Dissolution of biliary duct stones with mono-octanoin.
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Biomedical subjects
Publications and source records attributed to U Leuschner.
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In 21 female Beagle dogs an experimental pancreatitis was induced by injection of bile into the pancreatic duct system. Beside controls, dogs received 62.5 micrograms/h cyclic somatostatin (SRIF) a continuous i.v. infusion starting with a bolus of 250 micrograms 15 minutes before or 2 hours after bile injection. Following blood parameters were determined: lipase, amylase, blood count, minerals, glucose, insulin, gastrin, secretin and CCK. Two controls died within 24 hours, the others were sacrificed after 48 hours. All pancreata were examined morephologically. The controls developed all clinical signs of acute hemorrhagic pancreatitis, whereas all SRIF-treated dogs were in much better general condition. Lipase and amylase increased in all groups. In the controls insulin, gastrin and secretin remained unchanged and CCK rose slightly. SRIF-treatment diminished insulin, CCK and the test meal-induced increase of secretin. At autopsy the pancreata of the controls were nearly entirely apoplectic. The SRIF-treated dogs showed less damage of the pancreas and no severe hemorrhagic necrosis was noted. The beneficial effect of SRIF cannot only be due to an interaction with intestinal hormones. An additional direct protective effect on the exocrine parenchyma is proposed to exist.
Chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) dissolve cholesterol gallstones in man. Since CDCA has caused liver damage in animal experiments we have tried to elucidate the question whether such alterations could occur due to UDCA therapy as well. CDCA and UDCA were fed orally in doses of 20, 90, 150, 250 and 1000 mg/kg body-weight daily to female Wistar-Rats (CDCA: 75 animals; UDCA: 75 animals). After 5, 30 and 60 days we examined the liver by means of light- and electronmicroscopy. After 30 days all animals treated with 1000 mg/kg CDCA had died, whereas there were no pathological findings in the UDCA treated group. By means of electronmicroscopy we detected in the CDCA-group already with 20 mg/kg/day microstructural alterations of the liver that increased with elevation of the dosage and duration of treatment. With UDCA therapy liver tissue showed minimal changes only with 1000 mg/kg. The difference is explained by the decreased rate of transformation of UDCA to lithocholic acid and the lack of toxicity of UDCA in the hepatocyte.
Well-known methods for the photometric determination of antiepileptics in body fluids were tested from the aspect of their utilization in a pharmacokinetic therapy service of clinical pharmacology. In the framework of a comparative synopsis of methods, specifications are given for the determination of phenytoin, phenobarbital, methylphenobarbital, and carbamazepine.
In 38 patients with chronic hepatitis and 53 patients with liver cirrhosis the portal vein pressure was determined by wedged hepatic vein pressure (WHVP). There were significant differences among chronic persistent, chronic active hepatitis and liver cirrhosis. The wedged hepatic vein pressure increased in chronic active hepatitis according to the rate of hepatic connective tissue. The platelet count and the thromboplastin time were correlated to the values of wedged hepatic vein pressure not only in chronic active hepatitis but in liver cirrhosis as well. The correlation among serum albumin level, bromsulphalein retention and systolic blood pressure after Riva-Rocci and wedged hepatic vein pressure was significant in liver cirrhosis exclusively. Even if the determination of wedged hepatic vein pressure does not permit an absolute statement on the risk of hemorrhage of esophageal varicosis it is nevertheless suited for follow-up controls in chronic hepatitis and liver cirrhosis and renders possible an outlook on the progress of the disease.
Serum levels of phenytoin, phenobarbital, carbamazepine, and ethosuximide were determined in about 2,000 subjects treated on an outpatient and inpatient basis, respectively. Therapeutical serum level ranges were obtained in about 50 percent of the patients. In the other patients, the values determined were either too low or too high. These studies, in addition to enabling the drug-taking behavior of patients to be objectified, made possible "blood-level-oriented dosage" and allowed differential approaches to be adopted in the control of undesirable effects. Blood level determinations permit the therapeutical procedure to be improved and made more reliable especially in "problem cases". A pharmacokinetic therapy service has proved useful for long-time antiepileptic therapy.
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Dosage monitoring or "pharmacokinetic therapy service", respectively, covers blood level governed therapy schedule or blood level controlled dosage for certain types of therapy. It is also advantageous in applying drugs of a small therapeutic range or in "risk" patients such as children, old men and patients suffering from elimination disturbances. With the blood level data known, physicians can follow an optimum therapy schedule. The principle of this service is detailed using therapy with antiepileptics as an example. Through substantiation is given.
In male Wistar rats nonsulfated bile acids of small and large intestinal wall and feces are analysed after 2, 5, 9 and 14 days of oral administration of 20 or 90 mg chenodeoxycholic acid (CDCA)/kg. Development of body, intestinal, and fecal weights is assessed. A transient reduction of daily body weight gain and small and large intestinal weights is compensated after 14 days. Fecal weights are above controls under 20 mg/kg, below controls under 90 mg/kg. Containing about 2 mg, i.e. nearly 4% of the bile acid pool, the intestinal wall holds four times more bile acids than the liver. Under CDCA administration bile acid concentrations in the small intestinal wall and feces rise, and remain almost unchanged in the colonic wall. Changes after CDCA administration suggest that bile acid absorption is accompanied by an increase in mucosal bile concentration. In the colonic wall the increase in bile acid concentration after CDCA administration correlates with the passive permeability coefficient.
Light- and electron microscopic alterations of the liver and light microscopic findings in the gastro intestinal tract, the kidney and adrenal gland of 80 female Wistar-Rats under CDCA therapy are reported. CDCA was applied by means of an endopharnygeal tube over a period of 60 days in doses of 150, 250, 500 and 1000 mg/kg body weight. The organs were examined at different times. We compared the achieved findings to results obtained already beforehand by light- and electron microscopy after application of 20, 50 and 90 mg/kg body weight and day: Up to a dosage of 90 mg/kg morphological changes of the liver were only visible electron optically, from 150 mg/kg onward they could be seen light optically as well. After 60 days a cirrhosis-like picture had developed. The lethal dose was established at 1000 mg/kg. There were no pathological alterations in the gastrointestinal tract and no definite ones in the kidneys. The adrenal glands were unchanged.--Since there are in the rats, in spite of potent mechanisms of detoxication of CDCA and LCA, even at low doses morphological alterations to be seen, the existence of other toxic, at this moment still unknown metabolites is being discussed.
24 patients with cholesterol gallstones were treated with chenodeoxycholic acid. In 7 out of 10 patients the follow-up showed complete dissolution of the gallstones after 7 to 18 months of treatment with 1 g of chenodeoxycholic acid daily. Two patients with biliary duct concrements had to be operated, in a third patient no change could be observed after treatment for 17 months. A transient increase of the transaminase GOT was seen in four patients. There were no changes of serum cholesterol and triglyceride levels. 14 patients had chologenic diarrhoea lasting only a few days. Toxic side effects indisputably due to chenodeoxycholic acid therapy have not been seen so far.
103 non selected patients underwent laparoscopy with the photolaparoscope equipped first with Luminaoptic and subsequently with the magnifying optic of Lent (Wolf GmbH, Knittlingen, W-Germany). The results are compared with the histologic findings and among each other. In 83.5% there was a satisfactory correlation between laparoscopy and histological findings, in 16.5% there was none. It was only in 2.9% of all cases that a different diagnosis resulted by means of the magnifying optic. From these results it is concluded that the magnifying optic does not provide a higher effectivity of laparoscopy. Thus the magnifying optic should be preserved for instruction.
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Male Wistar rats were fed orally 20 mg, female rats were fed 20, 50 and 90 mg CDC/kg body weight. The animals were killed on the 5th, 14th, 20th, 30th and 60th day, female animals were killed in addition 14 days after end of treatment, their liver was examined by means of light- and electron microscopy. No pathological changes were to be seen in the light microscope. In the electron microscope we observed in male and female animals dilated bile capillaries and intracytoplasmic vacuoles, in female animals more over alterations of mitochondria and an increase of peribiliary lysosomes. Sex-linked differences were not to be detected. In female animals the findings were quantitatively better discernible. Even a tetrafold increase of dosage in female rats produced no change in findings. 14 days after end of therapy no alterations were visible any more. It is being assumed that CDCA or its metabolite lithocholic acid exert some influence upon the bile secretory apparatus of the liver cell.
Right of left ventricular biopsies were performed in 50 patients with late and early forms of congestive cardiomyopathy. Clinical data as well as light and electron microscopic findings are described. Chronical myocarditis could be detected by histological examination in three patients. Hypertrophy and degenerative changes of the heart muscle cells and interstitial fibrosis were the major morphological finding in the other cases. There is a good correlation between the severity of clinical symptoms and the extent of light and electron microscopical changes. In some patients with mild clinical symptoms advanced ultrastructural alternations were found.
The isolated liver of male Sprague-Dawley rats was perfused by means of media containing lithocholic acid, taurolithocholic acid, lithocholic acid sulfate and taurolithocholic acid sulfate. 150 minutes later the tissue was being examined light- and electrone microscopically. After LC and TLC perfusion considerable alterations were found in the bile capillaries, in the ergastoplasm and minor ones in mitochondria. After perfusion with sulfate esters the tissue was unchanged. Our investigations have shown that sulfation provides a highly effective mechanism of detoxication in rats; but detoxication results not only in a decrease of reabsorption of excreted lithocholic acid sulfate esters but sulfation tenders the very lithocholic acid untoxic for the liver cell. The primary point of action of lithocholic acid seems to be the lipoprotein membrane.
Electron microscopic findings of the liver are being described found in 4 patients aged from 12 months to 26 years after poisoning with Amanita phalloides. Marked alterations were seen in nuclei, in the endoplasmic reticulum, and in mitochondria. Morphologic criteria of cholestasis were observed in one patient. Extreme cellular edema was found in two patients. Since our findings differ considerably in several points from those patients with Amanita phalloides poisoning previously reported, one may suppose, that e.g. age, sex, preexisting damage and liver function might be highly important for the extent and form of resulting liver damage.
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