Bioavailability and metabolism of hydroquinone after intratracheal instillation in male rats.
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The purpose of this study was to investigate the rate and extent of hydroquinone (HQ) absorption and first pass metabolism in the lungs of male rats in vivo. [14C]HQ in physiological saline was administered intratracheally via an indwelling endotracheal tube to simulate inhalation exposure to HQ dust. The bioavailability of HQ was determined by blood sampling simultaneously at arterial and venous sites beginning immediately after administration to conscious rats. Pulmonary absorption and metabolism, and systemic metabolism and elimination were determined by chromatographic analysis of parent compound and metabolites in blood samples after intratracheal administration of [14C]HQ at 0.1, 1.0, and 10 mg/kg. Pulmonary absorption of HQ was found to be very rapid with [14C]HQ detectable in arterial blood, and to a lesser extent in venous blood, within 5 to 10 s after dose administration. Only [14C]HQ was detected in the initial (5-10 s) arterial blood samples at all dose levels, indicating that pulmonary metabolism of HQ was not extensive. However, later blood samples (45-720 s) indicated rapid metabolism and elimination of the parent compound and metabolites after intratracheal absorption. The elimination half-life from the 0.1 mg/kg dose was allometrically scaled to human proportions and used to estimate the steady-state (maximum) human blood concentrations of HQ resulting from presupposed workplace exposures. The estimates indicated minimal levels of HQ in human blood after respiratory exposures of greater than 1 h at 0.1 or 2.0 mg/m3; these levels were less than background concentrations of HQ detected in human blood in previous studies. (+info)
Extracorporeal rheopheresis in the treatment of acute ischemic stroke: A randomized pilot study.
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BACKGROUND AND PURPOSE: Extracorporeal rheopheresis is a safe method to optimize hemorheology. Our aim was to determine whether treatment with extracorporeal rheopheresis in patients with acute ischemic hemispheric stroke improves cerebral perfusion as assessed with serial 99mTc-ethyl-cysteinate-dimer single-photon emission CT (99mTc-ECD SPECT). We also investigated how clinical outcome is associated with treatment and imaging results. METHODS: Thirty-three patients (mean age, 64+/-10 years) with acute ischemic hemispheric stroke were included in a prospective, randomized, parallel group pilot study. First treatment with or without extracorporeal rheopheresis took place within 12 hours after the onset of symptoms and was repeated 3 times at intervals of 24 hours. Hemorheological parameters were measured before and after each session. Each patient underwent 99mTc-ECD SPECT immediately before treatment, 6 to 8 hours after treatment, and after 5 days. A semiquantitative SPECT graded scale was used to measure depth and extent of activity deficits and thus to quantify the perfusion deficit. RESULTS: Seventeen patients were actively treated with extracorporeal rheopheresis, and 16 patients did not receive extracorporeal rheopheresis. After 3 months, no differences were found in the functional or neurological outcome. Despite a rapid, sustained decrease of plasma viscosity and erythrocyte aggregation in the rheopheresis group, there was no significant difference in the SPECT graded scale after therapy between the 2 groups. Patients with early reperfusion (decrease in the SPECT graded scale >25% 6 to 8 hours after therapy compared with the baseline examination) experienced a better functional outcome (Modified Rankin Scale) after 3 months compared with patients without reperfusion (P=0.04). CONCLUSIONS: Since quantitative flow mapping and clinical follow-up did not reveal any differences between patients who were treated with extracorporeal rheopheresis and controls, it appears very unlikely that extracorporeal rheopheresis enhances reperfusion after acute cerebral ischemia. (+info)
Activation of the tissue factor pathway occurs during continuous venovenous hemofiltration.
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BACKGROUND: Activation of the tissue factor pathway occurs during continuous venovenous hemofiltration (CVVH). Despite adequate exogenous anticoagulation, the occlusion of CVVH circuits can occur within minutes to a few hours of use and is associated with evidence of thrombin generation. Having found no evidence of activation of the contact factor (intrinsic coagulation) pathway during CVVH, we sought to examine the effect of the first episode of CVVH on the tissue factor (extrinsic) pathway of coagulation and thrombin generation. METHODS: Twelve critically ill patients were studied prior to the commencement of hemofiltration and at regular intervals thereafter until the filter clotted. RESULTS: Prior to hemofiltration, most patients had increased levels of plasma tissue factor, thrombin-antithrombin (TAT) complexes, and tissue factor pathway inhibitor (TFPI); during hemofiltration, further generation of TAT complexes occurred. Initially, levels of activated factor VII (FVIIa) fell and TFPI increased, but during the course of hemofiltration, the levels of TFPI fell and FVIIa increased. Levels of tissue factor increased during CVVH in some patients, but this was not related to the generation of FVIIa. CONCLUSIONS: These data indicate that activation of FVII occurred during CVVH, which was related to levels of TFPI, but not tissue factor, and was coincidental to thrombin generation. (+info)
Influence of zero-balanced hemofiltration on the course of severe experimental pancreatitis in pigs.
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OBJECTIVE: To examine the impact of continuous venovenous hemofiltration (CVVH) on the course of experimental pancreatitis in pigs. SUMMARY BACKGROUND DATA: The activation of different mediator cascades is assumed to trigger multiple organ dysfunction or failure during necrotizing pancreatitis. CVVH has been suggested to be beneficial in those instances by eliminating several inflammatory mediators released in the circulation. METHODS: Pancreatitis was induced by a combined intraductal injection of sodium taurocholate and enterokinase. Control group animals received no treatment after induction. A second group underwent "therapeutic" CVVH after a 20% decline of mean arterial pressure. In the third group, "prophylactic" CVVH was started simultaneously with the induction of pancreatitis. The concentrations of tumor necrosis factor-alpha, transforming growth factor-beta1, kinin, and phospholipase A2 were measured at different time points in blood (pre- and postfilter) and in the hemofiltrate to calculate the respective sieving coefficients that reflect most accurately the plasma clearance of mediators by CVVH. RESULTS: Survival time was significantly prolonged both by therapeutic and prophylactic CVVH; it was more pronounced in the latter. CVVH did not influence the increase in transforming growth factor concentrations. However, 6 hours after induction, the increases of plasma concentrations of tumor necrosis factor, phospholipase, and kinin were significantly weakened by CVVH compared with controls. In the treatment groups, the plasma concentrations of tumor necrosis factor and phospholipase showed a significant negative correlation with the respective sieving coefficients, which decreased in the later course of the experiments. CONCLUSIONS: Experimental necrotizing pancreatitis was associated with a tremendous increase of plasma concentrations of tumor necrosis factor, phospholipase, and kinin. The effective removal of these mediators by CVVH resulted in significantly improved survival time. Animals that received prophylactic CVVH had a longer survival period than those in which CVVH was started after clinical impairment. The decreasing efficiency of CVVH in eliminating inflammatory mediators in the later course of the experiments suggested that the filter membranes were compromised by long-term application. These findings provide further evidence that CVVH offers therapeutic options even in the absence of conventional indications for blood-purifying treatments. (+info)
Cytokine removal during continuous hemofiltration in septic patients.
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A potential application of the continuous renal replacement therapies is the extracorporeal removal of inflammatory mediators in septic patients. Cytokine elimination with continuous renal replacement therapies has been demonstrated in several clinical studies, but so far without important effects on their serum concentrations. Improved knowledge of the cytokine removal mechanisms could lead to the development of more efficient treatment strategies. In the present study, 15 patients with septic shock and acute renal failure were observed during the first 24 h of treatment with continuous venovenous hemofiltration (CVVH) with an AN69 membrane. After 12 h, the hemofilter was replaced and the blood flow rate (QB) was switched from 100 ml/min to 200 ml/min or vice versa. Pre- and postfilter plasma and ultrafiltrate concentrations of selected inflammatory and anti-inflammatory cytokines were measured at several time points allowing the calculation of a mass balance. Cytokine removal was highest 1 h after the start of CVVH and after the change of the membrane (ranging from 25 to 43% of the prefilter amount), corresponding with a significant fall in the serum concentration of all cytokines. The inhibitors of inflammation were removed to the same extent as the inflammatory cytokines. Adsorption to the AN69 membrane appeared to be the main clearance mechanism, being most pronounced immediately after installation of a new membrane and decreasing steadily thereafter, indicating rapid saturation of the membrane. A QB of 200 ml/min was associated with a 75% increase of the ultrafiltration rate and a significantly higher convective elimination and membrane adsorption than at a QB of 100 ml/min. The results indicate that optimal cytokine removal with CVVH with an AN69 membrane could be achieved with a combination of a high QB/ultrafiltration rate and frequent membrane changes. (+info)
Regional citrate anticoagulation in continuous venovenous hemofiltration in critically ill patients with a high risk of bleeding.
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BACKGROUND: Systemic heparinization is associated with a high rate of bleeding when used to maintain patency of the extracorporeal circuit during continuous renal replacement therapy (CRRT) in critically ill patients. Regional anticoagulation can be achieved with citrate, but previously described techniques are cumbersome and associated with metabolic complications. METHODS: We designed a simplified system for delivering regional citrate anticoagulation during continuous venovenous hemofiltration (CVVH). We evaluated filter life and hemorrhagic complications in the first 17 consecutive patients who received this therapy at our institution. Blood flow rate was set at 180 ml/min. Ultrafiltration rate was maintained at 2.0 liters/hr and citrate-based replacement fluid (trisodium citrate 13.3 mM, sodium chloride 100 mM, magnesium chloride 0.75 mM, dextrose 0.2%) was infused proximal to the filter to maintain the desired fluid balance. Calcium gluconate was infused through a separate line to maintain a serum-ionized calcium level of 1.0 to 1.1 mM. RESULTS: All patients were critically ill and required mechanical ventilation and vasopressor therapy. Systemic heparin anticoagulation was judged to be contraindicated in all of the patients. A total of 85 filters were used, of which 64 were lost because of clotting, with a mean life span of 29.5 +/- 17.9 hours. The remaining 21 filters were discontinued for other reasons. Control of fluid and electrolyte balance and azotemia was excellent (mean serum creatinine after 48 to 72 hr of treatment was 2.4 +/- 1.2 mg/dl). No bleeding episodes occurred. Two patients, one with septic shock and the other with fulminant hepatic failure, developed evidence for citrate toxicity without a significant alteration in clinical status. Nine patients survived (52.9%). CONCLUSION: Our simplified technique of regional anticoagulation with citrate is an effective and safe form of anticoagulation for CVVH in critically ill patients with a high risk of bleeding. (+info)
Multicenter clinical trial of recombinant human insulin-like growth factor I in patients with acute renal failure.
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BACKGROUND: Patients with acute renal failure (ARF) have high morbidity and mortality rates, particularly if they have serious comorbid conditions. Several studies indicate that in rats with ARF caused by ischemia or certain nephrotoxins, insulin-like growth factor-I (IGF-I) enhances the recovery of renal function and suppresses protein catabolism. METHODS: Our objective was to determine whether injections of recombinant human IGF-I (rhIGF-I) would enhance the recovery of renal function and is safe in patients with ARF. The study was designed as a randomized, double-blind, placebo-controlled trial in intensive care units in 20 teaching hospitals. Seventy-two patients with ARF were randomized to receive rhIGF-I (35 patients) or placebo (37 patients). The most common causes of ARF in the rhIGF-I and placebo groups were, respectively, sepsis (37 and 35% of patients) and hypotension or hemodynamic shock (42 and 27% of patients). At baseline, the mean (+/- SD) APACHE II scores in the rhIGF-I and placebo-treated groups were 24 +/- 5 and 25 +/- 8, respectively. In the rhIGF-I and placebo groups, the mean (median) urine volume and urinary iothalamate clearances (glomerular filtration rate) were 1116 +/- 1037 (887) and 1402 +/- 1183 (1430) ml/24 hr and 6.4 +/- 5.9 (4.3) and 8.7 +/- 7.2 (4.4) ml/min and did not differ between the two groups. Patients were injected subcutaneously every 12 hours with rhIGF-I, 100 microgram/kg desirable body weight, or placebo for up to 14 days. Injections were started within six days of the onset of ARF. The primary end-point was a change in glomerular filtration rate from baseline. Other end points included changes from baseline in urine volume, creatinine clearance and serum urea, creatinine, albumin and transferrin, frequency of hemodialysis or ultrafiltration, and mortality rate. RESULTS: During the treatment period, which averaged 10.7 +/- 4.1 and 10.6 +/- 4.5 days in the rhIGF-I and placebo groups, there were no differences in the changes from baseline values of the glomerular filtration rate, creatinine clearance, daily urine volume, or serum urea nitrogen, creatinine, albumin or transferrin. In patients who did not receive renal replacement therapy, there was also no significant difference in serum creatinine and urea between the two groups. Twenty patients in the rhIGF-I group and 17 placebo-treated patients underwent dialysis or ultrafiltration. Twelve rhIGF-I-treated patients and 12 placebo-treated patients died during the 28 days after the onset of treatment. CONCLUSIONS: rhIGF-I does not accelerate the recovery of renal function in ARF patients with substantial comorbidity. (+info)
Advanced glycated end-products (AGE) during haemodialysis treatment: discrepant results with different methodologies reflecting the heterogeneity of AGE compounds.
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BACKGROUND: There has been much recent interest in accumulation of advanced glycation end-products (AGE) in uraemic patients. Analysis of AGE has been difficult, because commonly used methodologies, i.e. immunodetection assays or fluorescence measurements, reflect group reactivity and are not specific for chemically defined substances. Some investigators measured individual AGE compounds, e.g. pentosidine, carboxymethyllysine, pyrraline or imidazolone, but a systematic assessment of known compounds using specific HPLC methods in diabetic and non-diabetic end-stage renal disease (ESRD) patients during treatment has not been performed. METHODS: For the present study, the concentrations of early and late products of the Maillard reaction in plasma and ultrafiltrate were monitored during high-flux dialysis sessions in diabetic and non-diabetic patients. AGE were analysed by fluorescence spectroscopy and size exclusion chromatography with fluorescence detection. Specific HPLC methods were used to quantify the Amadori product fructoselysine and the AGE compounds pentosidine and pyrraline in acid or enzymatic hydrolysates. RESULTS: Using size exclusion chromatography, we confirmed a similar fluorescent peak distribution for diabetic and non-diabetic ESRD patients. Main fractions were found at approximately 70, approximately 14 and <2 kDa, confirming results obtained by other authors. In diabetic patients, the fluorescence intensity of the low molecular weight fraction was higher. Uraemic patients differed from controls mainly by the fluorescence of the low molecular weight fraction. The peak spectrum in ultrafiltrates was similar to that in plasma regarding low molecular weight fractions and the 14 kDa peak, but no protein-bound fluorescence was found at 70 kDa. HPLC analysis revealed a significant reduction of plasma pentosidine during high-flux dialysis in non-diabetic (from 9.1+/-5.1 to 8.5+/-4.7 pmol/mg protein; P<0.05) and diabetic patients (from 10.0+/-9.1 to 6.8+/-4.0 pmol/mg protein; P<0.05). In contrast, plasma fructoselysine showed only a non-significant trend to decrease in diabetic (from 3.24+/-0.88 to 3.05+/-0.77 nmol/mg protein) and non-diabetic patients (from 2.69+/-0.52 to 2.56+/-0.50 nmol/mg protein). Pyrraline, a nonfluorescent late AGE product derived from reaction of 3-deoxyglucosone with lysine, could not be detected (detection limit approximately 40 pmol/mg protein). Comparing HPLC and size exclusion analysis, it was found that pentosidine accumulated in the range of low molecular weight substances and was removed by high-flux dialysis. CONCLUSIONS: High-flux dialysis reduces the plasma concentration of fluorescent AGE compounds, i.e. pentosidine, but the Amadori product fructoselysine is not removed, indicating that this compound is protein associated. (+info)