Pharmacokinetics and metabolism of digoxin- and beta-methyl-digoxin-12aplha-3 H in patients with acute hepatitis.

Pharmocokinetics and metabolism of digoxin and beta-methyldigoxin have been studied in patients with acute hepatits after intravenous administration of both H-labeled glycosides. In contrast to digoxin, the rate of decline of radioactivity after administration of beta-methyldigoxin was significantly retarded in patients with acute hepatitis. The increase in plasma concentration after beta-methyldigoxin to patients with acute hepatitis is probably related to decreased demethylation.

Effects of cytostatic drugs on plasma level and renal excretion of beta-acetyldigoxin.

Mucosal defects decrease digoxin absorption in patients with malabsorption syndromes. Since the intestinal mucosa can be damaged by cytostatic drugs, we investigated their effects on digoxin plasma levels and urinary digoxin excretion. In six patients with malignant lymphoma who received 0.8 mg beta-acetyldigoxin before and 24 hr after treatment with a combination of cyclophosphamide, oncovin, procarbazine, and prednisone (COPP) or cyclophosphamide, oncovin, and prednisone (COP), plasma digoxin concentrations were measured 0 to 8 hr after the dose and areas under the plasma concentration-time curves were calculated. In 15 patients on 0.3 mg of beta-acetyldigoxin daily, plasma glycoside concentrations and renal excretion were measured daily before and after COPP, COP, cyclophosphamide, oncovin, cytosine-arabinosine, and prednisone (COAP), or adriamycin, bleomycin, and prednisone (ABP) treatment schemes. The diminished steady-state glycoside plasma concentrations and daily renal glycoside excretion during the 24 to 168 hr after the cytostatic drug established reversible impairment of digoxin absorption. The delayed time to peak after a single dose of digoxin during cytostatic drug therapy shows that extent and rate of digoxin absorption are reduced. To maintain adequate control of digoxin therapy in patients treated with cytostatic drugs, plasma levels should be monitored.

Influence of corticosteroid on hexobarbital and tolbutamide disposition.

The influence of 10 days' prednisone treatment on the disposition of hexobarbital and tolbutamide was studied in 7 healthy male volunteers. No significant changes in the pharmacokinetic parameters of the two drugs became apparent, which indicates that prednisone pretreatment does not affect their metabolic activities.

Influence of rifampicin on drug metabolism: differences between hexobarbital and antipyrine.

Six healthy volunteers were treated with 1,200 mg of rifampicin daily for 8 days. Before and immediately afterward each received indocyanine green, hexobarbital, galactose, and antipyrine by intravenous infusion on 3 consecutive days. The plasma concentrations of the drugs were determined several times after infusion. The average elimination half-life of hexobarbital had decreased from 407 to 171 min and its metabolic clearance had increased almost threefold. In contrast, the average elimination half-life of antipyrine was virtually the same on both occasions (6.9 and 7.2 hr) and there was no change in metabolic clearance. In a tuberculous patient treated with rifampicin the antipyrine elimination rate was unaffected. Rifampicin did not influence indocyanine green clearance or galactose elimination capacity. Serum gamma glutamyl transferase was not affected but urinary D-glucaric acid excretion was increased during rifampicin treatment. The experiment with hexobarbital was repeated after 2 weeks in all subjects; half-lives and clearance values had returned to near control values. It appears that rifampicin is a selective inducer of oxidative drug metabolism in man.

Pharmacokinetics of hexobarbital in acute hepatitis and after apparent recovery.

The pharmacokinetics of hexobarbital were studied in 13 patients with acute hepatitis. Hexobarbital sodium was administered by zero order intravenous (iv) infusion, and plasma concentrations were determined regularly by gas chromatography. For each patient the data were fitted according to 2-compartment kinetics. The results were compared to those obtained for 14 healthy volunteers. The elimination half-life of hexobarbital was 490 +/- 186 min in the hepatitis patients and 261 +/- 69 min in the control group. Clearance was significantly reduced in the hepatitis group, whereas the volume of distribution at steady state was not significantly altered. For some patients the initial distribution volume was reduced. In 6 patients the experiment with hexobarbital was repeated after apparent recovery from hepatitis as judged by normal transaminase and bilirubin levels. Generally the half-life of hexobarbital was shorter and the clearance value was higher than during the acute illness, but the values had not yet returned to normal. Clinical recovery from liver disease is not accompanied by corresponding recovery of drug-metabolizing capability.

The effect of dietary fiber on postprandial serum digoxin concentration in man.

The postprandial digoxin concentrations in serum were measured for 4 hr by radioimmunological assay in six healthy volunteers who had received 0.8 mg beta-acetyldigoxin by the oral route. Digoxin was given together with a formula diet containing as admixture, respectively, wheat bran, microcrystalline cellulose, pectin, carrageenan, and carob seed flour. The various additions did not reduce the mean digoxin concentrations in serum. After carob seed flour, the concentrations were significantly (P less than 5%) higher, as compared to the control. After microcrystalline cellulose, pectin, and wheat bran the mean peak concentrations were reached later than in the control state.

Pharmacokinetic interactions with rifampicin.

Rifampicin, a potent antituberculosis agent, is frequently combined with other antituberculosis drugs, or with drugs belonging to entirely different classes which may be required during a long period of antituberculous treatment, and therefore has a potential for drug interactions of practical clinical importance. The absorption of rifampicin is markedly decreased when it is simultaneously administered with para-aminosalicylic acid granules, due to adsorption by an excipient, bentonite. Several clinical observations and investigations have indicated that rifampicin itself accelerates the metabolism of various other compounds, including oral anticoagulants, the contraceptive pill, oral hypoglycaemic agents and digitoxin. Rifampicin seems to be a potent inducer of drug metabolism in humans and it causes a proliferation of the smooth endoplasmatic reticulum and an increase of cytochrome P450 content in the liver. It also increases its own rate of desacetylation. However, of the test compounds hexobarbitone and tolbutamide, the metabolic clearance increased 2-to 3-fold following rafampicin treatment, whereas antipyrine clearance was unaltered. This indicates that there is a certain selectivity in the enzyme induction effect of rifampicin, although it reamins unclear which compound will and which will not be affected. Rifampicin may also possibly interfere with hepatic uptake of other compounds, but the clinical significance of this type of interaction has not been clearly demonstrated; On the other hand, oral probenecid significantly increases the serum level of rifampicin, probably due to a similar depression of hepatic uptake.

The effect of pancreatic enzyme supplementation in patients with steatorrhoea after total gastrectomy.

OBJECTIVE: To assess the influence of pancreatic enzyme supplementation on symptoms, energy intake, bowel habits, and fat malassimilation in patients after total gastrectomy. DESIGN: A prospective, double-blind, randomized, parallel, placebo-controlled, multi-centre trial. SETTING: Institutionalized patients in three gastroenterological rehabilitation clinics. PARTICIPANTS: 52 institutionalized patients with a faecal fat output > or = 14 g/day, operated on for malignant gastric disease a median of 198 days (interquartile range (IQR) 47-608) previously, and free from recurrence and/or metastasis. INTERVENTIONS: Nine sachets of pancreatic enzymes per day (each containing lipase 36,000, amylase 27,000, protease 2400 FIP (Federation International Pharmaceutique)) or identical-looking placebo were given for 14 days. MAIN OUTCOME MEASURES: Abdominal symptoms, energy intake, bowel habits and fat malassimilation. RESULTS: After treatment, patients on enzyme therapy felt better overall (P = 0.006), but no improvement of a specific symptom could be identified. During the intervention, the median kilojoule intake per kilogram body weight was 9% higher in the placebo group (170.8 (IQR 146.9-202.6)) than in the enzyme-treated group (157.0 (IQR 134.8-170.4)) (P = 0.03). Enzyme treatment did not result in a significant difference between the placebo and the enzyme-treated group regarding bowel habits or fat malassimilation. CONCLUSIONS: The effect of high-dose pancreatic enzymes supplementation on symptoms and steatorrhoea after total gastrectomy is marginal and does not justify its routine use.

Determinants of medico-social functioning after total gastrectomy.

AIM: To describe medico-social functioning after total gastrectomy and the factors determining it. PATIENTS AND METHODS: In three medical rehabilitation centres, 173 consecutive patients (female/male = 62/111) after potentially curative total gastrectomy for gastric malignancy 206 days earlier (median, interquartile range = IQR 56-644) were evaluated for different pre- and post-operative parameters with potential influence on post-operative medico-social functioning as measured with the Edinburgh Rehabilitation Status Scale (ERSS). Parameters evaluated were: gender, age, time since operation, tumour stage, type of operation, clinical centre of admittance, haemoglobin, ferritin, albumin, presence of small bowel bacterial overgrowth, rapid oro-coecal transit, dyspepsia, early satiety, reflux, dysphagia, vomiting, a symptom based score, body mass index in health, at operation and on admission, weight loss since operation, calorie intake, bowel habits, and fat malassimilation. Independent influential factors for the ERSS were identified in a linear regression analysis. RESULTS: The median ERSS-score was 4 (IQR 2-6) on a scale from 0 (best) to 28 (worst). There was a significant difference in the ERSS-scores between the three different clinics. The ERSS-scores improved significantly with time since operation (ca. 22% per year). ERSS-scores were higher in patients with intestino-oesophageal reflux (+71%), with dyspepsia (+65%), or with dysphagia (+62%). CONCLUSION: Medico-social functioning was acceptable in this patient population. After total gastrectomy, dyspepsia, dysphagia, and intestinal reflux into the oesophagus need special attention.

Nutrient malassimilation following total gastrectomy.

BACKGROUND: The aim of the study was to elucidate the degree and the pathophysiology of abdominal symptoms, malnutrition and malassimilation after total gastrectomy. METHODS: In 174 consecutive patients, with potentially curative total gastrectomy for gastric malignancy, subjective symptoms and objective parameters of malassimilation were evaluated. RESULTS: Abdominal symptoms were present in 86% of the patients. In spite of a high daily calorie intake (median 37.8 kcal/kg body weight) mean body mass index had been decreasing since good health. Anaemia was found in 46%, sideropenia in 31% and oesophagitis in 26%. Mean faecal fat excretion was 17.4 (1.4) g/day and mean fat malassimilation 14.8% (1.1) of the intake. A shortened small-bowel transit was measured in 21.7% of the patients, and bacterial overgrowth was present in 37.7%. CONCLUSIONS: Malassimilation post total gastrectomy seems to be multifactorial. Shortened small-bowel transit and subsequent dyssynchrony of pancreatic enzyme supply seem to be of major importance.

[Drug clearance as a decision aid for further invasive liver diagnosis--studies with hexobarbital as a model substrate]. / Die Arzneimittelclearance als Entscheidungshilfe für eine weiterführende invasive Leberdiagnostik--Untersuchungen mit Hexobarbital als Modellsubstrat.

The clearance of a drug predominantly metabolized in the liver may serve as an estimate of quantitative liver function. In 260 consecutive patients presenting with a history of liver disease and abnormal laboratory findings but without a current definite diagnosis we have measured the clearance of hexobarbital and investigated if low values in patients are able to support the decision for an invasive diagnostic procedure such as needle biopsy or laparoscopy. 250 mg of hexobarbital was given orally to the patients between 8 and 10 hrs p.m. 12 hrs later blood samples were taken. Hexobarbital was determined by gas chromatography with N-selective detection, and a single point clearance was calculated. We recommended liver biopsy or laparoscopy to all patients with a hexobarbital clearance below 2.7 ml/min/kg body weight (normal 2.66-5.34 ml/min/kg). 73 out of 260 patients showed a reduced hexobarbital clearance. In 44 patients blind liver biopsy (n = 14) or laparoscopy (n = 30) was performed, 29 patients refused an invasive diagnostic procedure. 17 out of 26 patients with the tentative diagnosis chronic hepatitis had already an incomplete or complete liver cirrhosis. In 11 out of 18 patients with the tentative diagnosis alcohol toxic liver injury we found a progressive portal fibrosis or complete liver cirrhosis. Reduced drug clearance reflecting quantitative liver function can be an indicator of advanced liver disease, thus adding substantially to the decision for further invasive diagnostic procedures.

Chiba-needle percutaneous cholangiography - a method without risk to the patient?

This critical review of PTC with the skinny needle was prompted by an unexpected complication - an intrahepatic hematoma. A negative PTC does not exclude the presence of dilated bile ducts. In the case of an obstructed biliary tree, bile leakage occurs in approximately 5%. Even after the Chiba needle or other techniques have become established, peritoneoscopy is still of value in the diagnosis of cholestasis. Thus, this method is not without some risk and optimistic reports should be judged with a certain reserve.

[Clinical importance of organ-specific antibodies in ulcerative colitis and Crohn disease]. / Klinische Bedeutung organspezifischer Antikörper bei Colitis ulcerosa und Morbus Crohn.

In 479 patients with chronic inflammatory intestinal diseases and other abdominal diseases autoantibodies against intestinal goblet cells and exocrine pancreas were determined by indirect immunofluorescence. In ulcerative colitis 17% had serum antibodies against intestinal goblet cells, in Crohn's disease 26% against exocrine pancreas. Autoantibody prevalence and level of the titre were dependent on the inflammatory activity of both diseases but independent on the therapy. In Crohn's disease high level of titres of antibodies against exocrine pancreas we found in cases with multiple complications. Antibodies titres against intestinal goblet cells in ulcerative colitis and against exocrine pancreas in Crohn's disease exceeding 1:100 improved the diagnostic decision. Besides clinical states, endoscopic and histological findings a positive result of the antibody investigations had to be considered for final diagnosis.

[Percutaneous transhepatic--versus endoscopic retrograde cholangiography in the differential diagnosis of cholestasis? (author's transl)]. / Perkutane transhepatische oder endoskopisch-retrograde Cholangiographie in der Differentialdiagnostik der Cholestase?

Since the introduction of the Chiba needle the percutaneous transhepatic cholangiography (PTC) became an established method in the differential diagnosis of cholestasis beside the endoscopic retrograde cholangiography (ERC). From the clinical point of view it is sometimes difficult to decide which of these two techniques should be preferred. In case of absolute or relative contraindications or in case of failure of one of the two methods ERC and PTC can be used alternatively. In all other cases we feel that the PTC by means of the Chiba needle is superior because of easier technical handling and higher success rate. In addition PTC is less trying for the patients. However on the basis of our own experience is should be stressed, that even by using skinny needles there is danger of bile leakage, which necessitates an immediate surgical intervention in the presence of biliary obstruction.

[Studies on drug metabolism in obese men and mice (author's transl)]. / Klinische und tierexperimentelle Untersuchungen zum Arzneimittelmetabolismus bei Adipositas.

In 7 obese patients with an overweight of 53 +/- 19% of Broca we found a 2-fold enlarged apparent volume of distribution and a nearly 2-fold prolonged elimination halflife of hexobarbital; the hexobarbital plasma clearance however, which is nearly identical with the metabolizing capacity of the liver for hexobarbital, was not decreased. Phenobarbital induced the microsomal drugmetabolizing enzyme system in the fatty liver of genetically obese mice in the same way 2-3-fold as in the non-fatty liver of the lean littermates.

[Pharmacokinetics of digoxin and methyldigoxin in patients with acute hepatitis (author's transl)]. / Pharmakokinetik von Digoxin und Methyldigoxin bei Patienten mit akuter Hepatitis.

After i.v. application of 3h-digoxin or 3H-methyldigoxin to 5 healthy volunteers and 5 patients with acute hepatitis, respectively (0.75 mg daily for 3 days and 0.375 for the following 2 days) total radioactivity in urine and plasma were determined. Chloroform-soluble and -insoluble glycosides were separated and the chloroform-soluble fraction was determined by TLC. 3 days after methyldigoxin application plasma levels reached toxic values in the patient group (2.73 +/- 0.48 ng/ml), whereas in patients receiving digoxin a mean plasma level of 0.91 +/- 0.21 ng/ml was obtained. During the first 24 hours following administration of digoxin 44 +/- 12% of the dose were recovered in urine of control subjects and 48 +/- 13% in patients with acute hepatitis, after methyldigoxin 34 +/- 5% and 34 +/- 8%, respectively. Metabolism of digoxin in patients with acute hepatitis was unaltered, whereas a diminished demethylation rate of methyldigoxin could be observed. 16 patients with acute hepatitis and 7 healthy volunteers received unlabelled digoxin p.o. as maintenance dose. Plasma glycoside concentrations were studied by radioimmunoassay. The average glycoside plasma concentrations were 0.59 +/- 0.21 ng/ml and 0.63 +/- 0.24 ng/ml, respectively.