1,721,165 research outputs found
Limitations of MIC as sole metric of pharmacodynamic response across the range of antimicrobial susceptibilities within a single bacterial species
Full text linkCitation: Wen, X. S., Gehring, R., Stallbaumer, A., Riviere, J. E., & Volkova, V. V. (2016). Limitations of MIC as sole metric of pharmacodynamic response across the range of antimicrobial susceptibilities within a single bacterial species. Scientific Reports, 6, 8. https://doi.org/10.1038/srep37907The minimum inhibitory concentration (MIC) of an antimicrobial drug for a bacterial pathogen is used as a measure of the bacterial susceptibility to the drug. However, relationships between the antimicrobial concentration, bacterial susceptibility, and the pharmacodynamic (PD) inhibitory effect on the bacterial population are more complex. The relationships can be captured by multi-parameter models such as the E-max model. In this study, time-kill experiments were conducted with a zoonotic pathogen Pasteurella multocida and the fluoroquinolone enrofloxacin. Pasteurella multocida isolates with enrofloxacin MIC of 0.01 mu g/mL, 1.5 mu g/mL, and 2.0 mu g/mL were used. An additive inhibitory E-max model was fitted to the data on bacterial population growth inhibition at different enrofloxacin concentrations. The values of PD parameters such as maximal growth inhibition, concentration achieving a half of the maximal inhibition, and Hill coefficient that captures steepness of the relationships between the concentration and effect, varied between the isolate with low MIC and less susceptible isolates. While enrofloxacin PD against the isolate with low MIC exhibited the expected concentration-dependent characteristics, the PD against the less susceptible isolates demonstrated time-dependent characteristics. The results demonstrate that bacterial antimicrobial susceptibility may need to be described by a combination of parameters rather than a single parameter of the MIC
Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach
Full text linkCitation: Lin, Z. M., Cuneo, M., Rowe, J. D., Li, M. J., Tell, L. A., Allison, S., . . . Gehring, R. (2016). Estimation of tulathromycin depletion in plasma and milk after subcutaneous injection in lactating goats using a nonlinear mixed-effects pharmacokinetic modeling approach. Bmc Veterinary Research, 12, 10.
https://doi.org/10.1186/s12917-016-0884-4Background: Extra-label use of tulathromycin in lactating goats is common and may cause violative residues in milk. The objective of this study was to develop a nonlinear mixed-effects pharmacokinetic (NLME-PK) model to estimate tulathromycin depletion in plasma and milk of lactating goats. Eight lactating goats received two subcutaneous injections of 2.5 mg/kg tulathromycin 7 days apart; blood and milk samples were analyzed for concentrations of tulathromycin and the common fragment of tulathromycin (i.e., the marker residue CP-60,300), respectively, using liquid chromatography mass spectrometry. Based on these new data and related literature data, a NLME-PK compartmental model with first-order absorption and elimination was used to model plasma concentrations and cumulative excreted amount in milk. Monte Carlo simulations with 100 replicates were performed to predict the time when the upper limit of the 95% confidence interval of milk concentrations was below the tolerance. Results: All animals were healthy throughout the study with normal appetite and milk production levels, and with mild-moderate injection-site reactions that diminished by the end of the study. The measured data showed that milk concentrations of the marker residue of tulathromycin were below the limit of detection (LOD = 1.8 ng/ml) 39 days after the second injection. A 2-compartment model with milk as an excretory compartment best described tulathromycin plasma and CP-60,300 milk pharmacokinetic data. The model-predicted data correlated with the measured data very well. The NLME-PK model estimated that tulathromycin plasma concentrations were below LOD (1.2 ng/ml) 43 days after a single injection, and 62 days after the second injection with a 95% confidence. These estimated times are much longer than the current meat withdrawal time recommendation of 18 days for tulathromycin in non-lactating cattle. Conclusions: The results suggest that twice subcutaneous injections of 2.5 mg/kg tulathromycin are a clinically safe extra-label alternative approach for treating pulmonary infections in lactating goats, but a prolonged withdrawal time of at least 39 days after the second injection should be considered to prevent violative residues in milk and any dairy goat being used for meat should have an extended meat withdrawal time
Physiologisch basierte toxikokinetische Modellierung von lipophilen Schadstoffen und pflanzlichen Sekundärmetaboliten bei Milchkühen, Kälbern und Schweinen
No full textThe determination of the transfer of undesirable substances and contaminants from oral
exposure of farm animals into food of animal origin is essential to human risk assessment and management. The aim of this thesis was to develop physiologically-based toxicokinetic (PBTK) models that can be used to predict the concentration of specific contaminants in food of animal origin, based on the concentration in feed. Three groups of toxins were considered in the modelling approaches: polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), for short “dioxins”; polychlorinated biphenyls (PCBs); and quinolizidine alkaloids (QAs). As the first two groups, dioxins and PCBs, are quite similar from a kinetic point of view, they have been evaluated together and separately from the QAs. To gain a better understanding of the current state of research on the transfer of dioxins and PCBs to cow’s milk, a review of the literature was first compiled and published in two parts. This showed that although many modelling approaches have been developed, sufficiently complex models are often based on limited data sets. Therefore, there is still an urgent need for PBTK models that have been validated with sufficient data to accurately predict the transfer of dioxins and PCBs into milk and tissue. Within the framework of this thesis, two well parameterised PBTK models were successfully developed on a broad basis of experimental measurements. The first published model is based on data derived from a PCB contamination incident and describes the distribution of three non-dioxin-like (ndl) PCBs in various tissues
and milk of an adult cow during two lactations and one dry period as well as in their calves.
This also includes the transfer of the investigated ndl-PCBs from the adult cow to her calf via placenta and milk. Of particular note is the ability of the model to distinguish between
placental transfer and milk transfer through suckling with 10-14 % of the amount of congeners in calves at slaughter was due to placental transfer. Several parameters were derived for risk assessment quantifying theses transfer and distribution processes. The second published model uses data from a feeding study in which dairy cows were fed a mixture of numerous dioxins and PCBs at different time intervals during their negative energy balance (NEB) and positive energy balance (PEB) phases to assess the effects of different metabolic states on the transfer of contaminants into milk. This was done with a three-compartment model that was parameterised separately for the NEB and PEB phases and reliably predicts the concentration-time (ct) profile of the investigated contaminants in milk and blood. It is particularly worth mentioning that some of the parameters derived here were reported for the first time. Comparison of the parameters obtained in the different energy balance phases revealed that the transfer rates of the investigated contaminants are significant higher in the PEB phase than in the NEB phase. Significant differences were also found for other parameters such as β half-lives, but to a much lesser extent.
In the second part of the thesis, the knowledge gained from modelling approaches with
dioxins and PCBs in cows was used to develop a model describing for the first time the transfer of three ndl-PCBs from feed into tissues of fattening pigs. The PBTK model was based on a feeding study in which fattening pigs were fed with ndl-PCBs contaminated feed at different stages of their fattening period. The model consists of a liver and a fat compartment, which allows to describe the concentration of ndl-PCBs in the most relevant tissues for the consumer, i.e., muscle (based on its fat content) and liver. In addition, various transfer parameters were derived, which allows the quantification of the extent of transfer of these contaminants to these tissues under realistically changing feeding conditions and animal growth. The lowest transfer rate was obtained for PCB-28 with 9.57 % and the highest transfer rate was obtained for PCB-153 with 77.2 %. In the final part of this thesis, QAs in dairy cows were investigated, which are kinetically completely different in their behaviour in comparison to dioxins and PCBs. QAs are potentially
toxic plant secondary metabolites from lupins, a high-protein crop. Based on a feeding study in which dairy cows were fed subsequently with different amounts of QA-containing lupins, a PBTK model was developed to investigate the transfer of QAs into milk and its dose-dependency. As QAs are eliminated much faster from the body of the cows than dioxins and PCBs, aspects such as milking time and feeding time had to be taken into account. Since the ct-profile of QAs in milk during the depuration showed a biphasic behaviour, a three-compartment model was developed that induces a biphasic depuration phase in milk. This made it possible to describe the measured data quite well despite the high variability of the data points. The size of the experiment and the limited difference between the doses applies allowed no conclusion regarding a possible dose-dependent transfer. Several risk assessment parameters were derived, including transfer rates ranging from 1.05 % for angustifoline to 2.92 % for isolupanine and α-half-lives ranging from 0.26 d lupanine to 0.28 d hydroxylupanine. However, the very low concentrations covered by the β-half-lives are not expected to be relevant for risk assessment. In summary, in the scope of this work, several PBTK models were successfully developed that describe and quantify the transfer of various contaminants to dairy cows, calves and fattening pigs. To make these models accessible to risk assessors, they will be implemented in the web tool BfR ConTrans
Veterinary drug supply to subsistence and emerging farming communities in the Madikwe District, North West Province, South Africa
Full text linkDissertation (MMedVet (Pharmacology))--University of Pretoria, 2001.Veterinary Needs Appraisals have indicated that there is a need for improved supply of veterinary medicinal products to subsistence and emerging farmers in South Africa. No studies have been conducted to describe and assess the adequacy of the current routes and methods of supply of veterinary medicinal products to these farmers. A combination of focus groups, self-administered questionnaires and direct observations was used to collect information for the purpose of describing and understanding the situation regarding the supply of veterinary medicinal products to the farmers of the Madikwe district. A combination of semi-structured interviews, questionnaires and direct observation was used to gather information. The results indicated that the routes and methods of supply of veterinary medicinal products to the farmers of the Madikwe district were inadequate. The annual sales from outlets within the Madikwe district were poor, with a total of 396 units sold over a period of one year, although there were approximately 2000 farmers in the Madikwe district who were potential clients for these outlets. The majority of products sold by these outlets were ectoparasiticides, followed by Tetracycline antibiotics. The outlets within the Madikwe district were unable to supply vaccines, as they did not have adequate facilities for the storage of these thermolabile products. Farmers had to travel an average of 70 km if they wished to purchase veterinary medicinal products from farmers' co-operatives and pharmacies in larger towns outside the Madikwe district. The routes and methods of supply did not ensure correct storage, and safe and effective use of veterinary medicinal products. Several examples of misuse and incorrect storage and handling of veterinary medicinal products were discovered. Inadequate information transfer, inaccessibility of outlets, poor reliability and quality of outlets and poor service were discovered as reasons for the inadequacy of the routes and methods of supply. Wider distribution of veterinary medicinal products is required but a higher level of control is needed to ensure that products of an acceptable quality are sold. Information and advice must be disseminated together with products.Paraclinical Sciencesunrestricte
A study of the population pharmacokinetics of diminazene in dogs naturally infected with Babesia canis
Full text linkDissertation (MMedVet)--University of Pretoria, 2007.Diminazene is a drug that is commonly used in the treatment of canine babesiosis. Most of the
pharmacokinetic work on diminazene has been undertaken in healthy individuals, while the influence
of disease on diminazene pharmacokinetics has been investigated to a limited degree. Population
pharmacokinetics allows for the investigation of factors (covariates) that influence pharmacokinetic
parameters. The aim of this study was to provide a descriptive model of the population
pharmacokinetics of intramuscularly administered diminazene in dogs naturally infected with Babesia
canis. Thirty-nine dogs had 142 plasma samples collected. Another 56 samples from 8 healthy dogs,
from a previous study, were added to the data set. Population pharmacokinetics was performed using
WinNonMix® (Pharsight, Cary, NC). A one-compartment model was fitted to the data. Health status
(presence or absence of babesiosis), packed cell volume (PCV), serum albumin concentrations,
mental status (a marker for the severity of illness) and the presence of splenomegaly significantly
influenced the population pharmacokinetics model. The PCV lost its significance when these
covariates were modelled concurrently, due to its correlation to the health status. In the final model,
the volume of distribution (health status and albumin) and K01 (health status) was significantly
influenced by covariates.Companion Animal Clinical StudiesMMedVetUnrestricte
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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