Zebrafish (Danio rerio) is an emerging toxicity screening model for both human health and ecology. As part of the Computational Toxicology Research Program of the U.S. EPA, the toxicity of the 309 ...ToxCast™ Phase I chemicals was assessed using a zebrafish screen for developmental toxicity. All exposures were by immersion from 6–8h post fertilization (hpf) to 5 days post fertilization (dpf); nominal concentration range of 1nM–80μM. On 6dpf larvae were assessed for death and overt structural defects. Results revealed that the majority (62%) of chemicals were toxic to the developing zebrafish; both toxicity incidence and potency was correlated with chemical class and hydrophobicity (logP); and inter-and intra-plate replicates showed good agreement. The zebrafish embryo screen, by providing an integrated model of the developing vertebrate, compliments the ToxCast assay portfolio and has the potential to provide information relative to overt and organismal toxicity.
The aim of this study was to investigate the cardiotoxic effect of the combination of tilmicosin and diclofenac sodium in sheep. Thirty-two sheep were used and were randomly divided into four equal ...groups as tilmicosin (T), diclofenac sodium (D), tilmicosin+diclofenac sodium (TD) and control (C) group. Group T received a single dose of tilmicosin, Group D was administered diclofenac sodium once a day for 3 days, and group TD was administered diclofenac and tilmicosin at the same doses as group T and D. Group C received NaCl in a similar way. The blood samples were taken before dosing and at 4th, 8th, 24th and 72nd hour post-dosing for measurement of cardiac markers such as H-FABP, cTn-I, CK-MB. H-FABP level of group TD was found to be significantly (p⟨0.05) higher than of group C at the 8th, 24th and 72nd hour and group D and T at the 72nd hour. cTn-I and CK-MB levels of group TD were found significantly (p⟨0.05) higher compared with other groups. In conclusion, the combined use of tilmicosin and diclofenac in sheep causes an increase in cardiac biomarkers and it can be stated that this combination of drugs may cause cardiac damage.
The aim of this study was to determine the effect of benzylpenicillin on the pharmacokinetics of acyclovir in red‐eared slider turtles (Trachemys scripta elegans). Six clinically healthy red‐eared ...slider turtles weighing 400 and 580 g were used for the study. Acyclovir (40 mg/kg) and benzylpenicillin (30 mg/kg) were administered intravenously to turtles. In the study, the cross‐pharmacokinetic design (2 × 2) with a 30‐day washout period was performed in two periods. Plasma concentrations of acyclovir were assayed using the high‐performance liquid chromatography with fluorescence detection. Pharmacokinetic parameters were calculated by two‐compartment open pharmacokinetic model. Following the administration of acyclovir alone, elimination half‐life (t1/2β), area under the plasma concentration–time curve (AUC), total clearance (ClT), and volume of distribution at steady‐state (Vdss) were 20.12 hr, 1,372 hr * µg/mL, 0.03 L hr−1 kg−1, and 0.84 L/kg, respectively. Benzylpenicillin administration increased t1/2β, AUC, and Vdss while decreased ClT of acyclovir. These results showed that benzylpenicillin changed the pharmacokinetics of acyclovir following simultaneous administration in turtles. However, further research is needed to determine molecular mechanism of interaction in turtle.
1. The aim of this study was to determine the pharmacokinetics of meloxicam (MLX, 1 mg/kg body weight (BW)), ketoprofen (KETO, 2 mg/kg BW), and tolfenamic acid (TA, 2 mg/kg BW) in chukar partridge ...(Alectoris chukar) following intravenous (IV) administration.
2. Twenty-four healthy chukar partridges were randomly divided into three equal groups (n = 8) as MLX, KETO and TA. Plasma concentrations of MLX, KETO and TA were measured using high-performance liquid chromatography−ultraviolet detection and analysed using non-compartmental analysis.
3. No adverse effects were determined in chukar partridges after IV administration of MLX, KETO and TA. MLX, KETO and TA were detected in plasma up to 10, 12 and 12 h, respectively. The terminal elimination half-life of MLX, KETO and TA was 1.22, 1.77 and 1.95 h, respectively. MLX, KETO and TA exhibited volumes of distribution at a steady-state of 0.03, 0.23 and 0.41 l/kg BW, respectively. The total plasma clearance of MLX, KETO and TA was 0.02, 0.11 and 0.15 l/h/kg, respectively. The extraction ratios for MLX, KETO and TA were calculated as 0.002, 0.011 and 0.016, respectively.
4. MLX, KETO and TA offer treatment in chukar partridges for various conditions with an absence of adverse reactions and properties such as short elimination half-life and low volume of distribution. However, there is a need to establish the safety and adverse effects of repeated administration, pharmacokinetics of other administration routes and pharmacological efficacy of MLX, KETO and TA in chukar partridges.
Organic intermediates in coal fluids produced by anaerobic biodegradation of geopolymers in coal play a key role in the production of methane in natural gas reservoirs. Laboratory biodegradation ...experiments on sub-bituminous coal from Texas, USA, were conducted using bioreactors to examine the organic intermediates relevant to methane production. Production of methane in the bioreactors was linked to acetate accumulation in bioreactor fluid. Long chain fatty acids, alkanes (C
19–C
36) and various low molecular weight aromatics, including phenols, also accumulated in the bioreactor fluid and appear to be the primary intermediates in the biodegradation pathway from coal-derived geopolymers to acetate and methane.
Ketamine, at sub-anesthetic doses, is reported to rapidly decrease depression symptoms in patients with treatment-resistant major depressive disorder (MDD). Many patients do not respond to currently ...available antidepressants, (for example, serotonin reuptake inhibitors), making ketamine and its enantiomer, esketamine, potentially attractive options for treatment-resistant MDD. Although mechanisms by which ketamine/esketamine may produce antidepressant effects have been hypothesized on the basis of preclinical data, the neurobiological correlates of the rapid therapeutic response observed in patients receiving treatment have not been established. Here we use a pharmacometabolomics approach to map global metabolic effects of these compounds in treatment-refractory MDD patients upon 2 h from infusion with ketamine (n=33) or its S-enantiomer, esketamine (n=20). The effects of esketamine on metabolism were retested in the same subjects following a second exposure administered 4 days later. Two complementary metabolomics platforms were used to provide broad biochemical coverage. In addition, we investigated whether changes in particular metabolites correlated with treatment outcome. Both drugs altered metabolites related to tryptophan metabolism (for example, indole-3-acetate and methionine) and/or the urea cycle (for example, citrulline, arginine and ornithine) at 2 h post infusion (q<0.25). In addition, we observed changes in glutamate and circulating phospholipids that were significantly associated with decreases in depression severity. These data provide new insights into the mechanism underlying the rapid antidepressant effects of ketamine and esketamine, and constitute some of the first detailed metabolomics mapping for these promising therapies.
A central challenge in applied ecology is understanding the effect of anthropogenic fatalities on wildlife populations and predicting which populations may be particularly vulnerable and in greatest ...need of management attention. We used three approaches to investigate the potential effects of fatalities from collisions with wind turbines on 14 raptor species for both current (106 GW) and anticipated future (241 GW) levels of installed wind energy capacity in the United States. Our goals were to identify species at relatively high vs low risk of experiencing population declines from turbine collisions and to also compare results generated from these approaches. Two of the approaches used a calculated turbine‐caused mortality rate to decrement population growth, where population trends were derived either from the North American Breeding Bird Survey or from a matrix model parameterized from literature‐derived demographic values. The third approach was potential biological removal, which estimates the number of fatalities that allow a population to reach and maintain its optimal sustainable population set by management objectives. Different results among the methods reveal substantial gaps in knowledge and uncertainty in both demographic parameters and species‐specific estimates of fatalities from wind turbines. Our results suggest that, of the 14 species studied, those with relatively higher potential of population‐level impacts from wind turbine collisions included barn owl, ferruginous hawk, golden eagle, American kestrel, and red‐tailed hawk. Burrowing owl, Cooper’s hawk, great horned owl, northern harrier, turkey vulture, and osprey had a relatively lower potential for population impacts, and results were not easily interpretable for merlin, prairie falcon, and Swainson’s hawk. Projections of current levels of fatalities to future wind energy scenarios at 241 GW of installed capacity suggest some species could experience population declines because of turbine collisions. Populations of those species may benefit from research to identify tools to prevent or reduce raptor collisions with wind turbines.
Coal formation dewatering at a site in the Powder River Basin was associated with enhanced potential for secondary biogenic methane determined by using a bioassay. We hypothesized that dewatering can ...stimulate microbial activity and increase the bioavailability of coal. We analyzed one dewatered and two water-saturated coals to examine possible ways in which dewatering influences coal bed natural gas biogenesis by looking at differences with respect to the native coal microbial community, coal-methane organic intermediates, and residual coal oxidation potential. Microbial biomass did not increase in response to dewatering. Small Subunit rRNA sequences retrieved from all coals sampled represented members from genera known to be aerobic, anaerobic and facultatively anaerobic. A Bray Curtis similarity analysis indicated that the microbial communities in water-saturated coals were more similar to each other than to the dewatered coal, suggesting an effect of dewatering. There was a higher incidence of long chain and volatile fatty acid intermediates in incubations of the dewatered coal compared to the water-saturated coals, and this could either be due to differences in microbial enzymatic activities or to chemical oxidation of the coal associated with O2 exposure. Dilute H2O2 treatment of two fractions of structural coal (kerogen and bitumen+kerogen) was used as a proxy for chemical oxidation by O2. The dewatered coal had a low residual oxidation potential compared to the water-saturated coals. Oxidation with 5% H2O2 did increase the bioavailability of structural coal, and the increase in residual oxidation potential in the water saturated coals was approximately equivalent to the higher methanogenic potential measured in the dewatered coal. Evidence from this study supports the idea that coal bed dewatering could stimulate biogenic methanogenesis through partial oxidation of the structural organics in coal once anaerobic conditions are restored.
•Effects of dewatering on bioavailability and methanogenic activity were evaluated.•Oxidation associated with dewatering increased the bioavailability of coal carbon.•Increased methane potential likely resulted from the oxidation of coal.
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•Nonisothermal TGA: heating rate and detection method impact degradation temperature.•Isothermal TGA provides a more direct indication of chemical degradation.•Polymers can stabilize ...amorphous APIs from recrystallization to enable analysis.•TGA weight loss only reflects loss of volatiles, which under predicts degradation.•Use caution when extrapolating TGA results to suitable processing windows.
Thermogravimetric analysis (TGA) is frequently used to define the threshold of acceptable processing temperatures for hot melt extrusion. Herein, evaluation of chemical stability of amorphous drug and polymer systems was assessed by a critical evaluation of TGA nonisothermal and isothermal methods. Nonisothermal analysis of three crystalline APIs of high glass-forming ability (posaconazole, indomethacin, and bicalutamide), as well as six common polymers, identified a degradation onset temperature that ranged from 52 to 170 °C, depending on heating rate and degradation detection method employed. In particular, the tangent method significantly overestimated the onset of acceptable levels of degradation, while weight loss threshold criteria were more suitable. Isothermal analysis provided a more direct indication of chemical stability, however neat amorphous materials are likely to recrystallize. By forming an amorphous solid dispersion, the polymer can stabilize the amorphous drug against recrystallization, enabling isothermal analysis of chemical degradation. However, TGA mass loss of volatiles should be considered only as an approximate indicator of degradation, as actual potency loss is likely to be significantly higher; this was confirmed by high performance liquid chromatographic analysis of samples. TGA methods should be selected to generate highly sensitive outcomes, and caution should be applied when extrapolating suitability of processing conditions.
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