Telomere length, telomerase activity and telomerase RNA expression during mouse mammary tumor progression

The effects of intraportal administration of prostaglandin E1 (PGE1) on portal venous flow, hepatic arterial flow, peripheral tissue blood flow, and systemic arterial flow before and after 60 min total liver ischemia followed by 70% partial hepatectomy in rats were investigated. Total liver ischemia was induced by occluding the hepatoduodenal ligament for 60 min. PGE1 at a dose of 0.5 microg/kg/min was infused intraportally for 15 min before inducing hepatic ischemia (preischemic period) and for 60 min after ischemia (postischemic reperfusion period) in the treatment group. Normal saline was infused in the control group. Seventy percent partial hepatectomy was performed during ischemia. Serum biochemical analysis and liver tissue histology were carried out 1, 3, and 24 h, and 1 and 24 h after reperfusion respectively. One-week survival of the PGE1 group was improved to 70% compared to that of the control group of 30%. Postischemia reperfusion values of portal and peripheral tissue blood flows in the PGE1 group were 6.33 +/- 0.600 ml/min and 27.2 +/- 23.5 (arbitrary), and were significantly different from those of the control group of 4.34 +/- 0.400 ml/min and 23.5 +/- 5.54 (arbitrary), respectively. There was no significant difference in hepatic arterial flow between the two groups. Serum alkaline phosphatase decreased significantly in the prostaglandin group. Histological examination revealed a significant portal venous congestion in the control group 1 and 24 h after reperfusion. The extent of the sinusoidal congestion was also severe in the control group 24 h after reperfusion. It was concluded that PGE1 has a protective effect against liver damage when the liver was injured by warm ischemia and reperfusion followed by partial resection.     

Reduction of voltage-dependent currents by ethanol contributes to inhibition of NMDA receptor-mediated excitatory synaptic transmission

BACKGROUND/AIMS: Primary graft dysfunction is difficult to predict. We have previously shown that indocyanine green clearance measured at 24 h following orthotopic liver transplantation predicts graft survival and outcome. We prospectively evaluated the use of indocyanine green clearance (with a cut-off value of 200 ml/min) as a marker of graft function following orthotopic liver transplantation and investigated its relationship with the markers of reperfusion injury during orthotopic liver transplantation. METHODS: In all patients indocyanine green clearance was measured at 24 h. Repeated blood samples were taken before, during the anhepatic and reperfusion phase and up to 12 h following orthotopic liver transplantation to measure the levels of neutrophil elastase and reactive oxygen intermediates. All patients studied had normal hepatic arterial pulse on Doppler-ultrasound post orthotopic liver transplantation. RESULTS: All patients with indocyanine green clearance >200 ml/min recovered following orthotopic liver transplantation and remained well up to 3 months of follow up. Four patients had an indocyanine green clearance <200 ml/min; three were re-transplanted for graft failure within 3 days of the transplant, while one survived after prolonged intensive support and hospitalization. Indocyanine green clearance significantly correlated with reactive oxygen intermediates production and neutrophil elastase during orthotopic liver transplantation (r=-0.61, p<0.002 and r=-0.66, p<0.0009, respectively). Indocyanine green clearance was also significantly correlated with alanine aminotransferase and prothrombin time at 24 h post-transplantation (r=-0.35, p<0.02 and r=-0.4, p<0.0077, respectively). CONCLUSION: Indocyanine green reflects the degree of reperfusion injury and is a good early marker of primary graft function. Indocyanine green clearance over 200 ml/min is associated with favorable outcome.     

Bacteraemia during the aplastic phase after allogeneic bone marrow transplantation is associated with early death from invasive fungal infection

OBJECTIVE: The main objective of this study was to evaluate the effect of switching from parenteral to enteral feeding on liver blood flow and propofol steady-state blood concentrations in patients in the intensive care unit (ICU). DESIGN AND PATIENTS: Steady-state blood concentrations of propofol were measured in eight ICU patients before (on days D -3, D -2, and D -1) and after (on days D + 1, D + 2, and D + 3) switching from parenteral to enteral feeding (on day DO). All patients received a continuous intravenous infusion of propofol (4.5 mg x kg(-1) x h(-1)) from several days before the start of the study, continuing throughout the experimental period. Hepatic blood flow was estimated by measuring steady-state D-sorbitol hepatic clearance. RESULTS: Hepatic blood flow was high and was not affected by switching from parenteral to enteral feeding: 33 +/- 8 ml x min(-1) x kg(-1) (mean +/- SD) and 33 +/- 10 ml min(-1) x kg(-1) on D -3 and D -1, respectively, as compared to 37 +/- 11 ml x min(-1) kg(-1) and 34 +/- 8 ml x min(-1) x kg(-1) on days D + 1 and D + 3, respectively. Systemic clearance of propofol was much higher than liver blood flow with average values on the six observation days ranging from 74.0 to 81.2 ml x min(-1) x kg(-1) and was not affected by switching from parenteral to enteral feeding. CONCLUSIONS: Liver blood flow and systemic clearance of propofol were not affected by switching from parenteral to enteral feeding in the eight ICU patients studied. Extrahepatic clearance accounted for at least two thirds of the overall systemic clearance of propofol.     

Lung resection after pneumonectomy for bronchogenic carcinoma

AIMS/BACKGROUND: TIPS, an effective procedure applied for the treatment of complications of portal hypertension, is potentially followed by worsening of the hyperdynamic circulation of cirrhosis and the impairment of liver function. The aim of the present study was to evaluate short-term changes of functional liver plasma flow after application of TIPS, using the hepatic (extrarenal) clearance of D-sorbitol (S-HCl). METHODS: Twenty-five cirrhotic patients submitted to TIPS for prevention of variceal rebleeding entered the study. At steady-state, during constant infusion of a solution of D-sorbitol (25 mg/min), appropriate blood and urine samples were collected in order to calculate S-HCI before and 120 min after TIPS opening. In addition, the hepatic extraction ratio of D-sorbitol was directly measured at the level of the right (Er), where TIPS was applied, and of the left (El) hepatic veins; meanwhile the portocaval gradient (PCG) was registered, before and after stent dilation. A comparison of values obtained before and after TIPS application was performed by Student's t-test for paired data. RESULTS: After application of TIPS, a substantial reduction was observed in PCG (12.1+/-4.2 vs 24.8+/-4.3 mmHg; p<0.001) and Er values (20.6+/-14.8 vs 57.5+/-22.3 %; p<0.001) but not El values (47.4+/-22.0 vs 53.4+/-21.4 %; p=0.178). S-HCl measured 120 min after TIPS opening was not statistically different from pre-TIPS values (389.2+/-212.1 vs 394.6+/-152.7 ml/min; p=0.892), although S-HCl variations in Child-Pugh class B patients were positively correlated with portal pressure variations (r=0.63, p=0.016). CONCLUSION: Our results demonstrate that in patients with advanced cirrhosis, TIPS procedure, while effective in reducing portal hypertension, does not lead to alterations in the functional liver plasma flow within the first 2 h.     

Insulin kinetics after portal and peripheral injection of [125I] insulin: II. Experiments in the intact dog

Insulin metabolism in man is usually investigated by peripheral injection of the hormone, whereas native insulin undergoes hepatic extraction prior to mixing in the general circulation. To quantify this difference, in 10 dogs [125I] insulin was injected into a peripheral vein, and the initial distribution volume (IDV), the metabolic clearance rate (MCR), and the mean transit time (t) were computed from the plasma disappearance curve of the immunoprecipitable activity. The splenic vein was then cannulated under pentobarbital anesthesia, and the parameters were again computed from the peripheral activity after portal introduction of the tracer. The MCR after portal injection [15.1 +/- (SE) 1.1 ml/min per kg] was greater (P is less than 0.001) than the MCR after peripheral administration (13.4 +/- 0.9 ml/min per kg). Also, IDV was larger (P is less than 0.01) after portal injection (167 +/- 12 vs. 138 +/- 10 ml/kg). Mean transit times did not change significantly. Insulin secretion rate (0.29 +/-0.04 mU/min per kg) and body insulin mass (7.03 +/- 1.5 mU/kg) were also measured. An estimate of hepatic extraction was obtained from the difference between the clearance rate values calculated following portal and peripheral injection. Under our experimental conditions, hepatic retention of insulin was found to be 19.6% (range 9.6-36.2%). The method is recommended for investigations in man.     

Decrease of oxygen consumption in the dog liver during temporary arterial occlusion

The effects of occlusion of the hepatic artery on total and regional splanchnic oxygen consumption were studied in lightly anaesthetized dogs. Mean whole body oxygen uptake (+/- S.D.) was 4.72 +/- 0.55 ml/kg b.w. min-1, mean liver oxygen uptake (+/- S.D.) 1.18 +/- 0.42 ml/kg b.w. min-1 and mean oxygen uptake of the portally-drained tissues (+/- S.D.) was 0.80 +/- 0.54 ml/kg b.w. min-1 during the control period. The hepatic artery contributed 45 +/- 24% of the total liver oxygen uptake. The duration of occlusion was 45 min. Mean liver oxygen uptake was found to decrease to 64% of control values. The extraction of oxygen from the portal blood increased slightly. Mean whole body oxygen uptake and mean oxygen uptake of the portally-drained tissues were unchanged. 45 min after release of the hepatic artery occlusion, liver oxygen consumption had returned to control values. It is concluded that oxygen uptake in the liver is correlated to oxygen tension.     

Automatic continuous venovenous hemodiafiltration in cardiosurgical patients

Intermittent substitutive treatments in severely ill patients with acute renal failure are difficult or not suitable because of technical problems and/or hemodynamic instability. Continuous venovenous hemodiafiltration allows an adequate, slow removal of fluid, electrolytes, and waste products by combining diffusive and convective solute transport. Eight patients with acute renal failure, after cardiovascular surgery and cardiogenic shock, were treated by continuous venovenous hemodiafiltration. An automatic system (Equaline System, Amicon Division, USA) was employed. Venous accesses (femoral or subclavian) were used with double lumen catheters. A polysulfone filter (0.4 m2) was used in the study. Blood flow was 30 ml/min and dialysate flow rate 16.6 ml/min. Sterile pyrogen-free hemofiltration substitution fluid was used as dialysate. Mean duration of treatment was 10.3 +/- 3.2 days. After 72 hours blood urea nitrogen levels dropped from 136 +/- 46.13 to 53.5 +/- 12.3 mg/dl and creatinine levels dropped from 6.9 +/- 1.7 to 2.6 +/- 0.9 mg/dl. A controlled steady-state was then maintained. Mean urea clearance was 21 +/- 5.3 ml/min; mean ultrafiltration rate was 20.3 +/- 4.1 L/day. Continuous venovenous hemodiafiltration, with the Equaline System, is effective for the clearance of waste products and is able to maintain perfect fluid balance in catabolic patients with acute renal failure and multiple organ failure.     

Portal hemodynamics after large-volume paracentesis in patients with liver cirrhosis and tense ascites

Large-volume paracentesis with a plasma expander has been extensively evaluated and shown to be an effective and safe therapy. While hepatic and systemic hemodynamics have been studied extensively, there is little information on portal hemodynamics by duplex Doppler. Portal vein diameter, portal flow velocity, and portal blood flow were measured with duplex Doppler in 11 cirrhotic patients before and 24 hr after large volume paracentesis. There were no significant changes in the portal vein diameter (9.88+/-2.62 mm vs 10.09+/-2.73 mm), portal flow velocity (10.65+/-2.60 vs 10.01+/-2.58 cm/sec), and portal blood flow (488+/-288.9 vs 502+/-73.38 ml/min), before and 24 hr after large-volume paracentesis. Thus, significant changes in portal hemodynamics do not occur after large-volume paracentesis.     

Dialysis clearance of buflomedil in hemodialysed patients

Buflomedil (CAS 55837-25-7, Fonzylane) is a peripherally vasoactive drug which improves nutritional blood flow in ischaemic tissue of patients with peripheral vascular disease by the way of an increase of perfusion in the microcirculation. Ten hemodialysed patients with chronic renal failure treated with intravenous infusion of 400 mg of buflomedil during 4 h of dialysis were included in the first study. This study was carried out to determine the dialysis plasma clearance and the amount of drug dialysed during the first intravenous administration of buflomedil. The dialysis clearance calculated from the amount recovered in dialysate was (mean +/- SD) 25.4 +/- 25.6 ml/min. The drug recovery resulting from hemodialysis represented a small fraction of the dose (< or = 5%). A second study was carried out to determine the accumulation of buflomedil in chronic hemodialysed patient. The drug concentration were measured before and at the end (4 h) of the infusion of buflomedil in six other patients maintained on intermittent hemodialysis (3 per week) for 4 weeks. The average Cmin and Cmax were stable during the 12 successive dialyses (mean +/- SD intervals were between 0.36 +/- 0.53 and 0.66 +/- 0.79 microgram/ml for Cmin and between 5.15 +/- 2.19 and 7.37 +/- 1.76 micrograms/ml for Cmax), showing no trend of accumulation of buflomedil. These results agree with the pharmacokinetics of the drug which is mainly metabolised in the liver and has a low renal clearance. Dialysis is unable to modify significantly the plasma concentration of the drug in regularly dialysed patients.     

Responses of blood flow, oxygen consumption, and contractile function to inotropic stimulation in stunned canine myocardium

To examine the effects of inotropic stimulation on regional myocardial blood flow (MBF), oxidative metabolism, and contractile function in stunned myocardium, nine closed-chest dogs were studied 2 hours postreperfusion after a 25 minute occlusion of the left anterior descending coronary artery (LAD). MBF was determined with microspheres, and regional myocardial oxygen consumption (MVO2) was estimated from the rate constant k1 of the rapid clearance phase of [1-11C] acetate time activity curves, recorded with dynamic positron emission tomography. Myocardium at risk was determined from [13N] ammonia images obtained during occlusion. Wall motion, assessed by two-dimensional echocardiography, was impaired in postischemic myocardium in all dogs 2 hours after reperfusion. Dobutamine infusion increased the rate pressure product by 70% +/- 31% and significantly improved contractile function in the postischemic region in all dogs. In remote myocardium, MVO2 increased from 5.7 +/- 1.2 to 8.6 +/- 1.6 mumol/gm/min, and blood flow from 0.87 +/- 0.16 to 1.52 +/- 0.42 ml/gm/min in response to dobutamine. In reperfused myocardium, MVO2 increased from 3.1 +/- 0.7 to 7.4 +/- 1.5 mumol/gm/min, and blood flow from 0.51 +/- 0.12 to 1.2 +/- 0.4 ml/gm/min. Oxygen extraction increased significantly in reperfused myocardium relative to remote myocardium consistent with a flow-limited response to dobutamine stimulation. The improvement in contractile function failed to correlate significantly with relative increases in MBF or MVO2, suggesting that mechanical function is not as tightly coupled as MBF and MVO2 in postischemic myocardium during inotropic stimulation.     

Adenosine transport inhibition ameliorates postischemic hypoperfusion in pigs

Cerebral ischemia is often followed by a period of delayed hypoperfusion that may contribute to tissue injury. We tested the hypothesis that augmentation of interstitial adenosine can improve tissue perfusion under this condition 10 min global ischemia was produced in two groups of isoflurane-anesthetized newborn pigs by occlusion of subclavian and brachiocephalic arteries, and changes in local cortical blood flow and cortical interstitial purine metabolites were measured using the combined hydrogen clearance-microdialysis technique. In one group, the dialysis probe was perfused with artificial cerebrospinal fluid buffer containing nitrobenzyl-thioinosine (NBT1, 100 mumol/l), a competitive inhibitor of adenosine transport. In the untreated group (n = 9), baseline cortical blood flow (39 +/- 3 ml/min/100 g) was depressed by 51 +/- 5% and 42 +/- 6% at 40 and 60 min, respectively, of postischemic reperfusion. NBTI increased baseline interstitial adenosine levels 2.4-fold which increased baseline cortical blood flow 1.5-fold to 60 +/- 4 ml/min/100 g, and increased both absolute adenosine levels as well as adenosine as a percentage of total purine metabolites throughout ischemia and reperfusion. As a result, the extent of postischemic hypoperfusion was significantly lessened in NBTI-treated animals (n = 9), with reductions in cortical blood flow of only 28 +/- 3% and 24 +/- 5% at 40 and 60 min of reperfusion, respectively. These results indicate that inhibition of adenosine transport by NBTI elevates interstitial adenosine concentration during and following cerebral ischemia, and concomitantly improves cortical perfusion in the post-ischemic period. The latter effect may contribute to the documented neuroprotective efficacy of adenosinergic therapy in cerebral ischemia.     

Glucagon and insulin metabolism in cirrhotic patients

BACKGROUND/AIMS: The aim of this study was to investigate glucagon and insulin metabolism in order to clarify the mechanisms that lead to hyperglucagonemia and hyperinsulinemia in cirrhosis. METHODOLOGY: Splanchnic output and metabolic clearance rates were studied in 16 cirrhotic patients and 5 non-cirrhotic controls. Splanchnic glucagon and insulin output into the portal circulation were calculated by the difference between portal venous and systemic arterial concentration multiplied by portal plasma flow. The metabolic clearance rate was calculated as the ratio of output to systemic arterial concentration. Portal blood flow was measured by continuous local thermodilution. RESULTS: Arterial glucagon levels were higher in cirrhotics than in controls. Glucagon output was triple of that found in controls (52.4 +/- 7.0 vs 17.7 +/- 2.9 ng/min, p < 0.05). Both groups exhibited similar metabolic clearance rates of glucagon. Systemic arterial insulin values were higher in cirrhotics than in non-cirrhotics. Insulin output was not significantly different between the two groups. However, metabolic clearance of insulin in cirrhotics was reduced to one half of the rate found in controls (237.0 +/- 39.8 vs. 450.5 +/- 17.5 mL/min, p < 0.05). CONCLUSIONS: Hyperglucagonemia in cirrhotic patients results from increased pancreatic output, while hyperinsulinemia results from decreased insulin clearance.     

Alteration in regional blood flow in minipigs' femur under inadequate decompression studied by isotopes washout method

We studied the alteration in regional blood flow in minipigs' femur under inadequate decompression after hyperbaric air exposure. The animals were placed in the hyperbaric chamber and exposed to the pressure of 0.5 MPa for 1.5 h, which was reduced to atmosphere at an ascent rate of 0.03-0.04 MPa/min. Regional blood flow in the femur was measured by the isotopes washout method of inhaling 133Xe. The radioactivity was monitored by a multifunctional blood flowmeter interfaced to a minicomputer. Before exposure, the values of average blood flow (F) of femur on the left and right were 15.4 +/- 1.8 and 16.9 +/- 2.0 ml/100 g.min respectively. The values of blood flow (f1) of hematopoietic marrow were 19.1 +/- 2.0 and 21.3 +/- 2.0 ml/100 g.min (n = 7). After inadequate decompression, F values were reduced to 10.3 +/- 1.8 and 11.1 +/- 1.6 ml/100 g.min and f1 values reduced to 13.9 +/- 1.4 and 13.8 +/- 1.0 ml/100 g.min (n = 7), which were obviously lower than those before exposure (P < 0.05). This experiment showed that significant reduction in blood flow in the femur region occurred under inadequate decompression after the exposure of minipigs hyperbaric environment, suggesting that ischemia is a causative factor of osteonecrosis.     

Differential effects on portal and effective hepatic blood flow. A comparison between transjugular intrahepatic portasystemic shunt and small-diameter H-graft portacaval shunt

OBJECTIVE: This study was undertaken to determine the effects of transjugular intrahepatic portasystemic shunt (TIPS) and small-diameter prosthetic H-graft portacaval shunt (HGPCS) on portal and effective hepatic blood flow. SUMMARY BACKGROUND DATA: Mortality after TIPS is higher than after HGPCS for bleeding varices. This higher mortality is because of hepatic failure, possibly a result of excessive diminution of hepatic blood flow. METHODS: Forty patients randomized prospectively to undergo TIPS or HGPCS had effective hepatic blood flow determined 1 day preshunt and 5 days postshunt using low-dose galactose clearance. Portal blood flow was determined using color-flow Doppler ultrasound. RESULTS: Treatment groups were similar in age, gender, and Child's class. Each procedure significantly reduced portal pressures and portasystemic pressure gradients. Portal flow after TIPS increased (21 mL/second +/- 11.9 to 31 mL/second +/- 16.9, p < 0.05), whereas it remained unchanged after HGPCS (26 mL/second +/- 27.7 to 14 mL/second +/- 41.1, p = n.s.). Effective hepatic blood flow was diminished significantly after TIPS (1684 mL/minute +/- 2161 to 676 mL/minute +/- 451, p < 0.05) and was unaffected by HGPCS (1901 mL/ minute +/- 1818 to 1662 mL/minute +/- 1035, p = n.s.). CONCLUSIONS: Both TIPS and HGPCS achieved significant reductions in portal vein pressure gradients. Portal flow increased after TIPS, although most portal flow was diverted through the shunt. Effective hepatic flow is reduced significantly after TIPS but well preserved after HGPCS. Hepatic decompensation and mortality after TIPS may be because, at least in part, of reductions in nutrient hepatic flow.     

Three-vessel study of cerebral blood flow using phase-contrast magnetic resonance imaging: effect of physical characteristics

The development of phase-contrast magnetic resonance imaging (P-C MRI) provides a noninvasive method for measurement of volumetric blood flow (VFR). We performed P-C MRI to study the effects of physical characteristics on cerebral blood flow. VFR of the left and right internal carotid arteries and basilar artery were measured using P-C MRI and total cerebral blood flow (tCBF) was calculated by summing up the VFR values in the three vessels. Moreover, we investigated the changes in these blood flows as influenced by age, head size, height, weight, body surface area, and handedness. The blood flows were 142 +/- 58 ml/min (mean +/- standard deviation) in the basilar artery; and 229 +/- 86 ml/min in the left, and 223 +/- 58 ml/min in the right internal carotid artery; and tCBF was 617 +/- 128 ml/min. Significant increases were observed in head size-related change of VFR in the basilar artery (p = .028) and height-related change of tCBF (p = .045). The other characteristics did not significantly influence any VFR. The results suggest that head size and height may reflect CBF, and that these effects should be considered when changes of CBF are diagnosed. Phase-contrast MRI is useful for a noninvasive and rapid analysis of cerebral VFR and has potential for clinical use.     

Fc gamma RII on human B cells can mediate enhanced antigen presentation

As several reinjection procedures have shown encouraging results in terms of imaging, we investigated whether the kinetics of thallium-201 would differ between the standard stress-redistribution-reinjection approach and the stress-immediate reinjection approach. In 53 consecutive patients with undiagnosed chest pain, 75 MBq (2 mCi) 201Tl was injected at maximal exercise. In 26 of these patients (group I), 37 MBq (1 mCi) 201Tl was reinjected immediately after completing the exercise images (the immediate reinjection procedure) and in 27 patients (group II), 37 MBq (1 mCi) 201Tl was reinjected after completing 3-h redistribution images (the standard reinjection procedure). Mean peak 201Tl blood activity after exercise was 17.7+/-12.5 kBq/ml (4.8+/-3.4 mCi/ml) for group I versus 16.4+/-9.2 kBq/ml (4.4+/-2.5 mCi/ml) for group II (NS). The relative increase in 201Tl blood activity after reinjection of half the initial dose [37 MBq (1 mCi)] exceeded 50% of the initial peak in both groups. The relative amount of 201Tl delivered to the myocardium was assessed by the area under the curve after both exercise and reinjection, and was 117%+/-72% for group I and 112%+/-73% for group II (NS). Blood clearance of 201Tl was at least biexponential. Mean early decay constants (lambda 1) after exercise and reinjection were 0.30+/-0.18 min-1 and 0.22+/-0.046 min-1 respectively for group I (T 1/2 2.3 min and 3.2 min respectively, NS), and 0.30+/-0.12 min-1 and 0.24+/-0.07 min-1 respectively for group II (T1/2 2.3 min and 2.9 min respectively, NS). For both procedures no significant differences were found between lambda 1 after exercise and lambda 1 after injection. The mean late clearance (lambda 2) from the blood was 0.032+/-0.056 min-1 and 0.012+/-0.012 min-1 respectively for group I (T1/2 21.6 min and 57.7 min respectively, NS), and 0.036+/-0.030 min-1 and 0.014+/-0.014 min-1 respectively for group II (T1/2 19.3 min and 49.5 min respectively, NS). Also, no significant differences were found between lambda 2 after exercise for both groups and between lambda 2 after reinjection for both groups. We conclude that reinjection of 37 MBq (1 mCi) 201Tl (half the initial dose) results in a relative increase in the initial peak and a relative increase in the amount of 201Tl delivered to the myocardium of more than 50% for both the standard and the immediate reinjection procedure. The clearance of 201Tl from the blood was not influenced by exercise or by the time of reinjection. Based on 201Tl kinetics as measured in the peripheral blood, there is no reason to postpone reinjection until 3-4 h following exercise.     

Vasodilatory effects of propylthiouracil in patients with alcoholic cirrhosis

BACKGROUND/AIMS: An experimental study has shown that propylthiouracil increases portal blood flow in normal rats. Whether propylthiouracil has a similar effect in patients with alcoholic cirrhosis remains to be demonstrated. The aim of this study was to evaluate the effects of oral propylthiouracil (300 mg) on systemic and portal hemodynamics in patients with alcoholic cirrhosis. METHODS: Plasma propylthiouracil levels were also measured by high performance liquid chromatography in five patients with alcoholic cirrhosis. In eight patients with cirrhosis, mean arterial pressure, cardiac output and portal blood flow were evaluated before and after placebo and propylthiouracil administration. Hemodynamic measurements were performed by the Doppler technique. The plasma peak level of propylthiouracil was achieved at 1.4 +/- 0.1 h in patients with alcoholic cirrhosis. This time was chosen to express hemodynamic changes. RESULTS: Propylthiouracil administration caused a significant increase in portal blood flow (+16.5%, p < 0.05) in patients with alcoholic cirrhosis. This effect was associated with a mild and significant rise in cardiac output (from 5.8 +/- 0.2 to 6.1 +/- 0.3 l/min, p < 0.05) and a decrease in peripheral vascular resistance (from 1171 +/- 69 to 1070 +/- 67 dyn . s-1 . cm-5, p < 0.01). A significant correlation was observed between changes in portal blood flow and peripheral vascular resistance (r = 0.79, p < 0.05). No significant changes were observed after placebo. CONCLUSIONS: Our findings show that propylthiouracil has a vasodilatory effect in patients with alcoholic cirrhosis. We postulate that this effect could be the mechanism by which propylthiouracil decreases hypermetabolic state, and increases oxygen delivery to the liver, in patients with alcoholic liver diseases.     

Portal vein insulin flux and arterial glucose fluctuations in response to an oral meal test in islet cell-transplanted dogs

Insulin flux was determined in the portal vein and simultaneously arterial blood glucose was measured before and during an oral glucose meal in conscious normal and pancreatic islet cell-autotransplanted dogs to test their insulinogenic reserve. These dogs had previously been chronically instrumented with blood flow probes on the portal vein and carotid artery, and blood sampling catheters in the portal vein, hepatic vein, carotid artery, and right external jugular vein. Such a model permits quantitative portal-peripheral comparisons and assessment of hepatic extraction. Sixteen dogs, 10 normal (N) and six long-term (2 months to 2 yrs) islet cell-transplanted dogs (IT) were fed an oral glucose meal as a test (OMT). Baseline portal vein insulin fluxes (PVF) were similar in both groups (25.6 +/- 0.04 pmol/min in N and 24.7 +/- 19.4 pmol/min in IT). Immediately after OMT, PVF rose to 248.2 +/- 40.9 pmol/min in N, but only to 55.9 +/- 17.9 pmol/min in IT. After 30 min PVF peaked for the second time in N at 156 +/- 35.9 pmol/min, declining slowly to baseline after 3 h. In IT, a similar peak at 30 min was seen (143.7 +/- 22.1 pmol/min), declining to a value not different from baseline after 3 h. However, cumulative insulin PV fluxes in the two groups over 3 h were not different. Differences were also seen in postprandial glucose fluctuations, which reached a maximum excursion of 11.8 +/- 0.45 mM in IT, while never rising above 7.8 +/- 0.33 mM in N. After 3 h both groups had similar glucose values.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diagnosis of thoracic outlet syndrome in the emergency department

Gadodiamide at a dose of 0.1 mmol/kg was administered intravenously to 10 renal transplanted patients with stable, impaired, or slowly deteriorating renal function (serum creatinine 194-362 mumol/l). The patients were referred for contrast medium enhanced magnetic resonance imaging to rule out possible graft circulation abnormalities. The excretion of gadodiamide in urine was prolonged as compared with healthy controls. After 120 h 92% of the injected dose was excreted in urine and only 0.4% in faeces. The plasma clearance of gadodiamide was 28.6 +/- (SD) 5.5 ml/min (n = 10), and the renal clearance (0-72 h) was 26.3 ml/min. The renal clearance of 125I-iothalamate for the same time period was 27.9 +/- 5.3 ml/min. Thus, gadodiamide is eliminated by glomerular filtration also in renal transplant patients with moderately to severe impaired renal function, and gadodiamide clearance may serve as an alternative marker for the determination of the glomerular filtration rate. Serum values of creatinine and beta(2)-microglobulin and creatinine clearance were unchanged by gadodiamide and neither was the urinary enzyme excretion significantly changed. These results suggest that the renal tolerance to gadodiamide is good also in renal transplant patients with impaired renal function.     

Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration

The pharmacokinetics of imipenem-cilastatin were investigated in 12 critically ill patients with acute renal failure (ARF) managed by continuous veno-venous hemofiltration (CVVH) while receiving a fixed combination of 500 mg of imipenem-cilastatin intravenously three or four times daily. No adverse drug reactions were observed. Plasma and hemofiltrate samples were taken at specified times during one dosing interval, and the concentrations of imipenem and cilastatin were determined by high-performance liquid chromatography. Pharmacokinetic variables were calculated by a first-order, two-compartment pharmacokinetic model for both substances. Total clearances of imipenem and cilastatin (mean +/- standard deviations) were 122.2 +/- 28.6 and 29.2 +/- 13.7 ml/min, respectively, with hemofiltration clearances of 22.9 +/- 2.5 and 16.1 +/- 3.1 ml/min, respectively, and nonrenal, nonhemofiltration clearances of 90.8 +/- 26.3 and 13.2 +/- 13.9 ml/min, respectively. Mean imipenem dosage requirements were approximately 2,000 mg/24 h (2,111.8 +/- 493.4 mg/24 h). They were calculated in order to achieve an average steady-state concentration of 12 mg/liter to ensure that concentrations in plasma exceeded the MICs at which 90% of intermediately resistent bacteria are inhibited (8 mg/liter) during the majority of the dosing interval. By contrast, the recommended dosage for patients with end-stage renal failure (ESRF) and infections caused by intermediately resistant bacteria is 1,000 mg/24 h. This remarkable difference may be due (i) to differences in the nonrenal clearance of imipenem between patients with ARF and ESRF and (ii) to the additional clearance by the hemofilter. Since the total clearance of cilastatin was low, marked accumulation occurred, and this was particularly pronounced in patients with additional liver dysfunction. Thus, in patients with ARF managed by CVVH, rather high imipenem doses are required, and these inevitably result in a marked accumulation of cilastatin. The doses of imipenem recommended for patients with ESRF, however, will lead to underdosing and inadequate antibiotic therapy.