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. Total beta-receptor expression on undifferentiated (monocyte) and PMA-differentiated U937 cells was established using receptor binding studies on membrane fractions with a radio ligand. The expression of beta-receptors proved to be significantly lower on monocytes than on macrophages, additionally a predominant expression of beta 2-receptors was found. Production of the cytokines TNF-alpha, IL-6, and IL-10 by LPS-stimulated differentiated U937 cells was measured in time. Peak concentrations for TNF-alpha, IL-6 and IL-10 occurred at 3, 12 and 9 hrs, respectively. When differentiated U937 cells were incubated with both LPS and the beta-agonist clenbuterol the production of TNF-alpha and IL-6 was significantly reduced. However the production of IL-10 was increased. To study the mechanism of modulation of cytokine production in more detail, U937 macrophages were incubated with LPS/clenbuterol in combination with selective beta 1- and beta 2-antagonists. These results indicated that the beta 2- and not the beta 1-receptor is involved in the anti-inflammatory activity of clenbuterol.

The beta-agonist clenbuterol very potently suppresses the LPS-induced release of the pro-inflammatory cytokines TNF-alpha and IL-6 both in vitro and in vivo.

No abstract

The indications for use, side-effects, and pharmacokinetic parameters of trimethoprim, sulfonamides and their combinations in the horse are reviewed. Trimethoprim/sulfonamide (TMPS) combinations are used for the treatment of various diseases caused by gram-positive and gram-negative bacteria, including infections of the respiratory tract, urogenital tract, alimentary tract, skin joints and wounds. TMPS combinations can be administered orally, since absorption from the gastrointestinal tract is relatively good. However, peak serum concentrations can vary significantly between individual horses. Feed intake affects serum concentrations after oral administration. Concentrations of non-bound trimethoprim (TMP) and sulfadiazine (SDZ) in synovial fluid and peritoneal fluid are equal to serum concentrations after intravenous (i.v.) administration, and high concentrations are found in urine. Concentrations of TMP and sulfamethoxazole (SMX) in cerebrospinal fluid after i.v. administration exceed the minimum inhibitory concentration for common equine pathogens. The volume of distribution is 1.5-2.7 l/kg for TMP and 0.3-0.7 l/kg for various sulfonamides. The plasma half-life of TMP is 1.9-4.3 h, whereas the plasma half-lives of the different sulfonamides vary between 2.7 and 14.0 h. About 50% of total TMP is bound to plasma proteins. The binding of sulfadoxine to plasma proteins depends on total plasma concentration and varies between 14% and 72%. The binding of other sulfonamides to plasma proteins may range from 33% for sulfaphenazole (SPZ) to 93% for sulfadimethoxine (SDM). Sulfonamides are metabolized by acetylation of the para-amino (N4) group and by hydroxylation of the methyl group and the pyrimidine ring. The metabolic pathways of TMP in the horse are not fully known. Bacterial resistance to TMPS combinations is still relatively low. The sensitivity of different micro-organisms may vary with the relative activity of the sulfonamide used in the combination. The advised oral and i.v. dose rate is 15-30 mg/kg (in a 1:5 TMP/S ratio) with a dose interval of 12 h. The acute toxicity of TMPS is low, but there have been several reports of death after i.v. administration, probably due to vagal stimulation and subsequent bradycardia and vasodilatation caused by the pharmaceutical formulation (excipients, solvents) used. Future research should concentrate on establishing the optimum pyrimidine/sulfonamide combination and its dosing regimen for antimicrobial therapy in horses.

Infection evokes complex changes which are thought to be caused by production and release of pro-inflammatory cytokines such as tumour necrosis factor (TNF-alpha), interferons (INFs), and interleukins (ILs). They regulate local inflammatory reactions, but may also gain access to the circulation and induce systemic effects collectively known as the Acute Phase Response. To improve our understanding of the pathophysiology of pro-inflammatory cytokines in ruminants, studies have been performed with TNF-alpha, IL1-alpha/beta, and IFN-alpha/ gamma as well as with cytokine-inducers in dwarf goats. In relation to therapy, the following aspects may be of interest: a) Cytokine therapy given before or just after microbial challenge induces in vivo antimicrobial activity. Moreover, cytokines potentiate in vivo the antimicrobial activity of antibiotics, b) Cytokines may act as biological response modifiers for enhancing specific immunity to vaccines, and c) Cytokines may affect drug absorption, disposition, and metabolite formation in disease states. Although studies of the actions of corticosteroids, nonsteroidal anti-inflammatory and antipyretic agents, antibodies to endotoxin, TNF-alpha, or IL-1, synthetic E. coli lipid A precursors, hydrazine, isoniazid, chloroquine, polymyxin B, bicyclic imidazoles, hydroxamates, and tyrosine kinase inhibitors in endotoxaemic animals have shed further light on inflammatory processes, clinical studies in this field are urgently required to evaluate their beneficial effect.