Search

de Boever, S., Neirinckx, E.A., Meyer, E., de Baere, S., Beyaert, R., de Backer, P., Croubels, S. Pharmacodynamics of tepoxalin, sodium-salicylate and ketoprofen in an intravenous lipopolysaccharide inflammation model in broiler chickens. J. vet. Pharmacol. Therap. doi: 10.1111/j.1365-2885.2010.01184.x. The pharmacodynamic properties of tepoxalin, Na-salicylate and ketoprofen were determined in an intravenous lipopolysaccharide (LPS) inflammation model in broiler chickens. The drugs were administered orally at a dose of 30, 50 and 3 mg/kg, respectively. LPS administration induces an increase in the intracellular expression of interleukin (IL)-1β and IL-6 and the secreted IL-6 plasma concentration. Furthermore, an elevation in body temperature is noted. Despite pretreatment with a single dose of the drugs and LPS administration on the T of the drug after a second dose, no decrease was seen in systemic IL-6 levels. The intracellular expression of IL-1β in the heterophils was slightly decreased if LPS was administered in combination with each of the three drugs. Tepoxalin and Na-salicylate administration had no significant effect on the LPS-induced increase in prostaglandin E plasma concentration, in contrast to ketoprofen. None of the three drugs were able to influence the elevation in body temperature after LPS administration. The pharmacokinetic properties of Na-salicylate and ketoprofen were not altered in combination with LPS administration. However, LPS significantly decreased the AUC of the active metabolite of tepoxalin, RWJ-20142, indicating a perfusion-limited elimination for this molecule. [ABSTRACT FROM AUTHOR]

A flow cytometric method for the identification of chicken blood leukocyte subpopulations and thrombocytes was developed. An anti-chicken CD45 phycoerythrin-labelled antibody was used to separate leukocytes from red blood cell nuclei. Leukocytes and thrombocytes were identified using a combination of their CD45-positivity and their typical side scatter properties. The identity of the CD45-positive cells was confirmed by sorting the subpopulations and subsequent light microscopic evaluation. In these differentiated cell populations, intracellular expression analysis of the proinflammatory cytokines interleukin-1β and interleukin-6 was subsequently optimized on whole blood after in vitro stimulation with lipopolysaccharide from Escherichia coli strain O127:B8. [ABSTRACT FROM AUTHOR]

Intravenous administration of lipopolysaccharide (LPS) from Escherichia coli O127:B8 at a dose of 1,500,000 u/kg body weight evoked a hypothermic response followed by a fever phase in 5-week-old broiler chickens. The hypothermic phase coincided with a severe decrease in blood pressure. We assume that this decrease in blood pressure is, at least partly, responsible for the hypothermic phase of the body temperature curve. LPS administration also caused a decrease in circulating white blood cells. The heterophils were predominantly sequestered in the lungs. In LPS-treated chickens, far more apoptotic leukocytes were present in the circulation, compared with control chickens. The molecular players responsible for the LPS-induced inflammatory response could be TL1A, IL-1β and IL-6, since a slight increase in their mRNA levels in white blood cells was already seen 1 h after LPS administration. In accordance with these observations, the levels of secreted IL-6 were maximal 3 h after LPS administration. These parameters characterize this LPS-induced inflammation model in broiler chickens. [ABSTRACT FROM AUTHOR]

A comparison was made in the plasma concentration of the major metabolites of amoxicillin (AMO), i.e. amoxicilloic acid (AMA) and amoxicillin diketopiperazine-2′,5′-dione (DIKETO) in portal and jugular venous plasma after oral (p.o.) and intravenous (i.v.) AMO administration to pigs, in order to study a possible presystemic degradation of AMO in the gastro-intestinal tract and liver. Almost identical plasma concentration-time curves were obtained for AMO and its metabolites in portal and jugular venous plasma, both after p.o. and i.v. AMO administration. Almost immediately after i.v. AMO administration, high AMA and DIKETO concentrations were measured in plasma, while after p.o. dosing, the metabolites appeared in plasma after almost complete absorption of AMO. No significant differences in pharmacokinetic parameters of AMO, AMA and DIKETO, derived from the concentration-time profiles in portal and jugular venous plasma were calculated, both after i.v. and p.o. AMO administration ( P > 0.05). After p.o. administration, the half-life of elimination ( t1/2(el)) for AMA is at least two or three times the t1/2(el) of AMO (0.75 h for AMO vs. 2.69 h for AMA), indicating the slower clearance of the metabolite. It could be hypothesized that AMA is only eliminated by glomerular filtration, as its open β-lactam structure might not be recognized by the transport carrier in the proximal tubule of the kidney. The results of the study indicate that AMO is not substantially metabolized presystemically in the gut and liver. Therefore, it may be assumed that the kidney may be the major organ for AMO biotransformation. Future in vivo and in vitro experiments should be performed to state this hypothesis. [ABSTRACT FROM AUTHOR]

The reliability of a silicone double-lumen catheter implanted into the external jugular vein and tunnelled towards the neck region was investigated in eight pigs. Surgery was uneventful without interference with the normal homoeostasis during 8 days. After injection of amoxicillin/clavulanic acid through the distal port of the catheter, analysis of drug components in the simultaneous blood samples obtained by the proximal port and a Venoject® system were comparable in one pig. Histological control of the catheterized jugular veins pointed to an acceptable tissue reaction while bacteriological examination of the tip of the catheters was negative in only three animals. A moulding of the intestinal veins was made in a pig cadaver to determine the optimal length of insertion of a silicone portal catheter from the splenic vein towards the portal vein. Surgery was straightforward in four pigs whereby the catheter was exteriorized towards the back region. No complications were encountered during and after surgery for 9 days. The technique of a double-lumen catheter placed into the jugular vein and a transsplenic portal catheter is a useful tool for the study of the pharmacokinetics and also the first-pass effect of drugs in experimental pigs. [ABSTRACT FROM AUTHOR]

The article presents a study regarding the pharmacological effects of tepoxalin's metabolite in broiler chickens. It features experiments on potential cytokine drugs on chickens with inflammation problems. It calculates the pharmacokinetic parameters of tepoxalin with the use of a computer simulation model. In addition, it also discusses anti-inflammatory drugs.

Our objective was to create a standardized and reproducible inflammation model in chickens in order to study the pharmacodynamics of several anti-pyretic and anti-inflammatory drugs. We studied the influence of age and repeated lipopolysaccharide (LPS) administration on body temperature and the correlation of this with concentrations of interleukin-6 and IgM antibodies against LPS in plasma of chickens. Three-week-old and 5-week-old broilers were injected intravenously with LPS from Escherichia coli O127: B8 at a dose of 1 mg/kg. LPS administration was repeated after 2 or 7 days. After the first dose of LPS, the body temperature was initially decreased below normal and then later increased above normal. The second dose of LPS reduced the level of hypothermia and the duration of the febrile phase. Three-week-old birds responded to LPS with a higher maximum body temperature and a greater area under the body temperature versus time curve than 5-week-old chickens (P<0.05). Interleukin-6 reached its highest concentration 3 h after LPS administration and returned to baseline levels after 9 h. A second dose of LPS resulted in a significantly lower peak in interleukin-6. Significant higher levels of antibodies against LPS could be detected 7 days after LPS administration. However, there appeared to be no correlation between the reduced response to LPS and the presence of antibodies. [ABSTRACT FROM AUTHOR]

The pharmacokinetic properties of amoxicillin and clavulanic acid were studied in healthy, fasted pigs after single intravenous (i.v.) and oral (p.o.) dosage of 20 mg/kg of amoxicillin and 5 mg/kg of clavulanic acid. The plasma concentrations of the drugs were determined by validated high-performance liquid chromatographic methods and the pharmacokinetic parameters were calculated by compartmental and noncompartmental analyses. After i.v. administration of the two drugs, plasma concentration–time curves were best described by a three-compartmental open model for amoxicillin and a two-compartmental open model for clavulanic acid. Amoxicillin (with a t1/2γ = 1.03 h and a clearance of 0.58 L/h·kg) and clavulanic acid (with a t1/2β of 0.74 h and a clearance of 0.41 L/h·kg) were both rapidly eliminated from plasma. Both drugs had apparently the same volume of distribution of 0.34 L/kg. After p.o. administration of the two drugs, a noncompartmental model was used. Elimination half-lives of amoxicillin and clavulanic acid were not significantly different, i.e. 0.73 and 0.67 h respectively. The mean maximal plasma concentrations of amoxicillin and clavulanic acid were 3.14 and 2.42 mg/L, and these were reached after 1.19 and 0.88 h respectively. The mean p.o. bioavailability was found to be 22.8% for amoxicillin and 44.7% for clavulanic acid. [ABSTRACT FROM AUTHOR]

The pharmacokinetic properties of pentoxyfylline and its metabolites were determined in healthy chickens after single intravenous and oral dosage of 100 mg/kg pentoxyfylline. Plasma concentrations of pentoxyfylline and its metabolites were determined by a validated high-performance liquid chromatographic method. After intravenous (i.v.) and oral (p.o.) administration, the plasma concentration–time curves were best described by a one-compartment open model. The mean elimination half-life ( t1/2(el)) of pentoxyfylline was 1.05 h, total body clearance 1.90 L/h·kg, volume of distribution 2.40 L/kg and the mean residence time was 2.73 h, after i.v. administration. After oral dosing, mean maximal plasma concentration of pentoxyfylline was 4.01 μg/mL and the interval from p.o. administration until maximum concentration was 1.15 h. The mean oral bioavailability was found to be 28.2%. Metabolites I, IV and V were present in chicken plasma after both i.v. and p.o. administration, with metabolite V being the most dominant. [ABSTRACT FROM AUTHOR]

1. A study was conducted to determine the influence of sodium salicylate on the behaviour and the food and water consumption of broiler chickens after lipopolysaccharide (LPS) injection. 2. An oral dose of 100?mg/kg sodium salicylate was given and an acute phase reaction in broiler chickens was provoked through the intravenous injection of Escherichia coli LPS. 3. Water intake was higher in the LPS and salicylate-treated group than in the positive control group. The salicylate treatment, however, did not restore the food intake, or influence the behaviour of the chickens. 4. These data show that sodium salicylate has a positive effect on the water intake after intravenous injection of LPS in chickens and suggests that there is a difference in mechanism of action of food and water consumption after LPS injection in chickens. [ABSTRACT FROM AUTHOR]

1. A study was set up to investigate the influence of sodium salicylate on fever and acute phase reaction after lipopolysaccharide (LPS) injection in broiler chickens. 2. An acute phase reaction was provoked through the intravenous injection of Escherichia coli LPS. Four oral doses of sodium salicylate were tested. Apart from body temperature, other inflammation indices, such as plasma corticosterone and ceruloplasmin, serum thromboxane B2 and zinc concentrations were monitored. 3. Intravenous LPS induced a fever of about 1°C. A dose-dependent attenuation of the fever response of the chickens in the salicylate treated groups was observed. LPS-injected chickens also showed elevated plasma corticosterone and ceruloplasmin, while serum thromboxane and zinc concentrations decreased. Except for thromboxane B2, no linear relationship with increasing salicylate dose could be shown for the other blood variables. 4. These data confirm that sodium salicylate is an effective antipyretic agent after injection of LPS in chickens, if used at an appropriate dosage. No dose-related change could be found for the other inflammation indices. [ABSTRACT FROM AUTHOR]

Abstract: Species differences in oral bioavailability, first-pass metabolism and pharmacokinetics of biopharmaceutics classification system (BCS) class I compound acetaminophen were studied. The absolute bioavailability was 42.2%, 39.0%, 44.5%, 75.5% and 91.0% in chickens, turkeys, dogs, pigs and horses, respectively. After hydrolysis of metabolites by β-glucuronidase/sulfatase, apparent bioavailability increased significantly in all species (turkeys: 72.4%, dogs: 100.5%, pigs: 102.2%), except horses (91.6%). Mean metabolic ratios of [acetaminophen glucuronide]/[acetaminophen] between 0 and 1h were significantly higher after oral dosing in turkeys, dogs and pigs, revealing the role of first-pass metabolism in incomplete bioavailability. Evidence of species differences in acetaminophen metabolism is provided by differences in plasma clearance, which was inversely proportional to bioavailability. In conclusion, differences in BA appeared to originate predominantly from differences in first-pass metabolism, demonstrating that the BCS high permeability classification of acetaminophen is consistent across the mammalian species studied. In turkeys, however, incomplete absorption additionally seemed to contribute to the low BA. [Copyright &y& Elsevier]

Parenteral nutrition (PN) is typically administered to individuals with gastrointestinal dysfunction, a contraindication for enteral feeding, and a need for nutritional therapy. When PN is the only energy source in patients, it is defined as total parenteral nutrition (TPN). TPN is a life-saving approach for different patient populations, both in infants and adults. However, despite numerous benefits, TPN can cause adverse effects, including metabolic disorders and liver injury. TPN-associated liver injury, known as intestinal failure-associated liver disease (IFALD), represents a significant problem affecting up to 90% of individuals receiving TPN. IFALD pathogenesis is complex, depending on the TPN components as well as on the patient's medical conditions. Despite numerous animal studies and clinical observations, the molecular mechanisms driving IFALD remain largely unknown. The present study was set up to elucidate the mechanisms underlying IFALD. For this purpose, human liver spheroid co-cultures were treated with a TPN mixture, followed by RNA sequencing analysis. Subsequently, following exposure to TPN and its single nutritional components, several key events of liver injury, including mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, apoptosis, and lipid accumulation (steatosis), were studied using various techniques. It was found that prolonged exposure to TPN substantially changes the transcriptome profile of liver spheroids and affects multiple metabolic and signaling pathways contributing to liver injury. Moreover, TPN and its main components, especially lipid emulsion, induce changes in all key events measured and trigger steatosis., (© 2024. The Author(s).)

Introduction: The evaluation of the potential carcinogenicity is a key consideration in the risk assessment of chemicals. Predictive toxicology is currently switching toward non-animal approaches that rely on the mechanistic understanding of toxicity., Areas Covered: Adverse outcome pathways (AOPs) present toxicological processes, including chemical-induced carcinogenicity, in a visual and comprehensive manner, which serve as the conceptual backbone for the development of non-animal approaches eligible for hazard identification. The current review provides an overview of the available AOPs leading to liver cancer and discusses their use in advanced testing of liver carcinogenic chemicals. Moreover, the challenges related to their use in risk assessment are outlined, including the exploitation of available data, the need for semantic ontologies, and the development of quantitative AOPs., Expert Opinion: To exploit the potential of liver cancer AOPs in the field of risk assessment, 3 immediate prerequisites need to be fulfilled. These include developing human relevant AOPs for chemical-induced liver cancer, increasing the number of AOPs integrating quantitative toxicodynamic and toxicokinetic data, and developing a liver cancer AOP network. As AOPs and other areas in the field continue to evolve, liver cancer AOPs will progress into a reliable and robust tool serving future risk assessment and management.

Micro- and nanoplastics are vast anthropogenic pollutants in our direct surroundings with a robust environmental stability and a potential for a long-lasting and increasing global circulation. This has raised concerns among the public and policy makers for human health upon exposure to these particles. The micro- and nanoplastic burden on humans is currently under debate, along with criticism on the experimental approaches used in hazard assessment. The present review presents an overview of the human-relevant aspects associated with the current micro-and nanoplastic burden. We focus on environmental circulation and the estimation of exposure quantities to humans, along with a state-of-the-art overview of particle accumulation in over 15 human organs and other specimen. Additionally, data regarding particle characteristics used in toxicity testing was extracted from 91 studies and discussed considering their environmental and human relevance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sybren De Boever reports financial support was provided by the Research Foundation Flanders. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Pannexin1 proteins form communication channels at the cell plasma membrane surface, which allow the transfer of small molecules and ions between the intracellular compartment and extracellular environment. In this way, pannexin1 channels play an important role in various cellular processes and diseases. Indeed, a plethora of human pathologies is associated with the activation of pannexin1 channels. The present paper reviews and summarizes the structure, life cycle, regulation and (patho)physiological roles of pannexin1 channels, with a particular focus on the relevance of pannexin1 channels in liver diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Van Campenhout, Caufriez, Tabernilla, Maerten, De Boever, Sanz-Serrano, Kadam and Vinken.)

Validated in vitro assays for testing non-genotoxic carcinogenic potential of chemicals are currently not available. Consequently, the two-year rodent bioassay remains the gold standard method for the identification of these chemicals. Transcriptomic and proteomic analyses have provided a comprehensive understanding of the non-genotoxic carcinogenic processes, however, functional changes induced by effects at transcriptional and translational levels have not been addressed. The present study was set up to test a number of proposed in vitro biomarkers of non-genotoxic hepatocarcinogenicity at the functional level using a translational 3-dimensional model. Spheroid cultures of human hepatocytes and stellate cells were exposed to 5 genotoxic carcinogenic, 5 non-genotoxic carcinogenic, and 5 non-carcinogenic chemical compounds and assessed for oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, apoptosis, and inflammation. The spheroid model could capture many of these events triggered by the genotoxic carcinogenic chemicals, particularly aflatoxin B1 and hydroquinone. Nonetheless, no clear distinction could be made between genotoxic and non-genotoxic hepatocarcinogenicity. Therefore, spheroid cultures of human liver cells may be appropriate in vitro tools for mechanistic investigation of chemical-induced hepatocarcinogenicity, however, these mechanisms and their read-outs do not seem to be eligible biomarkers for detecting non-genotoxic carcinogenic chemicals., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate the influence of two ventilation modes on the performance of an anaesthetic conserving device (AnaConDa) in piglets., Study Design: Prospective randomized experimental trial., Animals: Eight female piglets weighing 24.7 +/- 2.2 kg., Methods: Anaesthesia was maintained with sevoflurane (in 60% oxygen) delivered from the AnaConDa placed between endotracheal tube (ETT) and Y-piece. Anaesthetic depth was guided using standard clinical parameters. Ventilation mode was volume controlled (VC) during the first and pressure support (PS) during the second period of anaesthesia in four piglets (group 1); the order was reversed in group 2. Anaesthetic gases were sampled before (at the proximal end of the ETT) and after the AnaConDa (Y-piece). Data were analysed using a model I anova, with treatment and group as fixed categorical effects. Using a paired t-test, partial pressures of carbon dioxide (Pe'CO(2)) on both sides of the device were compared., Results: Although the mean administration rate of sevoflurane was comparable in both groups (3.8 +/- 1.8 mL hour(-1)), E'Sevo was higher in group 1, more specifically during the first period (p = 0.035). Less sevoflurane escaped during VC (14.0 +/- 3.4%) compared with PS ventilation (17.2 +/- 5.7%) (p = 0.001). Pe'CO(2) was lower at the Y-piece (6.4 +/- 0.8 kPa, 48 +/- 6 mmHg) compared with the ETT (9.3 +/- 1.4 kPa, 70 +/- 11 mmHg) in both groups and ventilation modes. On average, inspiratory CO(2) tension was 2.0 +/-1.0 kPa (15 +/- 8 mmHg). Respiration rate was comparable in all piglets while tidal volume () and peak inspiratory pressure were lower during VC compared with PS (p < 0.001, p = 0.015 respectively)., Conclusions and Clinical Relevance: The observed differences in E'Sevo concentration and sevoflurane breakthrough were probably related to differences in . The observed high FiCO(2) indicated an excessive dead space with the AnaConDa for these piglets.

Paratyphoid caused by Salmonella enterica subsp. enterica serovar Typhimurium is the main bacterial disease in pigeons. The ability of Salmonella serovar Typhimurium to persist intracellularly inside pigeon macrophages results in the development of chronic carriers, which maintain the infection in the flock. In this study, the effect of drinking-water medication with florfenicol on Salmonella infection in pigeons was examined. The pharmacokinetics of florfenicol in pigeons revealed a relatively high volume of distribution of 2.02 liters/kg of body weight and maximum concentrations in plasma higher than the MICs for the Salmonella strain used (4 microg/ml) but quick clearance of florfenicol due to a short half-life of 1.73 h. Together with highly variable bioavailability and erratic drinking-water uptake, these parameters resulted in the inability to reach a steady-state concentration through the continuous administration of florfenicol in the drinking water. Florfenicol was capable of reducing only moderately the number of intracellular salmonellae in infected pigeon macrophages in vitro. Only at high extracellular concentrations (>16 microg/ml) was a more-than-10-fold reduction of the number of intracellular bacteria noticed. Florfenicol treatment of pigeons via the drinking water from 2 days after experimental inoculation with Salmonella serovar Typhimurium until euthanasia at 16 days postinoculation resulted in a reduction of Salmonella shedding and an improvement in the fecal consistency. However, internal organs in florfenicol-treated pigeons were significantly more heavily colonized than those in untreated pigeons. In conclusion, the oral application of florfenicol for the treatment of pigeon paratyphoid contributes to the development of carrier animals through sub-MIC concentrations in plasma that do not inhibit intracellular persistency.

A residue depletion study of amoxicillin (AMO) and its major metabolites, amoxicilloic acid (AMA) and amoxicillin diketopiperazine-2',5'-dione, was performed after a single oral (p.o.) and intravenous (i.v.) administration of amoxicillin (20 mg kg (-1)) and amoxicillin/clavulanic acid (20 and 5 mg kg (-1)) to pigs. Animals were slaughtered 12, 36, 48, 60, 72, and 84 h after dosing. Tissue samples were analyzed using liquid chromatography-tandem mass spectrometry. Kidney samples contained high concentrations of amoxicilloic acid metabolite, which depleted much slower from tissues than amoxicillin, both after p.o. (t1/2AMO = 4.5 h vs t1/2AMA = 8 h) and i.v. (t1/2AMO = 4 h vs t1/2AMA = 8 h) administration. Moreover, after oral administration, significantly higher amoxicilloic acid concentrations were measured in liver and kidney than after i.v. administration. The coadministration of amoxicillin with clavulanic acid provoked no significant differences in amoxicilloic acid tissue concentrations as compared to an amoxicillin dosing. The prolonged presence of residues of amoxicilloic acid in edible tissues can play an important role in food safety, because the compound could give rise to a possible health risk, although it is not included in the maximum residue limit legislation.

The purpose of this study was to develop and validate a method for the determination of clavulanic acid (CLAV) residues in edible tissues of swine by liquid chromatography-electrospray ionisation-tandem mass spectrometry (LC-ESI-MS/MS). After a simple extraction of CLAV using an aqueous phosphate buffer solution of pH 6.0, an ultrafiltration step was performed for protein removal. Chromatography of CLAV and the internal standard tazobactam (TAZO) was achieved on a reversed-phase PLRP-S polymeric column (150 mm x 2.1 mm i.d., 100 A) using a mixture of 0.05 (v/v)% formic acid in water and acetonitrile. The mass spectrometer was operated in the MS/MS selected reaction monitoring (SRM) mode. The method was validated for the analysis of porcine muscle, skin plus fat, liver and kidney, according to the requirements defined by the European Community. Calibration curves were prepared for all tissues and good linearity was achieved over the concentration ranges tested (correlation coefficient > or = 0.99 and goodness-of-fit coefficient < or = 10%). Limits of quantification of 50 ng g(-1) were obtained for the analysis of CLAV in the various tissues which corresponds in all cases to at least half the maximum residue limits (MRLs). Limits of detection ranged between 8.0 and 15.14 ng g(-1). The within-day, between-day precisions and trueness fell within the ranges specified in the EMEA/CVMP/573-00/FINAL document. Biological samples from pigs that received an oral or intravenous bolus of a commercial amoxicillin/clavulanic acid formulation were analyzed using the described method.