioprine/Micophenolate Mofetil. Data were analyzed by Student s t-test, univariate logistic regression and ROC curve. RESULTS: Tacrolimus blood levels measured at day +5 postransplant were the strongest predictor of acute graft rejection over a 1-year follow-up period (rejection 5.76 +/- 3.4 ng/ml vs no rejection 9.66 +/- 2.73 ng/ml, p = 0.016). A decrease of one unit in TAC trough level values at day +5 postransplant implied a 1.58 greater risk of rejection (p = 0.05). Overall incidence of treated acute rejection was lower for patients with trough levels higher than 8 ng/ml on day +5 postransplant (33 vs 80%, p = 0.055, Fisher s exact test). CONCLUSIONS: Data suggest that in heart transplant patients it may be crucial to achieve tacrolimus levels of at least 8 ng/ml during the first days postsurgery to avoid rejection.

Relación entre los niveles de tacrolimus en sangre y la incidencia de rechazo en enfermos trasplantados de corazón / Tacrolimus blood levels and incidence of graft rejection in heart transplantation

Objetivo: Evaluar la relación entre los niveles en sangre de tacrolimus, la incidencia de rechazo agudo en enfermos trasplantados de corazón y determinar el rango de concentración más adecuado para prevenir el rechazo. Estudiar otros factores predictores del rechazo. Método: Se realizó un estudio retrospectivo de todos los enfermos adultos trasplantados de corazón entre enero de 2000 y octubre de 2003 en tratamiento con tacrolimus, corticoides y azatioprina/ micofenolato mofetil. La eficacia del tratamiento se evaluó por confirmación histopatológica del rechazo agudo como grado ≥ 3A según criterios del Sociedad Internacional de Trasplante de Pulmón y Corazón (ISHLT). Se registraron los resultados de las biopsias endomiocárdicas y de los niveles mínimos de tacrolimus en sangre durante el primer año postrasplante. El análisis de los datos se realizó mediante la t de Student, regresión logística univariante y curva ROC. Resultados: Se encontraron diferencias significativas en la concentración mínima de tacrolimus en sangre alcanzada el día +5 postrasplante entre los enfermos que presentaron algún episodio de rechazo agudo el primer año y los que no (5,76 ± 3,4 vs 9,66 ± 2,73 ng/ml, p = 0,016). El nivel el día +5 fue el mejor predictor del rechazo (p = 0,05) de modo que el riesgo de un paciente respecto a otro con una unidad menos en el nivel de tacrolimus es 1,58 veces mayor. 8 ng/ml es el nivel con mayor poder de discriminación (sensibilidad = 75% y especificidad = 72,7%), de modo que alcanzar una concentración mínima en sangre de 8 ng/ml el día +5 reduce la incidencia de rechazo agudo de 33 a 80% (p = 0,055, p. exacta de Fisher). Conclusiones: Alcanzar niveles mínimos adecuados de tacrolimus en los primeros días postrasplante (al menos de 8 ng/ml el día +5) puede ser crucial para evitar el rechazo agudo en pacientes trasplantados de corazón

Objective: To determine the relationship between pharmacokinetic parameters and clinical outcomes after heart transplantation and to determine the range of tacrolimus blood levels which provides the most effective protection against graft rejection. To study other factors that predict graft rejection. Method: We retrospectively analyzed the clinical outcomes of all adult patients who received a heart transplant between January 2000 and October 2003 and had routine monitoring of tacrolimus trough levels at the time of scheduled endomyocardial biopsy. Rejection was defined as Grade ≥ 3, based on the International Society for Heart and Lung Transplantation (ISHLT) criteria. The follow-up period was 1 year. All patients were on a triple therapy regimen of Tacrolimus (TAC), Corticosteroids and Azatioprine/Micophenolate Mofetil. Data were analyzed by Student’s t-test, univariate logistic regression and ROC curve. Results: Tacrolimus blood levels measured at day +5 postransplant were the strongest predictor of acute graft rejection over a 1- year follow-up period (rejection 5.76 ± 3.4 ng/ml vs no rejection 9.66 ± 2.73 ng/ml, p = 0.016). A decrease of one unit in TAC trough level values at day +5 postransplant implied a 1.58 greater risk of rejection (p = 0.05). Overall incidence of treated acute rejection was lower for patients with trough levels higher than 8 ng/ml on day +5 postransplant (33 vs 80%, p = 0.055, Fisher’s exact test). Conclusions: Data suggest that in heart transplant patients it may be crucial to achieve tacrolimus levels of at least 8 ng/ml during the first days postsurgery to avoid rejection

Rupatadine 10 mg and cetirizine 10 mg in seasonal allergic rhinitis: a randomised, double-blind parallel study.

This randomised, double-blind, parallel-group, multicentre clinical trial evaluated the efficacy and safety of rupatadine, a new antihistamine with antiplatelet-activating factor (PAF) activity, and cetirizine in the treatment of patients with seasonal allergic rhinitis (SAR). A total 249 patients were randomised to receive rupatadine 10 mg once daily (127 patients) or cetirizine 10 mg (122 patients) for two weeks. The main efficacy variable was the mean total daily symptom score (mTDSS) and was based on the daily subjective assessment of the severity of each rhinitis symptom--nasal (runny nose, sneezing, nasal itching and nasal obstruction) and non-nasal (conjunctival itching, tearing, and pharyngeal itching)--recorded by patients in their diaries. The mTDSS was 0.7 for both treatment groups (intention to treat analysis). In the investigator's global evaluation of efficacy at the seventh day, 93.3% and 83.7% patients in the rupatadine and cetirizine groups, respectively, showed some or great improvement (p = 0.022). In the per protocol analysis (n = 181), runny nose at the seventh day of treatment was absent or mild in 81.1% of patients in the rupatadine group and in 68.6% of patients in the cetirizine group (p = 0.029). In any case statistical significance was not maintained at the second week. Overall, all treatments were well tolerated. Adverse events (AEs) were similar in both treatment groups, i.e. headache, somnolence and fatigue/asthenia as the most often reported. Somnolence was reported in 9.6% and 8.5% of patients treated with rupatadine or cetirizine, respectively. The most reported AEs (67%) were mild in intensity. Our results suggest that rupatadine 10 mg may be a valuable and safe alternative for the symptomatic treatment of SAR.

Rupatadine 10 mg and ebastine 10 mg in seasonal allergic rhinitis: a comparison study.

BACKGROUND: The aim of this study is to establish the efficacy and safety of rupatadine vs ebastine and placebo in the treatment of seasonal allergic rhinitis (SAR). Rupatadine is a new second generation H(1)-antihistamine with once-daily dosing that may provide better control of symptoms than the currently used H(1)-receptor blockers because of its dual pharmacological profile (anti-PAF and anti-H(1)). METHODS: In a multicentre study, 250 patients with SAR were included in a double-blind, randomized, parallel-group and placebo-controlled study. Patients received either rupatadine 10 mg, ebastine 10 mg or placebo once daily for 2 weeks. The main efficacy outcome was based on the patient's record of severity of nasal symptoms (sneezing, nasal itching, runny nose and nasal obstruction) and nonnasal symptoms (conjunctival itching, tearing and pharyngeal itching). The daily total symptom score (DTSS) was the mean of the DSS recorded for each of the seven symptoms assessed, and the mean DTSS (mDTSS) was the mean of the DTSS values for each study day. RESULTS: Significant differences in mDTSS were detected between rupatadine and placebo (33% lower for rupatadine group; P = 0.005) after 2 weeks of treatment. The TSS for rupatadine were 22% lower than for ebastine, although the differences were not statistically significant. No serious adverse events were reported during the study period. CONCLUSIONS: Rupatadine 10 mg once daily was clearly superior to placebo in alleviating the symptoms of SAR over a 2-week period. In comparison with ebastine, rupatadine shows a trend towards a better profile as regard several secondary efficacy variables.

New strategies of cyclosporine monitoring in heart transplantation: initial results.

The aim of this study was to evaluate cyclosporine (CyA) absorption profiles in heart transplantation to establish the most adequate monitoring strategy and determine the optimal therapeutic range for AUC(0-4) or C2 levels. A total of 22 full pharmacokinetic studies were performed at steady-state in 22 adult heart transplant recipients (18 men, 4 women). Twelve studies were performed during the first month posttransplant (group I), and 10 studies were done after 1 month (group II). In 9 outpatients we performed an abbreviated AUC(0-4). The mean age of the patients was 49+/-15 years (range, 15-72 years), and the mean weight was 70.4+/-10.8 kg (mean, 54-98 kg). The CyA dosage had been adjusted to maintain trough levels (C0) in the putative target ranges of 200 to 400 ng/mL in group I and between 100 to 300 ng/mL in group II. Blood samples were drawn prior to and at 0.5, 1, 2, 4, 6, 8, and 12 hours after the morning dose. The CyA blood levels were measured by the AxSYM cyclosporine assay. The AUC was calculated by the trapezoidal rule. Multiple linear regression was done to evaluate the predictive ability of various limited sampling strategies. The C0 correlated poorly, either with the full AUC (r2=0.64) or the AUC(0-4) (r2=0.43), while C2 seemed to be the most accurate single predictor of drug exposure (r2=0.92 for AUC(0-12); r2=0.74 for AUC(0-4)). For both AUC(0-4) and AUC(0-12), all 2- or 3-point strategies had r2 values approaching that of the C2 value. In conclusion, C2 is a simple, fast, and accurate value to predict AUC(0-4) in routine clinical practice. Its implementation must focus on ensuring the commitment of all unit staff, thus ensuring that patients are sampled on time and minimizing the impact on workload.

Clinical pharmacokinetics of tacrolimus in heart transplantation: new strategies of monitoring.

The aim of this study was to investigate the absorption profile of tacrolimus (TAC) in heart transplant patients in order to find the best sampling time to predict the total exposure and to explore the target range for optimal clinical immunosuppression. Twenty-five full pharmacokinetic studies were performed in 22 heart transplant patients (11 men and 7 women) at less than 1 year posttransplant. The immunosuppressive treatment was steroids plus azathioprine or mycophenolate mofetil and TAC. The mean age was 55 years (36-64 years) and the mean weight 70.49 kg (50-111 kg). After three days of receiving the same dose, eight blood samples were collected at 0.5, 1, 2, 4, 6, 8, and 12 hours postmorning dose. TAC concentrations were measured by microparticle enzyme immunoassay (IMx). Area under the concentration-time curve(AUC(0-12)) was calculated by the trapezoidal rule. Using 0-4 hours TAC blood concentrations, a projected 12 hours AUC (extrapolated AUC(0-4)) was calculated assuming C0 and C12 were comparable. A high interpatient TAC pharmacokinetics variability that was greater during the absorption phase was observed. A Cmax (30.5+/-13.8 ng/mL) was reached at 2.3+/-1.5 h. When target trough levels were achieved (10-20 ng/mL), the mean tacrolimus exposure was 230.6+/-59.2 ng h/mL (120.14-327.7) (n=19). Correlation between AUC(0-12) and C0 was relatively good (r2=0.74). Between individual time points, C4 showed the best correlation (r2=0.88). In any case the best strategy to monitor is to obtain the extrapolated AUC(0-4) (r2=0.98), as a good approach to patients with a poor response to treatment.

Equivalent asthma control and systemic safety of inhaled budesonide delivered via HFA-134a or CFC propellant in a broad range of doses.

The aim of the present study was to demonstrate an equivalent asthma control and safety of inhaled budesonide 200 microg unit-dose via a spacer device (Jet Spacer, Chiesi Farmaceutici S.p.A.) given with an HFA-134a or CFC propellant in stable patients treated with inhaled corticosteroids. A total number of 270 patients, 134 in the HFA-134a group and 136 in the CFC group, completed a 2-week run-in period and were then randomised to receive a daily dose of inhaled budesonide (low dose: 400 microg, medium dose: 800 microg, high dose: 1200 or 1600 microg), defined on the basis of the dose of previous inhaled steroids given twice daily for 12 weeks. Morning and evening PEFR, intake of rescue salbutamol, number of day-time and night-time asthma attacks, number of night-time awakenings due to asthma and clinical symptoms were recorded daily by patients on diary cards. Pulmonary function tests (FEV1, FVC, PEFR and MEF50) and vital signs were measured at the clinics at study entry, at the start of treatment and after 2, 4, 8 and 12 weeks thereafter. Morning serum cortisol (8.00-10.00 AM) was measured at baseline and in the final visit. Adverse events and vital signs were recorded throughout the total study period. Small increases vs. baseline for lung function (more markedly in the high-dose subsets) and significant decreases of symptoms and use of rescue salbutamol were similarly observed in both groups. Equivalence was demonstrated for the primary endpoint morning PEFR (difference between means = -1.51 l/min; 95% CI: -9.40-6.37 l/min; pre-defined limits: +/- 42.16 l/min, i.e. +/- 10% of the reference LSM) as well as for evening PEFR and FEV1, both in the ITT population or on a per-protocol basis. No statistically significant differences between groups were observed in any of the other efficacy variables. A similar proportion of drug-related adverse events was observed in the two groups, without drug-related serious events in either group. No evidence of adrenal depletion was also noted with both propellants. In conclusion, the budesonide HFA-134a formulation given with a spacer device provided an equivalent asthma control with that of a corresponding CFC product, when administered in stable patients treated with inhaled corticosteroids in a broad range of daily doses. The use of the new propellant did not modify the safety profile of inhaled budesonide.