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Short-term studies with acarbose have demonstrated its efficacy in reducing postprandial blood glucose levels and glycated haemoglobin (HbA1c) levels. These effects would be expected to translate into improvements in long-term complications of diabetes, but such data are not yet available due to the long follow-up times required. Animal models of diabetes have, however, demonstrated the efficacy of acarbose in combating the long-term complications of the disease. The 18 animal studies reviewed here showed that acarbose treatment reduced postprandial blood glucose concentrations and decreased protein glycation. Through these actions, acarbose delayed or prevented the onset of renal, retinal, lens and neurological changes and the development of ischaemic myocardial lesions. Acarbose treatment can therefore be expected to benefit patients with Type 2 and, in combination with insulin, Type 1 diabetes. This is being investigated in ongoing clinical studies in patients with Type 2 diabetes and impaired glucose tolerance (IGT). Copyright © 1999 John Wiley & Sons, Ltd.

Short‐term studies with acarbose have demonstrated its efficacy in reducing postprandial blood glucose levels and glycated haemoglobin (HbA1c) levels. These effects would be expected to translate into improvements in long‐term complications of diabetes, but such data are not yet available due to the long follow‐up times required. Animal models of diabetes have, however, demonstrated the efficacy of acarbose in combating the long‐term complications of the disease. The 18 animal studies reviewed here showed that acarbose treatment reduced postprandial blood glucose concentrations and decreased protein glycation. Through these actions, acarbose delayed or prevented the onset of renal, retinal, lens and neurological changes and the development of ischaemic myocardial lesions. Acarbose treatment can therefore be expected to benefit patients with Type 2 and, in combination with insulin, Type 1 diabetes. This is being investigated in ongoing clinical studies in patients with Type 2 diabetes and impaired glucose tolerance (IGT). Copyright © 1999 John Wiley & Sons, Ltd.

This study investigates digestive and lysosomal enzyme secretion of azaserine-induced pancreatic acinar carcinomas in response to cholecystokinin in rats. After 15–20 months of treatment, 95% of the animals developed pancreatic acinar carcinomas encompassing more than 90% of the tissue. In anesthetized rats basal trypsin output was significantly elevated in the tumor group despite diminished fluid secretion. There was a linear correlation between tumor size and basal amylase and trypsin secretion. Intravenous infusion of cholecystokinin (25 IDU · kg−1· h−1) induced a significantly lower secretion of fluid per gram pancreas, as well as decreased amylase and trypsin output, in the tumor group compared with the control group. Plasma amylase and lipase levels were significantly elevated in the tumor group under both basal and stimulated conditions. The output of the lysosomal enzymes β-d-glucuronidase and α-d-glucosidase was significantly increased in the tumor group under background secretin infusion. Additional cholecystokinin infusion caused a sharp increase in glucuronidase output in this group with only minimal increase in controls. Glucosidase output increased similarly in both groups. Amylase, lipase, and trypsin tumor tissue concentrations were markedly reduced by 85%, 90%, and 87%, respectively. It was concluded that the decreased secretory response of digestive enzymes may result from decreased synthesis, lowered storage capabilities, and/or a decreased/increased responsiveness to cholecystokinin. Increased glucuronidase secretion may reflect an augmented cell turnover of malignant tissue.

Background/Aims:The role of cholecystokinin (CCK) in the regulation of gastric acid secretion is still controversial. This study examined the effect of the CCK-A receptor antagonist loxiglumide (lox) on gastrin- or CCK-induced gastric acid secretion and meal-stimulated plasma gastrin levels in a placebo-controlled study. Methods:Acid output was studied in eight subjects who received intravenously gastrin-17 (15, 30, and 60 pmol·kg−1·h−1); gastrin-17 plus lox; cholecystokinin octapeptide (CCK-8) (15, 30, and 60 pmol·kg−1·h−1); CCK-8 plus lox; or gastrin plus CCK-8. Sham feeding-induced acid output and meal-stimulated gastrin secretion were studied during lox infusion. Results:Gastrin-17 dose-dependently stimulated acid output to near-maximal levels. CCK-8 (15 pmol· kg−1·h−1) increased acid secretion 2.5-fold over basal; higher infusion rates had less or no effect. When combined with lox, CCK-8 produced a near-maximal acid response (6-fold over basal). CCK-8 together with gastrin-17 inhibited gastrin-induced acid output by 67%. Meal-stimulated plasma gastrin concentrations were elevated 3.2-fold, whereas sham feeding-induced acid secretion was not modified by lox. Conclusions:Blockade of CCK-A receptors converts CCK-8 into a potent acid secretagogue and augments postprandial gastrin secretion. A CCK-mediated stimulation of paracrine somatostatin secretion from antrat and fundic D cells represents a candidate mechanism for the inhibition of the parietal and gastrin cell in humans.

Insulin action was studied in rats with CCl4/phenobarbital-induced cirrhosis of the liver using the euglycemic hyperinsulinemic clamp technique coupled with isotopic measurement of individual tissue glucose uptake, glycogen formation, and lipogenesis. In cirrhotic rats, dose response curves showed a reduction of insulin-stimulated total body glucose disposal of about 30%. Insulin action on tissue glucose uptake and initial phosphorylation (assessed with [3H]2-deoxyglucose) were unchanged; however, incorporation of [14C]glucose into lipids and particularly into glycogen was reduced substantially (being most pronounced in skeletal muscle and diaphragm) at maximally as well as half-maximally effective serum insulin concentrations during euglycemic clamping. At identical IV insulin infusion rates, steady-state serum insulin concentrations were elevated up to fourfold in cirrhotic animals. Antilipolytic action of insulin was unaltered. These data suggest that the principal metabolic pathway affected in insulin resistance of rats with experimental cirrhosis appeared to be insulin-stimulated glycogen formation in muscle tissues.

Background:The effects of chronic drug-induced hypergastrinemia on the exocrine and endocrine stomach are still incompletely understood. Chronic hypergastrinemia in rats and humans is associated with gastric argyrophil cell hyperplasia. Methods:Seventy-four patients with chronic ranitidine-resistant ulcerations were treated chronically with omeprazole (median observation period 48 [6–84] months). Results:Median fasting serum gastrin levels increased from a pretreatment value of 74–145 pg/mL after 3 months. No further increase was observed thereafter. The finding of atrophic gastritis increased from 1.8% to 20.8% after 5 years. A doubling of the mean argyrophil cell volume density (0.36% vs. 0.74% after 5 years; P< 0.01%) was paralleled by a decrease in the normal endocrine cell growth pattern from 64.3% to 33.3% and an increase in micronodular hyperplasia (8.9% vs. 16.7%). These changes correlated with the severity of corpus gastritis and seemed to be more disease- than drug-related. No statistically significant changes were observed in the antral G- and D-cell volume densities under therapy. Conclusions:Long-term omeprazole therapy in humans results in moderate hypergastrinemia and a significant argyrophil cell hyperplasia, which are correlated to the grade of corpus gastritis. Because hypergastrinemia and gastritis are closely related, it is difficult to quantitatively assess their respective role in this process.

Summary: The response of immunoreactive gastric inhibitory polypeptide (IR-GIP), immunoreactive insulin (IRI) and immunoreactive C-peptide (IR-C-peptide) to the ingestion of mixed liquid test meals containing 1031 kcal (550 ml) and 422 kcal was studied in 17 obese and 17 normal weight control subjects. When the 422 kcal load was ingested in a volume of 550 ml, the plasma IR-GIP response was significantly greater than in a volume of 225 ml at 15 and 30 min in lean and obese subjects, but the total integrated IR-GIP response was not significantly different between the obese and lean group. Also intraduodenal infusion of 150 ml (280 kcal) of the test meal elicited identical plasma IR-GIP concentrations in lean and obese subjects. An exaggerated IR-GIP response in obese subjects was seen only following the 1031 kcal load (integrated IR-GIP response: 23.61.9 in lean subjectsvs 50.33.8 nmol/1/180 min in obese subjects; p<0.01). The IRI response was always significantly greater in obese than in lean subjects and not related to the GIP response. Fasting plasma IR-C-peptide levels were significantly elevated in obese subjects (lean: 0.520.04; obese: 1.420.12 nmol/l; p<0.005), but the postprandial integrated IR-C-peptide responses in the obese and lean group were identical, indicating decreased hepatic insulin extraction in obesity. It is concluded that an exaggerated IR-GIP response in obesity occurs only after ingestion of a high calorie meal probably as consequence of an increased gastric emptying rate and that the hyperinsulinemic response of obese subjects is not attributable to GIP hypersecretion.

Hypergastrinaemia-associated changes of non-antral argyrophil cells in man are of increasing interest, because of the development of potent inhibitors of gastric acid secretion. Using an antibody against chromogranin A, we identified micronodular endocrine cell hyperplasia of the oxyntic mucosa in gastric biopsy specimens of patients with hypergastrinaemia of different backgrounds. Consecutive ultrathin sections were examined at the electron-microscopical level. Endocrine cell types within the (extraepithelial) micronodules closely resembled those in the adjacent mucosa. Micronodules were classified into two groups. The first group was composed of endocrine cells only and predominated in patients with drug-induced hypergastrinaemia and/or chronic gastritis, and in a gastrinoma/MEN I patient. The second group represented "neuroendocrine complexes", showing a close intermingling of non-myelinated nerve fibres with endocrine cells, and was found predominantly in pernicious anaemia. Micronodular argyrophil cell growth in man is therefore heterogeneous and depends on the background of the hypergastrinaemia.

A peptide derived from the N-terminal region of porcine prosomatostatin, proSS 1–32, has been purified to homogeneity from extracts of porcine upper intestine. Amino acid analysis revealed that the peptide consists of 32 residues. The complete primary structure was determined as: A P S D P R L R Q F L Q K S L A A A A G K Q E L A K Y F L A E L This sequence obviously comprises residues 1–32 of porcine prosomatostatin since it is identical to the corresponding sequence in human preprosomatostatin. The postulated cleavage site in porcine prosomatostatin is a Leu-Leu bond between residues 32 and 33, thus confirming previous studies of the processing of the somatostatin precursor in the rat and transgenic mouse.

The isolation and primary structure of a novel gastrointestinal peptide, designated valosin, is described. The peptide was purified from porcine upper gut extracts using an HPLC and N-terminal sequence screening strategy which depends on Chromatographic and structural characteristics as isolation criterion. The amino acid sequence of this peptide consists of 25 amino acid residues: V Q Y P V E H P D K F L K F G M T P S K G V L F Y.

Release of immature secretory granules rich in incompletely processed proinsulin has been proposed to explain the relative hyperproinsulinemia in type 2 diabetic and insulinoma patients because of a constant secretory drive resulting from hyperglycemia and autonomous secretion, respectively. To test this hypothesis, insulin secretion was stimulated by a combination of hyperglycemia (11 mmol/L clamp), intravenous (i.v.) tolbutamide (1 g), and i. v. glucagon (initial bolus 10 fig/kg body weight, maintenance infusion 2 μg/kg body weight per hour) for 3 h. Circulating IR-insulin and IR-C-peptide concentrations increased 89-fold and 14-fold over basal values, respectively, but IR-proinsulin concentrations increased only ninefold over basal values. Estimation of the amount of insulin secreted (based on deconvolution analysis of plasma C-peptide values) showed that ∼76 ± 21 U were secreted during the stimulation period. This amount is a significant proportion of pancreatic insulin content in normal humans. In molar terms, IR-proinsulin (integrated incremental response multiplied by metabolic clearance rate of proinsulin) relative to IR-C-peptide (= insulin) secretion (deconvolution analysis) was estimated to be equal or even lower than the known proportion in islets (0.22 ± 0.05). Thus, using a near-maximal stimulation of insulin secretion maintained long enough to cause release of amounts of insulin approaching the estimated pancreatic content, no preferential release of proinsulin was observed in normal humans. Therefore, the hyperproinsulinemia of type 2 diabetes and in insulinoma patients may be caused by additional defects in the proinsulin to insulin conversion process.

We investigated the total, free, and acetylated polyamine concentrations in pancreatic tissue, serum, and urine of 20 patients with pancreatic cancer, 30 healthy volunteers, and 40 patients with nonmalignant, gastrointestinal diseases by reversed-phase liquid chromatography. Tissue concentrations in carcinoma compared to histologically unaffected pancreas were significantly higher for putrescine, elevated for cadaverine, and nearly identical for spermidine and spermine, while N1-acetylspermidine was detectable in cancer tissue only. With the exception of free spermine in urine and total spermine in serum, all other polyamines were significantly elevated in the urine and serum of cancer patients compared to healthy controls. These data support the concept that polyamines play an important role in rapidly growing tissues. However, nonmalignant gastrointestinal diseases partly showed similar elevations. Because of this low specificity, polyamines are of little value only as diagnostic markers of pancreatic carcinoma. Since polyamine concentrations normalized in patients after curative operation while they were further elevated in patients with tumor relapse or metastases, polyamines might play a clinical role in predicting therapeutic success or indicating relapse of the tumor. A significant linear correlation of polyamine concentrations and the size of the tumor was found while a significant correlation to CEA, CA 19–9, and CA 125 or the presence of organ metastases did not exist.

Using a specific radioimmunoassay for cholecystokinin (CCK) we have studied the relation between circulating CCK concentrations and the feedback regulation of pancreatic enzyme secretion in conscious rats. Recirculation of diverted bile-pancreatic juice into the duodenum or intraduodenal perfusion of trypsin during biliary-pancreatic juice diversion produced basal output of amylase and trypsin and low portal CCK levels (<10 pmol/L). Biliary-pancreatic juice diversion or inactivation of trypsin caused increased CCK concentrations (peak values 50–100 pmol/L) and enzyme outputs. During biliary-pancreatic juice diversion, infusion of the CCK receptor antagonist proglumide suppressed the enzyme response without altering the increase in CCK. Measurement of portal and peripheral CCK during biliary-pancreatic juice diversion yielded values of 131 ± 37 and 32 ± 5 pmol/L, respectively. The peripheral CCK levels corresponded to concentrations achieved during exogenous CCK-8 infusion which resulted in similar enzyme outputs. Gel chromatography of portal plasma during diversion of biliary-pancreatic juice revealed one peak of CCK corresponding to CCK-8, and a larger peak eluted between CCK-33 and CCK-8, probably representing CCK-22. Similar CCK components were found in water extracts of jejunal mucosa, whereas the acetic acid extracts mainly contained CCK-33/39. We conclude that the negative feedback regulation of pancreatic enzyme secretion in rats is mediated by the release of CCK from the intestine and that the major molecular form of CCK in plasma is probably CCK-22.

Historically, carcinoids have long been known to be a morphologically distinct class of rare intestinal tumors that behave less aggressively than the more common intestinal adenocarcinomas. It was not until much later that their endocrine nature was recognized. Some authors restrict the term carcinoid to intestinal endocrine tumors, whereas others include a large variety of neuroendocrine tumors. In the WHO classification of 1980, carcinoids were defined as tumors of the diffuse neuroendocrine system that are either benign or neoplasms with a more favored prognosis than carcinomas. They are characterized by a typical growth pattern, silver affinity, and positive immunohistochemical reaction with neuron-specific markers; and they can express different peptides and biogenic amines. Neuroendocrine tumors originating from endocrine glands (pituitary, thyroid, adrenals, pancreas) and highly malignant neuroendocrine carcinomas are excluded from the carcinoid group of neoplasms. For the natural history of carcinoid tumors several independent predictive parameters can be defined: size, site of origin, growth pattern, and hormone dependence. The number of neuropeptides and amines expressed by a carcinoid or the amount of biologically active neurohormones secreted are of no prognostic significance regarding malignant behavior. The carcinoid syndrome is a rare clinical entity that occurs with a prevalence of 1.6% for carcinoid tumors and almost only if liver metastases are present. The complex clinical symptoms are only partially explained by the secretion of serotonin and tachykinins.

The effect of a 550-kcal mixed meal and of an intravenous injection of pentagastrin (0.06 μg/kg body wt) upon peripheral blood serotonin concentrations has been compared in 10 carcinoid patients with hepatic metastases and healthy subjects. The fasting concentrations of blood serotonin in the patients (range 790–4500 ng/ml) were elevated compared with healthy subjects (range 71–310 ng/ml; n = 15). Urinary output of 5-hydroxyindole acetic acid was elevated in 8 patients but was in the healthy range for 2 patients. The healthy subjects (n = 9) responded to food with an increase in blood serotonin (maximum rise over mean basal of 32% ± 4%) that was significant at 60, 75, 90, and 105 min postcibal. All carcinoid patients responded to food with a comparable (25% ± 11% over basal) rise in serotonin but the pattern of release was erratic. All patients with tumor metastases exhibited symptoms of the carcinoid flush after eating, but there was no correlation between occurrence and severity of the flush and occurrence and magnitude of the rise in serotonin. Intravenous pentagastrin evoked a flush in all carcinoid patients, but there was no significant increase in peripheral blood serotonin either in the patients or in healthy subjects.

Therapeutic measurements for acute pancreatitis depend on the severity of the disease and its complications. Since complications of acute pancreatitis may develop at any time, patients should be admitted to an intensive care unit for assessment (and frequent reassessment) of the severity of the disease and of the development of complications; they should remain in the intensive care unit for the first 48 hours at least, even if no signs of shock are apparent. The only exceptions to this rule are mild cases without signs of peritonitis. Basic therapy should include relief of pain, total fasting, nasogastric suction, parenteral replacement of fluids, electrolyte, albumin, and blood, and antibiotics. Hyperglycemia should be corrected and heparin should be given in cases of disseminated intravascular coagulation. In renal insufficiency, peritoneal dialysis is important, and in respiratory complications, humidified oxygen or artificial ventilation including positive end expiratory pressure therapy should be applied. Although the effect of peritoneal dialysis has been proven only in animal experiments and in retrospective studies in man, it is recommended in severe cases for shock therapy and for correction of electrolyte imbalance when ascites is present, even before anuria occurs.

Results of the SPT and the ERCP staged for their severity were compared in 202 patients. The correlation between both investigations was significant (p< 0.001); however, ERCP showed significantly more severe changes (p0.04). Furthermore, we found that 129 (64) patients had parallel SPT and ERCP results, matching in all four gradings of severity. Forty-three (21) patients had abnormal results for both SPT and ERCP, but the severity gradings did not parallel. Finally, 30 (15) patients showed totally nonparallel results, a normal SPT and abnormal ERCP, or vice versa. Abnormal ERCP but normal SPT results were found in 23 of these 30 patients (group 1), and normal ERCP but abnormal SPT results in the seven remaining cases (group 2). In the first group, more patients had a history of acute pancreatitis compared to the second group (19 vs. one, p< 0.005). Based on medical history, laboratory and functional test results, and other morphological tests, chronic pancreatitis was diagnosed in two of 23 patients in group 1 and in all seven patients in group 2. Follow-up interviews (86 ± 54 months) were possible in 20 of the remaining 21 patients in group 1 and showed definite chronic pancreatitis in one and probable chronic pancreatitis in another two of them, whereas in the other 17 patients no symptoms of acute pancreatitis or abdominal pain suggestive of chronic pancreatitis had occurred. In conclusion, both SPT and ERCP should be used to complement each other when chronic pancreatitis is suspected. ERCP seems to over-diagnose the disease since duct changes may onlyreflect scars after severe acute pancreatitis, or old age, and are not necessarily a sign of chronic pancreatitis. SPT seems to diagnose chronic pancreatitis with more reliability.

The natural course of pain in chronic pancreatitis was followed up in 318 patients over 10.6 ± 8.0 years (median, 9.0 years). By the end of our follow-up, a significant decline in pain in alcoholics (n228) and nonalcoholics (n90) (p< 0.001 and p< 0.03) was marred by the fact that, even after more than 10 years, 50 of alcoholics and 62 of nonalcoholics still reported pain attacks (difference insignificant). Only alcoholics had pain relief with increasing exocrine pancreatic insufficiency (p< 0.02), but 54 of alcoholics and 73 of nonalcoholics still had pain attacks despite severe, enzyme substitution-requiring exocrine pancreatic insufficiency. The development of severe endocrine pancreatic insufficiency did not significantly influence the course of pain. It is concluded that no clinically relevant differences exist in the course of pain in alcoholic and nonalcoholic chronic pancreatitis.

The binding and biological effect of pituitary adenylate cyclase activating polypeptide (PACAP), a novel hypothalamic peptide with high sequence homology to vasoactive intestinal polypeptide (VIP), were studied in rat AR 4–2 J pancreatic carcinoma cells and isolated rat pancreatic acini. PACAP(1–27) and analogue PACAP(1–23, VIP-24-28), but not VIP, displaced potently and reversibly 125I-PACAP(1–27) from binding to an abundantly expressed high affinity PACAP-preferring receptor on AR 4–2 J cells, referred to as “PACAP-1 receptor.” High affinity binding was dependent on N-terminal and C-terminal residues of PACAP(1–27): PACAP(1–24,Cys-25) (7.3 ± 1.6 PIM), PACAP(1–23) (8.2 ± 1.5 μM), VIP (>30 μM), PACAP(3–27), PACAP(1–19), PACAP(3–19), PACAP(1–12), and PACAP(18–38) (all >50 μM) showed low or no binding potency. In contrast, high and low affinity binding of 125I-VIP to AR 4–2 J cells was displaced equipotently by PACAP(1–27) and VIP, thus defining on these cells, in addition, two scarcely expressed binding sites, designated “VIPIPACAP-2 receptor,” similar or identical to the previously described high and low affinity acinar VIP receptor. Binding of 125I PACAP(1–27) to a high and low affinity binding site on rat pancreatic acini was inhibited equipotently by PACAP(1–27) and VIP, identifying these sites as VIPPACAP-2 receptors. PACAP(1–23) recognized both type 2 binding sites with only slightly lower affinity. PACAP(1–27), PACAP(1–38), PACAP(1–23,VIP-2428), and PACAP(1–23) equipotently stimulated acinar lipase release and cyclic AMP production in pancreatic acini. Co-incubation of PACAP(1–27) or VIP with cholecystokinin-8 or carbachol revealed additive effects on enzyme secretion. Our results suggest the predominant expression of VIPPACAP-2 receptors on rat pancreatic acini, whereas AR 4–2 J cells express mainly PACAP-1 receptors. PACAP is a potent ligand for both receptor types and has to be regarded as a novel VIP-like pancreatic secretagogue.

We investigated the trophic effect on the pancreas of male Wistar rats fed up to 20 days with either raw soybean flour (RSF) containing an active trypsin inhibitor or heat-inactivated soybean flour (HSF). The concentrations of the polyamines putrescine, spermidine, and spermine in the pancreas as well as cholecystokinin (CCK) concentrations in arterial and portal vein plasma were measured. Plasma CCK concentrations were measured by a sensitive radioimmunoassay specific for the sulfated region of CCK, whereas polyamine concentrations are determined by reversed phase high-performance liquid chromatography. The levels of CCK in both arterial and-portal vein plasma were significantly higher in RSF- compared with HSF-fed rats, the concentration in the portal vein being twice as high compared with the aorta. A significant increase in pancreatic weight and protein content was positively correlated to an increase in putrescine and spermidine in the pancreas of RSF-fed rats compared with HSF-fed controls, whereas the spermine content did not differ between the two groups. The pancreatic DNA content in RSF-fed rats was significantly above control values of day 20 only. These data support the hypothesis that the trophic effect of soybean trypsin inhibitor on the pancreas is mediated by CCK and that polyamines might play an important role in CCK-induced pancreatic growth.

This study investigates the role of platelet-activating factor (PAF) in experimental pancreatitis. The concentration of PAF quantified in ascites of bile-induced pancreatitis by radioimmunoassay (RIA) ranged from 3.67 ± 0.39 pmol/mL 2 h to 0.954 ± 0.39 pmol/mL 10 h after injection of taurocholate. Administration of a potent PAF antagonist, WEB-2170, prior to injection of taurocholate prolonged mean survival time in rats receiving iv camostate and albumin (46.4 h,n= 15, vs controls 38.3 h,n= 13). However, the survival rate after 72 h was not improved. The histologically estimated severity of pancreatitis and pancreatic enzymes in blood, tissue, or ascites was not affected. WEB-2170 had no effect on survival when injected simultaneously with taurocholate into the pancreatic duct or given iv after induction of pancreatitis (1, 0.1, or 0.01 mg/kg WEB-2170 vs controls). Subcutaneous injection of 10 mg/kg WEB-2170 also did not improve survival in pancreatitis induced by choline-deficient, ethionine-supplemented diet in mice. It is concluded that administration of a PAF antagonist after the onset of severe experimental pancreatitis does not influence its outcome, although activation of PAF may play a role in the pathogenesis of pancreatitis.

The effect of cyclosporine A (CsA) and α-difluoromethylornithine (DFMO) on the camostate-induced increase in pancreatic ornithine decarboxylase (ODC) activity and polyamine biosynthesis has been studied in vivo. Six hours after application of the synthetic trypsin inhibitor camostate (200 mg/kg b wt orally) pancreatic ODC activity increased about 140-fold and putrescine concentration about ninefold. CsA inhibited the elevation of both parameters in a dose-dependent manner. CsA pretreatment for 3 d with doses of 7.5, 10.0, and 12.5 mg/kg b wt orally once a day and consecutive CsA blood levels 24 h after the last CsA application of 751 ±62, 968 ±70, and 1,395 ±79 ng/mL, respectively, resulted in a complete inhibition of the camostate-stimulated increase in pancreatic ODC activity and putrescine concentration in vivo. DFMO (2% in drinking water and additionally 300 mg/kg b wt intraperitoneally at 8 AM, 12 noon, and 4 PM) inhibited the increase in both, ODC activity, and putrescine, significantly in an equipotent degree as 2.5 mg CsA/kg b wt, whereas higher doses of CsA proved to be more effective than DFMO in the chosen subtoxic dose. In all cases, no significant changes in pancreatic spermidine and spermine concentration, DNA and protein content, or pancreatic and body weight were observed. It is concluded that CsA in doses used for immunosuppression in clinical practice is a very potent and more effective inhibitor of ODC activity and polyamine synthesis in vivo than DFMO. This ODC inhibitory effect of CsA is a further detail to elucidate the up to now incompletely understood mechanisms of action of this immunosuppressive agent.

It does not show structural homology to known protein or nucleotide sequences. According to preliminary experiments, valosin possesses biological effects on the gastrointestinal tract of the dog.

Therapeutic measurements for acute pancreatitis depend on the severity of the disease and its complications. Since complications of acute pancreatitis may develop at any time, patients should be admitted to an intensive care unit for assessment (and frequent reassessment) of the severity of the disease and of the development of complications; they should remain in the intensive care unit for the first 48 hours at least, even if no signs of shock are apparent. The only exceptions to this rule are mild cases without signs of peritonitis. Basic therapy should include relief of pain, total fasting, nasogastric suction, parenteral replacement of fluids, electrolyte, albumin, and blood, and antibiotics. Hyperglycemia should be corrected and heparin should be given in cases of disseminated intravascular coagulation. In renal insufficiency, peritoneal dialysis is important, and in respiratory complications, humidified oxygen or artificial ventilation including positive end expiratory pressure therapy should be applied. Although the effect of peritoneal dialysis has been proven only in animal experiments and in retrospective studies in man, it is recommended in severe cases for shock therapy and for correction of electrolyte imbalance when ascites is present, even before anuria occurs. Les principes de traitement de la pancréatite aigüe dépendent de la gravité de la maladie et de ses complications. Comme cellesci peuvent apparaître n'importe quand, le malade doit être placé dans une unité de soins intensifs pour surveillance constante et appréciation continue de la gravité de son état. Il doit rester dans cette unité pendant les 48 premières heures au moins, même s'il n'a aucun signe de choc. La seule exception à cette règle peut être la pancréatite bénigne sans signe de péritonite. Le traitement de base doit comporter des antalgiques, un jeûne absolu, l'aspiration gastrique, des antibiotiques, le remplacement par voie parentérale de l'eau, des électrolytes, de l'albumine et du sang. Toute hyperglycémie doit être corrigée. Il faut administrer de l'héparine s'il y a coagulation intravasculaire disséminée. La dialyse péritonéale est importante en cas d'insuffisance rénale. Toute complication pulmonaire exige de l'oxygène humidifié ou un respirateur avec PEEP. L'effet bénéfique de la dialyse péritonéale n'a été démontré que chez l'animal et dans des études rétrospectives chez l'homme; il faut cependant la recommander en cas de choc grave et pour corriger les désordres électrolytiques s'il y a de l'ascite, même avant que ne survienne l'anurie.

A peptide derived from the N‐terminal region of porcine prosomatostatin, proSS1–32, has been purified to homogeneity from extracts of porcine upper intestine. Amino acid analysis revealed that the peptide consists of 32 residues. The complete primary structure was determined as: A P S D P R L R Q F L Q K S L A A A A G K Q E L A K Y F L A E L This sequence obviously comprises residues 1–32 of porcine prosomatostatin since it is identical to the corresponding sequence in human preprosomatostatin. The postulated cleavage site in porcine prosomatostatin is a Leu‐Leu bond between residues 32 and 33, thus confirming previous studies of the processing of the somatostatin precursor in the rat and transgenic mouse.

Cyclosporine was fed to male Wistar rats in a dose of 5, 10, or 50 mg/kg b.wt. for 7 days, and the effect on insulin secretion from the isolated perfused pancreas was investigated. Dose-dependently plasma insulin and pancreatic insulin content decreased while whole-blood CsA levels increased. An increase in blood glucose was only observed after feeding 50 mg/kg b.wt. CsA resulting in whole-blood CsA levels of 7735 ng/ml. Glucose (20 mM)-stimulated total insulin secretion (ng/50 min) was not affected during feeding 5 mg/kg b.wt. CsA, but was significantly reduced after feeding 10 or 50 mg/kg b.wt. CsA. The biphasic insulin secretion was reduced after 5 mg/kg b.wt. during the initial peak (0–10 min) but not during the second peak (10–50 min), whereas after 10 or 50 mg/kg b.wt. CsA both peaks were markedly reduced. The arginine (20 mM) and the arginine (20 mM)-plus-glucose (20 mM) stimulated insulin secretion was less affected after feeding 10 mg/kg b.wt. CsA than after stimulation with glucose (20 mM) alone. The addition of CsA to the perfusate did not influence glucose-stimulated insulin release from normal rat pancreas.

Abstract. Historically, carcinoids have long been known to be a morphologically distinct class of rare intestinal tumors that behave less aggressively than the more common intestinal adenocarcinomas. It was not until much later that their endocrine nature was recognized. Some authors restrict the term carcinoid to intestinal endocrine tumors, whereas others include a large variety of neuroendocrine tumors. In the WHO classification of 1980, carcinoids were defined as tumors of the diffuse neuroendocrine system that are either benign or neoplasms with a more favored prognosis than carcinomas. They are characterized by a typical growth pattern, silver affinity, and positive immunohistochemical reaction with neuron-specific markers; and they can express different peptides and biogenic amines. Neuroendocrine tumors originating from endocrine glands (pituitary, thyroid, adrenals, pancreas) and highly malignant neuroendocrine carcinomas are excluded from the carcinoid group of neoplasms. For the natural history of carcinoid tumors several independent predictive parameters can be defined: size, site of origin, growth pattern, and hormone dependence. The number of neuropeptides and amines expressed by a carcinoid or the amount of biologically active neurohormones secreted are of no prognostic significance regarding malignant behavior. The carcinoid syndrome is a rare clinical entity that occurs with a prevalence of 1.6% for carcinoid tumors and almost only if liver metastases are present. The complex clinical symptoms are only partially explained by the secretion of serotonin and tachykinins.:

Zusammenfassung 1. Sulfonylharnstoffe (Tolbutamid und Chlorpropamid) senken an der eviscerierten, nephrektomierten Ratte den Blutzucker nicht und erhöhen nicht den Glucoseverbrauch.

Zusammenfassung Heparin in hohen Dosen über 6 Tage verändert weder die Größe noch die histologische Struktur der Nebennierenrinde der intakten Ratte. Bei der hypophysektomierten Ratte läßt sich die Nebennierenrindenatrophie durch Heparin nicht rückgängig machen, wie es für ACTH typisch ist. Eine ACTH-ähnliche Wirkung des Heparin ist damit in der von uns gewählten Versuchsanordnung nicht nachzuweisen.

Adrenalectomy of eviscerated, nephrectomised rats constantly infused with glucose induces increased glucose consumption. Doses of deoxycorticosterone acetate and epinephrine alter this to the conditions found in eviscerated rats with intact adrenals. This could be mainly due to a circulatory effect of both hormones. – Eviscerated nephrectomised rats, constantly infused with glucose show a reproducable sensitivity-value for i. v. injected insulin. The value of this dose is over 0.05 U/kg insulin. Adrenalectomy momentarily causes an increase in the insulin sensitivity of the eviscerated animal. – The augmented insulin sensitivity following adrenalectomy is not clearly affected by deoxycorticosterone, but can be reduced by very high doses of prednisolone. The diaphragmatic glycogen values do not differ from those found in untreated animals. – Epinephrine completely abolishes the increased insulin sensitivity of the adrenalectomised eviscerated animal. This is probably due to a peripheral metabolic effect occurring mainly in the muscle tissue. The reduction in the diaphragmatic glycogen content suggests activation of the phosphorylase system with consequent inhibition of hexokinase. DHE abolishes the action of epinephrine on the hyper-sensitivity to insulin and on muscle glycogenolysis. Glucagon has no synergistic insulin action in the eviscerated nephrectomised rat, either in high or low doses. The insulin effect on the blood sugar of the highly insulin sensitive adrenalectomised eviscerated rat, is even diminished by high doses of glucagon. The mechanism of this peripheral insulin antagonistic action of glucagon occurs without glycogenolysis and has not yet been elucidated. The effect is however much slighter than that of epinephrine.

Zusammenfassung 1. Bei der experimentellen Pankreatitis der Ratte durch Injektion von Natriumtaurocholat, Trypsin oder Enterokinase kommt es trotz schwerer morphologischer Veränderungen nicht zu einer nachweisbaren Aktivierung von Trypsin oder proteolytischen Enzymen. Der Zymogengehalt ist unverändert.

Zusammenfassend: ergibt sich, da beim Thymusinvolutions-Test keine Inaktivierung des ACTH durch Heparin nachzuweisen ist. Heparin fhrt vielmehr zu einer signifikanten Thymusverkleinerung und verstrkt die ACTH-Wirkung auf den Thymus. Eine ACTH-hnliche Wirkung des Heparin ist damit jedoch nicht bewiesen, weil die Nebennieren anscheinend nicht mitreagieren.