Influence of indomethacin on the intrarenal uptake of gentamicin in endotoxemic rats.

Gentamicin is a commonly used antibiotic for the treatment of gram-negative-bacterial infections. Bacterial endotoxin is liberated during antibiotic therapy, and we have shown that endotoxemic animals accumulate more aminoglycosides in their renal parenchyma than normal animals. Vasoactive mediators, such as prostaglandins and thromboxanes, are released after endotoxin and are involved in inflammation. Indomethacin, a nonsteroidal anti-inflammatory drug known to inhibit the synthesis of these hormones, was infused intravenously as a bolus (3.0 mg/kg) or as a bolus followed by a continuous infusion (0.75 mg/kg per h) to rats given gentamicin. Levels of gentamicin in serum and kidney were increased 2 h post-antibiotic treatment in the endotoxemic animals. Renal function was not significantly disturbed. Indomethacin given as a bolus failed to correct the disturbed intrarenal pharmacokinetics of gentamicin induced by endotoxin. However, a bolus followed by continuous infusion of indomethacin resulted in low cortical and high papillary levels of antibiotic. These changes were correlated with the inhibition of prostaglandin synthesis from the kidney. These observations suggest an important role for prostaglandins in the interaction among endotoxin, aminoglycosides, and the kidney. Specific inhibitors of arachidonic acid metabolites should be investigated to further understand the mechanisms of this interaction.     

Lipoic acid supplementation and endothelial function

Endothelial dysfunction is caused by all the recognized cardiovascular risk factors and has been implicated in the complex processes leading to the initiation and progression of atherosclerosis. Short-term treatment with lipoic acid is shown in the current issue of the British Journal of Pharmacology to improve endothelial function of aortic rings of old rats. The age-related decrease in phosphorylation of nitric oxide synthase and Akt was improved by lipoic acid supplementation. The improved phosphorylation status may have been due to reduced activity of the phosphatase PPA2, associated with decreased levels of endothelial ceramide induced by lipoic acid. Neutral sphingomyelinase activity was also reduced by lipoic acid, which was due, at least in part, to increased glutathione levels in endothelial cells. The favourable antioxidant, anti-inflammatory, metabolic and endothelial effects of lipoic acid shown in rodents, in this and other recently published studies, warrant further assessment of its potential role for prevention and treatment of cardiovascular diseases.     

Intraarticular corticosteroids,supervised physiotherapy,or a combination of the two in the treatment of adhesive capsulitis of the shoulder: A placebo‐controlled trial

Objective

To compare the efficacy of a single intraarticular corticosteroid injection, a supervised physiotherapy program, a combination of the two, and placebo in the treatment of adhesive capsulitis of the shoulder.

Methods

Ninety‐three subjects with adhesive capsulitis of <1 year's duration were randomized to 1 of 4 treatment groups: group 1, corticosteroid injection (triamcinolone hexacetonide 40 mg) performed under fluoroscopic guidance followed by 12 sessions of supervised physiotherapy; group 2, corticosteroid injection alone; group 3, saline injection followed by supervised physiotherapy; or group 4, saline injection alone (placebo group). All subjects were taught a simple home exercise program. Subjects were reassessed after 6 weeks, 3 months, 6 months, and 1 year. The primary outcome measure was improvement in the Shoulder Pain and Disability Index (SPADI) score.

Results

At 6 weeks, the total SPADI scores had improved significantly more in groups 1 and 2 compared with groups 3 and 4 (P = 0.0004). The total range of active and passive motion increased in all groups, with group 1 having significantly greater improvement than the other 3 groups. At 3 months, groups 1 and 2 still showed significantly greater improvement in SPADI scores than group 4. There was no difference between groups 3 and 4 at any of the followup assessments except for greater improvement in the range of shoulder flexion in group 3 at 3 months. At 12 months, all groups had improved to a similar degree with respect to all outcome measures.

Conclusion

A single intraarticular injection of corticosteroid administered under fluoroscopy combined with a simple home exercise program is effective in improving shoulder pain and disability in patients with adhesive capsulitis. Adding supervised physiotherapy provides faster improvement in shoulder range of motion. When used alone, supervised physiotherapy is of limited efficacy in the management of adhesive capsulitis.

     

Development of coronary aneurysm after cutting balloon angioplasty: Assessment by intracoronary ultrasound

We report the case of a coronary aneurysm observed 6 mo after cutting balloon angioplasty complicated by a mild perforation. Intravascular ultrasound allowed characterization of the malformation as a true aneurysm. The clinical course was uneventful. Cathet. Cardiovasc. Diagn. 44:449–452, 1998. © 1998 Wiley-Liss, Inc.     

Increased renal uptake of gentamicin in endotoxemic rats receiving concomitant thromboxane A2 antagonist therapy.

This report describes the effects of endotoxin and a thromboxane receptor antagonist, L-655,240, on kidney function and the intrarenal pharmacokinetics of aminoglycosides. The rationale for these studies was that thromboxane antagonists may eventually be used in combination with aminoglycosides in patients with gram-negative sepsis and endotoxemia. As aminoglycosides are nephrotoxic and endotoxin has already been shown to increase the renal uptake of gentamicin, we investigated the possibility that thromboxane antagonists might interfere with the nephrotoxic potential of both substances. A decrease in the volume of distribution and an increase in the intracortical concentration of gentamicin were observed in animals given endotoxin. Compared with animals given endotoxin alone, those which received endotoxin plus L-655,240 had significant accumulation of gentamicin in the renal cortex and medulla, as determined by the area under the concentration-time curve, and a significant reduction in the total clearance of the antibiotic (P < 0.05). This difference in uptake could not be attributed to hypotension or changes in the glomerular filtration rate or renal plasma flow. L-655,240 alone did not modify gentamicin pharmacokinetics but did decrease p-aminohippuric acid secretion. Thromboxane antagonists in the context of endotoxemia increase intrarenal uptake of aminoglycosides. If these compounds are to be used as therapeutic agents when endotoxin is present, their influence on renal handling of nephrotoxic drugs needs to be considered. Multiple-dosing regimens deserve investigation.     

Sensitivity of voxel-based morphometry analysis to choice of imaging protocol at 3 T

The objective of this study was to determine which 3D T(1)-weighted acquisition protocol at 3 T is best suited to voxel-based morphometry (VBM), and to characterize the sensitivity of VBM to choice of acquisition. First, image quality of three commonly used protocols, FLASH, MP-RAGE and MDEFT, was evaluated in terms of SNR, CNR, image uniformity and point spread function. These image metrics were estimated from simulations, phantom imaging and human studies. We then performed a VBM study on nine subjects scanned twice using the three protocols to evaluate differences in grey matter (GM) density and scan-rescan variability between the protocols. These results reveal the relative bias and precision of the tissue classification obtained using the different protocols. MDEFT achieved the highest CNR between white and grey matter, and the lowest GM density variability of the three sequences. Each protocol is also characterized by a distinct regional bias in GM density due to the effect of transmission field inhomogeneity on image uniformity combined with spatially variant GM T(1) values and the sequence's T(1) contrast function. The required population sample size estimates to detect a difference in GM density in longitudinal VBM studies, i.e. based only on methodological variance, were lowest for MDEFT. Although MP-RAGE requires more subjects than FLASH, its higher cortical CNR improves the accuracy of the tissue classification results, particularly in the motor cortex. For cross-sectional VBM studies, the variance in morphology across the population is likely to be the primary source of variability in the power analysis.     

The importance of measured end-points in demonstrating the occurrence of interactions: a case study with methylchloroform and m-xylene.

Mixed exposures may result in significant changes in one biomarker of exposure without altering another biomarker, and this may have unknown significance in terms of exposure assessment and overall toxicity of the mixture. Results from a previous investigation showed that human exposure to methylchloroform (MC, 400 ppm) and m-xylene (XYL, 200 ppm) during 4 h did not result in any significant effect on blood concentrations of these solvents, suggesting the absence of interaction between MC and XYL. Those results were adequately described by conducting a physiologically-based toxicokinetic (PBTK) modeling of the MC-XYL interaction in humans; however, the model suggested that urinary excretion of MC metabolites would be reduced as a result of combined exposure, whereas that of XYL metabolites would not be modified. An experimental verification of this model prediction was then undertaken with rats. In this study, Sprague-Dawley rats (n, 5) were exposed during 4 h to MC (400 ppm) or XYL (200 ppm), alone or as a mixture. Results showed that combined exposure did not affect the blood concentration of MC whereas that of XYL was increased throughout the 2-h blood collection period following exposure. The excretion of MC metabolites during a period of 48 h following the onset of exposure, i.e., trichloroethanol (TCE: -71%) and trichloroacetic acid (TCA: -73%), were significantly reduced. Methylhippuric acid (MHA) was not affected by co-exposure to MC as expected from the PBTK model forecasts. These results exemplify the use of a priori PBPK modeling for designing interaction studies and choosing appropriate/sensitive end-points for demonstrating the occurrence of potential interactions.