Pharmacodynamic interactions of amikacin with selected ß-lactams and fluoroquinolones against canine Escherichia coli isolates.

Knowledge of in vitro antimicrobial interactions can serve as a guide for clinical application of combination antimicrobial regimens. The aim of the present study was to determine the pharmacodynamic interactions of amikacin with either amoxicillin/clavulanic acid, ceftazidime, enrofloxacin or marbofloxacin against clinical canine Escherichia coli isolates. Bactericidal activity of individual antimicrobials was assessed by use of static kill curves. Interactions between amikacin and each of the ß-lactams or fluoroquinolones were subsequently analyzed by employing the fractional maximal effect method. Amikacin, compared with all other agents, displayed the most rapid and extensive bacterial killing, the lowest level (with respect to MIC) at which half the maximal effect was observed and the most linear concentration-effect relationship. The combinations of amikacin with amoxicillin/clavulanic acid or ceftazidime were completely synergistic in four and three out of the five investigated isolates, respectively, with additivity being sporadically observed. On the other hand, the combinations of amikacin with enrofloxacin or marbofloxacin yielded a mosaic of interaction types with no discernible pattern or differentiation between fluoroquinolone-susceptible and resistant isolates; synergy was only infrequently observed, mainly at increased fluoroquinolone concentrations. In conclusion, the combinations of amikacin with the two ß-lactams were found to be more promising, in terms of synergy achievement, compared with the respective combinations with the two fluoroquinolones.

Peripheral distribution of amoxicillin in sheep and influence of local inflammation.

The pharmacokinetics of amoxicillin (AMX) in blood serum (SBS) and tissue cage fluid (TCF) was studied in sheep. Four tissue cages, prepared from silicone rubber tubing, were subcutaneously inserted in the neck area (two on each side) of the experimental animals and AMX was administered both intravenously (IV) and intramuscularly (IM) at the dose rate of 15mg/kg bodyweight. The impact of local inflammation on AMX distribution in TCF was studied after intra-cavity injection of a lambda carrageenan solution in one of the two tissue cages used after each administration. In contrast to the three-compartment AMX disposition after IV injection, two-compartment, absorption-limited pharmacokinetics was observed after IM administration. Non-inflamed and inflamed TCF data revealed, in all cases, the attainment of low, but prolonged concentrations and absence of an inflammation-induced effect on AMX penetration into and elimination from TCF.

The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites.

This study investigates the effect of theophylline along the rabbit gastrointestinal tract in comparison with the pharmacodynamic effect produced by the combined application of its three major metabolites. At concentrations up to 10(-3) m, theophylline relaxed, in a declining order from the lower oesophageal sphincter (LOS) to pylorus, all regions of the upper gastrointestinal tract, but only the ascending colon from the intestinal regions studied. At concentrations higher than 10(-3) m, instead of relaxing, theophylline strongly contracted the antrum and pylorus. In all three small intestinal regions, at concentrations up to 10(-3) m, theophylline produced a weak contraction, which at higher concentrations became very strong, and at 10(-2) m was comparable to that produced by a supramaximal dose of acetylcholine. The additive relaxing effect resulting from the combined application of the theophylline's metabolites was, from oesophagus to pylorus, weaker than that produced by theophylline, while on the ascending colon it was comparable to that of the parent drug. In contrast, the additive contractile effect of the metabolites on the three small intestinal regions was four to five times higher the one produced by theophylline. In conclusion, this study shows that the additive effect of the combined application of theophylline's major metabolites on the rabbit gastrointestinal tract plays a major role in the final response of the intestine, and a minor one in the final responses of the gastric regions, while both the parent drug and the metabolites contribute to the final responses of the oesophagus and LOS.

Application and validation of a LC/fluorescence method for the determination of amoxicillin in sheep serum and tissue cage fluid.

A LC method with fluorescence detection after pre-column mercury dichloride derivation was developed and validated for the quantitative determination of amoxicillin in sheep blood serum and tissue cage fluid at levels down to 100 and 200ng/mL, respectively. Spiked blood serum and tissue cage fluid samples were deproteinized, derivatized with mercury dichloride and extracted prior to reversed phase LC analysis with fluorescence spectrophotometric detection at an excitation wavelength of 355nm and an emission wavelength of 435nm. Separation was carried out on a C(18) column with a mobile phase consisting of phosphate buffer, octanesulphonate sodium (OCT), and acetronitrile. A regression model using 1/concentration weighting was found the most appropriate for quantification. The intra-day precision for serum was 1.65-8.74% and for tissue cage fluid was 2.48-6.27%. The inter-day precision for serum was 0.39-3.57% and for tissue cage fluid was 0.44-2.54%. The overall precision over 3 days for blood serum using of 108 replicates was 1.70-9.44% and for tissue cage fluid using of 54 replicates was 2.51-6.76%. Studies of amoxicillin stability in blood serum and tissue cage fluid indicated that amoxicillin was stable after 4 weeks storage at -85 degrees C. The method was successfully applied for the determination of amoxicillin in blood serum and tissue cage fluid samples collected from rams after intravenous administration.

Relaxing and contracting effects of theophylline's metabolites on the rabbit upper gastrointestinal tract.

The present study, aimed to clarify whether the gastrointestinal adverse effects following administration of the bronchodilator theophylline are owing to the action of the drug itself or its metabolites, investigates the pharmacodymanic effects of theophylline's metabolites on the spontaneous contractility in the rabbit upper gastrointestinal tract. Comparative examination reveals that while two of the metabolites, namely 1-methylxanthine (1-MX) and 3-methylxanthine (3-MX), cause a similar, but less pronounced than the parent drug, concentration-dependent relaxation on the isolated oesophagus, lower oesophageal sphincter (LOS), fundus, antrum and pylorus, the remaining two metabolites, 1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU), produce either a weak stimulating effect, or an even weaker relaxation. The relaxation which is muscle-mediated, non-adrenergic non-cholinergic (NANC) and nitric oxide (NO)-independent is probably mediated via inhibition of the metabolites on phosphodiesterases (PDEs), while a presynaptic cholinergic pathway is involved in the weak stimulating effect. The effects of all substances are additive. As a consequence, the net result of the cumulative action of all metabolites in the oesophagus, LOS, antrum and pylorus is, at 10(-3) m, comparable with that of theophylline, but in the fundus it is lower than that of the parent drug, because in the latter tissue the stimulating effect of 1,3-DMU and 1-MU counteracts the relaxing effect of the other two metabolites. However, combination of the parent drug with its metabolites leads to a considerable relaxation in all the gastrointestinal regions extending from the oesophagus to pylorus. Conclusively, upper gastrointestinal adverse effects following theophylline's administration are also because of theophylline's metabolites.

Enhancing and inhibitory effects of H2-receptor antagonists on the GABA and the GABAA-agonist muscimol responses of the isolated guinea pig ileum: a pharmacodynamic interaction.

This study investigates the effect of histamine H(2)-receptor antagonists on the GABA-responses of the intestine. GABA and the GABA(A)-agonist muscimol were applied to isolated ileal guinea pig preparations in the absence, and presence of two H(2)-receptor antagonists, famotidine and cimetidine. Both GABA and muscimol produced a concentration-dependent contractile effect on the guinea pig ileum. Famotidine and cimetidine modified this contractile effect, either by enhancing or by inhibiting it. The differing results depended not only on the antagonist concentration, but also on the concentration of GABA or muscimol. When tested at the concentration of 10(-5)M, famotidine enhanced the contractile response of the ileum to either GABA or muscimol, while cimetidine did not modify it. At the concentration of 3 x 10(-4)M, both H(2)-receptor antagonists tested inhibited the contractile effect of either GABA or muscimol. However, the famotidine-induced inhibition was more potent than the one produced by cimetidine. In conclusion, the interaction of H(2)-receptor antagonists with GABA receptors is not limited to the central nervous system, but it also extends to the peripheral nervous system. The receptor interaction mainly involves GABA(A)-receptors and depends on both the specific H(2)-antagonist and the concentration used.