We compared the pharmacodynamic activities of vancomycin and ampicillin with or without gentamicin once daily or thrice daily in an in vitro infection model with fibrin-platelet clots (FPCs) infected with Enterococcus...
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We compared the pharmacodynamic activities of vancomycin and ampicillin with or without gentamicin once daily or thrice daily in an in vitro infection model with fibrin-platelet clots (FPCs) infected with Enterococcus faecalis. Antibiotics were administered as a bolus to simulate human pharmacokinetics with regimens consisting of vancomycin 1 g q12h, ampicillin 2 g q6h and gentamicin 1.3 mg/kg q8h and 5 mg/kg qd. Model experiments were performed in duplicate over 72 h. FPCs were removed from the models in triplicate at 0, 8, 24, 32, 48 and 72 h, weighed, homogenized, diluted and plated to determine colony counts. Additional FPCs were removed at over 72 h post-antibiotic dose to determine antibiotic concentrations. The inoculum density at 72 h was used to compare bactericidal activity between the regimens. Overall, all antibiotic regimens containing either ampicillin or vancomycin significantly (P < 0.01) decreased the bacterial load at 72 h compared with the growth control although monotherapy regimens with either vancomycin or gentamicin had little impact. Ampicillin was superior to vancomycin with or without the addition of gentamicin (P < 0.01). There were no significant differences in reduction of bacterial density at 72 h between the combination of ampicillin or vancomycin plus gentamicin q8h and ampicillin or vancomycin plus gentamicin once daily. This was despite achieving unmeasurable FPC gentamicin concentrations after the 8 h time point during the once-daily aminoglycoside regimen. Vancomycin plus gentamicin either every 8 h or once daily was significantly (P < 0.01) better than vancomycin alone. Ampicillin plus either of the two gentamicin regimens was also better than ampicillin alone but this did not reach statistical significance. Our data suggest that once-daily gentamicin in combination with ampicillin or vancomycin demonstrates equivalent bacterial reductions to combination therapy with thrice-daily gentamicin. Once-daily aminoglycoside combination
Objectives. To evaluate the anticancer effects of a lipophilic macromolecular anticancer agent, poly(styreneco-maleic acid)-conjugated neocarzinostatin (SMANCS), dissolved in a lipid contrast medium (Lipiodol) given v...
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Objectives. To evaluate the anticancer effects of a lipophilic macromolecular anticancer agent, poly(styreneco-maleic acid)-conjugated neocarzinostatin (SMANCS), dissolved in a lipid contrast medium (Lipiodol) given via the renal artery to patients with renal cell carcinoma. Methods, Among 467 patients with renal cell carcinoma treated between April 1984 and March 1993, 191 were treated with SMANCS dissolved in a lipid contrast medium (a 3:2 mixture of Lipiodol F and Lipiodol Ultrafluid;Lpd). Selective arterial infusion of SMANCS/Lpd was performed at a dose of 1.0 or 1.5 mg/mL. The infusion was repeated at intervals of about 2 weeks or longer, but the doses and the total number of infusions varied among patients, according to results of computed tomography analysis. Results. Statistical analysis was performed for 415 patients who met the criteria of this study. Twenty-six surgical patients with metastases who underwent infusion therapy of SMANCS/Lpd for primary lesions showed 3 and 5-year survival rates of 23.0% and 12.8%, respectively;the rates were 19.3% and 9.7% in 31 patients who did not receive SMANCS infusion therapy. In 125 surgical patients without metastases who underwent SMANCS/Lpd infusion, the 5 and 10-year survival rates were 83.0% and 75.2%, respectively, whereas rates of 84.6% and 78.9% were observed in 199 surgical patients whose median tumor size was significantly smaller, however, than the SMANCS/Lpd infusion group. The maximal tumor diameter at the beginning of treatment was significantly larger (mean diameter 70.8 mm) in the SMANCS/Lpd infusion group than in the noninfusion group (59.1 mm). The survival rate was statistically better for patients with tumors of 100 mm diameter or larger in the SMANCS/Lpd infusion group (P <0.05): 5 and 10-year survival rates were 70.4% and 61.6%, respectively, for the infusion group and 64.6% and 50.9% for the group receiving no drug. In patients with larger tumor (greater than 110 mm), the survival rate at 13 yea
The coupled conservation of mass equations for oxygen, carbon dioxide and nitrogen are written down for a lung model consisting of two homogeneous alveolar compartments (with different ventilation-perfusion ratios) an...
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The coupled conservation of mass equations for oxygen, carbon dioxide and nitrogen are written down for a lung model consisting of two homogeneous alveolar compartments (with different ventilation-perfusion ratios) and a shunt compartment. As inspired oxygen concentration and oxygen consumption are varied, the flux of oxygen, carbon dioxide and nitrogen across the alveolar membrane in each compartment varies. The result of this is that the expired ventilation-perfusion ratio for each compartment becomes a function of inspired oxygen concentration and oxygen consumption as well as parameters such as inspired ventilation and alveolar perfusion. Another result is that the "inspired ventilation"-perfusion ratio and the "expired ventilation"-perfusion ratio differ significantly, under some conditions, for poorly ventilated lung compartments. As a consequence, we need to distinguish between the "inspired ventilation"-perfusion distribution, which is independent of inspired oxygen concentration and oxygen consumption, and the "expired ventilation"-perfusion distribution, which we now show to be strongly dependent on inspired oxygen concentration and less dependent oxygen consumption. Since the multiple inert gas elimination technique (MIGET) estimates the "expired ventilation"-perfusion distribution, it follows that the distribution recovered by MIGET may be strongly dependent on inspired oxygen concentration. (C) 2000 Academic Press.
Several lower respiratory tract infection (LRTI) trials have documented a correlation between clinical response and area under the inhibitory curve (24 h AUC/MIC;AUIC). The AUIC values in these studies were based on m...
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Several lower respiratory tract infection (LRTI) trials have documented a correlation between clinical response and area under the inhibitory curve (24 h AUC/MIC;AUIC). The AUIC values in these studies were based on measured MICs and measured serum concentrations. This study evaluates AUIC estimates made using population pharmacokinetic parameters, and MICs from an automated microbiological susceptibility testing system. A computer database review over 2 years yielded 81 patients at Millard Fillmore Hospital with a culture-documented Gramnegative LRTI who had been treated with piperacillin and an aminoglycoside, ceftazidime, ciprofloxacin or imipenem. Their AUIC values were estimated using renal function, drug dosages and MIC values. Outcome groups (clinical and microbiological cures and failures) were related to the AUIC values using Kruskal-Wallis ANOVA, linear regression and classification and regression tree (CART) analysis. A significant breakpoint for clinical cures was an AUIC value at least 72 SIT-1.24 h (inverse serum inhibitory titre integrated over time). All antibiotics performed significantly better above this value than below it. Clinical cure was well described by a Hill-type equation. Within the piperacillin/aminoglycoside regimen, most of the activity came from the piperacillin, which had a higher overall AUIC value than the aminoglycoside. AUIC estimations based upon MIC values derived from the automated susceptibility testing method differed from NCCLS breakpoint data and from tube dilution derived values in this hospital by as much as three tube dilutions. These automated methods probably overestimated the MIC values of extremely susceptible organisms. The lack of precise MIC estimates in automated clinical microbiology methods impairs the use of AUIC to prospectively optimize microbiological outcome. Even ignoring this limitation and using the values as they are reported, the results of this analysis suggest that AUIC targets between 72 and 275
Antenatal administration of glucocorticoids has been shown to improve postnatal lung function after preterm birth in the ovine fetus. Mechanisms of steroid-induced lung maturation include increased surfactant producti...
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Antenatal administration of glucocorticoids has been shown to improve postnatal lung function after preterm birth in the ovine fetus. Mechanisms of steroid-induced lung maturation include increased surfactant production and altered parenchymal lung structure. Whether steroid treatment also affects lung vascular function is unclear. Because nitric oxide contributes to the fall in pulmonary vascular resistance at birth, we hypothesized that the improvement of postnatal lung function of preterm lambs after treatment with prenatal glucocorticoids may be in part caused by an increase in endothelial nitric oxide synthase (eNOS) activity. To determine whether glucocorticoid treatment increases lung eNOS expression, we measured eNOS protein content by Western blot analysis of distal lung homogenates and immunostaining of formalin-fixed lungs from ovine fetuses delivered at preterm and term gestation after prenatal administration of glucocorticoids. Treatment protocols were followed in which ewes were treated with intramuscular betamethasone (0.5 mg/kg) at single or multiple doses at weekly intervals, and fetuses were delivered at 125, 135, or 145 d gestation. All groups were compared with saline-treated controls. Western blot analysis of whole lung homogenates demonstrated a 4-fold increase in eNOS protein content in lambs treated with repetitive doses of glucocorticoids and delivery at term (145 d;p < 0.002). In addition, a small increase in lung eNOS protein content was seen in lambs treated with a single dose of betamethasone at 128 d gestation with delivery at 135 d gestation. In comparison with control animals, there were no differences in lung eNOS content from the remaining lambs treated with glucocorticoids when delivery occurred at preterm ages (125 and 135 d). Immunostaining showed eNOS predominantly in the vascular endothelium in all vessel sizes. Pattern of staining was not altered by treatment with antenatal glucocorticoids. We conclude that maternal treatment
Statins belong to a class of drugs known to inhibit 3-hydroxy 3-methylglutaryl coenzyme A reductase, and block hepatic cholesterol synthesis. Since the initial statin was approved by the Food and Drug Administration i...
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Statins belong to a class of drugs known to inhibit 3-hydroxy 3-methylglutaryl coenzyme A reductase, and block hepatic cholesterol synthesis. Since the initial statin was approved by the Food and Drug Administration in 1987, these agents quickly became the gold standard for treatment of hypercholesterolemia. Effective lipid-lowering has been found to improve the long-term prognosis of patients with coronary artery disease. In addition, statins have also been found to be highly effective in primary and secondary stroke prevention among medically managed patients with cardiovascular disease, and it appears that this benefit is largely due to the non- cholesterol-loweri ng, so-called pleiotropic, effects of statins. During the past decade, agents such as beta-blockers, aspirin, or other antiplatelet medications have proven to reduce the incidence of adverse postoperative outcomes among vascular surgical patients, and have rightfully assumed a place in our overall therapeutic armamentarium. There is growing evidence that statins may be especially effective in reducing cardiovascular morbidity and improving outcomes after major vascular surgery. A recent study from Johns Hopkins Hospital demonstrated a threefold reduction in the rate of perioperative stroke (P <.05) and fivefold reduction of perioperative mortality (P <.05) among 1,566 patients undergoing carotid endarterectomy (CEA). This benefit was confirmed in a series of 3,360 CEAs performed at multiple hospitals throughout Western Canada. Statin use was independently associated with a 75% reduction (odds ratio [OR] = 0.25;95% confidence interval [Cl], 0.07-0.90) in the odds of death and 45% reduction (OR = 0.55;95% Cl, 0.32-0.95) in the odds of ischemic stroke or death among patients with symptomatic carotid disease. Further, there is some data indicating that statin use may reduce long-term incidence of restenosis following CEA. Preliminary work indicates that a similar benefit of statin use in reducing neurologic
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