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A pharmacokinetic-pharmacodynamic study was performed in opioid-dependent patients in the Netherlands, who were currently treated with high doses of pharmaceutically prepared heroin on medical prescription. Besides intravenous heroin, heroin was prescribed for inhalation by "chasing the dragon" method. In this technique, heroin base is heated on aluminium foil, and heroin vapours are inhaled into the lungs. Not much is known about the pharmacokinetics profile and bioavailability of this specific administration method. Therefore, a study was performed on pharmacokinetics and pharmacodynamics of heroin inhalation and intravenous use. Eleven patients who injected heroin and 9 patients who inhaled heroin entered the study. They were on steady-state heroin treatment for at least 12 months. For safety reasons, there was no crossing-over between heroin injection or inhalation. In a double-blind randomised study, 67-100-150% of the regular heroin maintenance dose was administered to each patient. Maximal single heroin dose was 450 mg. Plasma concentrations of heroin and its metabolites 6-monoacetylmorphine, morphine and morphine-glucuronides were analysed using LC-MS-MS. Blood pressure, heart rate, skin temperature and reaction time were assessed. Furthermore, visual analogue scales regarding craving and appreciation of heroin effect were scored by the subjects. Both in inhaling and injecting patients, the areas under curve of heroin and all measured metabolites were linearly related to heroin dose. Mean C(max) of heroin and its metabolites were 2-6 times lower after inhalation, than after intravenous injection. Bioavailability (F) of heroin inhalation was estimated as 52% (95% CI 44-61%). Heroin was rapidly cleared from plasma. Cl/F was 930 l/hr (95% CI 799-1061 l/hr) after intravenous administration, and 1939 l/hr (95% CI 1661-2217 l/hr) after inhalation. Heroin Cl and Vd were correlated to body weight (R(2) 15-19%). Morphine-glucuronides levels were inversely related to creatinine clearance. After heroin administration, the reaction time was significantly prolonged with 28+/-5.3 msec. in injecting and 13+/-4.9 msec. in inhaling patients. Cardiovascular changes were only mild after heroin administration. Craving-scores declined immediately after heroin administration in both administration groups. Subjective heroin effect was rated more positively in heroin inhaling than in injecting patients, despite the lower C(max) levels following heroin inhalation. In both groups, in this blinded study heroin dose increments were more appreciated than dose reductions. Increments of 50% of the regular heroin dose did not cause any serious side effect.

In preparation for a treatment program concerning the medical coprescription of heroin and methadone to treatment-resistant addicts in the Netherlands, we studied a novel strategy for monitoring co-use of illicit (nonprescribed) heroin. A deuterated analogue of heroin was added (1:20) to pharmaceutical, smokable heroin (a powder mixture of 75% w/w diacetylmorphine base and 25% w/w caffeine anhydrate), to be used by inhalation after volatilization ("chasing the dragon"). Plasma and urine samples were collected from nine male patients who had used pharmaceutical, smokable heroin during a four-day stay in a closed clinical research unit, and these samples were analyzed by liquid chromatography coupled with tandem mass spectrometry. Ratios of deuterated and undeuterated diacetylmorphine and 6-acetylmorphine (MAM/MAM-d3) in plasma and urine were calculated from peak areas of these substances in the respective chromatograms. The MAM/MAM-d3 ratios in plasma and urine were normally distributed (with small standard deviations) and independent from concentrations of 6-acetylmorphine and from time after use of pharmaceutical heroin. A MAM/MAM-d3 ratio in urine above 32.8 was considered indicative of co-use of illicit heroin, and this value was associated with a false-positive rate of only 1% (95% confidence interval: -1 to 3%). The MAM/MAM-d3 ratio was detectable in urine for 4-9.5 h after use of pharmaceutical, smokable heroin. Addition of stable, isotopically labelled heroin to pharmaceutical, smokable heroin is considered to be a feasible strategy for the detection of co-use of illicit heroin by patients in heroin-assisted treatment.

International audience; GrazeIn is a model for predicting herbage intake and milk production of grazing dairy cows. The objectives of this paper are to test its robustness according to a planned arrangement of grazing and feeding scenarios using a simulation procedure, and to investigate the precision of the predictions from an external validation procedure with independent data. Simulations show that the predicted effects of herbage allowance, herbage mass, herbage digestibility, concentrate supplementation, forage supplementation and daily time at pasture are consistent with current knowledge. The external validation of GrazeIn is investigated from a large dataset of twenty experiments representing 206 grazing herds, from five research centres within Western Europe. On average, mean actual and predicted values are 14 center dot 4 and 14 center dot 2 kg DM d-1 for herbage intake and 22 center dot 7 and 24 center dot 7 kg d-1 for milk production, respectively. The overall precision of the predictions, estimated by the mean prediction error, are 16% (i.e. 2 center dot 3 kg DM d-1) and 14% (i.e. 3 center dot 1 kg d-1) for herbage intake and milk production, respectively. It is concluded that the GrazeIn model is able to predict variations in herbage intake and milk production of grazing dairy cows in a realistic manner over a wide range of grazing management practices, rendering it suitable as a basis for decision support systems.

Many infectious diseases that cause significant morbidity and mortality, especially in the developing world, could be preventable through vaccination. The effort to produce safe, thermally stable, and needle-free mucosal vaccines has become increasingly important for global health considerations. We have previously demonstrated that a thermally stable nanoemulsion, a mucosal adjuvant for needle-free nasal immunization, is safe and induces protective immunity with a variety of antigens, including recombinant protein. The successful use of nanoemulsion-based vaccines, however, poses numerous challenges. Among the challenges is optimization of the formulation to maintain thermal stability and potency and another is accuracy and efficiency of dispensing the vaccines to the nasal mucosa in the anterior and turbinate region of the nasal cavity or potentially to the nasopharynx-associated lymphoid tissue.We have examined the effects of different diluents [phosphate-buffered saline (PBS) and 0.9% NaCl] on the stability and potency of nanoemulsion-based vaccines. In addition, we have determined the efficiency of delivering them using commercially available nasal spray devices (Pfeiffer SAP-62602 multidose pump and the BD Hypak SCF 0.5 ml unit dose Accuspray(TM)).We report the stability and potency of PBS-diluted ovalbumin-nanomeulsion mixtures for up to 8 months and NaCl-diluted mixtures up to 6 months when stored at room temperature. Significant differences in spray characteristics including droplet size, spray angle, plume width, and ovality ratios were observed between the two pumps. Further, we have demonstrated that the nanoemulsion-based vaccines are not physically or chemically altered and retain potency following actuation with nasal spray devices. Using either device, the measured spray characteristics suggest deposition of nanoemulsion-based vaccines in inductive tissues located in the anterior region of the nasal cavity.The results of this study suggest that nanoemulsion-based vaccines do not require specially engineered delivery devices and support their potential use as nasopharyngeal vaccine adjuvants.

International audience; Reduction in grazing intensity and the use of traditional instead of commercial breeds have frequently been recommended to meet biodiversity and production goals in sustainable grazing systems. The impact of such practices within a range of contrasting grassland vegetation types was studied. This paper describes the effects on foraging behaviour in a study conducted over three years on mesotrophic or semi-natural grasslands in UK (steers), Germany (steers), France (heifers) and Italy (sheep). Three treatments were performed: (i) a moderate grazing intensity using a commercial breed, (ii) a more lenient grazing intensity with a commercial breed and (iii) a more lenient intensity with a traditional breed. Livestock at all sites preferentially selected bites containing legumes and forbs, and also short rather than tall vegetative patches. Grazing intensity affected not only diet consumed, largely reflecting the different availabilities of dietary components, but also some differences in diet selection. Livestock grazing the more productive mesotrophic grasslands more frequently exploited short patches of higher nutritive value, which is expected to reinforce the spatial heterogeneity of the pastures. Studies in the UK and Germany also revealed that steers showed a more pronounced selection for short patches at the lenient grazing intensity. More homogeneous grazing by livestock on the semi-natural grasslands with fine-scale heterogeneity is likely to decrease their spatial heterogeneity. There were few differences in the choices made by commercial and traditional breed livestock. North Devon steers in the UK expressed a greater selection for tall grass-forb bites than Charolais × Holstein crossbreds, whereas traditional breeds appeared slightly less selective than commercial breeds at the other three sites.

Summary This paper explores the management and policy implications of research findings investigating the use of grazing intensity and traditional breeds to achieve biodiversity outcomes on grasslands in four countries of Europe. An economic analysis, based on these research findings, indicated that financial assistance and/or premium prices are required to achieve sustainable grazing systems with a high biodiversity. The research findings suggested that existing agri-environment scheme prescriptions based only on blanket stocking rates are too crude to increase plant diversity, lacking consideration of initial site conditions. Conversely, some invertebrates seem to rapidly benefit from lenient stocking, highlighting the importance of clear goals for agri-environment schemes. Recommendations for an appropriate support package to deliver grazing systems with high biodiversity are presented.

International audience; From a review of the literature, we conclude that the main mechanism by which grazing livestock affect biodiversity in pastures is the creation and maintenance of sward structural heterogeneity, particularly as a result of dietary choice. We identify lack of understanding of the currencies used by animals in their foraging decisions and the spatial scale of these decisions as major constraints to better management. We conclude that there are important differences between domestic grazing animal species in their impact on grazed communities and that these can be related to differences in dental and digestive anatomy, but also, and probably more importantly, to differences in body size. Differences between breeds within species appear to be relatively minor and again largely related to body size. We conclude that there is an urgent need to understand the genetic basis of these differences and also to separate true breed effects from effects of rearing environment. We also review the economic implications of using different animal types and conclude that there is a need for more research integrating these aspects with biodiversity outcomes.

Data are presented which show that the constitution of the recovery medium exerts an appreciable effect on the apparent thermal resistance of spores of Putrefactive Anaerobe 3679. The routine use of a simple yeast extract-starch medium (YES) as a recovery medium in thermal resistance studies on this organism is recommended. In addition to giving thermal resistance values comparable to those obtained in Yesair's pork infusion, it has the advantages of ease of production, reduced cost, and a standardized method of preparation.