Influence of a Bacterial Lipopolysaccharide on the Pharmacokinetics of Tobramycin in Rats

Abstract— The effects of Klebsiella pneumoniae O3 lipopolysaccharide on the renal handling and distribution characteristics of the aminoglycoside tobramycin were investigated in rats. Tobramycin (2 mg kg^?1) and inulin (100 mg kg^?1) were administered intravenously 2 h after administration of 50,250 or 500 μg kg^?1 lipopolysaccharide. Lipopolysaccharide delayed the disappearance of tobramycin from plasma in a dose-dependent manner. A dose-dependent decrease in systemic clearance of tobramycin was observed, although the elimination rate constant and fraction of urinary recovery of unchanged drug were not significantly different in any group. Lipopolysaccharide significantly decreased the central compartment volume of distribution of tobramycin, but did not influence the steady-state volume of distribution. A dose-related increase in the ratio of the rate constant of transfer to the peripheral compartment to the rate constant of transfer from peripheral compartment to central compartment was observed. The glomerular filtration rate was significantly decreased by pretreatment with 250 μg kg^?1 lipopolysaccharide and the clearance ratio was decreased by 20%, indicating that lipopolysaccharide increases the tubular reabsorption of tobramycin. Our findings suggest that K. pneumoniae O3 lipopolysaccharide modifies the glomerular filtration rate and tubular reabsorption without change in the terminal half-life and that drug distribution characteristics from the rapidly-distributing compartment to the peripheral compartment were altered without expansion of the extracellular fluid volume.     

A Randomized Comparison of the Straight Linear Approach with Electrogram Mapping Focal Approach in Selective Slow Pathway Ablation

HAYASHI, M., et al. : A Randomized Comparison of the Straight Linear Approach with Electrogram Mapping Focal Approach in Selective Slow Pathway Ablation. The aim of this study was to evaluate the efficacy and safety of the anatomic linear approach in selective AVN slow pathway ablation, in comparison to the widely used electrogram mapping focal approach. It remains undetermined whether or not anatomic linear ablation has a greater potential for eliminating slow pathway conduction than does focal ablation. Fifty consecutive patients (21 men, 29 women, age  56 ± 14  years) with common type AVNRT were randomly assigned to the linear approach (25 patients) or local electrogram mapping approach (25 patients). A linear lesion was created between the tricuspid annulus, at the midlevel of the coronary sinus (CS) ostium, and the anterior aspect of the CS infundibulum. In 22 (88%) patients in the linear group, the AVNRT was successfully eliminated by  1.5 ± 0.8  linear RF applications without any complications. All 25 patients in the focal group satisfied the endpoint criteria after  3.8 ± 2.4  focal RF deliveries. The success rate did not significantly differ between the two groups. Out of the 22 patients with a successful outcome in the linear group, 17 (77%) attained complete abolition of the slow pathway conduction, whereas this was observed in only eight (32%) patients in the focal group (  P < 0.005  ). The session time was significantly shorter in the linear group. Recurrence of the tachycardia was not documented in any patient during a mean follow-up of  18 ± 8  months except one with residual slow pathway conduction in the focal ablation group. In conclusion, the anatomic linear approach can be performed safely and possesses a greater potential for slow pathway interruption compared to the electrogram mapping focal approach.     

Phenytoin-induced cerebral thrombosis in rats: cerebral ultrastructure, water content and ischaemic volume in the acute phase

A new rat model for multifocal cerebral thrombosis has recently been reported (Tani et al. , 1994; 1995). Ultrastructural changes in the cerebral neocortex in the acute phase were investigated in order to characterize the early pathological events in this model. A bolus injection of alkaline phenytoin solution (pH 10.8) into one internal carotid artery in the rat caused severe endothelial injury accompanied by thrombosis in the cerebral vasculature within 5 minutes, and severe oedema of the ipsilateral hemisphere within an hour. Cerebral water content was measured by the simple dry–wet method, and cerebral surface area and the surface area and volume of the ischaemic zone were measured using computer-aided image analysis. Good correlations were demonstrated between cerebral water content and cerebral surface area, and between the surface area and volume of the ischaemic zone. We report here that quantitative evaluation of acute cerebral damage induced by phenytoin solution is possible with high reliability using simple image analysis.     

Brain Distribution Characteristics of Xanthine Derivatives and Relation to their Locomotor Activity in Mice

The relationship between the brain distribution and motor activity in mice of the xanthines, theophylline, enprofylline, 1-methyl-3-propylxanthine (MPX) and oxpentifylline was investigated. Their plasma protein binding and hydrophobicity were also examined. When these xanthines were administered orally, enprofylline and oxpentifylline had no effect on motor activity. While theophylline increased motor activity over 10 mg kg^?1, MPX caused a decrease in such activity over 10 mg kg^?1. The protein-binding behaviour varied among these xanthines and was closely related to their hydrophobicity, which is represented as a logarithmic partition coefficient (log PC). MPX had the highest hydrophobicity, while oxpentifylline had the lowest. Brain distribution characteristics varied among these xanthines, with the rank order of their brain penetration ratio, calculated as the ratio of brain to unbound plasma concentrations, being theophylline > oxpentifylline > MPX > enprofylline. The inhibition constants (K_i) for adenosine A₁ receptors and cyclic 3′,5′-adenosine monophosphate (cAMP)-phosphodiesterase (PDE) of these xanthines were 44·6 and 134, > 1000 and 112, 26·4 and 49, and > 1000 and 111 μm for theophylline, enprofylline, MPX, and oxpentifylline, respectively. These findings suggest that the lack of effects of enprofylline and oxpentifylline on motor activity is probably due to their low brain penetration ratio or low adenosine A₁ affinity in comparison with theophylline. The decrease in the motor activity by MPX may be, in part, mediated by cAMP or adenosine.     

Successful bone marrow transplantation for idiopathic hypereosinophilic syndrome

A 21-year-old man who had an increased number of eosinophils with morphological abnormalities, bone marrow fibrosis and multiple organ dysfunction failed to respond to methylprednisolone and hydroxyurea. He was diagnosed with hypereosinophilic syndrome (HES) probably due to myeloproliferative disorder, and underwent allogeneic bone marrow transplantation (allo-BMT) from an HLA-identical sibling. The engraftment was confirmed on day 21 after BMT, but the patient developed acute graft-versus-host disease (GVHD) with grade I veno-occlusive disease, and transient increase of eosinophils of the donor type followed by chronic GVHD of the extensive type. These complications were eventually controlled with cyclosporin A. The patient survived free of disease for more than a year after BMT. Allo-BMT seems to be a possible treatment of HES/MPD.