1,721,463 research outputs found
The Year of the Wisent
Get PDFDelving into European prehistory, two recent studies analyze ancient DNA from bison species depicted by our ancestors on the walls of their caves. The DNA tells a story of migrations driven by climate change but leaves some mystery clouding the genetic descent and climate preference of the still-extant wisent, otherwise known as the European bison.See research articles: https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-016-0317-7 http://www.nature.com/articles/ncomms13158
Neurotoxicity screening of new psychoactive substances (NPS): Effects on neuronal activity in rat cortical cultures using microelectrode arrays (MEA)
No full textWhile the prevalence and the use of new psychoactive substances (NPS) is steadily increasing, data on pharmacological, toxicological and clinical effects is limited. Considering the large number of NPS available, there is a clear need for efficient in vitro screening techniques that capture multiple mechanisms of action. Neuronal cultures grown on multi-well microelectrode arrays (mwMEAs) have previously proven suitable for neurotoxicity screening of chemicals, pharmaceuticals and (illicit) drugs. We therefore used rat primary cortical cultures grown on mwMEA plates to investigate the effects of eight NPS (PMMA, α-PVP, methylone, MDPV, 2C-B, 25B-NBOMe, BZP and TFMPP) and two 'classic' illicit drugs (cocaine, methamphetamine) on spontaneous neuronal activity. All tested drugs rapidly and concentration-dependently decreased the weighted mean firing rate (wMFR) and the weighted mean burst rate (wMBR) during a 30 min acute exposure. Of the 'classic' drugs, cocaine most potently inhibited the wMFR (IC50 9.8 μM), whereas methamphetamine and the structurally-related NPS PMMA were much less potent (IC50 100 μM and IC50 112 μM, respectively). Of the cathinones, MDPV and α-PVP showed comparable IC50 values (29 μM and 21 μM, respectively), although methylone was 10-fold less potent (IC50 235 μM). Comparable 10-fold differences in potency were also observed between the hallucinogenic phenethylamines 2C-B (IC50 27 μM) and 25B-NBOMe (IC50 2.4 μM), and between the piperazine derivatives BZP (IC50 161 μM) and TFMPP (IC50 19 μM). All drugs also inhibited the wMBR and concentration-response curves for wMBR and wMFR were comparable. For most drugs, IC50 values are close to the estimated human brain concentrations following recreational doses of these drugs, highlighting the importance of this efficient in vitro screening approach for classification and prioritization of emerging NPS. Moreover, the wide range of IC50 values observed for these and previously tested drugs of abuse, both within and between different classes of NPS, indicates that additional investigation of structure-activity relationships could aid future risk assessment of emerging NPS
Single-Dose Pharmacokinetics of Piperacillin/Tazobactam in Hispaniolan Amazon Parrots ( Amazona ventralis )
No full textTo determine the pharmacokinetics of piperacillin/tazobactam in Hispaniolan Amazon parrots ( Amazona ventralis ), 8 healthy adult parrots of both sexes were used in a 2-part study. In a pilot study, piperacillin (87 mg/kg) in combination with tazobactam (11 mg/kg) was administered intramuscularly (IM) to 2 birds, and blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after administration. Based on the results obtained, a main study was done in which piperacillin/tazobactam was administered at 2 different doses. In 3 birds, the initial dose of piperacillin (87 mg/kg)/tazobactam (11 mg/kg) IM was administered, and in 3 birds, the dose was doubled to piperacillin (174 mg/kg)/tazobactam (22 mg/kg) IM. In all 6 birds, blood samples were obtained at 0, 5, 15, and 30 minutes and at 1, 1.5, 2, 2.5, 3, and 4 hours after administration. Quantification of plasma piperacillin and tazobactam concentrations was determined by validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were determined by noncompartmental analysis. After intramuscular administration, the mean ± standard error values of T1/2 (h) was 0.52 ± 0.05 and 0.32 ± 0.07, Tmax (h) was 0.28 ± 0.09 and 0.25 ± 0.10, Cmax (μg/mL) was 86.34 ± 20.62 and 9.03 ± 2.88, and Cmax/dose was 0.99 ± 0.24 and 0.83 ± 0.26 for piperacillin (87 mg/kg) and tazobactam (11 mg/kg), respectively. When the doses were doubled, the T1/2 (h) was 0.65 ± 0.08 and 0.34 ± 0.02, Tmax (h) was 0.28 ± 0.12 and 0.14 ± 0.06, Cmax (μg/mL) was 233.0 ± 6.08 and 22.13 ± 2.35, and Cmax/dose was 1.34 ± 0.03 and 1.02 ± 0.11 for piperacillin and tazobactam, respectively. Results indicate that piperacillin is rapidly absorbed and reaches high initial concentrations; however, it is also rapidly eliminated in the Hispaniolan Amazon parrot, and tazobactam has similar pharmacokinetics as piperacillin. Administration of piperacillin at 87 mg/kg IM q3-4h is recommended for this species to control infections attributed to susceptible bacteria with a minimum inhibitory concentration of ≤4 μg/mL
Changes in neuronal activity in rat primary cortical cultures induced by illicit drugs and new psychoactive substances (NPS) following prolonged exposure and washout to mimic human exposure scenarios
No full textThe use of new psychoactive substances (NPS) is increasing despite associated health risks and limited pharmacological and toxicological knowledge. Information is available mainly for acute effects on specific targets like monoamine transporters and receptors. Recently, we have shown the ability of several NPS and illicit drugs to modulate neuronal activity during acute exposure. While these acute measurements provide valuable information regarding the potency and possible structure-activity relationships, an exposure scenario more representative of human exposure would increase insight and aid translation to the human situation. Therefore, we investigated the effects on neuronal activity after acute (30 min) and prolonged (5 h) exposure to amphetamine-type stimulants, cathinones, hallucinogens, piperazines and cocaine using rat primary cortical cultures grown on multi-well microelectrode arrays. To investigate the reversibility of effects, activity was also measured after a washout period of 19 h. During acute exposure, all compounds concentration-dependently decreased neuronal activity. Compared to acute exposure, prolonged exposure did not further decrease neuronal activity. Following washout, effects of 3 out of 11 drugs (methamphetamine, cocaine, and benzylpiperazine) were fully reversible, whereas effects induced by MDMA, PMMA and α-PVP were partially reversible. Neuronal activity did not recover after 19 h washout following exposure to the highest concentration of MDPV, 2C-B, 25B-NBOMe, and TFMPP. On the contrary, exposure to low concentrations of methylone, and to some extent of 2C-B, increased neuronal activity after the washout period. Hazard characterization of emerging NPS should include at least an acute exposure to determine a potency rank order. Supplementing the (acute and prolonged) exposure scenario with a washout period allows investigation of the reversibility of effects. The possibility of a neuronal network to regain activity after drug exposure appears independent of drug class or IC50 values for acute and prolonged exposure. Even though neuronal activity (partly) recovers after washout following exposure to most drugs, it is perturbing that complete recovery of neuronal activity is observed only for a minority of the tested drugs
Comparative Pharmacokinetics of Meloxicam Between Healthy Post-partum vs. Mid-lactation Dairy Cattle
Get PDFLactating dairy cattle are at risk for various painful conditions throughout their life, such as lameness, parturition, mastitis, and metabolic disorders. These conditions necessitate adequate methods of analgesia to address welfare concerns through efficacious pain mitigation. As no method of analgesia has been approved for lactating dairy cattle, to date, research is necessary to determine effective pain management strategies for dairy cattle. In both the European Union and Canada, meloxicam has been approved for use in lactating dairy cattle as a methodology for pain control. The objective of this study was to characterize the pharmacokinetics of meloxicam administered orally and intravenously to lactating dairy cattle in the post-partum vs. mid-lactation period. In this parallel study design, 12 healthy, lactating Holsteins were enrolled within 24 h of freshening and randomly allocated to intravenous (0.2 mg/kg) or oral (1.0 mg/kg) meloxicam administration treatment groups. They were matched based on parity to 12, healthy cows that were considered mid-lactation [>150 days-in-milk (DIM)] to receive the same treatment. Based on meloxicam formulation, sampling times varied and plasma was collection via jugular venipuncture for 6 days. Plasma drug concentrations were evaluated using liquid chromatography coupled with mass spectroscopy and pharmacokinetic properties were evaluated using non-compartmental (i.e., statistical moments) analysis. Results indicated a decreased systemic clearance of meloxicam in post-partum relative to mid-lactation cows, which resulted in a longer half-life and increased total exposure independent of mode of administration. These results suggest a need for dose adjustments based on stage in lactation and further assessment of the impact of days-in-milk on milk withholding period
Development and application of a population physiologically based pharmacokinetic model for penicillin G in swine and cattle for food safety assessment
No full textPenicillin G is a widely used antimicrobial in food-producing animals, and one of the most predominant drug residues in animal-derived food products. Due to reduced sensitivity of bacteria to penicillin, extralabel use of penicillin G is common, which may lead to violative residues in edible tissues and cause adverse reactions in consumers. This study aimed to develop a physiologically based pharmacokinetic (PBPK) model to predict drug residues in edible tissues and estimate extended withdrawal intervals for penicillin G in swine and cattle. A flow-limited PBPK model was developed with data from Food Animal Residue Avoidance Databank using Berkeley Madonna. The model predicted observed drug concentrations in edible tissues, including liver, muscle, and kidney for penicillin G both in swine and cattle well, including data not used in model calibration. For extralabel use (5× and 10× label dose) of penicillin G, Monte Carlo sampling technique was applied to predict times needed for tissue concentrations to fall below established tolerances for the 99th percentile of the population. This model provides a useful tool to predict tissue residues of penicillin G in swine and cattle to aid food safety assessment, and also provide a framework for extrapolation to other food animal species
The effects of titanium dioxide coatings on light-derived heating and transdermal heat transfer in bovine skin
No full textThe effects of titanium dioxide coatings of bovine hides on light absorption and transdermal transfer of light-derived heat were investigated. Four hair-on rug hides from Holstein cattle were purchased. Twelve samples about 20 cm on a side were cut from each hide; nine from the black-colored areas, and three from the white areas. Samples were randomized and assigned to four coating treatments: (1) white hide with no coating (White), (2) black hide with no coating (Black), (3) black hide with 50% coating (Mid), and (4) black hide with 100% coating (High). Coatings were applied to the black hide samples using a hand sprayer. Lux measurements were taken using a modified lux meter at three light intensities generated with a broad spectrum, cold halogen light source. Reflectance over a wavelength range of 380 to 900 nm was measured using a spectroradiometer. The transdermal transfer of heat derived from absorbed light was measured by applying a broad spectrum, cold halogen light source to the stratum corneum (coated) side of the sample and recording the temperature of the dermis-side using a thermal camera for 10 min at 30-s intervals. At the high light level, the White, Black, Mid, and High coating treatments had different (P < 0.001) lux values of 64,945, 1741, 15,978, and 40,730 lx, respectively. In the visible wavelength range (400 to 750 nm), Black hides reflected 10 to 15% of the light energy, hides with the Mid coating treatment reflected 35 to 40%, and hides with the High coating treatment reflected 70 to 80% of the light energy. The natural White hide samples reflected 60 to 80% of the light energy. The average maximum temperatures at the dermis-side of the hides due to transferred heat were 34.5, 70.1, 55.0, and 31.7, for the White, Black, Mid, and High treatments, respectively. Reflective coatings containing titanium dioxide on cattle hides were effective in reducing light energy absorption and reduced light-derived heat transfer from the skin surface to deeper skin layers
Design and validation of an ontology-driven animal-free testing strategy for developmental neurotoxicity testing.
Get PDFDevelopmental neurotoxicity entails one of the most complex areas in toxicology. Animal studies provide only limited information as to human relevance. A multitude of alternative models have been developed over the years, providing insights into mechanisms of action. We give an overview of fundamental processes in neural tube formation, brain development and neural specification, aiming at illustrating complexity rather than comprehensiveness. We also give a flavor of the wealth of alternative methods in this area. Given the impressive progress in mechanistic knowledge of human biology and toxicology, the time is right for a conceptual approach for designing testing strategies that cover the integral mechanistic landscape of developmental neurotoxicity. The ontology approach provides a framework for defining this landscape, upon which an integral in silico model for predicting toxicity can be built. It subsequently directs the selection of in vitro assays for rate-limiting events in the biological network, to feed parameter tuning in the model, leading to prediction of the toxicological outcome. Validation of such models requires primary attention to coverage of the biological domain, rather than classical predictive value of individual tests. Proofs of concept for such an approach are already available. The challenge is in mining modern biology, toxicology and chemical information to feed intelligent designs, which will define testing strategies for neurodevelopmental toxicity testing
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