Transarterial chemoembolization of liver metastases in patients with uveal melanoma.

Metastases from uveal melanoma are often confined to the liver. Palliative hepatic chemoembolization has been considered to be a reasonable treatment approach. We enrolled 14 patients with hepatic metastases from uveal melanoma into a pilot trial of transarterial chemoembolization (TACE). All patients received additional systemic immuno-chemotherapy or best supportive care. In 31 procedures 100mg/m(2) of cisplatine was continuously infused by means of a power injector preceding embolization by manual injection of polyvinyl alcohol particles. In three procedures cisplatine was replaced by 200mg/m(2) carboplatine because of increased serum creatinine levels. Tumor response was evaluated using RECIST criteria. Fourteen patients received 34 TACE's (mean: 2.4 treatments). Eight patients (57%) achieved partial response (PR), four patients (29%) had stable disease and two patients (14%) tumor progression. Median time to progression was 8.5 months (5-35 months). Median survival after first TACE was 14.5 months in responders compared to 10 months in non-responders (p=0.18, not significant) and 11.5 months (3-69 months) in all patients. In seven patients with metastases occupying less than 25% of liver volume median survival was 17 months compared to 11 months in seven patients with tumor involvement of more than 25% (p=0.02) with partial response rate of 86% and 29%, respectively. TACE of liver metastases from uveal melanoma is well tolerated and may prolong survival in patients with limited tumor extension.

[C-arm CT for chemo-embolization of liver tumors]. / C-Arm-CT bei der Chemoembolisation von Lebertumoren.

Local efficacy of transarterial chemo-embolization (TACE) is enhanced if selective treatment is performed. Selectivity of TACE mainly depends on vascular anatomy but also on the identification and catheterization of tumor feeding arteries. Correlation of vascular territories and target tumor volume in angiographic projection images is more difficult if tumors are not hypervascularized and contrast of liver parenchyma is inhomogeneous.C-arm CT offers the option of selective perfusion imaging via tumor-feeding arteries. This allows the comparison of perfusion images and baseline cross-sectional imaging to evaluate if tumors are covered completely by local treatment and to change the catheter position if necessary. Furthermore the uptake of embolization material, such as lipiodol can be checked by C-arm CT.In a prospective study of 75 TACE of liver tumors and liver metastases we evaluated the appropriateness of 85 catheter positions ready for delivery by perfusion C-arm CT and compared the diagnostic confidence of angiography and perfusion C-arm CT in terms of judgment of correct catheter position for the planned treatment. Diagnostic confidence was improved by perfusion C-arm CT in 55% of cases and in 11 cases (13%) catheter positions were inappropriate and had to be corrected. The reasons for catheter repositioning were incomplete coverage of the target tumor by perfusion volume (mismatch) in 6 cases, inappropriate perfusion of adjacent liver parenchyma in 2 cases and non-selective tumor perfusion via collateral arteries in 3 cases. C-arm CT allowed sufficient visualization of uptake of lipiodol in all cases evaluated.The diagnostic benefit of C-arm CT increases if tumors are treated more selectively, are not strongly hypervascular, are located centrally and if the enhancement of liver parenchyma is inhomogeneous. C-arm CT causes additional working time and contrast load, which is relatively low compared to angiography. Radiation exposure of 151 microGy per C-arm series necessitates careful and therapy-oriented assessment of indications.

[Secondary and primary prophylaxis of gastropathy associated with nonsteroidal antiinflammatory drugs or low-dose-aspirin: a review based on four clinical scenarios]. / Sekundär- und Primärprophylaxe der ASS-/NSAR-Gastropathie: Eine Ubersicht anhand vier klinischer Szenarien.

Based on current references four clinical scenarios were discussed and different management strategies were compared for secondary and primary prophylaxis of ulcer or peptic ulcer bleeding under continuous therapy with non-steroidal antiinflammatory drugs (NSAID) or low-dose-aspirin, for H.pylori-positive and H.pylori-negative patients. Used as secondary prophylaxis eradication alone is insufficient in preventing recurrent peptic ulcer or recurrent ulcer bleeding for H.pylori-positive patients who continue to take unselective NSAIDs. Maintenance therapy with PPIs or switching from nonselective NSAID to COX-2-inhibitors is required after eradication of H.pylori or primary H.pylori-negative patients. Further evaluation is needed of what kind of secondary prophylaxis - maintenance therapy with PPI or switching to COX-2-inhibitor - is more (cost-)effective. It is sufficient to use eradication of H.pylori alone as secondary prophylaxis in preventing recurrent peptic ulcer or recurrent ulcer bleeding for H.pylori-positive patients, who continue to take low-dose-aspirin. Maintenance therapy with PPI is not generally required. However it can be considered for patients with increased risk for gastrointestinal complications (previous history of peptic ulcer, age over 65 years, concomitant use of corticosteroids, anticoagulants or individual NSAID with higher risk for gastrointestinal complications, serious cardiovascular disease). Switching from low-dose-aspirin to clopidogrel is not required. Used as primary prophylaxis in preventing peptic ulcer or ulcer bleeding before starting long-term therapy with NSAIDs, COX-2-inhibitors or unselective NSAIDs concomitant with PPIs are recommended for patients with increased risk for gastrointestinal complications. Patients starting long-term therapy with unselective NSAIDs should be screened for H.pylori and eradicated. There are no valid data supporting screening for H.pylori and eradication for patients starting long-term therapy with low-dose-aspirin. Further studies are needed to evaluate a possible benefit for patients with increased risk for gastrointestinal complications.

Prospective investigation of autonomic cardiac neuropathy in diabetes mellitus.

Forty-five patients with clinically manifest diabetes mellitus were investigated (25 male, 20 female, 48 +/- 10 yrs, 14 diabetes type 1, 31 type 2). Duration of manifestation was 12.2 +/- 9.7 yrs.Vibration thresholds and thermal thresholds were assessed. Respiratory sinus arrhythmia (RSA) was measured during deep respiration at 6/min. The QTc-interval was assessed according to Bazett's formula. MIBG-SPECT was carried out in all 45 cases. Patients with abnormal MIBI perfusion scintigraphy had previously been excluded from the study. RSA was abnormal in 12/45 patients. The MIBG-SPECT was abnormal in 28/45 cases with dorso-septal lack of activity. No difference was seen between type 1 and 2 diabetics with regard to either vibration and thermal thresholds or RSA and MIBG-SPECT. Abnormal MIBG-SPECT was correlated with vibration threshold and abnormal heart RSA tests but not with abnormality in QTc. The mean QTc-interval was 419 +/- 24 ms (QTc normal in 36, abnormal > or = 440ms in 9). It was longer in female than in male patients. There exists no significant correlation of QTc-interval results with either heart rate variability or MIBG-SPECT. The QTc-interval is not a sensitive parameter of autonomic cardiac denervation.

[Crohn's disease and stromal sarcoma of the small bowel--a rare coincidence]. / Morbus Crohn und Stromasarkom des Dünndarmes - eine seltene Kombination.

We report the case of a 29-year-old female who suffers for more than 13 years from Crohn's disease. A small bowel resection had to be performed because of a complicated and insufficiently controlled course of the disease with beginning subileus. At laparotomy a leiomyosarcoma was found. This case represents the forth case in the literature of an association between chronic inflammatory bowel disease and malign mesenchymal tumors. Tumors of epithelial and lymphoreticular origin are known as a much more common complication in Crohn's disease and especially ulcerative colitis. An exact histological characterization of these sarcomas is important to define the prognosis of the disease. If recurrent subileus is poorly controlled in Crohn's disease stromal tumors with their frequent intraluminal growth have to be considered as part of the differential diagnosis.

Stimulation of bile acid 6 alpha-hydroxylation by rifampin.

BACKGROUND: Rifampin was shown to relieve pruritus in cholestatic liver diseases. There has been much speculation about the origin of pruritus, but it has not yet been comprehensively explained. The role of bile acids in producing pruritus is obscure and still under debate. Since rifampin both inhibits the uptake of bile acids into the hepatocyte and strongly induces mixed-function oxidases in the liver, the beneficial effects of this drug might be a consequence of altered bile acid metabolism. METHODS: We investigated the influence of rifampin on urinary bile acid excretion with special respect to glucuronide and sulphate conjugates in 14 healthy volunteers before and after administration of rifampin, 600 mg x 7 days, using each subject as his or her own control. RESULTS: Bile acid glucuronide excretion increased from 0.55 to 1.19 mumol/24 h. This was in particular due to a significant increase of the urinary excretion of the 6 alpha-hydroxylated hyocholic and hyodeoxycholic acids, the relative amounts of which accounted for about two thirds of the urinary bile acid excretion. Excretion of sulphates, however, decreased from 1.40 to 0.86 mumol/24 h due to a significantly reduced excretion of lithocholic acid sulphate. No changes in the excretion rates of other primary and secondary bile acids and no changes in their conjugation patterns were observed. CONCLUSIONS: The results provide evidence that rifampin induces 6 alpha-hydroxylation of bile acids. The products are subsequently glucuronidated at the 6 alpha-hydroxy group, thus stimulating renal excretion of potentially toxic bile acids.

The influence of rifampin treatment on caffeine clearance in healthy man.

BACKGROUND/AIMS: Since cytochrome P450IA2 is involved in the metabolism of procarcinogens and carcinogens, there is debate about whether induction of this enzyme system by pharmaceuticals leads to a higher risk of malignancy. We investigated rifampin as a potent inducer of the hepatic mixed function oxygenase system and its effect on caffeine metabolism which can be taken as an in vivo marker of cytochrome P450IA2 activity. METHODS: Caffeine clearance was measured in ten healthy volunteers before and after a 7-day treatment with 600 mg rifampin. Urinary 6 beta-hydroxycortisol output was used as endogenous marker of microsomal enzyme function. RESULTS: 6 beta-hydroxycortisol increased from 7.6 to 26.0 micrograms/24 h per kg after treatment with rifampin, consistent with the induction of mixed function oxidases in the liver. There were significant changes in caffeine plasma half-life (6.2 vs. 3.5 h; p < 0.004) and caffeine plasma clearance (1.3 vs. 2.2 ml/kg per min; p < 0.004) with rifampin. CONCLUSIONS: The hypothesis that induction of cytochrome P450IA2 entails accelerated activation of procarcinogens would predict rifampin to be associated with a higher risk of malignancy. As with other inducers of cytochrome P450IA2, such as phenytoin or omeprazole, no such linkage is known. Therefore the role of pharmaceutical induction of cytochrome P450IA2 in tumor promotion remains unclear.

Caffeine demethylation measured by breath analysis in experimental liver injury in the rat.

To assess the effects of experimental liver injury on caffeine metabolism, 1 muCi/kg b.w. of [3-methyl 14C]-caffeine (together with 5 mg/kg b.w. of the cold compound) was injected i.p. to four different experimental groups and respective controls of unanesthetized male Sprague-Dawley rats. Exhaled 14CO2 was completely collected during 4 h and peak exhalation rate and fraction of dose recovered were calculated. 1/3 hepatectomy affected 14CO2 exhalation to a limited extent, decreasing solely peak exhalation rate (p < 0.05 compared to sham-operated controls). 2/3 hepatectomy, on the other hand, resulted in significant reduction (p < 0.01) in both peak exhalation rate (by 59%) and fraction of dose recovered (by 47%), that were proportionate to the loss of liver mass (59%). End-to-side portocaval shunt led to the well-documented hepatic "atrophy", liver weight being diminished on average to 50% within 2 weeks of surgery; however, reductions in peak exhalation rate (by 75%) and fraction of dose recovered (by 64%) were even more pronounced. Finally, 48 h bile duct ligation was equivalent to "functional 2/3 hepatectomy", peak exhalation rate (by 65%) and fraction of dose recovered (by 56%) being markedly diminished despite increased liver weight. These results indicate that 14CO2 exhalation curves following administration of specifically labelled caffeine are quantitative indicators of acute or chronic loss of functioning liver mass. In addition, the 3-demethylation pathway appears to be particularly sensitive to the inhibitory effects of cholestasis on microsomal function.

The major metabolites of ursodeoxycholic acid in human urine are conjugated with N-acetylglucosamine.

Ursodeoxycholic acid (750 mg/day) was administered orally to ten healthy subjects over a period of 10 days; 24 hr urine samples were collected the day before and on the last day of the study. Urinary bile acids were extracted, separated into groups of conjugates and analyzed by gas chromatography-mass spectrometry and fast atom bombardment mass spectrometry. Excretion of ursodeoxycholic acid rose from 70 to 2,915 micrograms/24 h. The highest increase was observed among N-acetylglucosamine conjugates, 90% of which constituted the previously unknown double conjugate of ursodeoxycholic acid with N-acetylglucosamine and glycine. Excretion of isoursodeoxycholic acid increased from 50 to 738 micrograms/24 h. This isomerization product of ursodeoxycholic acid was excreted almost exclusively as N-acetylglucosamine conjugate. In total, N-acetylglucosamine conjugates constituted 50% of urinary metabolites of ursodeoxycholic acid. In addition, metabolites of ursodeoxycholic acid hydroxylated at carbon atoms 1, 6, 22 and possibly 21 were observed. These compounds were also found as conjugates with N-acetylglucosamine. Their formation from ursodeoxycholic acid was definitely demonstrated by 13C-labeling after giving [24-13C]ursodeoxycholic acid to one of the healthy subjects and to a patient with extrahepatic cholestasis in whom hydroxylation of ursodeoxycholic acid at C-23 was also observed. The patient was also found to excrete the double conjugate of ursodeoxycholic acid with N-acetylglucosamine and taurine. The N-acetylglucosaminidation of ursodeoxycholic acid in vivo was shown to occur at C-7.(ABSTRACT TRUNCATED AT 250 WORDS)

Positions of conjugation of bile acids with glucose and N-acetylglucosamine in vitro.

In order to establish the position of conjugation of bile acids with glucose or N-acetylglucosamine, glucosides of chenodeoxycholic and hyodeoxycholic acids and of 13C-labeled cholic, lithocholic, chenodeoxycholic, hyodeoxycholic, and ursodeoxycholic acids, and N-acetylglucosaminides of ursodeoxycholic, isoursodeoxycholic, 3-dehydro-ursodeoxycholic, and ursodeoxycholylglycine were synthesized in vitro. The conjugates were purified by anion-exchange chromatography and reversed-phase HLPC and were analyzed by gas chromatography-mass spectrometry. The glucosides of chenodeoxycholic and hyodeoxycholic acids were also analyzed after periodate and chronic acid oxidation. All conjugates were analyzed by fast atom bombardment mass spectrometry with collision-induced dissociation. Glucose conjugation was shown to occur at C-3 in all bile acid glucosides studied. In contrast, the selective N-acetylglucosaminidation of 7 beta-hydroxy bile acids was shown to occur at the 7 beta-position.

Prevalence of Helicobacter pylori in patients with chronic renal failure.

The prevalence of Helicobacter pylori (H. pylori) was investigated in 164 consecutive patients with different degrees of renal function; group I (normal renal function) n = 84, group II (chronic renal failure, CLCR > or = 5 < 90 ml/min) n = 45, group III (haemodialysis therapy) n = 35, to test the hypothesis that the resulting different concentrations of urea in the gastric juice would have an influence on the colonization of the gastric mucosa by these urea-splitting bacteria. As every individual method for the detection of H. pylori shows disadvantages, the results of the detection methods used (urease test, Warthin-Starry stain, bacterial cultivation, direct examination of the processed sample by phase-contrast microscopy) were combined in a cumulative evaluation. These calculated cumulative indices for the antrum and corpus showed no statistically significant differences between the studied groups. The prevalence of H. pylori ranged from 34 to 54%. The histopathological findings were similar in all groups. In spite of the fact that patients with renal dysfunction had significantly higher levels of serum gastrin (P < 0.05), there was no influence on the gastric juice pH value. The relationship between the cumulative index and ammonia concentration in gastric juice was found to be linear (P < 0.05). The higher urea levels in the blood and gastric juice of patients with renal failure do not seem to be a risk factor for infection with H. pylori.

Bile acid N-acetylglucosaminidation. In vivo and in vitro evidence for a selective conjugation reaction of 7 beta-hydroxylated bile acids in humans.

The aim of this study was to define whether N-acetylglucosaminidation is a selective conjugation pathway of structurally related bile acids in humans. The following bile acids released enzymatically from N-acetylglucosaminides were identified: 3 alpha,7 beta-dihydroxy-5 beta-cholanoic (ursodeoxycholic), 3 beta, 7 beta-dihydroxy-5 beta-cholanoic (isoursodeoxycholic), 3 beta,7 beta-dihydroxy-5 alpha-cholanoic (alloisoursodeoxycholic), 3 beta,7 beta-dihydroxy-5-cholenoic, 3 alpha,7 beta,12 alpha-trihydroxy-5 beta-cholanoic, and 3 alpha,6 alpha,7 beta-trihydroxy-5 beta-cholanoic acids. The selectivity of conjugation was studied by administration of 0.5 g ursodeoxycholic (UDCA) or hyodeoxycholic (HDCA) acids, labeled with 13C, to patients with extrahepatic cholestasis, and of 0.5 g of 13C-labeled chenodeoxycholic acid (CDCA) to patients with extra- or intrahepatic cholestasis. After administration of [24-13C]-CDCA, labeled glucosides, and the glucuronide of CDCA were excreted in similar amounts. Labeled N-acetylglucosaminides of UDCA and isoUDCA were also formed. When [24-13C]-UDCA was given, 13C-label was detected in the N-acetylglucosaminide, the glucosides, and the glucuronide of UDCA, and in the N-acetylglucosaminide of isoUDCA. In the patient studied, 32% of the total UDCA excreted in urine was conjugated with N-acetylglucosamine. In contrast, 96% of the excreted amount of [24-13C]HDCA was glucuronidated, and 13C-labeled glucosides but no N-acetylglucosaminide were detected. The selectivity of N-acetylglucosaminidation towards bile acids containing a 7 beta-hydroxyl group was confirmed in vitro using human liver and kidney microsomes and uridine diphosphate glucose (UDP)-N-acetylglucosamine. These studies show that N-acetylglucosaminidation is a selective conjugation pathway for 7 beta-hydroxylated bile acids.

Portacaval shunt as an experimental model of impaired hepatic release of vitamin A in liver disease.

Vitamin A concentrations in serum and liver were studied in rats with a portacaval shunt for 48 days after shunt surgery. In addition, serum and tissue concentrations of zinc were analyzed. Following portacaval shunting serum vitamin A concentration decreased to 25% of the level in sham-operated controls, whereas serum zinc concentration decreased to 80%. The mean urinary excretion rate of zinc increased in shunted rats [18.7 +/- 2.1 micrograms/day (0.28 +/- 0.03 mumol/day)] compared with controls [13.8 +/- 1.7 micrograms/day (0.21 +/- 0.03 mumol/day)] (P less than 0.01). The concentration of retinol and total retinoids in liver tissue increased 2-3-fold in rats with a portacaval shunt, and the ratio of retinol to retinoids was slightly increased. The differences were reduced when the total organ content was calculated, because of the reduced liver weight in the shunted rats. The concentration of zinc in liver tissue decreased in rats with portacaval shunts [30.8 +/- 4.9 micrograms/g wet wt (0.47 +/- 0.07 mumol/g) vs. 35.6 +/- 3.7 micrograms/g wet wt (0.54 +/- 0.06 mumol/g) in controls; P less than 0.01]. The concentration of zinc was inversely correlated with retinol (r = -0.52, P less than 0.05) and total retinoid levels (r = -0.70, P less than 0.05) in rats with portacaval shunts but not in controls. The data are consistent with the hypothesis of an impaired release of vitamin A from the liver in rats with portacaval shunts, an impairment that could be due to liver zinc deficiency.

Urinary excretion of bile acid glucosides and glucuronides in extrahepatic cholestasis.

Recently the formation of bile acid glucosides has been described as a novel conjugation mechanism in vitro and in vivo. In 10 patients with extrahepatic cholestasis caused by carcinoma of the head of the pancreas we investigated excretion rates and profiles of urinary bile acid glucosides. Urinary bile acid glucosides and, for comparison, bile acid glucuronides were extracted and characterized according to established methods. In controls total urinary bile acid glucoside excretion was 0.22 +/- 0.03 mumol/24 hr (mean +/- S.E.M.)-in the range of bile acid glucuronide excretion (0.41 +/- 0.06 mumol/24 hr; mean +/- S.E.M.). A gas chromatography-mass spectrometry-characterized trihydroxy bile acid glucoside of still-unknown hydroxyl positions accounted for 65% of total urinary bile acid glucosides. In extrahepatic cholestasis total urinary bile acid glucoside excretion was 0.52 +/- 0.13 mumol/24 hr (mean +/- SEM), yet significantly lower than bile acid glucuronide excretion (1.53 +/- 0.13 mumol/24 hr; mean +/- SEM; p less than 0.001). In cholestasis the primary bile acid derivatives cholic and chenodeoxycholic acid glucosides amounted to 90%, whereas the trihydroxy bile acid glucoside had decreased to 5% of total bile acid glucoside excretion, indicating its alteration during enterohepatic circulation. The data establish the composition and quantity of urinary bile acid glucosides in healthy controls and cholestasis and constitute a quantitative comparison with another glycosidic conjugation reaction, bile acid glucuronidation.

Pharmacokinetics of caffeine in patients with decompensated type I and type II diabetes mellitus.

Diabetes may alter the pharmacokinetics of aminopyrine and antipyrine, which are used to assess liver function. Caffeine has recently been used to test liver function, but the effect of diabetes on caffeine kinetics is not known. The kinetics of caffeine has been examined in patients with decompensated Type I and Type II diabetes and in two age- and sex-matched control groups. In both types of diabetes the apparent caffeine clearance, half-life, and apparent volume of distribution were similar to controls. It is concluded that decompensated diabetes does not influence the cytochrome P-448 mono-oxygenase system responsible for caffeine metabolism.

Xipamide disposition in liver cirrhosis.

The pharmacokinetics of the sulfonamide-type diuretic xipamide was studied in patients with liver cirrhosis and ascites and compared with healthy control subjects. After oral administration of 40 mg xipamide, the diuretic was rapidly distributed in the blood and the ascites. The ratio of the area under the concentration-time curve (AUC) of plasma and ascitic fluid was 7:2, as was the protein content in the respective compartments. The AUC in plasma of cirrhotic patients was significantly greater than in control subjects (p less than 0.001). The most striking finding was the increase of the amount (Ae) of parent drug and main metabolite excreted into the urine (p less than 0.001). The renal clearance of xipamide was only moderately reduced in patients with liver cirrhosis. Both AUC and Ae were positively correlated to the plasma concentration of direct bilirubin of the patients (p less than 0.05). We concluded that nonrenal drug clearance in patients with liver cirrhosis was reduced as a result of the blockade of hepatobiliary excretion during cholestatic conditions.

Effect of phenytoin, carbamazepine, and valproic acid on caffeine metabolism.

Three groups of non-smoking epileptic patients without liver disease receiving antiepileptic monotherapy have been compared with 10 healthy non-smoking volunteers. Group 1 received phenytoin (n = 10), Group 2 carbamazepine (n = 10) and Group 3 valproic acid (n = 6). Cytochrome P-450 activity was monitored by measuring urinary 6-beta-hydroxycortisol output and systemic antipyrine clearance. Both, 6-beta-hydroxycortisol output and antipyrine clearance were significantly enhanced in patients on phenytoin and carbamazepine, but not in those on valproic acid. On the other hand, phenytoin alone increased the clearance of caffeine from 1.5 (controls) to 3.6 ml.min-1.kg-1, and reduced its half life from 4.8 to 2.4 h. Carbamazepine and valproic acid had no effect on caffeine metabolism. The results are in keeping with the well known heterogeneity of the hepatic monooxygenase system, as phenytoin and carbamazepine induce different panels of cytochrome P-450 isoenzymes. Phenytoin treatment may impair the validity of the caffeine liver function test.

Differential effect of type I and type II diabetes on antipyrine disposition in man.

As the influence of diabetes on drug metabolism in patients is controversial, a study was performed to assess antipyrine (AP) disposition in controlled Type I and Type II diabetics and 2 age- and sex-matched control groups. In Type I diabetics, the half-life of AP was significantly reduced from 12.0 (controls) to 7.9 h, and the volume of distribution (V) was lowered from 733 to 569 ml.kg-1. The resulting plasma clearance and cumulative urinary excretion of AP and its metabolites over 24 h did not differ from controls. In Type II diabetics, the AP half-life (14.5 h) and V (568 ml.kg-1) did not differ from their age- and sex-matched controls (11.1 h and 643 ml.kg-1, respectively), but the plasma clearance of AP was significantly reduced by 30%, and urinary excretion was significantly reduced to 44% of controls. The differential effects of Types I and II diabetes on AP metabolism may explain, at least in part, the controversial data in the literature.