[Oedema and haemorrhagic diathesis in a 50-year-old woman with thyrotoxicosis]. / 50-jährige Patientin mit Ödemen und Blutungsneigung bei Schilddrüsenhormonexzess.

We describe the case of a 50-year-old woman who presented with tachyarrhythmia, mild fever, peripheral oedema, ascites, epistaxis and gastrointestinal haemorrhage. Blood analysis revealed hyperthyroxinaemia. Analysis of thyroid-stimulating antibodies highlighted Graves' disease being the cause of the prevailing thyrotoxic crisis. Remarkable in this case of thyrotoxicosis is a liver affection without elevated transaminases but disturbed serum protein synthesis leading to hypalbuminaemic oedema and haemorrhagic complications. Thyrostatic treatment led to clinical response.

[Incidence and differential diagnosis of cholestasis in AIDS--a retrospective analysis of 73 patients]. / Inzidenz und Differentialdiagnose der Cholestase bei AIDS--eine retrospektive Analyse bei 73 Patienten.

A significant cholestasis constellation (alk. phosphatase and GGT each increased to twice as much as the norm) in 73 consecutive patients with AIDS was found in the course of the disease in 29 patients (= 39.7%). In most of the patients advanced immunodeficiency with an average of 2.5 AIDS-defining diseases already existed. In the predominant number of cases it was intrahepatic cholestasis with only slight icterus. Therapeutic measures such as medicamentous treatment or high-caloric parenteral nutrition were causal in two thirds of the cases; in a quarter of the cases opportunistic infections, above all disseminating mycobacteriosis were found. One third of the patients had already existing liver diseases. Liver biopsy frequently proved diagnostic and should be performed more often in the case of unclear liver findings in AIDS patients.

[Lidocaine elimination and MEGX formation after oral lidocaine administration--a practicable test for assessment of quantitative liver function]. / Lidocainelimination und MEGX-Bildung nach oraler Lidocainbelastung--Ein praktikabler Test zur Abschätzung der quantitativen Leberfunktion.

Oral load with 200 mg Lidocain was performed in 370 patients with chronic liver disease. The 120- and 240-minute Lidocain plasma concentrations as well as the 30- and 60-minute MEGX plasma concentrations, main metabolite of Lidocain, were measured by means of gas chromatography and with the commercial TDX test from the firm Abbott. No side effects caused by the load were observed and all of the patients resorbed Lidocain. Peak concentrations were found both for Lidocain and for MEGX in the 60-minute tests. Patients with liver cirrhosis of different aetiology showed significantly higher Lidocain plasma concentrations and lower MEGX values than patients with chronic non-cirrhotic liver disease. The differentiation of these two groups of patients was most successful via the determination of the 240-minute Lidocain plasma concentration. Oral load with 200 mg Lidocain has turned out to be a practicable and meaningful test for the estimation of the Cytochrom P450-dependent liver function.

Caffeine elimination in cirrhotic and non-cirrhotic liver disease of different etiology.

Caffeine elimination was studied in 419 patients with cirrhotic and noncirrhotic liver disease of different etiology (hepatitis B virus infection n = 79; hepatitis NANB virus infection n = 74; ethanol-induced liver damage n = 143; primary biliary cirrhosis I-IV n = 63; cryptogenic liver cirrhosis n = 60) following oral administration of 366 mg caffeine. Caffeine clearance in the control group was 69 +/- 33 ml/min (age-matched healthy volunteers and patients without liver disease). Caffeine clearance in acute hepatitis B (70 +/- 60 ml/min) chronic persistent hepatitis B (81 +/- 56 ml/min), chronic aggressive hepatitis B (107 +/- 66 ml/min), posthepatitic liver cirrhosis B (84 +/- 62 ml/min), acute hepatitis NANB (94 +/- 69 ml/min), chronic persistent hepatitis NANB (122 +/- 60 ml/min), chronic aggressive hepatitis NANB (87 +/- 52 ml/min) and posthepatitic cirrhosis NANB (59 +/- 26 ml/min) is not reduced in comparison with controls. In patients with alcoholic fatty liver (127 +/- 71 ml/min, p < 0.05) caffeine clearance is enhanced, in alcoholic hepatitis (57 +/- 72 ml/min) comparable to controls and in alcoholic cirrhosis reduced (36 +/- 44 ml/min, p < 0.05). In primary biliary cirrhosis I-IV caffeine clearance is higher than in controls (117 +/- 59 ml/min, p < 0.05). In cirrhotic liver disease of different origin caffeine clearance is inversely related to the serum bilirubin level. However, the absolute value is determined in addition by the underlying disease.(ABSTRACT TRUNCATED AT 250 WORDS)

[Taenia crassiceps infection in AIDS]. / Taenia-crassiceps-Infektion bei AIDS.

A 33-year-old patient with AIDS, and a history of episodes of Pneumocystis carinii pneumonia and cerebral toxoplasmosis, developed a subcutaneous paravertebral infiltrate, which at first resembled a haematoma. Over a period of several weeks, the lesion spread to cover almost the entire back. Initially, numerous investigations failed to reveal the aetiology. His general condition worsened progressively, and intermittent bleeding into the soft tissue of the back occurred, requiring transfusion. This was associated with the development of an isolated deficiency of clotting factor V and a fall in Quick values to 10%. On the 22nd day after admission, the infiltrate ruptured spontaneously, releasing blood and a large number of whitish spherical masses 2-3 mm in diameter. These were identified as Cysticerci longicolles, the larval form of Taenia crassiceps, a tapeworm occurring in Canidae. The blood clotting values returned to normal within two days of incision of the infiltrate and commencement of therapy with mebendazole (6 g/day) and praziquantel (3.6 g/day). The infiltrate subsequently regressed almost completely. After combination treatment for 2 weeks, treatment was continued with praziquantel alone, which, however, the patient stopped himself after 10 weeks. A recurrence at the same site 4 months later was successfully treated with a further course of mebendazole and praziquantel.

[One point determination of oral caffeine clearance in patients with liver diseases]. / Einpunktbestimmung der oralen Koffeinclearance bei Patienten mit Lebererkrankungen.

Caffeine clearance has been determined in 117 volunteers and patients (including 27 patients with liver cirrhosis) after oral application of 366.1 mg caffeine according to conventional pharmacokinetic methods (Cl = D/AUC). The resulting clearance values can be estimated with adequate accuracy from the plasma concentration at 12h for a concentration range of 2.0 to 6.5 mg/l according to Cl max = Doses/C 12h x t 12h x e and for concentrations higher than 6.5 mg/l according to Cl = Vd x (1n (D/Vd) - 1n C 12h/t 12h Vd is estimated from body weight as Vd = 0.42 x BW. "One - point" - estimation does not provide reliable data for plasma concentrations below 2.0 mg/l.

Systemic availability of propionate and acetate in liver cirrhosis.

In 15 patients with cirrhosis of the liver and 10 control subjects, 7.5 mmol sodium propionate and 7.5 mmol sodium acetate were instilled endoscopically into the duodenum. Venous concentrations of propionate and acetate were measured for 90 min after administration of the enteral dose by gas-liquid chromatography. In patients with liver cirrhosis, propionate rose from a basal value of 6.1 +/- 4.7 (SD) microM to a peak concentration of 50.1 +/- 25.6 microM, whereas, in controls, it rose only from 1.4 +/- 1.6 to 10.3 +/- 7.6 microM. The oral propionate clearance was significantly lower in patients with cirrhosis (4.51 +/- 1.63 L/min) than in controls (118.47 +/- 154.79 L/min). Acetate went up from 39.5 +/- 16.3 to 134.1 +/- 62.7 microM in patients with cirrhosis and from 60.9 +/- 19.0 to 102.0 +/- 44.0 microM in controls. The oral acetate clearance was lower in patients with liver cirrhosis (2.80 +/- 2.17 L/min) than in control persons (10.86 +2- 5.72 L/min). The differences between the groups were more striking for propionate than for acetate values. It is concluded that the systemic availability of propionate and acetate is higher in patients with liver cirrhosis than in controls. This may be due to portosystemic shunting and/or diminished hepatic and extrahepatic extraction of the acids.

Influence of smoking on caffeine elimination in healthy volunteers and in patients with alcoholic liver cirrhosis.

The effect of smoking on caffeine elimination was measured in 7 healthy volunteers and in 18 smoking and in 30 nonsmoking patients with alcoholic liver cirrhosis following oral application of 366 mg caffeine. In an intraindividual experiment in smoking health probands, caffeine clearance decreased from 118 +/- 33 to 77 +/- 22 ml per min (p less than 0.05) after abstaining cigarette smoking for 3 weeks. In a control group without liver disease (8 smokers, 15 nonsmokers), we found a caffeine clearance of 114 +/- 40 ml per min in smokers and 64 +/- 20 in nonsmokers (p less than 0.05). Smoking and nonsmoking patients with alcoholic liver cirrhosis did not differ with respect to clinical and laboratory data and hexobarbitone elimination. However, caffeine clearance was 63 +/- 63 ml per min in smoking patients compared to 34 +/- 49 ml per min in nonsmokers (p less than 0.05). Fasting plasma concentrations of caffeine were higher in nonsmokers (5.1 +/- 6.2 micrograms per ml) than in smokers (2.1 +/- 4.5 micrograms per ml, p less than 0.05). We conclude that smoking habits have to be taken into account if caffeine is used as a model compound for measuring quantitative liver function.

Influence of the rate of hepatic portal vein infusion on hexobarbital pharmacokinetics in the rat.

Pharmacokinetic parameters of hexobarbital were estimated in rats after hepatic portal infusion of a 10-mg dose. Infusion during 10 min resulted in an area under the blood concentration-time curve (AUC) of 556 +/- 83 micrograms.min/ml and a clearance of 83 +/- 13 ml/min.kg, whereas infusion of the same dose during 40 min resulted in values of 272 +/- 36 micrograms.min/ml and 169 +/- 30 ml/min.kg, respectively (mean values +/- SD, n = 3). Infusion during 15 and 20 min provided intermediate values. The decrease of the AUC and the increase of the blood clearance of hexobarbital following decreasing infusion rates clearly indicate nonlinear pharmacokinetics related to the hepatic inflow concentration of hexobarbital.

Influence of mexiletine on caffeine elimination.

In an acute experiment in healthy volunteers and in patients under long-term treatment for cardiac arrhythmias, mexiletine inhibits caffeine elimination by about 50%. The clearance of mexiletine is not influenced by caffeine. Some side effects of mexiletine may possibly at least partially be attributable to a retention of caffeine.

Factors influencing the caffeine test for cytochrome P 448-dependent liver function.

Liver functions in patients with liver disease can be estimated by caffeine clearance. Our data, however, demonstrate the additional influence of factors other than liver disease on the caffeine test. Smoking enhances caffeine clearance in both healthy volunteers and patients with severe hepatic disorders, whereas co-medication with mexiletine strongly inhibits caffeine elimination.

Correlation between the in vivo metabolism of hexobarbital and antipyrine in rats with a portacaval shunt.

To investigate how hepatic malfunction affects the disposition of hexobarbital (HB), an intermediate 'high-clearance' compound, and antipyrine (AP), a low-clearance compound, as well as the correlation between the rates of elimination of these drugs, their pharmacokinetics, were studied in control rats (n = 8) and in rats with a portacaval shunt (PCS; n = 9). Blood concentrations of parent drugs were measured, and urinary excretion of the following metabolites was determined: 3-hydroxymethylantipyrine (HMA), 4-hydroxyantipyrine and norantipyrine as primary metabolites of AP, and 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) as primary metabolites of HB. Blood elimination half-lives of AP and HB were more than four times longer in PCS rats than in control rats, increasing from 63.7 +/- 3.9 to 291 +/- 66 min, and from 20.1 +/- 1.8 to 84.2 +/- 7.6 min, respectively. Intrinsic clearance of HB (CLint, HB) was 167 +/- 19 ml/min/kg in controls and 27 +/- 4 ml/min/kg in PCS rats (CLpcs, HB). Intrinsic clearance of AP (CLint, AP) in control rats was 15.1 +/- 0.7 ml/min/kg and 5.9 +/- 0.7 ml/min/kg in PCS rats (CLpcs, AP). PCS reduced clearance for production of metabolites (CLMn) of AP by 50%, but CLMn of HB metabolites was decreased by more than 80%. The CLint, AP, CLint, HB CLpcs, HB, CLpcs, AP, and CLMn data were correlated. Total clearance correlated better in PCS rats than in control rats: r = 0.77 versus r = 0.10, respectively, thus suggesting a decrease in substrate selectivity under pathological conditions. CLOH-HB+K-HB, reflecting the major metabolic pathway of HB, correlated most closely with CLHMA in PCS (r = 0.91). Therefore, the underlying metabolic conversions of HB and AP may be mediated by the same or very similar forms of cytochrome P-450. Our results suggest that the predictive value of the model substrate approach is valid under pathological conditions.

Correlation between the in vivo metabolism of hexobarbital and antipyrine in rats.

Two model substrates for oxidative hepatic enzyme activity, viz. hexobarbital (HB) and antipyrine (AP), were given simultaneously to rats by the oral route of administration. Blood concentrations of HB and AP were measured simultaneously by a gas chromatographic method and the urinary excretion of six metabolites arising from AP and HB also was determined; norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine (HMA) by high-performance liquid chromatography; 3'-hydroxyhexobarbital, 3'-ketohexobarbital and 1,5-dimethylbarbituric acid by gas-liquid chromatography. The apparent intrinsic clearances of HB (CL*int,HB) and AP (CL*int,AP) and the clearance for production of the various metabolites were correlated in an attempt to establish whether HB and AP have metabolic pathways mediated by the same or very similar forms of cytochrome P-450. In order to create broadly ranging and evenly distributed clearance values, 3-methylcholanthrene (3-MC)- and phenobarbital (PB) pretreated rats were employed in conjunction with a control group of untreated animals. CL*int,HB and CL*int,AP were both increased by PB pretreatment, but 3-MC-pretreatment increased CL*int,AP, whereas CL*int,HB was decreased. CL*int,HB and CL*int,AP were found to correlate poorly, when all groups were taken into consideration (r = -0.08). The formation of AP-metabolites was inducible by both PB and 3-MC, and good correlations between rates of formation of AP-metabolites and CL*int,HB and CL3'-hydroxy-HB + 3'-keto-HB were obtained.(ABSTRACT TRUNCATED AT 250 WORDS)

Disposition of hexobarbital enantiomers in the rat.

The enantiomers of hexobarbital (HB), designated as (+)-HB and (-)-HB, were administered orally to separate groups of rats. Blood concentration-time curves of the parent compounds and the metabolites 3'-hydroxyhexobarbital (OH-HB) and 3'-ketohexobarbital (K-HB) were determined, as well as the cumulative urinary excretion of unconjugated OH-HB, K-HB, and 1,5-dimethylbarbituric acid (DMBA). The t1/2,(+)-HB was 13.4 +/- 0.8 min, and the t1/2,(-)-HB was slightly longer, 16.7 +/- 0.6 min (mean +/- SEM, N = 6). The intrinsic clearance values, CLint,(+)-HB and CLint,(-)-HB, were 2947 +/- 358 and 411 +/- 65 ml min-1 kg-1, respectively. The extraction ratios (E) were 0.94 for (+)-HB and 0.68 for (-)-HB. The t1/2,OH-(+)-HB and t1/2,OH-(-)-HB as calculated from blood data, were nearly the same: 20.0 +/- 2.6 and 22.2 +/- 1.5 min, respectively. Such data could not be established for the K-HB metabolites, since the curves exhibited no clear elimination phase. DMBA was undetectable in blood. The cumulative excretion of the measured metabolites in 24-hr urine was 44.0 +/- 1.8% for (+)-HB and 78.9 +/- 2.9% for (-)-HB, which was predominantly due to a substantial difference in the percentage of K-HB excreted. It is concluded that, to apply HB as a model substrate to assess oxidative enzyme activity, the use of only (-)-HB should be preferred to (+)-HB or (+/-)-HB because of a lower intrinsic clearance and a more complete recovery of oxidized metabolites in urine.

Influence of 9-hydroxyellipticine and 3-methylcholanthrene treatment on antipyrine metabolite formation in rats in vivo.

The influence of pretreatment of rats with 9-hydroxyellipticine and 3-methylcholanthrene on different enzymes of the hepatic mixed-function oxidase system were studied using antipyrine as model compound. Antipyrine half-lives and clearances were estimated in blood, and the metabolite profile was determined in urine. 3-Methylcholanthrene treatment resulted in an increase in antipyrine clearance from 17 to 75 ml/min per kg. Partial clearance of formation of 4-hydroxyantipyrine was selectively increased from 3.9 to 28.2 ml/min kg, whereas clearance of 3-hydroxymethylantipyrine was decreased from 3.2 to 1.2 ml/min per kg. Norantipyrine formation was increased from 2.7 to 7.2 ml/min per kg, while 4,4'-dihydroxyantipyrine formation was unchanged. 9-Hydroxyellipticine treatment resulted in no change in the total clearance, and only the clearance of 4,4'-dihydroxyantipyrine was decreased, from 2.5 to 1.5 ml/min per kg. After pretreatment with 3-methylcholanthrene, 9-hydroxyellipticine treatment resulted in a selective decrease in the clearances of 4-hydroxyantipyrine, from 28.2 to 15.8 ml/min per kg, and of 4,4'-hydroxyantipyrine, from 3.8 to 1.6 ml/min per kg. From these results it is concluded, that 9-hydroxyellipticine is a selective inhibitor of the activity of some of the cytochrome P-450s involved in antipyrine metabolism, though this inhibition does not effect all of these enzymes, nor is it restricted to polycyclic hydrocarbon-induced activity. These results further substantiate the value of antipyrine as a model substrate, for they indicate that the formation of all four metabolites of antipyrine in rats is mediated by different (iso-)enzymes.

Pharmacokinetics of oral brotizolam in patients with liver cirrhosis.

Disposition of oral brotizolam (0.5 mg) was studied in male patients with liver cirrhosis (patients) and in other patients (control) matched for age, weight, smoking and drinking habits. Absorption of brotizolam was relatively rapid in both groups with a median peak time (range) of 1.0 (0.5-2.0) h. Peak concentrations were also similar with median values of 7.1 (3.2-10.7) ng/ml in patients and 9.4 (2.9-19.0 ng/ml) in controls. Elimination half-life was longer in patients than in controls. The median values were 12.8 (9.4-25) h and 6.9 (4.4-8.4) h respectively (P less than 0.01). In two patients hardly any drug elimination was observed, indicating severe impairment of drug metabolizing activity. The prolongation of the elimination half-life was likely to be due to a decrease in clearance (45 ml/min in patients compared with 64 ml/min in controls), and an increase in volume of distribution (0.62 l/kg and 0.39 l/kg respectively). Median values of protein unbound fraction of brotizolam were 9.2 (7.8-10.4) % in controls and 12.4 (10.4-18.9) % in patients. Clearance of unbound drug was 612 ml/min and 380 ml/min respectively.