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1.  L-651,392, a potent leukotriene inhibitor, controls inflammatory process in Escherichia coli pyelonephritis. 
In this study, the relationship between leukotrienes, peritubular cell infiltration with polymorphonuclear cells (PMNs) and renal tubular damage was investigated in a rat model of acute ascending pyelonephritis. Infection was induced by the injection of 10(5) CFU of Escherichia coli into the bladder and occlusion of the left ureter for 24 h. Treatment of infected animals was started 24 h after the induction of pyelonephritis with either hydrocortisone (25 mg/kg of body weight per day), the leukotriene inhibitor L-651,392 (10 mg/kg/day), or the vehicle of L-651,392 and was maintained for 5 days. At the end of treatment, the animals were killed, serum was collected, and both kidneys were removed for colony counts and histopathology. Renal function was evaluated by the measurement of blood urea nitrogen levels and creatinine clearance. The numbers of PMNs and mononuclear cells (MNs) in the cortex and medulla were recorded for all groups on plastic sections done from the left kidney. Infection alone (vehicle of L-651,392) resulted in intensive interstitial infiltration and a severe tubular destruction in the cortex. Treatment with hydrocortisone did not prevent PMN migration and tissue damage. By contrast, treatment with L-651,392 resulted in a significant reduction in PMNs (P < 0.001 in comparisons with all other groups) and greater preservation of the tubular structure despite identical bacterial counts than in the group receiving hydrocortisone. We conclude that L-651,392 prevents inflammatory cells from reaching the site of infection and protects the kidney from tubular damage associated with inflammation during pyelonephritis. Inhibitors of leukotrienes should be further investigated for their potential benefit as adjuvants to antibiotherapy in the treatment of pyelonephritis.
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PMCID: PMC284592  PMID: 7979288
2.  Daptomycin may attenuate experimental tobramycin nephrotoxicity by electrostatic complexation to tobramycin. 
The lipopeptidic antibiotic daptomycin is reported to reduce experimental tobramycin nephrotoxicity (D. Beauchamp, M. Pellerin, P. Gourde, M. Pettigrew and M. G. Bergeron, Antimicrob. Agents Chemother. 34:139-147, 1990; C. A. Wood, H. C. Finkbeiner, S. J. Kohlhepp, P. W. Kohnen, and D. C. Gilbert, Antimicrob. Agents Chemother. 33:1280-1285, 1989). In an attempt to explain these results, the in vivo and in vitro interactions between daptomycin and tobramycin were studied. Tobramycin alone and preincubated with negatively charged phospholipid bilayers (liposomes) was dialyzed against increasing concentrations of daptomycin in buffer at pH 5.4. A significant drop in the concentration of tobramycin was observed when daptomycin was added to the opposite half cells. Furthermore, daptomycin induced a concentration-dependent release of lipid-bound tobramycin. Gold labeling experiments showed that daptomycin could be incorporated into phospholipid layers. Female Sprague-Dawley rats were treated with daptomycin alone, with tobramycin alone, or with the combination over 2 to 10 days. Levels of daptomycin and tobramycin in serum were similar in all groups. The levels of tobramycin in the renal cortex increased significantly with time and, on day 10, reached values of 654 +/- 122 and 844 +/- 298 micrograms/g of tissue (mean +/- standard deviation; not significant) in animals treated with tobramycin and the combination of daptomycin-tobramycin, respectively. No significant difference was observed in the levels of tobramycin in the kidneys between animals treated with tobramycin or the daptomycin-tobramycin combination at any time. By contrast, daptomycin levels were significantly higher in the renal cortexes of animals treated with daptomycin-tobramycin in comparison with those in the renal cortexes of animals treated with daptomycin alone on days 6,8, and 10 (P < 0.01). For immunogold labeling studies, animals were killed 4 h after a single injection of daptomycin alone or daptomycin in combination with tobramycin. Daptomycin was found throughout the matrixes of the lysosomes of proximal tubular cells of animals treated with daptomycin alone. In animals treated with the combination of daptomycin and tobramycin, daptomycin was associated with intralysosomal myeloid bodies. Our results suggest that daptomycin might attenuate experimental aminoglycoside nephrotoxicity by interacting with the aminoglycoside, perhaps electrostatically, and thereby protecting intracellular targets of toxicity.
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PMCID: PMC284536  PMID: 8031040
3.  Concentrations of teicoplanin in serum and atrial appendages of patients undergoing cardiac surgery. 
The concentrations of teicoplanin in sera and heart tissues of 49 patients undergoing coronary bypass were measured. Each patient received a 6- or 12-mg/kg dose of teicoplanin administered in a slow intravenous bolus injection over 3 to 5 min beginning at the time of induction of anesthesia. Mean +/- standard error of the mean concentrations in serum were, for the two doses, respectively, 58.1 +/- 1.7 and 123.3 +/- 7.4 micrograms/ml 5 min after administration and 22.2 +/- 0.7 and 56.5 +/- 2.8 micrograms/ml at the time of removal of atrial appendages. Mean +/- standard error of the mean concentrations in tissue were 70.6 +/- 1.7 and 139.8 +/- 2.2 micrograms/g, respectively, giving mean tissue/serum ratios of 3.7 +/- 0.3 and 2.8 +/- 0.2, respectively. Teicoplanin penetrates heart tissue readily and reaches levels in the serum far in excess of the MICs for most pathogens that have been found to cause infections following open heart surgery.
PMCID: PMC171908  PMID: 2149493
4.  Enoxacin penetration into human prostatic tissue. 
Concurrent enoxacin concentrations in serum and prostatic tissue were determined in 14 patients. The mean ratios of enoxacin concentration in tissue over concentration in serum were 1.4 +/- 0.2 (standard error of the mean). The levels in serum and prostatic tissue were above the MICs for most urinary pathogens.
PMCID: PMC175883  PMID: 3196004
5.  Renal pharmacokinetic changes of gentamicin during enterococcal pyelonephritis. 
In the present study, the renal pharmacokinetics of gentamicin was investigated in pyelonephritic rats infected with Streptococcus (Enterococcus) faecalis. Four days after the induction of infection, animals were given either a single dose of gentamicin or two daily injections for 7 days. The treated animals were evaluated from 1 h to 6 months posttreatment. After a single injection, limited pharmacokinetic variations were observed, whereas after 14 injections infected kidneys demonstrated significantly higher concentrations and a more extended renal elimination phase of the antibiotic. Analysis of the area under the curve of the concentration in kidney versus time showed more marked renal accumulation by the infected and long-term treated animals than by normal animals or those receiving only one injection of aminoglycoside. Renal function remained normal in both the infected and normal animals treated with this aminoglycoside. These results demonstrate that S. faecalis pyelonephritis disturbs the renal handling of gentamicin and may increase the susceptibility of the kidney to aminoglycosides.
PMCID: PMC172262  PMID: 3134849
6.  Norfloxacin penetration into human renal and prostatic tissues. 
Concurrent norfloxacin concentrations in serum, kidney, and prostatic tissue were determined in 14 patients. Mean ratios of norfloxacin concentration in tissue over concentration in serum were 6.6 +/- 2.8 for the kidney and 1.7 +/- 0.2 for the prostate samples. The levels were above the MICs of most urinary pathogens.
PMCID: PMC180245  PMID: 3834837
7.  Concentrations of fusidic acid, cloxacillin, and cefamandole in sera and atrial appendages of patients undergoing cardiac surgery. 
The concentrations of cefamandole, cloxacillin and fusicid acid were measured in the serum and heart tissue of 100 recipients of these drugs before cardiac surgery. During cardiopulmonary bypass, mean (+/- standard deviation) peak concentrations in serum of all patients were 63.0 +/- 34.0 micrograms of cefamandole per ml, 30.8 +/- 17.7 micrograms of cloxacillin per ml, and 32.4 +/- 10.8 micrograms of fusidic acid per ml. Mean (+/- standard deviation) concentrations in atrial appendages taken 1 h (+/- 15 min) after infusion were 21.3 +/- 11.0 micrograms of cefamandole per g, 23.8 +/- 17.3 micrograms of cloxacillin per g, and 10.7 +/- 4.2 micrograms of fusidic acid per g. No cloxacillin could be detected in 5 of 39 heart specimens. Mean tissue-to-serum ratios at 1 h for cefamandole, cloxacillin, and fusidic acid were respectively 0.35, 0.73, and 0.33. Fusidic acid, a drug which is highly effective in vitro against both methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, was detectable in heart tissue in concentrations which were 12 times higher than the MICs of this agent against these resistant microorganisms.
PMCID: PMC180189  PMID: 4026265
8.  Intrarenal distribution of trimethoprim and sulfamethoxazole. 
In the present study, rats were given trimethoprim (TMP, 10 mg/kg), sulfamethoxazole (SMZ, 50 mg/kg), or a combination of the respective doses of TMP and SMZ. Thirty-six rats received each of the drugs studied. Six recipients of a compound (or mixture) were evaluated hourly, from 1 to 6 h after intraperitoneal injection of the agent. At each timed interval, serum, urine, cortex, medulla, and papilla were analyzed for drug content. Peak serum values of 1.1 microgram of TMP and 131.1 microgram of active SMZ (nonacetylated sulfonamide) per ml were observed after injection of the combination TMP-SMZ. Although the cortical, medullary, and papillary TMP concentrations were severalfold higher than the respective serum values (P < 0.01), microbiologically active SMZ did not concentrate in the renal parenchyma and was found in lower concentration there than in the serum (P < 0.01). The levels of SMZ in all parts of the kidney of animals which received the mixture SMZ-TMP were lower than those detected in the animals which were given SMZ alone. The average ratio of active SMZ to TMP within the medulla and the papilla was less than 20 to 1 in the first 2 h. The intrarenal distribution of these drugs may have therapeutic implications.
PMCID: PMC283795  PMID: 7425603
9.  The RNA of both polarities of the peach latent mosaic viroid self-cleaves in vitro solely by single hammerhead structures. 
Nucleic Acids Research  1995;23(5):745-752.
Hammerhead self-cleavage of dimeric, monomeric, truncated and mutated transcripts derived from both polarities of the peach latent mosaic viroid (PLMVd) were characterized. In contrast to some results previously published for a very close sequence variant (see ref. 1), these RNAs exhibit a virtually identical self-cleavage during transcription and after purification. By self-cleavage of dimeric transcripts with normal and mutated hammerhead domains and by complementation experiments, we show that the cleavage reactions involve only single hammerhead structures. This observation contrasts with the case of avocado sunblotch viroid (ASBVd), the other self-cleaving viroid, whose mechanism involves mostly double hammerhead structures, whereas single hammerhead cleavage is associated with viroid-like plant satellite RNAs. The difference in stability between the native secondary structures adopted by viroids and the autocatalytic structures, including the hammerhead motif, governs the efficiency of the self-cleavage reaction. The transition between these conformers is the limiting step in catalysis and is related exclusively to the left arm region of PLMVd secondary structure, which includes the hammerhead sequences. Most of the mutations between the variant we used and the sequence variant previously published are located in this left arm region, which may explain to a great extent the differences in their cleavage efficiency. No interactions with long-range sequences contributing to the autocatalytic tertiary structure were revealed in these experiments.
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PMCID: PMC306754  PMID: 7708488

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