Altered Plasma and Brain Disposition and Pharmacodynamics of Methadone in Abstinent Rats

The pharmacokinetics and pharmacodynamics of methadone were investigated in control and abstinent rats. Minipumps filled with saline (control group) or saline-morphine (abstinent group) solutions were used to induce physical dependence. Solutions were delivered continuously by minipumps for 6 days. The physical dependence was evaluated 12 h after minipump removal by measuring specific withdrawal signs. Animals from the abstinent group showed clear withdrawal signs such as hostility on handling and weight loss. Plasma and brain disposition and pharmacodynamics of methadone were evaluated after a 0.35 mg/kg i.v. bolus dose administered 12 h after minipump removal. Plasma clearance, distribution clearance, and volume of distribution at steady-state were significantly decreased (P < 0.05) in the abstinent group. Plasma levels of alpha1-acid glycoprotein and plasma protein binding were significantly increased (P < 0.05) in the abstinent group. The estimates of pharmacokinetic parameters based on unbound plasma concentrations did not differ between groups, with the sole exception of the unbound apparent volume of distribution. The access of methadone to the brain was significantly faster (P < 0.05) in the abstinent group, although the extent of distribution in the brain was diminished in comparison with the control group. Analgesia recorded with tail-flick was used as the pharmacodynamic endpoint. Analgesic response and effect compartment concentrations of methadone were related by the sigmoidal Emax model. Estimates of C50 [steady-state plasma concentrations eliciting half of maximum effect (Emax)]] based on unbound concentrations did not differ between groups. On the other hand, the estimate of Emax had decreased by 65% in the abstinent group

Direct and indirect use of water in a dairy system

La gestión de los recursos hídricos se ha convertido en un tema de suma importancia a nivel mundial. El objetivo del trabajo fue evaluar el uso del agua en un sistema de producción de leche Se evaluó el uso directo e indirecto del agua en un sistema de base pastoril (40%), con una carga de 2 VT/ha, contemplando el alimento importado al sistema versus el suministrado a los animales. El periodo evaluado fue desde junio de 2011 hasta julio de 2012. El agua directa es aquella usada en las tareas de higiene de la máquina de ordeño (MqO) y del equipo de frío (EF), en la placa de refrescado (PR) y como bebida animal. Los consumos de agua para la limpieza de la instalación de ordeño, corrales anexos y el agua de bebida se obtuvieron por caudalímetro y por fórmula para: MqO, litros/día (l/d)=27,75*número de unidades de ordeño+134,4 y EF, l/d=0,0403*capacidad tanque (l)+11,153. Para la PR se utilizó un valor promedio de 2,75 l agua/l leche a refrescar. El agua indirecta es la necesaria para producir los alimentos importados (balanceado, grano maíz, semilla algodón y pellet soja) y propios (pasturas y cultivos anuales en secano). Para su cálculo se utilizaron los programas CLIMWAT 2.0 y CROPWAT de la FAO, adaptando los ciclos de los cultivos con datos del sistema y regionales. En el Cuadro se observa que el consumo de agua total en el sistema considerando el alimento suministrado fue de 951,2 y con alimento importado fue 1.151,5 l/l (21,1% mayor). El consumo directo de agua solo representó menos del 1% de la cantidad total utilizada en el sistema, siendo el agua de bebida y la de PR las principales contribuyentes. El consumo indirecto representó más del 99%, compuesto mayoritariamente por el agua utilizada por las pasturas y por los alimentos importados. El análisis más detallado de esta fracción permitiría detectar las variables de mayor peso en el uso del agua, mejorando el manejo de este recurso en un sistema de producción lechero.Fil: Tieri, M. P.. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Santa Fe. Estación Experimental Agropecuaria, Rafaela; Argentina;Fil: Pece, Marta Graciela del Valle. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Santa Fe. Estación Experimental Agropecuaria, Rafaela; Argentina;Fil: Charlon, Veronica. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Santa Fe. Estación Experimental Agropecuaria, Rafaela; Argentina;Fil: Comerón, E.. Instituto Nacional de Tecnología Agropecuaria. Centro Regional Santa Fe. Estación Experimental Agropecuaria, Rafaela; Argentina;Fil: Civit, Bárbara María. Universidad Tecnológica Nacional. Facultad Regional de Mendoza; Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico - CONICET - Mendoza. Instituto de Ciencias Humanas, Sociales y Ambientales; Argentina

Pharmacokinetic-pharmacodynamic modeling of the antinociceptive effects of main active metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, in rats.

The pharmacokinetics and pharmacodynamics of the two main metabolites of tramadol, (+)-O-desmethyltramadol and (-)-O-desmethyltramadol, were studied in rats. Pharmacodynamic endpoints evaluated were respiratory depression, measured as the change in arterial blood pCO(2), pO(2), and pH levels; and antinociception, measured by the tail-flick technique. The administration of 10 mg/kg (+)-O-desmethyltramadol in a 10-min i.v. infusion significantly altered pCO(2), pO(2), and pH values in comparison with baseline and lower-dose groups (P <.05). However, 2 mg/kg administered in a 10-min i.v. infusion was enough to achieve 100% antinociception without respiratory depression. Moreover, the beta-funaltrexamine pretreatment completely eliminated the antinociception of the 2-mg/kg dose, suggesting that such an effect is due to mu-opioid receptor activation. To describe and adequately characterize the in vivo antinociceptive effect of the drug, (+)-O-desmethyltramadol was given at different infusion rates of varying lengths (10-300 min). Pharmacokinetics was best described by a two-compartmental model. The time course of response was described using an effect compartment associated with a linear pharmacodynamic model. The estimates of the slope of the effect versus concentration relationship were significantly decreased (P <. 05) as the length of infusion was increased, suggesting the development of tolerance. Doses of up to 8 mg/kg (-)-O-desmethyltramadol given in 10-min i.v. infusion did not elicit either antinociception in the tail-flick test or respiratory effects. These in vivo results are in accordance with the opiate and nonopiate properties reported for these compounds in several in vitro studies

Modeling of the In Vivo Antinociceptive Interaction between an Opioid Agonist, (+)-O-Desmethyltramadol, and a Monoamine Reuptake Inhibitor, (—)-O-Desmethyltramadol, in Rats

The pharmacokinetic-pharmacodynamic (pk-pd) characterization of the in vivo antinociceptive interaction between (+)-O-desmethyltramadol [(+)-M1] and (-)-O-desmethyltramadol [(-)-M1], main metabolites of tramadol, was studied in three groups of rats. (+)-M1 and (-)-M1, both with different pd properties, were studied under steady-state and nonsteady-state conditions, depending on the group. Plasma drug concentration and antinociception were simultaneously measured in each animal by using an enantioselective analytical assay and the tail-flick test, respectively. Respiratory depression also was evaluated in another series of experiments according to the same experimental conditions. The pk behavior was similar for both enantiomers and no significant (P >.05) interaction between two compounds was found at this level. However, a significant (P .05) respiratory effects were seen during or after (+)-M1 and (-)-M1 administration

Assessment of the impact of a clinical and health services research call in Catalonia

This article presents the ex-post assessment of a program of clinical and health services research and the evaluation of the social impact. The Catalan Agency for Health Information, Assessment, and Quality (CAHIAQ) promotes a biannual open, public, competitive extramural research call to conduct non-commercial clinical and health services research. Its aim is to address local needs of research (knowledge gaps) and to assess the implementation of innovation. Approximately 5.8 million Euros have been allocated to the call. To meet the Agency’s mission, a periodical ‘call for expressions of interest’ and topic prioritization is organized prior to the research call. The awarded projects are submitted to an ex-ante, ongoing, and ex-post assessment. Impact assessment of the research call on advancing knowledge and healthcare decision making is based on the Canadian Academy of Health Sciences framework (Panel on Return on Investment in Health Research, 2009). The methods used include bibliometric analysis, surveys to researchers and decision-makers, and a more in-depth case study of translation pathways. This includes a crossover of cases from 1996 to 2004. Some results are compared against other international health services research calls. The conclusion is that local agencies can significantly contribute to fill knowledge gaps in a specific context. Assessment of the complete research cycle provides opportunities for improving the entire research process (identification of knowledge needs, call for proposals, funding allocation, research completion, subsequent impact). Specifically, assessment of the different types of impact of research development on knowledge generation and decision making closes the evaluation cycle fulfilling the Agency's mission.Fil: Adam, Paula. Catalan Agency for Health Information; España. Epidemiologia y Salud Pública; EspañaFil: Solans Doménech, Maite. Catalan Agency for Health Information; España. Epidemiologia y Salud Pública; EspañaFil: Pons, Joan M. V.. Catalan Agency for Health Information; España. Epidemiologia y Salud Pública; España. Gobierno de Catalunya. Ministerio de Salud; EspañaFil: Aymerich, Marta. Gobierno de Catalunia. Ministerio de Salud; España. Universidad de Girona; EspañaFil: Berra, Silvina del Valle. Universidad Nacional de Córdoba. Facultad de Medicina. Escuela de Salud Pública; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Guillamon, Imma. Catalan Agency for Health Information; España. Epidemiologia y Salud Pública; EspañaFil: Sánchez, Emilia. Universitat Ramon Llull; EspañaFil: Permanyer Miralda, Gaieta. Catalan Agency for Health Information; España. Epidemiologia y Salud Pública; España. Universidad Autonoma de Barcelona. Hospital Vall D; Españ

Are clam-seagrass interactions affected by heatwaves during emersion?

The increased frequency of heatwaves expected in the context of global warming will affect socio-ecological systems such as shellfish beds at intertidal seagrass meadows. A mesocosm experiment was performed to assess the effects of a simulated atmospheric heatwave during low tide on the bioturbation indicators and growth of the commercial juvenile native Ruditapes decussatus and the introduced clam R. philippinarum, and on their interactions with the seagrass Zostera noltei. Under the heatwave, heat dissipation at 5 cm depth was significantly greater in the sediments below Z. noltei than below bare sand, the photosynthetic efficiency (Fv/Fm) of Z. noltei decreased and the clams tended to grow less. Furthermore, after the heatwave clams below bare sand tended to burrow deeper than those below Z. noltei, indicating that seagrass provided a refuge for clams. Ruditapes philippinarum grew less, and did not burrow as deeply as R. decussatus, which may imply greater vulnerability to desiccation and heat at low tide. The particle displacement coefficient (PDC) of R. philippinarum indicated lower bioturbation values in Z. noltei than in bare sand and was a suitable bioturbation indicator for juvenile Ruditapes spp. clams. In Z. noltei coexisting with R. philippinarum, the Fv/Fm values were higher than without clams after a recovery period, which may be linked to the assimilation of phosphate excreted by the clams and suggests a facilitative interaction. No such interaction was observed with R. deccusatus, probably because of its deeper burrowing depth. The findings suggest reciprocal facilitative interactions between R. philippinarum and Z. noltei and the potential contribution of Z. noltei to the sustainability of clams under global warming scenarios, which may support management actions aimed at enhancing the coexistence between shellfishing activities and seagrass conservation.Agencia Estatal de Investigación | Ref. RTI2018-095583-B-I00Xunta de Galicia | Ref. ED431C 2021/42Xunta de Galicia | Ref. ED481A-2020/199Universidade de Vigo/CISU

Striatal dopamine D2-muscarinic acetylcholine M1 receptor-receptor interaction in a model of movement disorders

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor control deficits, which is associated with the loss of striatal dopaminergic neurons from the substantia nigra. In parallel to dopaminergic denervation, there is an increase of acetylcholine within the striatum, resulting in a striatal dopaminergic-cholinergic neurotransmission imbalance. Currently, available PD pharmacotherapy (e.g., prodopaminergic drugs) does not reinstate the altered dopaminergic-cholinergic balance. In addition, it can eventually elicit cholinergic-related adverse effects. Here, we investigated the interplay between dopaminergic and cholinergic systems by assessing the physical and functional interaction of dopamine D2 and muscarinic acetylcholine M1 receptors (D2R and M1R, respectively), both expressed at striatopallidal medium spiny neurons. First, we provided evidence for the existence of D2R-M1R complexes via biochemical (i.e., co-immunoprecipitation) and biophysical (i.e., BRET1 and NanoBiT®) assays, performed in transiently transfected HEK293T cells. Subsequently, a D2R-M1R co-distribution in the mouse striatum was observed through double-immunofluorescence staining and AlphaLISA® immunoassay. Finally, we evaluated the functional interplay between both receptors via behavioral studies, by implementing the classical acute reserpine pharmacological animal model of experimental parkinsonism. Reserpinized mice were administered with a D2R-selective agonist (sumanirole) and/or an M1R-selective antagonist (VU0255035), and alterations in PD-related behavioral tasks (i.e., locomotor activity) were evaluated. Importantly, VU0255035 (10 mg/kg) potentiated the antiparkinsonian-like effects (i.e., increased locomotor activity and decreased catalepsy) of an ineffective sumanirole dose (3 mg/kg). Altogether, our data suggest the existence of putative striatal D2R/M1R heteromers, which might be a relevant target to manage PD motor impairments with fewer adverse effects

Effects of warming on biological interactions between clams and the seagrass Zostera noltei: A case study using open top chambers

Financiado para publicación en acceso aberto: Universidade de Vigo/CISUGBivalves and seagrasses can interact through diverse environmentally-modulated mechanisms. To assess the effects of climate warming on bivalve-seagrass interactions, we carried out a pioneering field experiment in which open top chambers (OTCs) were used to increase air and sediment temperature in a shellfish bed in NW Spain during two consecutive spring tides (16 days of exposure to OTCs). The temperature increase produced by OTCs was significant, as observed in the daily maximum and mean temperature and in degree hours, although the difference was greater in air and at the sediment surface (up to 8 ◦C and 3 ◦C, respectively) than at 5 cm depth (up to 1 ◦C). Warming was less acute in boxes with the seagrass Zostera noltei, which acted as a thermal buffer, reducing the mean temperature by 1 ◦C at the sediment surface in OTC boxes and control boxes (without OTCs). Although the short-term increase in temperature did not greatly affect physiological responses of Z. noltei, the carbohydrate reserves and nutrient content increased in the presence of clams. Growth of the native clam Ruditapes decussatus was significantly slower in OTC boxes with bare sediment, and the seagrass thus buffered the negative effect of warming on growth. The presence of Z. noltei may save clams from having to spend energy to burrow deeper to encounter cooler conditions, leaving more energy available for growth. Conversely, growth of the introduced clam R. philippinarum did not differ between habitats or treatments. Our findings confirm a twoway facilitative interaction that may be particularly important in relation to the resilience of both species in the current context of global warming.Ministerio de Ciencia e Innovación | Ref. RTI2018-095583-B-I00Xunta de Galicia-FEDER | Ref. ED431C 2021/42Xunta de Galicia | Ref. ED481A- 2020/199NASA | Ref. 80NSSC20K007