[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.

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.

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.

Bioavailability of zinc from zinc-histidine complexes. I. Comparison with zinc sulfate in healthy men.

Zinc supplementation is beneficial in some clinical conditions. Histidine has been shown to improve zinc absorption in animals. To test its influence on zinc absorption in humans, we studied the bioavailability of zinc from zinc-histidine complexes as compared to zinc sulfate in 10 healthy volunteers. Ingestion of zinc complexed with histidine at a ratio of 1:2 or 1:12 increased serum-zinc concentration 25% more than ingestion of zinc sulfate. Calculated uptake was 30-40% increased with zinc histidine over zinc sulfate. Urinary excretion was not different with any preparation. Application of 15 mg zinc as zinc histidine 1:2 gave an identical serum-zinc response as 45 mg zinc taken as zinc sulfate. Zinc histidine complexes are better absorbed than zinc sulfate in humans.

Bioavailability of zinc from zinc-histidine complexes. II. Studies on patients with liver cirrhosis and the influence of the time of application.

Supplementation may benefit patients with liver cirrhosis. Zinc uptake from zinc-histidine complex 1:2 was assessed in eight patients with liver cirrhosis. Influence of the time of application was also studied. Compared with healthy controls, patients showed a 40% lower uptake of zinc after 20 mg zinc from zinc histidine. Bioavailability was identical when zinc was taken 6 h or 1 h before a meal but an order of magnitude greater than with or 1 h after a meal. No significant increase of serum zinc was found when zinc was given with a meal or 1 h after. Lower doses of zinc-histidine complexes than of zinc sulfate may be used to supplement patients with liver cirrhosis. Time of application is of great importance if this substitution is to be successful.

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.

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.

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.

[The behavior of gamma-glutamyltranspeptidase and other liver enzymes in the plasma during alcohol withdrawal treatments]. / Das Verhalten der gamma-Glutamyltranspeptidase und anderer Leberenzyme im Plasma während der Alkohol-Entziehungskur

90 chronic alcoholics (55 men and 35 women, aged between 20 and 60 years) were investigated to determine how alcohol withdrawal effects the pattern of enzymes in plasma and if changes in this enzyme pattern could be used as criteria for evaluation of the recovery process. Among the different enzymes tested, gamma-glutamyl-transpeptidase (GGTP) and the transamines seemed the most suitable parameters. At the beginning of the alcohol withdrawal course, 79 out of 90 patients (80%) showed elevated values of one of these enzymes in plasma. GOT was elevated in 31 (34%), GPT in 24 (23%) and GGTP in 79 (88%) of the cases. In 49 patients (54%) GGTP was the only enzyme found to be elevated. The values of GGTP were on the average higher than those of GOT and GPT. GGTP has thereforeto be regarded as the most sensitive enzyme since it was elevated in most of the patients. GGTP reacted with 6.8 times more sensitivity than GOT and 6.3 times that of GPT. After withdrawal of alcohol the three enzymes showed a decline in all 79 patients. The transaminases normalized faster than GGTP. GTP fell into the upper normal limit after only 30 days. Among the 90 alcoholics examined, 14 relapsed during the alcohol withdrawal course. After the new excess of alcohol intake, the GGTP in plasma rose immediately. Alcohol abuse was suspected in 50% of the patients due to the increase in this enzyme and was subsequently confirmed by the patients. Acute alcohol loading in normal volunteers did not lead to an increase in GGTP activity. A comparison of the histology of liver biopsy material showed that neither the transaminases nor the alkaline phosphatase and GGTP served to differentiate the various forms of alcoholic liver damage. However, GGTP represents the most sensitive enzymatic parameter for the detection of alcoholic liver disease. This enzyme is useful in evaluating the success of a course of alcohol deprivation. The decreasing values during such treatment, as well as the prompt increase after a relapse, points to the high sensitivity of this enzyme. A further argument is that in 54% of the patients elevation of GGTP only was present. Since no liver damage could be demonstrated in these patients with the aid of the other liver enzymes, the elevation of GGTP may be related to the alcohol intake through an enzyme induction mechanism such as has been demonstrated for this enzyme with certain drugs.

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.

[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.

[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.

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.

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.

Assessment of the cytochrome P-448 dependent liver enzyme system by a caffeine breath test.

[1-Methyl-14C], [3-Methyl-14C] and [7-Methyl-14C] caffeine were used to investigate demethylation in control rats, and in rats pretreated with phenobarbital or 3-methylcholanthrene, by a 14CO2-exhalation test. Compared to controls, pretreatment with phenobarbital did not enhance demethylation of any of the labelled caffeines. In contrast, induction by 3-methylcholanthrene, presumably of cytochrome P-448, resulted in highly significant increases in peak 14CO2 exhalation rates, 14CO2 disappearance constants and areas under the exhalation rate - time curves. Based on these results, [7-methyl-14C] and [3-methyl-14C] caffeine were chosen for assessing the feasibility of a caffeine breath test in man, using 5 normal volunteers and 2 patients with compensated liver cirrhosis. 14CO2 exhalation curves in cirrhotics were clearly different from those in normal volunteers, being characterised by a slower rise and a lower specific activity of exhaled 14CO2. Since the variability of the levels of the specific activity in subjects with normal livers suggested the influence of extraneous factors, a second group of normal volunteers, smokers and nonsmokers, was investigated. With either labels, the average 14CO2 exhalation rate was doubled in smokers. From these studies in rats and preliminary results in man it is concluded that specifically labelled caffeine is a suitable and promising substrate for studying demethylation by breath analysis. Presumably, caffeine represents a safe and sensitive indicator of the activity of the cytochrome P-448 system.