[Therapy of hemochromatosis].
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Bloodletting↗
Biomedical subjects
C Niederau
Publications and source records attributed to C Niederau.
Therapeutic regimens in acute experimental hemorrhagic pancreatitis. Effects of hydration, oxygenation, peritoneal lavage, and a potent protease inhibitor.
In this study we evaluated the effects of hydration, oxygenation, peritoneal lavage, and the protease inhibitor gabexate mesilate in acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented diet. Different groups of mice were kept at various concentrations of O2 (21%, 35%, and 45% O2), or were treated by either s.c. injections or i.p. injections of electrolyte solution at various doses (0, 4, 6, or 8 ml/day). Further groups were treated either with i.p. lavage, lavage with 1.5 mg/ml of gabexate, or i.p. injections of 100 mg/kg of gabexate without lavage. The potential benefits of the various regimens were assessed by measuring survival, various biochemical and histologic features, and alterations in hematocrit, pH, and blood gases. Increasing O2 concentrations reversed hypoxemia and acidosis, but had no effect on biochemical or morphologic alterations and did not improve survival. However, hydration by s.c. fluid markedly improved survival and normalized the hematocrit without having major effects on biochemical or morphologic alterations. Intraperitoneal fluid did not improve survival. Gabexate injections without lavage had a slight effect on survival and serum amylase concentration and very little effect on histology. Lavage without gabexate had a greater effect on survival, serum amylase, and histology. Addition of gabexate to the lavage fluid increased the beneficial effect of lavage. Increases in amylase and activated trypsin in ascites were markedly reduced by lavage and even more so by lavage with addition of gabexate. We conclude that sufficient hydration appears to be an important factor in supportive care for severe acute pancreatitis, whereas oxygenation without sufficient hydration has no major benefit. Peritoneal lavage with gabexate showed the greatest benefit of the various regimens for acute severe pancreatitis and is worthy of clinical trials.
Acute Disease↗
Abnormalities in estrogen, androgen, and insulin metabolism in idiopathic hemochromatosis.
Of 44 male patients with idiopathic hemochromatosis who were diagnosed at an early stage without morphological or biochemical evidence of liver disease, 25% suffered from impotence and 34% manifested glucose intolerance. Impotence was correlated with a 50% reduction in plasma testosterone, resulting from a 63% decrease in testosterone production. Testicular atrophy was caused by insufficient secretion of gonadotropins due to the selective accumulation of iron in gonadotropic cells of the pituitary gland. However, peripheral sexual hormone metabolism, in particular the conversion of androgens to estrogens, remained unaltered. It was therefore possible to employ substitution therapy successfully with testosterone in these men, and hyperestrogenism was not observed as a side effect. The pathogenetic factors in the development of diabetes mellitus in patients with idiopathic hemochromatosis include impaired insulin secretion caused by the selective deposition of iron in B-cells of the pancreas and insulin resistance due to iron accumulation in the liver. In particular, the insulin resistance is markedly improved after depletion of body iron stores by phlebotomy treatment, resulting in lower insulin requirements in patients with insulin-dependent diabetes as well as improvement of carbohydrate metabolisms in about half of the patients with non-insulin-dependent diabetes. We have concluded that hypogonadism and carbohydrate intolerance are caused by the specific distribution pattern of excess iron in the organism, accompanied by functional impairment of affected parenchymal cells.
Adult↗
Survival and causes of death in hemochromatosis. Observations in 163 patients.
Survival and causes of death were analyzed among 163 patients with hemochromatosis diagnosed between 1959 and 1983. Mean followup was 10.5 +/- 5.6 years (+/- SD). Cumulative survival was 76% at 10 years and 49% at 20 years. Life expectancy was reduced in patients who presented with cirrhosis or diabetes compared to patients who presented without these complications at the time of diagnosis. Patients who could be depleted of iron during the first 18 months of venesection therapy had a markedly better prognosis compared to those patients who could not be depleted during this time period, probably due to greater amounts of excessive iron. Prognosis was not influenced by sex. Patients without cirrhosis or diabetes had a life expectancy that was virtually identical to that of an age-matched normal population. Analysis of the causes of death in 53 patients showed that liver cancer (n = 16) was 219 times more frequent, cardiomyopathy (n = 3) was 306 times more frequent, liver cirrhosis (n = 10) was 13 times more frequent, and diabetes mellitus (n = 3) was seven times more frequent compared to death rates expected for an age-matched normal population. The risk of death from other causes, including extrahepatic cancer (n = 7), did not differ from rates expected. Thus, patients with hemochromatosis diagnosed in a precirrhotic stage and treated by venesection have a normal life expectancy. Cirrhotic patients had a shortened life expectancy and a high risk of death from liver cancer even when complete iron depletion has been achieved.
Adult↗
Intracellular vacuoles in experimental acute pancreatitis in rats and mice are an acidified compartment.
The appearance of vacuoles inside acinar cells characterizes an early stage of development in different models of acute pancreatitis and, possibly, also in human disease. The vacuoles have been shown to contain both digestive and lysosomal enzymes. This abnormal admixture may have important implications for the pathogenesis of pancreatitis because the lysosomal enzyme cathepsin B can activate trypsinogen and may, by this way, trigger pancreatic autodigestion. For the activation process of trypsinogen by cathepsin B, however, an acidic pH is required. This study, therefore, looked for evidence of vacuole acidification in two different models of acute pancreatitis. Edematous pancreatitis was induced in rats by hyperstimulation with cerulein and hemorrhagic pancreatitis was induced in mice by feeding a choline-deficient, ethionine-supplemented diet. Pancreatic acinar cells were isolated at different times after induction of pancreatitis and incubated with 50 microM of acridine orange to identify acidic intracellular compartments. As shown in previous work, zymogen granules are the main acidic compartment of normal acinar cells; they remained acidic throughout the course of pancreatitis in both models. Vacuoles became increasingly more frequent in both models as pancreatitis progressed. Throughout development of pancreatitis, vacuoles accumulated acridine orange indicating an acidic interior. Addition of a protonophore (10 microM monensin or 5 microM carbonyl cyanide m-chlorophenylhydrazone [CCCP] or a weak base (5 mM NH4Cl) completely and rapidly abolished acridine orange fluorescence inside both zymogen granules and vacuoles providing further evidence for an acidic interior. The acidification of vacuoles seen in two different models of pancreatitis may be an important requirement for activation of trypsinogen by cathepsin B and thus for the development of acute pancreatitis.
Acute Disease↗
[Exocrine pancreas secretion after a dose of medium- and long-chain triglycerides].
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Acute Disease↗
[Alcohol and pancreatic diseases].
The epidemiological correlation between the incidence of acute and chronic pancreatitis and the amount of alcohol intake is well known. In contrast to alcoholic cirrhosis, there appears to be no threshold above which alcohol intake is associated with an increased risk to develop pancreatitis, but instead the risk increases with increasing consumption of alcohol in a logarithmic fashion. The incidence of alcoholic pancreatitis has continuously increased in recent decades and exceeds the combined incidence from all other causes. In very recent years, this increase appears to slow down. The pathophysiology of acute alcoholic pancreatitis is not known in detail. Alcohol may directly damage the acinar cell or the ductal epithelium. The pathogenesis of chronic pancreatitis involves an increase of protein concentration in pancreatic secretion leading to protein precipitations which may finally form calculi. The pancreas-stone-protected may play a crucial role in the lithogenic process. Little is currently known about the influence of alcohol on motility and pressure in biliary and pancreatic ducts. The course of alcoholic pancreatitis is more progressive and severe compared with nonalcoholic pancreatitis and markedly depends on discontinuation of alcohol consumption. The incidence of pancreatic carcinoma has continuously increased during the last 20 years in industrialized countries. Although diagnosis has been improved, long-term survival continues to be dismal. Several epidemiological studies have shown that there is no major correlation between alcohol consumption and the risk to develop pancreatic carcinoma.
Alcoholism↗
Gabexate mesilate (FOY) protects against ceruletide-induced acute pancreatitis in the rat.
Acute pancreatitis (AP) is believed to result from intraparenchymal activation of trypsin and other digestive enzymes within the pancreas followed by autodigestion of the gland. Gabexate mesilate (FOY), a synthetic guanidino acid ester exhibiting potent and versatile inhibitory actions on a number of proteinases (e.g., trypsin, kallikrein, C1-r, C1 esterase, plasmin, thrombin, phospholipase A2), was examined for its ability to protect the rat pancreas against development of AP induced by pharmacological doses of ceruletide (CRT). Rats were i.v. infused for 6 h with either CRT (5 micrograms/kg/h) or CRT + FOY (50 mg/kg/h). In FOY-treated rats the serum amylase and trypsinogen concentrations were reduced by 60 and 80%, respectively, compared to rats infused with CRT alone. Histologically, the extent of acinar cell vacuolization in the pancreas was significantly reduced and interstitial edema, although not assessed by quantitative morphometric techniques, appeared to be qualitatively lessened in the FOY-treated rats. The ability of FOY to inhibit significantly AP produced by supramaximal doses of CRT, coupled with its inhibitory properties on components of the coagulation and complement cascades, stress the importance of continued research on this compound as a potential therapeutic agent for treatment of AP and its systemic sequelae.
Acute Disease↗
Iron uptake by rat duodenal microvillous membrane vesicles: evidence for a carrier mediated transport system.
The mechanism of iron translocation from intestinal lumen to portal plasma is poorly understood. To examine these processes, uptake of Fe2+ and Fe3+ by rat duodenal microvillous membrane vesicles prepared by a Ca2+ precipitation procedure was studied. Membrane aliquots were incubated with increasing concentrations of 59FeCl3 in the presence of a one-thousand-fold molar excess of citrate or 59FeSO4 with a twenty-fold molar excess of L-ascorbic acid. After various time intervals the incubation reaction was stopped by addition of 0.1 mM FeCl3 (4 degrees C), and uptake of 59Fe was determined by a vacuum filtration assay. Initial uptake velocity of 59FeCl3 and 59FeSO4 was determined from the slope of the cumulative uptake curves, which was linear for the first 60 s. Initial uptake rates of both, 59Fe3+ and 59Fe2+ revealed an identical saturable uptake component with a Km of 19-22 nM and Vmax of 8 pmol min-1 mg protein-1. In addition, transport of Fe2+ revealed a linear unspecific uptake phase, which was predominant at high substrate concentrations. Saturable uptake of Fe2+ and Fe3+ was temperature dependent, and significantly reduced by trypsin pretreatment of the microvillous membrane vesicles, indicating the involvement of a protein in the uptake process. This suggestion was pursued by isolation of an iron binding protein from duodenal brushborder membranes. After solubilization of microvillous plasma membranes with 1% Triton X 100, affinity chromatography of the membrane protein mixture over an iron chelate gel derived from epoxy activated Sepharose and elution with 50 mM EDTA yielded a single 52,000 dalton protein. The protein co-chromatographed over an Ultro-Pac TSK G 3000SW HPLC column together with 59FeCl3 and 59FeSO4. It showed no immunologic activity to rabbit antibodies against whole rat serum or rat transferrin. Furthermore, by photoaffinity labelling technique a single iron binding protein with a molecular weight of about 52,000 dalton was identified in microvillous membranes of the rat duodenum. These data are compatible with the hypothesis that intestinal iron absorption is mediated by a specific carrier-dependent transport system.
Animals↗
Pancreatic growth: interaction of exogenous cholecystokinin, a protease inhibitor, and a cholecystokinin receptor antagonist in mice.
The effects on pancreatic growth and plasma CCK concentration of chronic feeding of camostate (400 mg/kg day for 10 days), a potent inhibitor of serine proteases including trypsin, were assessed in the mouse. For comparison, the trophic effects of chronic exogenous administration of CCK octapeptide (sc injection of 1 microgram/kg day every eight hours for 10 days) were also studied. In addition, the effects of a proglumide-analogue CCK-receptor antagonist (CR1409) on the stimulatory actions of camostate feeding and chronic administration of exogenous CCK were studied. The effects of the combination of chronic camostate feeding and sc injections of CCK, the effects of acute camostate feeding, and the effects of the CCK-receptor antagonist given without camostate or CCK were also studied. The results show that chronic camostate feeding markedly increased CCK plasma concentrations eight-fold over control values, and that acute camostate feeding increased plasma concentration to four fold of control values. Correspondingly, chronic camostate feeding markedly increased pancreatic weight, protein and DNA content. Exogenous CCK-8 also had qualitatively similar, but quantitatively less potent stimulatory effects. The combination of camostate and CCK-8 resulted in an additive stimulatory effect. The trophic actions of exogenous and endogenous CCK grossly increased chymotrypsinogen content, but left amylase content unaffected. The CCK-receptor antagonist CR 1409 completely abolished the trophic effects of exogenous CCK and greatly inhibited the effects of chronic camostate feeding. The CCK antagonist decreased pancreatic weight, DNA and protein content compared to control values when given without any CCK or camostate. We conclude that the protease inhibitor camostate is a very strong release effector of CCK and exerts a powerful trophic effect on mouse pancreas which is probably mediated by CCK. Furthermore, physiological increases of CCK during feeding of regular chow appear to exert trophic effects on the exocrine pancreas.
Amylases↗
Experimental acute pancreatitis. In vitro magnetic resonance characteristics.
The effect of pancreatitis on magnetic resonance T1 and T2 relaxation times was evaluated in two different models of acute pancreatitis in the rat. Acute edematous pancreatitis was induced by repetitive intraperitoneal injections of the cholecystokinin-analogue caerulein; acute hemorrhage pancreatitis was induced by retrograde infusion of the bile salt sodium taurocholate into the pancreatic duct. T1 and T2 relaxation times were obtained in vitro from fresh pancreatic specimens at 37 degrees C with a 0.25 resistive spectrometer. In both edematous and hemorrhagic pancreatitis, significant prolongation of T1 and T2 was noted as early as 1.5 hours after the initiation of pancreatitis when compared with normal rat pancreas. Maximal prolongation occurred at 7 hours in the caerulein model with T1 of 966 +/- 46 msec (mean +/- SEM) (normal + 278 +/- 12 msec) and T2 of 75.9 +/- 2.9 msec (normal = 32.8 +/- 3.3 msec), and after 6 hours in the bile salt model with T1 of 798 +/- 40 msec and T2 of 92.5 +/- 3.3 msec. After the time point of maximal prolongation, T1 and T2 gradually decreased toward the normal values. The prolongation of T1 and T2 paralleled each other throughout the time course of pancreatitis in both models. The prolongation of both relaxation times correlated closely with pancreatic weight, water content, and amylase concentration in serum and ascites. The present determination of T1 and T2 relaxation times by in vitro spectrometry suggests that magnetic resonance imaging has the potential for detecting early pathologic changes in acute pancreatitis and thus may be helpful for an early clinical diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Digestive end products release pancreatic enzymes from particulate cellular pools, particularly zymogen granules.
The effects of various amino acids and phosphorylated forms of glucose on the release of digestive enzymes from particulate cellular pools, particularly zymogen granules, were evaluated in rat pancreas. Whole tissue homogenates, as well as zymogen granules isolated either by differential centrifugation in 0.3 M sucrose or by preparation in buffered sucrose and subsequent centrifugation in a Percoll gradient, were studied. The basic amino acids L-arginine and L-lysine, sites of tryptic cleavage, caused the release of trypsinogen, but not chymotrypsinogen, whereas the aromatic amino acids L-phenylalanine and L-tryptophan, sites of chymotryptic cleavage, caused release of both trypsinogen and chymotrypsinogen. Neither led to the release of the starch-splitting enzyme amylase. All effects occurred within the range of normal plasma concentrations for these amino acids in the rat. Two amino acids, L-threonine and hydroxy-L-proline, that are not sites of cleavage by trypsin or chymotrypsin, and a nonmammalian amino acid, aminoadipic acid, did not lead to release of trypsinogen, chymotrypsinogen, or amylase. Two phosphorylated forms of glucose, glucose 1-phosphate and glucose 1,6-diphosphate, caused the release of amylase, but of neither trypsinogen nor chymotrypsinogen. Contrary to previous results, D-glucose was without effect, as was glucose 6-phosphate. We propose that certain digestive end products, by direct action on zymogen granules, cause the selective release of the enzymes involved in their evolution from polymeric substrates during digestion.
Amino Acids↗
Rat pancreatic zymogen granules. An actively acidified compartment.
In this study, we looked for acidification in pancreatic zymogen granules as recently reported for other secretory vesicles. In intact dispersed acinar cells, acidic intracellular compartments identified by fluorescence microscopy using acridine orange corresponded exactly to the distribution of zymogen granules visualized by light microscopy. Acridine orange fluorescence in zymogen granules was reversibly dissipated by protonophores (carbonyl cyanide m-chlorophenylhydrazone, monensin) and NH4Cl; and the percentages of cytoplasmic area occupied by the acidic compartments and by zymogen granules were identical under fasting conditions and decreased in parallel after in vivo cholinergic stimulation. Zymogen granules released acutely from hypotonically disrupted cells without homogenization also accumulated acridine orange. Red-orange fluorescence in released granules was also abolished by protonophores and NH4Cl; and it reappeared after washout of protonophores in the presence, but not absence of adenosine triphosphate. Dicyclohexylcarbodiimide, which inhibits all proton pumps, and N-ethylmaleimide, which inhibits the proton pump of endocytic vesicles and lysosomes, but not mitochondria, prevented this adenosine triphosphate-dependent reappearance of acridine orange fluorescence, whereas vanadate did not. In contrast to these observations with zymogen granules in situ or acutely released from disrupted cells, granules isolated by conventional multistep homogenization/centrifugation procedures did not exhibit adenosine triphosphate-dependent acidification or development of a positive membrane potential as measured by quenching of acridine orange or Oxonol V, respectively. The latter findings may indicate release of inhibitors or granule damage during isolation. Collectively, the present results provide direct evidence that zymogen granules contain an active acidification mechanism which appears similar to that of other secretory vesicles and endosomes. This acidification process may have important implications for the storage, stabilization, and secretion of intragranular proteins including proenzymes.
Acridine Orange↗
New proglumide-analogue CCK receptor antagonists: very potent and selective for peripheral tissues.
The present study evaluates the ability of two recently synthesized analogues of proglumide, both 4-benzamido-N,N-di-alkyl-glutaramic acid derivatives, to act as cholecystokinin receptor antagonists. Both new antagonists inhibited cholecystokinin-stimulated amylase release and, similarly, binding of 125I-cholecystokinin to isolated rat pancreatic acini. These effects displayed competitive kinetics; both antagonists showed no agonist activity and were specific in that only those secretagogues were inhibited that interact with the cholecystokinin receptor. Both antagonists also inhibited binding of 125I-cholecystokinin to mouse pancreatic membrane particles similarly to results with rat pancreatic acini. With the more potent of the two new antagonists, half-maximal inhibition of action and binding of cholecystokinin was observed with low concentrations of approximately 10(-7) M; compared with proglumide, the new antagonists were as much as 4,000 times more potent. Unlike proglumide, which inhibits binding of cholecystokinin to pancreas and brain tissue similarly, both antagonists inhibited binding of cholecystokinin to the pancreas at much lower concentrations compared with brain. The more potent of the inhibitors was 300 times more potent in inhibiting binding of cholecystokinin to pancreatic tissues compared with brain.
Amylases↗
Characteristics of rat pancreatic zymogen granules prepared by different methods.
Zymogen granules isolated from tissue homogenates by differential centrifugation in isotonic sucrose solutions show substantial release of digestive enzyme when suspended in isotonic NaCl and in sucrose solutions at pH values above neutrality. A recent study reported a new method for isolating granules, involving the use of a complex homogenization medium and a Percoll gradient that was claimed to produce "stable" granules, i.e., granules that do not release their content in salt solutions and at pH values at or above neutrality. In the present study, we compare granules prepared in both ways, particularly in terms of their tendency to release amylase in isotonic ionic solutions and as a function of pH. The relative absence of amylase release from granules isolated by the new technique was found to be attributable to simple differences in the details of the experimental procedures that were used and not to actual differences in the characteristics of the two granule preparations. For example, previous studies with granules prepared in sucrose solutions reported substantial salt-induced release at 37 degrees C, whereas the recent study reporting the absence of salt-induced release from granules obtained from a Percoll gradient was done at 24 degrees C. Under the identical experimental conditions as used in the present study, little amylase release was seen at 24 degrees C for granules isolated by either technique, but substantial release was seen for both at 37 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)
Amylases↗
Beneficial effects of cholecystokinin-receptor blockade and inhibition of proteolytic enzyme activity in experimental acute hemorrhagic pancreatitis in mice. Evidence for cholecystokinin as a major factor in the development of acute pancreatitis.
The effects of the cholecystokinin (CCK)-receptor antagonist proglumide, the protease inhibitor gabexate, and the hormones secretin and cholecystokinin-octapeptide (CCK-8) were studied in a model of acute hemorrhagic pancreatitis induced by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. Injections of gabexate and proglumide from initiation of CDE diet (before induction of pancreatitis) increased survival from 37% (diet alone) to 85 and 75%, respectively, and also ameliorated histological alterations and increases in serum amylase concentration and pancreatic activated trypsin. Secretin had no major beneficial effect. When proglumide or gabexate were given after induction of pancreatitis, proglumide still increased survival to 75%, whereas gabexate no longer did. Injection of nontoxic doses of CCK-8 before proglumide or gabexate injections completely abolished all beneficial effects and also increased the severity of pancreatitis due to CDE diet alone. Blockade of CCK receptors and early inhibition of protease activity may be beneficial in severe acute pancreatitis. Cholecystokinin appears to play a contributory role in the development of pancreatitis.
Acute Disease↗
[Experimental acute pancreatitis].
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Acute Disease↗