Endotoxin-induced liver damage in rats is minimized by beta 2-adrenoceptor stimulation.

Objective And Design: To investigate the effects of beta(2)-adrenoceptor (beta(2)-AR) stimulation on endotoxin-induced liver damage and systemic cytokine levels in rats.

Subjects: Standard male Wistar rats.

Treatment: A disease-model of lipopolysaccharide (LPS)-induced acute systemic inflammation was used.

Present concepts on the inflammatory modulators with special reference to cytokines.

The pro- and anti-inflammatory cytokines create a network of interactions between cells that lead to both stimulatory and inhibitory responses that maintain an effective homeostatic regulation. The anti-inflammatory cytokines are a family of peptides that modulate the pro-inflammatory cytokine response. Cytokines act in concert with non-cytokine mediators, such as prostaglandin E2, glucocorticosteroids, lipocortins, and catecholamines.

Pharmacokinetics of sulfadimethoxine and sulfamethoxazole in combination with trimethoprim after oral single- and multiple-dose administration to healthy pigs.

The pharmacokinetics were studied of sulfadimethoxine (SDM) or sulfamethoxazole (SMX) in combination with trimethoprim (TMP) administered as a single oral dose (25 mg + 5 mg per kg body weight) to two groups of 6 healthy pigs. The elimination half-lives of SMX and TMP were quite similar (2-3 h); SDM had a relatively long half-life of 13 h. Both sulfonamides (S) were exclusively metabolized to N4-acetyl derivatives but to different extents.

Differential effects of pentoxifylline on the hepatic inflammatory response in porcine liver cell cultures. Increase in inducible nitric oxide synthase expression.

Pentoxifylline (PTX) has been shown to exert hepatoprotective effects in various liver injury models. However, little information is available about the effect of PTX on the hepatic acute phase response. In the present study, the effect of PTX on a lipopolysaccharide (LPS)-induced acute phase response in primary porcine liver cell cultures was examined.

Direct cell-to-cell contact between Kupffer cells and hepatocytes augments endotoxin-induced hepatic injury.

This study focuses on the importance of direct contact between Kupffer cells (KCs) and hepatocytes (HCs) during the hepatic inflammatory response using an in vitro approach. The lipopolysaccharide (LPS)-induced inflammatory response in monocultures of porcine HCs and KCs were compared with cocultures prepared either with direct contact between KCs and HCs (DC cocultures) or without direct contact using cell culture membrane inserts. Our data show that DC cocultures exhibited the highest production of tumor necrosis factor (TNF)-alpha, interleukin-6, and nitric oxide (NO) compared with the other cultures.

Stereoselectivity at the beta2-adrenoceptor on macrophages is a major determinant of the anti-inflammatory effects of beta2-agonists.

Previous research has shown that beta-adrenoceptor (beta-AR) agonists have potent anti-inflammatory capabilities, e.g. represented by suppression of release of the proinflammatory cytokines.

Prevention of pleuropneumonia in pigs by in-feed medication with sulphadimethoxine and sulphamethoxazole in combination with trimethoprim.

The prophylactic effect of in-feed medication of conventional pigs with sulphadimethoxine (SDM), sulphamethoxazole (SMX), and trimethoprim (TMP) was tested by using an Actinobacillus pleuropneumoniae infection model. In each of five experiments, six pigs were given medicated feed twice daily and three pigs received antibiotic-free feed and served as positive (unmedicated, infected) controls. The following drugs or drug combinations were tested (in mg per kg feed): 500 SDM + 100 TMP, 500 SMX + 100 TMP, 125 SMX + 25 TMP, 125 SMX (alone) and 25 TMP (alone).

Suppression of the acute inflammatory response of porcine alveolar- and liver macrophages.

During infection and inflammation drug disposition and hepatic metabolism are markedly affected in mammals. Pro-inflammatory mediators play an important role in the suppression of (cytochrome-P450-mediated) drug metabolism. Inflammatory mediators like cytokines, nitric oxide (NO), reactive oxygen species (ROS) and eicosanoids are released by activated macrophages from various sources, including liver and lung.

Cocultures of porcine hepatocytes and Kupffer cells as an improved in vitro model for the study of hepatotoxic compounds.

In this study primary hepatocyte cultures (HC cultures) and cocultures comprised of hepatocytes and Kupffer cells (HC/KC cocultures) were compared to investigate the inflammatory response induced by lipopolysaccharide (LPS). In addition both culture types were compared to study the hepatotoxic effects of two frequently used drugs: tiamulin and chlorpromazine. The inflammatory response in both culture types was determined by measurement of tumour necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6) and nitric oxide (NO).

Trends in veterinary clinical and fundamental pharmacology: past and future in The Netherlands.

Veterinary pharmacology has undergone a gradual development in the Netherlands during this century. Starting from a historical perspective the paper aims to provide an overview of future trends and important issues in the area of veterinary pharmacology and toxicology. It is pointed out that this discipline comprises several subdisciplines as the comparative aspect of both, pharmacology and toxicology, is inherent to veterinary medicine which has to address a broad variety of animal species.

The beta-adrenoceptor agonist clenbuterol is a potent inhibitor of the LPS-induced production of TNF-alpha and IL-6 in vitro and in vivo.

Objective And Design: To investigate the suppressive effects of the beta-agonist clenbuterol on the release of TNF-alpha and IL-6 in a lipopolysaccharide (LPS)-model of inflammation, both in vitro and in vivo.

Material And Subjects: Human U-937 cell line (monocyte-derived macrophages), and male Wistar rats (200-250 g).

Treatment: U-937 macrophages were incubated with LPS at 1 microg/ml, with or without 1.

17alpha-ethyl-5beta-estrane-3alpha, 17beta-diol, a biological marker for the abuse of norethandrolone and ethylestrenol in slaughter cattle.

The metabolism of the illegal growth promoter ethylestrenol (EES) was evaluated in bovine liver cells and subcellular fractions of bovine liver preparations. Incubations with bovine microsomal preparations revealed that EES is extensively biotransformed into norethandrolone (NE), another illegal growth promoter. Furthermore, incubations of monolayer cultures of hepatocytes with NE indicated that NE itself is rapidly reduced to 17alpha-ethyl-5beta-estrane-3alpha, 17beta-diol (EED).

In vitro complex formation and inhibition of hepatic cytochrome P450 activity by different macrolides and tiamulin in goats and cattle.

In humans, clinically relevant drug-drug interactions occur with some macrolide antibiotics via the formation of stable metabolic intermediate (MI) complexes with enzymes of the cytochrome P4503A (CYP3A) subfamily. The formation of such complexes can result in a decreased biotransformation rate of simultaneously administered drugs. In previous studies it was shown that the veterinary antibiotic tiamulin was also able to form a stable MI complex in pigs and rats.

Participation of beta-adrenergic receptors on macrophages in modulation of LPS-induced cytokine release.

For several years it is known that beta-adrenergic receptor agonists have anti-inflammatory effects. However, little is known about the role of beta-adrenergic receptors on macrophages in the modulation of cytokine production by beta-agonists during inflammation. In this study, the presence of beta-receptors on PMA-differentiated U937 human macrophages, and the participation of these receptors in the modulation of LPS-mediated cytokine production by beta-agonists was investigated.

Characterization of cytochrome P450 isoenzymes in primary cultures of pig hepatocytes.

Despite the fact that pigs are increasingly used in pharmacological and toxicological studies, knowledge on the enzymes which metabolize xenobiotics, in particular cytochrome P450 (CYP) enzymes, in pigs is still very limited. Primary cultures of pig hepatocytes were used to characterize CYP enzymes. The characterization was performed at the level of enzymatic activities, apoprotein and mRNA analyses.

Novobiocin inhibits both UDP-glucuronosyltransferase and cytochrome P450-mediated enzyme activities in pig liver microsomes.

The effects of novobiocin (range 0.0125-2 mmol/L) on the hydroxylation of testosterone, the N-demethylation of erythromycin, and the glucuronidation of alpha-naphthol and paracetamol were studied using pig hepatic microsomes, pooled from five animals. The final concentrations of these substrates in the incubation mixtures were selected to meet Vmax conditions.

The effect of sulfaphenazole and sulfadoxine on tolbutamide disposition in dwarf goats (Caprus hircus aegagrus).

The aim of the present study was to investigate the effects of intravenously administered sulfadoxine (5 mg kg-1 bodyweight) or sulfaphenazole (5 mg kg-1 bodyweight) on the in vivo elimination of i.v. tolbutamide (5 mg kg-1 bodyweight), as both compounds were shown to inhibit tolbutamide hydroxylation in vitro.

Structure-activity relationships between antibacterial activities and physicochemical properties of sulfonamides.

Relationships between the antimicrobial activities of sulfonamides and physicochemical properties including the acid dissociation constant (pKa) and the hydrophobicity constant (pi) were determined. The minimal inhibitory concentrations (MIC) of sulfonamides against Actinobacillus pleuropneumoniae, a gram-negative veterinary pathogen, were used. High performance liquid chromatography was applied for the determination of the electronic and hydrophobic parameters.

Isolation of a bovine full length cytochrome P450 (CYP3A) cDNA sequence and its functional expression in V79 cells.

From a bovine liver cDNA library in λMaxl a 1870 bp cDNA was isolated using the human CYP3A4 cDNA as a probe. The cDNA-deduced amino acid sequence encoded a protein of 507 amino acids and exhibited homologies of 76, 72 and 64% with canine CYP3A12, human CYP3A4 and rat CYP3A1, respectively. Furthermore, a very high homology of 91.