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1.  Pain assessment during conscious sedation for cervical cancer high-dose-rate brachytherapy 
Current Oncology  2013;20(4):e307-e310.
This observational study set out to evaluate the effectiveness of conscious sedation anesthesia for pain control during high-dose-rate (hdr) brachytherapy using a ring-and-tandem applicator system for patients with cervical cancer.
At the time of initiation of the hdr cervical cancer brachytherapy program at our institution, patients received a detailed symptom assessment during the procedures. Brachytherapy was carried out using a Smit sleeve, together with a ring-and-tandem applicator. Midazolam and an opioid—hydromorphone, morphine, or fentanyl—were the main agents used to achieve conscious sedation.
From January 2009 to October 2010, 20 patients (median age: 45 years) underwent 57 procedures. All patients received chemoradiation with curative intent. The median duration of the procedures was 1.4 hours, and no significant cardiovascular events were noted. The total dose of intravenous midazolam used ranged from 0.5 mg to 8.5 mg (median: 2.5 mg). The total dose of intravenous morphine equivalent used ranged from 2.5 mg to 60 mg (median: 8 mg). The mean and median pain scores during the procedures were 1.4 and 1.1 respectively. Brief moments of moderate to severe incidental pain were noted at the time of certain events during the procedure—specifically during insertion of the ring-and-tandem applicator. The maximal pain score during the entire procedure ranged from 0 to 10 (median: 4.7). The period of recovery from conscious sedation was relatively brief (median discharge time: 1 hour).
We were able to demonstrate that patients undergoing hdr brachytherapy for cervical cancer can achieve good pain control with conscious sedation.
PMCID: PMC3728059  PMID: 23904769
Cervical cancer; carcinoma of the cervix; conscious sedation; high-dose-rate brachytherapy; pain and symptom assessment; incidental pain; recovery time
2.  Time-restricted feeding schedules modify temporal variation of gentamicin experimental nephrotoxicity. 
The effect of timing of gentamicin dosing relative to food access periods was evaluated in experimental animals. Female Sprague-Dawley rats were treated for 4 and 10 days with gentamicin (40 mg/kg of body weight/day) intraperitoneally at either 0700, 1300, 1900, or 0100 h according to three food presentation schedules: food was available from 0800 to 1600 h in the first group, from 1600 to 0000 h in the second group, and from 0000 to 0800 h in the last group. Animals were thus subjected to a restricted feeding period. Results indicate that time-restricted feeding schedules displace the peak and the trough of gentamicin-induced renal toxicity, as evaluated by changes in the inhibition of sphingomyelinase activity, cellular regeneration (incorporation of [3H]thymidine into DNA of renal cortex), and blood urea nitrogen and serum creatinine levels, as well as histopathological lesions observed after 10 days of treatment. In fact, the toxicity was minimal when gentamicin was injected during the feeding period, while the maximal toxicity was found when gentamicin was administered during the fasting period. It is concluded that the feeding period can modulate aminoglycoside nephrotoxicity. The time of dosing of gentamicin relative to the time of feeding seems to be a more important modulator of gentamicin nephrotoxicity than the light-dark cycle.
PMCID: PMC163942  PMID: 9210668
3.  Attenuation of gentamicin-induced nephrotoxicity in rats by fleroxacin. 
The effect of fleroxacin on gentamicin-induced nephrotoxicity was evaluated with female Sprague-Dawley rats. Animals were injected during 4 or 10 days with saline (NaCl; 0.9%), gentamicin alone at doses of 10 and 40 mg/kg of body weight/12 h (subcutaneously), fleroxacin alone at a dose of 25 mg/kg/12 h (intraperitoneally), or the combination gentamicin-fleroxacin in the same regimen. Gentamicin induced a dose- and time-dependent renal toxicity as evaluated by gentamicin cortical levels, sphingomyelinase activity in the renal cortex, histopathologic and morphometric analysis, blood urea nitrogen and serum creatinine levels, and cellular regeneration ([3H]thymidine incorporation into DNA of cortical cells). The extent of these changes was significantly reduced when gentamicin was given in combination with fleroxacin. Although the mechanisms by which fleroxacin reduces the nephrotoxic potential of gentamicin are unknown, we propose that the fleroxacin-gentamicin combination enhances exocytosis activity in proximal tubular cells, as suggested by the higher excretion of urinary enzymes and lower cortical levels of gentamicin observed in animals treated with the combination fleroxacin-gentamicin compared with those treated with gentamicin alone. The protective effect of fleroxacin on gentamicin nephrotoxicity should be investigated further.
PMCID: PMC163893  PMID: 9174177
4.  Effects of fasting on temporal variations in nephrotoxicity of gentamicin in rats. 
Evidence for temporal variations in the nephrotoxicity of low doses of aminoglycosides were recently shown by using specific and sensitive parameters of renal toxicity. The aim of the present study was to evaluate the effect of a short period of fasting on the temporal variations in the renal toxicity of gentamicin. Twenty-eight normally fed (i.e., food and water were available ad libitum throughout the experiment) female Sprague-Dawley rats (weight, 175 to 220 g) and 28 fasted rats (i.e., only water was available during a 12-h fast before and a 24-h fast after gentamicin injection) were used. The animals were synchronized on a 14-h light, 10-h dark cycle (lights on at 0600 h) for 1 week before gentamicin administration. In July 1993, each group of animals was treated with a single intraperitoneal injection of saline (NaCl, 0.9%) or gentamicin (150 mg/kg of body weight) at either the peak (1400 h) or the trough (0200 h) of the previously determined toxicity. On day 1, the 24-h urinary excretion of beta-galactosidase, N-acetyl-beta-D-glucosaminidase, and gamma-glutamyltransferase was significantly higher in normally fed animals treated with gentamicin at 1400 h than in their time-matched controls and in normally fed animals treated at 0200 h (P < 0.01), which had normal levels of these enzymes. By contrast, the urinary excretion of these enzymes was significantly higher in both groups of gentamicin-treated, fasted rats than in their time-matched control groups (P < 0.01), reaching levels similar to those measured in normally fed rats treated at 1400 h. The accumulation of gentamicin was significantly lower in the renal cortex of normally fed rats treated at 0200 h than in rats treated at 1400 h (P < 0.05), but this time-dependent difference was not found in fasted rats treated at 0200 and 1400 h. Immunogold labeling done on ultrathin sections and observed by electron microscopy showed a similar subcellular localization of gentamicin in normally fed and fasted rats treated at either 1400 or 0200 h. These results suggest that the feeding period is of crucial importance in the temporal variations of the nephrotoxicity of gentamicin in rats.
PMCID: PMC163178  PMID: 8851591
5.  Temporal variation in nephrotoxicity of low doses of isepamicin in rats. 
The temporal variation in the nephrotoxicity of low doses of isepamicin was studied in male Sprague-Dawley rats treated with a single daily intraperitoneal injection of saline (NaCl, 0.9%) or isepamicin (80 mg/kg of body weight) at either 0800, 1400, 2000, or 0200 h for 4 and 10 days. On day 10, the cellular regeneration (incorporation of [3H] thymidine into DNA of renal cortex) and cortical accumulation of isepamicin were significantly higher in animals treated at 1400 h than at 0200 h (P < 0.01). Immunogold labeling studies showed that isepamicin was essentially localized in the lysosomes of proximal tubular cells in all treated groups, but the density of the gold particles over the lysosomes was higher in animals treated at 1400 than at 0200 h. The results of the present study show that the renal toxicity of isepamicin was maximal at 1400 h (midlight period) and minimal at 0200 h (middark period).
PMCID: PMC163205  PMID: 8851618
6.  Attenuation by daptomycin of gentamicin-induced experimental nephrotoxicity. 
Previously, daptomycin was shown to reduce tobramycin nephrotoxicity in vivo (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). Female Sprague-Dawley rats were treated with saline (NaCl, 0.9%), daptomycin (10 mg/kg of body weight every 12 h, subcutaneously), gentamicin (30 mg/kg/12 h, intraperitoneally) or with a combination of daptomycin plus gentamicin over a 10-day period. Animals were killed 4, 10, and 20 days after the end of treatment. Four days after the end of drug administration, gentamicin and daptomycin levels in the renal cortices of animals treated with the combination of daptomycin and gentamicin were significantly higher than in those of rats given gentamicin or daptomycin alone (P < 0.01). Despite the higher cortical concentrations of gentamicin, rats given the combination of gentamicin and daptomycin had less reduction in renal cortex sphingomyelinase activity, less evidence of regeneration of cellular cortical cells ([3H]thymidine incorporation into cortex DNA), lower creatinine concentration in serum, and less histopathologic evidence of injury than rats given gentamicin alone. By immunogold technique, both daptomycin and gentamicin were localized to the lysosomes of proximal tubular cells, regardless of whether animals received the drugs alone or in combination. Interestingly, myeloid body formation occurred in both those animals given gentamicin alone and those given daptomycin plus gentamicin. No significant changes were observed for all groups between 10 and 20 days after the end of therapy, suggesting that the toxicity of gentamicin was not delayed by the concomitant injection of daptomycin. The results confirm that daptomycin can attenuate experimental gentamicin nephrotoxicity.
PMCID: PMC188145  PMID: 8067733
7.  Ceftriaxone protects against tobramycin nephrotoxicity. 
The effect of ceftriaxone on tobramycin-induced nephrotoxicity was investigated. Female Sprague-Dawley rats were treated during 4 and 10 days with saline (NaCl, 0.9%), ceftriaxone at a dose of 100 mg/kg of body weight/12 h subcutaneously, tobramycin at doses of 40 and 60 mg/kg/12 h intraperitoneally, or the combination ceftriaxone-tobramycin. Creatinine levels in serum were significantly higher in animals treated with tobramycin alone given at 60 mg/kg/12 h during 10 days, compared with control animals (P < 0.01) or animals receiving the combination tobramycin-ceftriaxone (P < 0.01). After 10 days of treatment, ceftriaxone did not accumulate in renal tissue but did reduce the renal intracortical accumulation of tobramycin (P < 0.05). Tobramycin given alone at either 40 or 60 mg/kg/12 h induced a significant inhibition of sphingomyelinase activity compared with control animals (P < 0.05). However, this enzyme activity was significantly less inhibited when tobramycin was injected in combination with ceftriaxone (P < 0.05). Ceftriaxone alone had no effect on the activity of this enzyme. The [3H]thymidine incorporation into the DNA of renal cortex was also significantly lower in animals treated with tobramycin-ceftriaxone compared with animals receiving tobramycin alone (P < 0.05). The 24-h urinary excretion of beta-galactosidase was significantly reduced in animals treated with the combination tobramycin-ceftriaxone compared with the administration of tobramycin alone at 40 and 60 mg/kg/12 h after 5 and 10 days (P < 0.05). Histologically, ceftriazone induced very few cellular alterations and reduced considerably the presence of typical signs of tobramycin nephrotoxicity. This investigation demonstrated that ceftriaxone protects animals against tobramycin-induced nephrotoxicity.
PMCID: PMC284537  PMID: 8031041
8.  Temporal changes of pharmacokinetics, nephrotoxicity, and subcellular distribution of tobramycin in rats. 
The present study was designed to determine the temporal changes in tobramycin nephrotoxicity during the dark and the light periods of the day and to look for the mechanisms of such changes. Female Sprague-Dawley rats (9 to 11 weeks old) were housed in a 14-h-light-10-h-dark cycle (lights on 0600 to 2000 h). A bolus of tobramycin (60 mg/kg of body weight) was intravenously injected into a first group of 15 rats, at either 1400 or 0200 h. Six blood samples were taken from each rat, 30 to 210 min after the bolus injection. The total clearance of the drug was reduced during the rest period (1400 h) of rats compared with the activity period (0200 h) (P = 0.0007). Another group of 99 rats was given intraperitoneally a single dose of tobramycin (40 mg/kg), and renal cortices were collected 2 to 222 h after injection. The cortical drug levels were always higher in animals injected at 1400 h than in those injected at 0200 h. A last group of 32 rats was used in the studies of tobramycin (30 mg/kg/day, once daily for 10 days, intraperitoneally) nephrotoxicity and subcellular distribution. Weight gain in the rats receiving tobramycin (both 1400 and 0200 h) was significantly (P = 0.028) less than that in the controls. Nephrotoxicity, indicated by the incorporation of [3H]thymidine into cortical DNA and urinary excretion of N-acetyl-beta-D-glucosaminidase, was significantly higher in animals treated at 1400 h than in those treated at 0200 h. No difference in the subcellular distribution of tobramycin was observed. The data indicate that the reduction in the clearance of tobramycin during the rest period is in part responsible for the higher nephrotoxicity in rats.
PMCID: PMC284396  PMID: 8141580

Results 1-8 (8)