[The influence of galenic and biologic factors on the bioavailability of Berlocombin]. / Der Einfluss galenischer und biologischer Faktoren auf die Bioverfügbarkeit von Berlocombin.

The analysis of the influence of galenical and biological factors on the biological availability of Berlocombin (sulfamerazin and trimethoprim combination) has been performed by a single Berlocombin juice administration compared to tablets and by a tablet administration combined with nourishment. In case of the juice administration, the biological availability of trimethoprim and sulfamerazin has been reduced. The tablet administration at an empty stomach and a subsequent 5-h waiting period revealed a more complete trimethoprim resorption, which compared to an administration immediately after the standard breakfast is expressed by a significantly greater area under the concentration-time curve (AUC) in serum. In tablet application subsequent to a fatty breakfast, the trimethoprim and sulfamerazin resorption is compared to the relative group some increased; the differences, however, were insignificant ones. The results of this study failed to be of practical consequences, because the dosage applied and recommended by the producer significantly exceeded the minimum inhibition concentrations in serum and urine 3 h after administration. The required therapeutic level in no case fell short of up to the 12. hour.

[The relative bioavailability of co-trimoxazole suspensions]. / Zur relativen Bioverfügbarkeit von Cotrimoxazol-Suspensionen.

The relative bioavailability of a co-trimoxazole suspension manufactured by VEB Berlin-Chemie (B); Belocid-Suspension was compared with a widespread used suspension (V) in healthy male students (22-29 ys. aged). A single oral dose of 160 mg trimethoprim (TPM) and 800 mg sulphamethoxazole (SMZ) produced similar blood levels with either preparation. The TMP peak levels were 1.44 +/- 0.18 (B) and 1.40 +/- 0.26 mg/l (V), respectively after 1.5 and 1.0 h on an average. The AUC amounted to 18.94 +/- 2.25 (B) and 17.19 +/- 3.62 mg . h/l (V), respectively. About one half (52.5%) of the given TMP dose was excreted unchanged by kidney within 48 h after administration of the respective suspension. The SMZ peak levels run to 37.2 +/- 10.3 (B) and 38.6 +/- 5.4 mg/l (V) after 3.6 +/- 3.5 and 1.3 +/- 0.8 h. The AUC were identical: 682.3 +/- 126.2 (B) vs. 686.9 +/- 165.8 mg . h/l (V). After both preparations 67% of the given SMZ dose could be detected in urine within 48 h. In two out of the eight volunteers the absorption of B was delayed, but it passed off to the same extent. In all other cases absorption of the suspension was accelerated in comparison with tablet administration studies reported. Peak blood levels of TMP and SMZ after ingestion of the suspensions reach the lower range of values resulting from tablet intake. Both suspensions are regarded interchangeable with respect to bioavailability, which is also comparable to co-trimoxazole tablets.

[Epidemiology of liver diseases in the GDR, 1979-1989]. / Die Epidemiologie der Lebererkrankungen in der DDR von 1979-1989.

From 1979 to 1988 in the GDR the number of patients with alcoholic liver cirrhosis increased from 2,387 to 3,958 (61.2%). An evident decrease of patients with acute virus hepatitis was observed (from 7,037 in 1979 to 1,578 in 1989). In future a further increase of alcoholic liver diseases with the resulting complications (e.g. coma, bleeding varices and withdrawal symptoms) has to be expected.

Cytochrome P-450-dependent biotransformation in Uje:WIST rats with chronic liver injury induced by thioacetamide.

In female Uje:WIST rats micronodular liver cirrhosis was produced by thioacetamide (TAA) given in the drinking water (0.3 g/l) from the 4th to 6th months of life. 14 d after TAA cessation it was examined, whether this animal model reflects the restricted cytochrome P-450-dependent biotransformation in severe stages of human liver cirrhosis by in vivo (caffeine and metamizol elimination) and in vitro methods (cytochrome P-450, 7-ethoxycoumarin and 7-ethoxyresorufin O-deethylation, ethylmorphine N-demethylation). The total biotransformation capacity was unchanged in TAA rats, partly even enhanced. Only several in vitro parameters reflect diminished cytochrome P-450-dependent biotransformation calculated per weight unit comparable to severe stages of human liver cirrhosis. Therefore, the chosen experimental conditions are suitable for conclusions concerning cytochrome P-450-dependent biotransformation in early rather than in severe stages of human liver cirrhosis.

[Resorption and biotransformation of model substances in primary idiopathic hemochromatosis (siderophilia)]. / Resorption und Biotransformation von Modellsubstanzen bei der primären ideopathischen Hämochromatose (Siderophilie).

In 12 patients with primary idiopathic haemochromatosis absorption and biotransformation were measured by model substances. Aim of the investigation was the correlation of the biotransformation of the liver with the degree of liver injury and the clinical picture. We determined in patients and compared with control group: elimination of metamizol in urine, absorption and elimination of caffeine in serum, serum concentrations and elimination of sulfamethazin in urine, absorption of xylose, - In patients with haemochromatosis accompanied with slight liver damage only demethylation of metamizol was slackened. In patients with higher degree of liver damage the elimination of metamizol as well as of caffeine was decreased. Because of the high percentage of slow acetylators in the patient group metabolism of sulfamethazine is decreased. - There was no correlation between iron loading of the organism, absorption of xylose and biotransformation of the model substances.

Studies on the in-vitro biotransformation in patients with liver diseases.

The activity of 7-ethoxycoumarin O-deethylase (ECOD) was determined in the human liver bioptate of 53 patients with chronic liver diseases. Remarkable are the lower values of ECOD in the hepatoses, chronic hepatitis and cirrhosis as compared to patients with normal histology or residual hepatitis. The decline in the activity of ECOD in the patients with chronic hepatitis and cirrhosis has to be seen in connection with parenchymatous necrosis, nodular liver transformation and intracinar fibrosis. For the time being it is not possible to give a satisfactory explanation of the decrease in the ECOD activity of the hepatoses.

[Emergency endoscopy in chronic liver diseases]. / Notfallendoskopie bei chronischen Lebererkrankungen.

Emergency endoscopy has to be regarded as a method of high diagnostic value. Based on the resulting therapeutic consequences and with allowance for the prerequisites and contraindications, emergency endoscopy in chronic liver diseases is to be considered a purposeful method. If endoscopic treatment possibilities in bleedings of the gastrointestinal tract continue to improve, the demonstration of an improvement in prognosis by emergency endoscopy seems to be merely a question of time.

[Comparison of ICG elimination with biotransformation of model substances and histological features of liver biopsy in liver diseases]. / Vergleich der ICG-Elimination mit der Biotransformation von Modellsubstanzen und mit histologischen Merkmalen im Leberbioptat bei Lebererkrankungen.

The elimination of indocyanine green (ICG) was measured in 45 patients with histologically proved liver disease to evaluate liver blood flow. Furthermore, the elimination of caffeine and metamizol was determined in serum as a parameter of in vivo biotransformation. In a further step the activity of 7-ethoxycoumarin O-deethylation was measured in liver biopsy samples of 30 out of 45 patients (in vitro parameter of biotransformation). The half-life of ICG was compared with the data of biotransformation by means of the calculation of correlations with special consideration of histological findings in liver biopsy samples (monocellular necrosis, intra-acinar fibrosis, structural transformation). Results demonstrate that ICG-elimination is a nonsufficient criterion of liver blood flow in patients with liver disease, because of considerable variation and many influencing factors including the function of the liver cells. Therefore, it is difficult to evaluate results.

Comparison of in vitro and in vivo biotransformation in patients with liver disease of differing severity.

The activity of 7-ethoxycoumarin O-deethylase (ECOD) has been measured in liver biopsy samples from 23 patients (smokers and non-smokers) with different degrees of structural liver damage. The results, which reflect in vitro cytochrome P450-dependent biotransformation, were correlated with various measures of the P450-dependent in vivo elimination of caffeine and metamizol. The relatively non-specific, low affinity component of ECOD activity was significantly correlated with the kinetics of metamizol (mean residence time, apparent clearance, half-life, area under the concentration-time curve, and metabolite excretion in the urine). Thus, metamizol elimination, which is mainly due to P450 IIB, and the low affinity component of ECOD both reflect, at least in part, the activity of the same form of P450. In contrast, caffeine biotransformation, which is via P450 IA, was not correlated with ECOD activity. There was no relation between the kinetics of metamizol and caffeine, perhaps because of the inducing effect that smoking has on caffeine elimination. In patients with liver disease, smoking appears to alter the elimination of caffeine more than the degree of liver disease.

[7-ethoxycoumarin o-deethylase and fibrosis in chronic liver diseases]. / Die 7-Ethoxycoumarin O-Deethylase und der fibrosierende Prozess bei chronischen Lebererkrankungen.

In the liver biopsy of 100 patients with chronic liver diseases, the activity of 7-ethoxycoumarin O-deethylase (ECOD) was determined as a parameter of hepatic monooxygenase system and was compared with some markers of fibrosis e.g. collagen peptidase and hydroxyproline. ECOD was significantly different in healthy liver, fatty liver, chronic active hepatitis (CAH) and cirrhosis. The importance of the fibrotic process was shown by the significant correlations between ECOD and the signs of fibrosis in the liver biopsy. A connection between ECOD and the markers of fibrosis was not found. Further research is necessary to clarify this difference.

[Simultaneous administration of various model substances for characterizing in vivo biotransformation in chronic liver diseases]. / Die simultane Gabe verschiedener Modellsubstanzen zur Charakterisierung der in-vivo Biotransformation bei chronischen Lebererkrankungen.

16 patients with different chronic liver diseases were given single doses of the model substances caffeine, metamizol, sufamethacine and debrisoquine. This was followed by the simultaneous administration of all these substances as a "cocktail". A comparison between the single and the "cocktail" dosage did not reveal any significant differences in the pharmacokinetic parameters. So the "cocktail" administration is even possible in chronic liver diseases. Requiring relatively little time, it makes statements possible concerning various cytochrome P450 enzymes including the types of hydroxylation and acetylation. Intraindividual variations can be ruled out.

[Causes of gastrointestinal hemorrhages in chronic liver diseases]. / Ursachen gastrointestinaler Blutungen bei chronischen Leberkrankheiten.

356 patients with chronic liver diseases hospitalized in our clinic during the period from January 1, 1981, to December 12, 1983, were enrolled in a retrospective study. Of them 55 had been admitted for acute gastrointestinal hemorrhage. It appears that gastroscopy is the only method allowing to localize the origin of the bleeding with high certainty. Bleedings from varices (45%) and ulcers or erosions (22%) were seen most frequently. With regard to case history, clinic, paraclinic and prognosis, no significant differences were found between these various origins of the hemorrhages. Also it is remarkable that all bleedings occur with higher frequency in portal hypertension.