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Gastrointestinal bleeding (GIB) still presents a demanding situation with high morbidity and mortality rates; thus hemostatic powders such as EndoClot (EC) have been developed to improve endoscopic armament. The aim of the present study was to determine which indications triggered the application of EC and to assess resulting hemostasis rates. Forty three patients undergoing endoscopical procedures in three hospitals; two tertiary care and one university hospital, were included. EC was applied in 48 endoscopies in 43 patients (27 male, age 65.5 years, range 28 - 92 years) following four different indications. EC was used in active GIB as rescue or first-line therapy giving a short-term and long-term hemostasis in 13/17 patients (76.5%). In the setting of non-active GIB, following conventionally achieved hemostasis or endoscopic interventions, EC was found to prevent bleeding in 19/21 patients (90.4%). EC induced hemostasis in 8/10 patients (80%) with impaired coagulation. EC failures resulted from tumor bleeding, Forrest I lesions or perforated duodenal ulcers. No major adverse events were recorded and one technical failure (2.1%) occurred. EC was applied as first line or salvage treatment in ongoing bleedings with promising results. Furthermore, EC was used after successful hemostasis or following endoscopic interventions to further reduce re-bleeding rates. We saw promising results in all indications, albeit lacking a control group.

Background and Study Aims: Cytological methods may be used to differentiate benign from malignant biliary strictures. We evaluated the diagnostic accuracy of an endobiliary cytotechnique which can easily be performed during endoscopic retrograde cholangiopancreatography. Patients and Methods: Cytological samples were obtained by brushing biliary strictures via a guide wire in 86 patients with strictures of unknown status. Samples were classified by an expert cytologist as normal (including reactive cells), severely dysplastic (atypical cells suspicious of malignancy) and clearly malignant. A final diagnosis was achieved in 78 patients based on intraoperative findings and histological investigation, autopsy or prolonged follow-up. Strictures were malignant in 57 cases (31 pancreatic carcinoma, 20 cholangiocarcinoma, 6 others) and benign in 21 cases (11 chronic pancreatitis, 5 chronic nonspecific inflammation, 5 others). Results: The overall results for brush cytological investigation were sensitivity 56.1 %, specificity 90.5 %, positive predictive value 94.1 %, negative predictive value 43.2 %, and accuracy 65.4 %. Sensitivity was significantly higher (P

In gastrointestinal research the in vitro release of prostaglandins from incubated or cultured biopsies is a widely used method to estimate prostaglandin synthesis. We therefore investigated the rate limiting mechanisms of PGE2 release in organ cultured gastric mucosa of the rabbit, determining PGE2 secretion from organ cultured mucosal biopsies by radioimmunoassay and prostaglandin synthesizing capacity by in vitro incubation of mucosal homogenate or microsomes with [14C]-arachidonic acid. Freshly taken biopsies secreted PGE2 at an initial high rate, that decreased during the following 4 hrs of culture. This PGE2 release was dose dependently reduced by inhibitors of the prostaglandin cyclooxygenase. 5mM acetylsalicylic acid (ASA) maximally suppressed PGE2 secretion to 7% of controls, and the inhibition by ASA was quantitatively similar at every given culture period. PGE2 release was markedly increased by carbenoxolone but was only slightly activated by extracellular calcium and the Ca(++)-ionophore A23187. However, Ca++/A23187 were unable to maintain PGE2 secretion at the initial rate. PGE2 secretion was undisturbed in calcium-free medium but was reduced to 50-60% of controls by excess EDTA. The intracellular calcium chelator 1,2-bis-(2-aminophenoxy)-ethane-N,N,N',N',-tetraacetic acid-acetoxymethyl ester (BAPTA-AM) similarly inhibited PGE2 release to 72% of controls. In contrast, PGE2 release was unaffected by the intracellular calcium antagonist 3,4,5-trimethylene-bis(4-formylpyridinium bromide) dioxime (TMB-8), the calmodulin antagonists N-(6-aminohexyl)-1-5-chloro-1-naphthalenesulfonamide (W-7) and calmidazolium (compound R24571) or various direct inhibitors of endogenous arachidonic acid release like tetracaine, bromophenacyl bromide, neomycin or low dose quinacrine, indicating that the reduction of PGE2 release by EDTA or BAPTA may be mediated by mechanisms different from substrate release. In contrast, an inhibition of PGE2 secretion by quinacrine at high concentrations (greater than or equal to 0.8 mM) was attributed to a direct inhibition of the prostaglandin cyclooxygenase, similar to ASA. Finally, the reduction of the prostaglandin synthesizing capacity by ASA was strongly correlated with the inhibition of PGE2 secretion, also at low concentrations and minor degrees of inhibition. From these data we conclude, that the activity of the prostaglandin cyclooxygenase is rate limiting for PGE2 secretion from organ cultured mucosal biopsies rather than arachidonic acid release by a phospholipase A2. This should be considered for interpretation of studies based on prostaglandin release from cultured mucosa.

Aims: To compare the diagnostic value of endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) in the differentiation of malignant from benign masses in the pancreatic head. Methods: Within 14 months 95 prospective patients with masses in the pancreatic head were assigned for preoperative EUS and ERCP. Both procedures were performed and recorded according to a standardized protocol. Based on intraoperative findings and histology, 50 patients (53%) suffered from malignant and 45 patients (47%) from benign (inflammatory) tumors. Results: Success rates were 96% for EUS and 95% for ERCP. The overall results for EUS and ERCP to predict malignant masses were, respectively: sensitivity 78 and 81%, specificity 93 and 88%, positive predictive value 93 and 89%, negative predictive value 78 and 80%, and diagnostic accuracy 85 and 84%. When EUS and ERCP were taken together, the sensitivity was 92% (specificity 85%), but the diagnostic accuracy (89%) was not significantly enhanced. The results for EUS to diagnose lymph node metastases preoperatively were: sensitivity 55%, specificity 91%, positive predictive value 69%, negative predictive value 84%, and accuracy 81%. Conclusions: EUS and ERCP have similar diagnostic accuracies to separate malignant from benign masses in the pancreatic head. Combination of both procedures is not superior to the use of one modality alone. Abnormal lymph nodes visualized on EUS in patients with inflammatory masses in the pancreatic head due to chronic pancreatitis should be interpreted cautiously.

Neben den endoskopischen Techniken und der Sonographie stehen an bildgebenden Verfahren die konventionelle Rontgendiagnostik, die Computertomographie, die Magnetresonanztomographie (MRT) sowie nuklearmedizinische Verfahren zur Verfugung.

Objective: To determine the efficacy of antibacterial prophylaxis in preventing infectious complications after percutaneous endoscopic gastrostomy. Design: Prospective, randomised, placebo controlled, double blind, multicentre study. Setting: Departments of internal medicine at six German hospitals. Subjects: Of 106 randomised adult patients with dysphagia, 97 received study medication, and 84 completed the study. The median age of the patients was 65 years. Most had dysphagia due to malignant disease (65%), and many (76%) had serious comorbidity. Interventions: A single intravenous 2.2 g dose of co-amoxiclav or identical appearing saline was given 30 min before percutaneous endoscopic gastrostomy performed by the thread pull method. Main outcome measures: Occurrence of peristomal wound infections and other infections within one week after percutaneous endoscopic gastrostomy. Results: The incidence of peristomal and other infections within one week after percutaneous endoscopic gastrostomy was significantly reduced in the antibiotic group (8/41 (20%) v 28/43 (65%), P Conclusions: Antibiotic prophylaxis with a single dose of co-amoxiclav significantly reduces the risk of infectious complications after percutaneous endoscopic gastrostomy and should be recommended. Key messages Percutaneous endoscopic gastrostomy for enteral feeding can be associated with substantial rates of infectious complications, notably peristomal wound infection Small, single centre studies on prevention of wound infection by antibiotic prophylaxis have given conflicting results This prospective, randomised, placebo controlled, double blind, multicentre study showed that a single dose of 2.2 g co-amoxiclav significantly reduced the rate of infection The favourable effect of antibiotic prophylaxis included a reduction in the rate of clinically important peristomal wound infection Intention to treat analysis indicated a significant reduction in the need for therapeutic antibiotics

In a prospective study, we investigated stone recurrence in high risk patients with difficult common bile duct stones treated with extracorporeal shockwave lithotripsy (ESWL) after futile endoscopic attempts at stone extraction with sphincterotomy.Endoscopic stone extraction proved unsuccessful in 35 of 659 patients presenting with common bile duct stones (5.5%, 11 males and 24 females: mean age 71.0+/-10.0 yrs; BMI 25.8+/-3.9; ASA-Classification 2.63+/-0.65), due to large stone size (10 patients), incarcerated stones (15 patients), stones inaccessible to the Dormia basket (7 patients) or an impacted Dormia basket (3 patients). The stones were localized radiologically. ESWL was performed using the HM3 lithotripter (Dornier, Munich/FRG).Immediately following ESWL, 17.1% of the patients treated showed complete stone clearance. In an additional 57.1%, further endoscopic stone extraction was required to achieve complete stone clearance, while 20.0% were discharged with small residual stone fragments. The remaining 2 patients (5.7%) required surgical intervention. Thirty four of 35 patients (97.1%) were followed-up for an average of 27+/-11 months. Five patients (14.3%) experienced stone recurrence at an average of 13.8+/-5.7 months post ESWL.ESWL is a useful and safe adjunct to endoscopic management of difficult common bile duct stones in older, high-risk patients. The stone recurrence rate was about 14% after one year. All recurrent stones were treatable by endoscopy.

For the first time, magnetic resonance cholangiopancretography (MRCP) provides images of the biliary and pancreatic ducts based on 3D data similar to those we are used to from endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC). Extraordinarily impressing is the fact that no contrast media have to be applied. The following manuscript shows technical basics and the development of this technique from gradient echo sequences to the recent single-shot techniques. Furthermore possibilities and limitations of MRCP will be discussed with respect to certain illnesses.

Patients with bleeding upper gastrointestinal ulcers were observed during the period 1989–1991. The clinical outcome was examined by retrospective analysis. Of all patients with benign gastric or duodenal ulcers, 85 patients presented with stigmata of bleeding, e.g., Forrest grades Ia-IIb. This group was treated endoscopically by the injection of fibrin sealant with or without additional hypertonic saline plus epinephrine. Endoscopic therapeutic procedures were repeated until the ulcers reached Forrest grade III. While initial hemostasis was achieved in all patients, permanent hemostasis declined to 85.9% in our series. The overall bleeding-associated mortality was 7.0%, and in 9.4% continuous bleeding required surgery. No therapy-associated complications were seen. Interestingly, fibrin glue f to induce a rapid healing process. It may be concluded that fibrin sealing is a complication-free highly effective endoscopic therapy.

Opie suggested in 1901 that a common channel between the pancreatic duct and the common bile duct is created when a gall stone becomes impacted at the duodenal papilla. He proposed that bile would regurgitate into the pancreas and trigger pancreatitis. The case is reported of a 22 year old woman with an impacted stone at the duodenal papilla creating a common channel. The patient suffered from acute pancreatitis. Three days before the onset of pancreatitis, however, a T drain had been inserted into the common bile duct from which bile had been flowing freely and continuously. Moreover, amylase activity in fluid from the T drain was 49,000 U/l at the onset of pancreatitis pointing to reflux of pancreatic juice into the biliary tract. The amylase activity in bile decreased rapidly after endoscopic papillotomy and retrieval of the stone. The events participating in the development of acute gall stone induced pancreatitis in this patient with a common channel situation permitted reflux of pancreatic juice into the biliary tract rather than bile into the pancreas. Impairment of pancreatic outflow by a gall stone was probably the primary triggering event, rather than the regurgitation of bile into the pancreas. Preventive or therapeutic treatment in gall stone pancreatitis should be aimed at the urgent restoration of pancreatic flow rather than at the prevention of a hypothetical bile reflux.

In a retrospective analysis of bleeding upper gastrointestinal ulcers we examined the clinical outcome of the patients observed during the period 1989-1991. Out of 452 patients with benign gastric or duodenal ulcers, 85 patients exhibited stigmata of fresh bleeding (5.9% Forrest Ia, 24.7% Ib, 45.9% IIa and 23.5 IIb) and were treated endoscopically by the injection of fibrin sealant with or without additional hypertonic saline plus epinephrine. The endoscopic therapy was repeated until Forrest grade III was reached. Initial endoscopic hemostasis was achieved in all, permanent hemostasis in 85.9%, of the patients treated. The overall bleeding-associated mortality was 7.0%, in 9.4% continued bleeding required surgery. No therapy-associated complications were seen. Interestingly, the fibrin clot appeared to induce rapid healing of ulcers. It may be concluded that fibrin sealing is a complication-free, highly effective endoscopic therapy.

A 75-year-old man with angiodysplasia of the sigmoid and rectum and recurrent lower gastrointestinal bleeding episodes, despite repeated endoscopic laser-coagulation, was successfully treated with oestrogen-progesterone. Besides angiodysplasia he had aortic valvular stenosis, monoclonal gammopathy, mild renal insufficiency, and moderate peripheral arteriosclerosis obliterans. Oestrogen-progesterone may be a valuable alternative therapy in elderly patients with repeated bleeding, despite endoscopic coagulation, secondary to gastrointestinal angiodysplasia which cannot be treated surgically, in patients who deny surgery, or with rebleeding after surgery.

We investigated the utilization of exogenous 14C-labelled arachidonic acid by the cyclooxygenase system of the gastric mucosa and its alteration by cytosolic factors, protein binding, glutathione peroxidase (GSH-Px), and hydrogen peroxides. Total prostaglandin (PG) synthesis from gastric microsomes was reduced in a dose- dependent manner to 12% and 68% of controls by increasing amounts of the 105,000g supernatant or albumin (8mg protein/ml), respectively (p less than 0.01). The inhibitory cytosolic factor was heat labile, protease sensitive, and was retained by a 300,000 Dalton ultrafiltration membrane. Thus, it was likely a protein. Other possible inhibitory mechanisms like protease- or heme-induced destabilization of the cyclooxygenase, haptoglobin-mediated inhibition, or self-inactivation by endogenous substrate were excluded. N-ethylmaleimide (NEM), an agent that alkylates sulfhydryl-groups thereby inhibiting GSH-Px, abolished the inhibitory effect of cytosol in a dose-dependent fashion. In contrast to their inhibition of prostaglandin synthesis, the binding of arachidonic acid by albumin or cytosolic proteins accounted to 75% and 19% under comparable conditions, respectively, however, cytosolic fatty acid binding was unaffected by NEM. Thus, it was concluded that the inhibitory effect of cytosol, in contrast to albumin, was mediated by a sulfhydryl-depending process, probably a GSH-Px. This conclusion was supported by a qualitatively comparable inhibition by a purified GSH-Px from bovine erythrocytes. The inhibitory action of cytosolic proteins was reduced significantly by increasing concentrations or repeated application of arachidonic acid; therefore, cytosolic GSH-Px was likely to affect substrate utilization by the microsomal PGH synthase through reduction of activating substrate peroxides. Similarly, the in vitro formation of cyclooxygenase products by mucosal homogenate or gastric microsomes in the absence of cytosol was limited at substrate concentrations below 80 microM, despite sufficient nonesterified arachidonic acid remaining in the incubate. This limitation was mediated only partially by self-inactivation of the prostaglandin cyclooxygenase. Neither N-ethylmaleimide nor repeated application of hydrogen peroxides increased substrate utilization by isolated microsomes, excluding contamination by GSH-Px or simply a lack of hydrogen peroxides as possible mechanisms for the limited utilization. From these results, a special role of substrate-linked lipid peroxides in the activation of mucosal prostaglandin synthesis is proposed. The reduction of these peroxides by glutathione dependent or independent peroxidases, e.g. the PGH synthase-linked hydroperoxidase activity itself, could explain the reduced utilization of nonesterified arachidonic acid by the gastric mucosa.

We determined the capacity and the profile of prostaglandin synthesis in the antral mucosa of patients with erosive (n = 43) or non-erosive (n = 24) Type B gastritis in comparison with normal controls (n = 24). Prostaglandin synthesis was measured by the incorporation of 14C-labelled arachidonic acid into cyclooxygenase products in mucosal homogenate. There was no significant difference between controls and patients with antral gastritis. Furthermore, there was no correlation of the prostaglandin synthesis with helicobacter colonisation or with the degree of inflammation. In another group of 15 patients there was a 17% increased synthesizing capacity nearby the erosions, compared to a non-erosive area (p = 0.05). In these patients with chronic Type B gastritis the treatment with an antacid (Maalox 70, 4 x 10 ml) for 4 weeks did not affect the synthesizing capacity or the profile of mucosal prostaglandin synthesis.

We investigated the effects of an exogenous Type I phospholipase C (PLC) from clostridium perfringens on arachidonic acid release and prostaglandin synthesis from gastric mucosa by determining PGE2 release from organ cultured rabbit mucosal biopsies as well as PGE2 synthesis and substrate-dependent inactivation of the prostaglandin cyclooxygenase from endogenously released arachidonic acid in mucosal homogenate. PLC dose dependently stimulated PGE2 secretion from organ cultured mucosa to 145% and 245% at 0.1 and 1.0 U/ml during a 60 minute culture period. This effect was not affected by the calmodulin antagonist N-(6-aminohexyl)-1-5-chloro-1-naphthalene-sulfonamide (W-7) or the intracellular calcium chelator 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N',-tetraacetic acid-acetoxymethyl ester (BAPTA-AM). PLC could not be substituted by phorbol-12-myristate 13-acetate (PMA), an analogue of the diacylglycerol second messenger functions. During a 15 minute preincubation of mucosal homogenate at 37 degrees C, 1mM CaCl2 stimulated PGE2 synthesis from endogenous arachidonic acid about 5-fold compared to an EDTA-control. In contrast, the residual prostaglandin synthesizing capacity, determined by incubation with excess 14C-labelled arachidonic acid, was reduced by CaCl2 to 37% of the EDTA-value. Quinacrine, an inhibitor of arachidonic acid release from phosphatidylethanolamine, reduced both the stimulation of PGE2 synthesis and the inactivation of prostaglandin cyclooxygenase. Therefore we conclude, that this Ca(2+)-effect reflects activation of the Ca-dependent phospholipase A2 (PLA2) and, as a consequence, substrate-induced inactivation of the prostaglandin cyclooxygenase.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the action of the new aminosalicylate olsalazine (disodium azodisalicylate) on arachidonic acid metabolism in comparison with 5-aminosalicylic acid (5-ASA) and sulphasalazine (SASP) by in vitro incubation of cellular homogenates from human polymorphonuclear (PMNL) and mononuclear (MNL) leukocytes with 14C-labelled arachidonic acid. Olsalazine reduced the synthesis of leukotriene B4 (LTB4), 5-hydroxyeicosatetraenoic acid (5-HETE), 11-HETE, 12-HETE, and 15-HETE in PMNL and MNL slightly less than SASP. 5-ASA was significantly less inhibitory than olsalazine and SASP on the formation of lipoxygenase products in PMNL and on LTB4 synthesis in MNL. In contrast, in MNL the formation of 5-HETE was unaffected, and the production of 11-HETE, 12-HETE, and 15-HETE was even slightly activated by 5-ASA. Total prostaglandin synthesis was dose-dependently reduced by the aminosalicylates (SASP greater than olsalazine greater than 5-ASA), but only SASP markedly altered the prostaglandin (PG) profile, with an increase in PGE2 and PGF2 alpha at the expense of other cyclooxygenase products. It may be concluded that olsalazine resembled SASP with regard to the inhibition of the lipoxygenase but had effects intermediate between the other salicylates on cyclooxygenase. Furthermore, the alteration of the prostaglandin profile by SASP points to an overlying cofactor effect of this drug.

Self-destruction of the prostaglandin cyclooxygenase has been suggested to be an important factor in the regulation of endogenous prostaglandin synthesis. The present study was done in order to define the role of this substrate-induced inactivation in the regulation of prostaglandin synthesis in gastric mucosa. In tissue homogenate, the prostaglandin synthesizing capacity is rapidly inactivated at 37°C, even in the absence of exogenous arachidonic acid. It was shown that this inactivation can be prevented both by EDTA as a chelator of calcium-ions and by tetracaine, a specific inhibitor of the phospholipase A2. Additional exogenous arachiodonic acid again inactivated prostaglandin synthesis in a dose dependent manner. In contrast, prostaglandin synthesizing capacity in organ cultured mucosal biopsies is well preserved, although the release of endogenous substrate was activated by extracellular calcium and Ca-ionophore A23187. Furthermore, even at high concentrations of exogenous arachidonic acid present in the culture medium, the synthesizing capacity in intact biopsies was only slighly and reversibly reduced. These large differences between intact biopsies and cell free tissue preparations point to very efficient mechanisms controlling the substrate availability for the cyclooxygenase system both from endogenous and exogenous sources in intact gastric mucosa.

The endocrine regulation of the key enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.34) and of the brush border enzyme alkaline phosphatase (EC 3.1.3.1) was studied in short (2 h) and long term (24 h) organ culture of rabbit ileum mucosa. In contrast to the hepatic enzyme, intestinal reductase is not subject to regulation by insulin or glucagon even at a pharmacological level. This applies to both 'total' and 'active' reductase, prepared in the absence or presence of sodium fluoride, respectively. During culture, there is a gradual, time-dependent increase in the active, dephosphorylated enzyme form. This endogenous activation was found to be unaffected by all hormones tested. Similarly, alkaline phosphatase was not influenced by both pancreatic hormones. In contrast, triamcinolone significantly (P less than 0.05) suppressed reductase in a dose-dependent fashion to 38% of controls after 24 h, but not after 2 h culture. Alkaline phosphatase was induced after both periods, but the effect was more marked after 24 h. A parallel minor stimulation of both enzyme activities was noted in the presence of 10(-9)M triiodothyronine (P less than 0.05), lower and very high (10(-5)M) concentrations were ineffective. In view of the role of glucocorticoids as intestinal growth inhibitors and of thyroid hormones as growth stimulators, it is suggested that changes in reductase reflect alterations of crypt membrane cholesterol synthesis, whereas the induction of alkaline phosphatase is mediated through an enhanced enterocyte regeneration and/or maturation.

Regulation of the key enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC: 1.1.1.34), by heterologous human lipoproteins and hormones was studied in a maintenance culture of rat hepatocytes. The liver cells were cultured under hormone and serum free conditions and maintained differentiated morphology and specific function. Under control conditions total HMG-CoA reductase increased by 50% after 24 h culture compared to 0 h values immediately after isolation. Thereafter a plateau of enzyme activity was reached lasting until 48 h, with a slight decline at 72 h. Concomitantly the "expressed" enzyme activity increased steadily, probably through dephosphorylation of latent reductase, the activation was largely complete at 48 h. During the steady state period of total reductase VLDL added to the medium at concentrations up to 50 μg/ml protein had no effect on HMG-CoA reductase activity. In contrast, LDL suppressed the enzyme in a dose-dependent fashion to 40% of controls at 100 μg/ml. On the other hand, HDL had the opposite effect with a significant induction up to 252% of controls at 50 μg/ml. Insulin also caused a comparable dose-dependent stimulation of enzyme activity at 10 −8 and 10 −7 M, whereas glucagon inhibited reductase activity. Compared to the insulin action, triiodothyronine and triamcinolone prompted a minor, but still significant increase of reductase activity. Insulin and triamcinolone acted synergistically, but the combination of triamcinolone and triiodothyronine was only additive. All hormonal inductions of reductase could be blocked by cycloheximide. The present data establish that HMG-CoA reductase of maintenance cultured hepatocytes is subject to a complex regulation by heterologous lipoproteins as well as pancreatic, adrenal and thyroid hormones.

Using 14C-labeled arachidonic acid as precursor for in vitro prostaglandin synthesis, the effect of an antacid containing Al (OH)3, Mg(OH)2 and CaCO3 on endogenous prostaglandin synthesis was investigated in antral and duodenal mucosa of healthy volunteers. After three weeks of treatment with a high-dose antacid, there was no detectable change in the total capacity of the mucosa for prostaglandin synthesis, but the prostaglandin profile was markedly altered. The relative amounts of PGE2 and PGF2 alpha synthesized by antral and duodenal mucosa increased at the expense of the prostaglandins A2/B2, thromboxane A2, and prostacyclin. In a short-term study, this change was not observed following a single antacid dose within 1 hr after application. It is concluded that long-term antacid treatment may alter the prostaglandin pattern formed by gastroduodenal mucosa and this may be related to its therapeutic effect.

The effect of a low dose antacid treatment on mucosal prostaglandin metabolism was studied in 15 healthy volunteers. A daily dose of 46 mmol (= 138 mval) Al(OH)3 and 42 mmol (= 84 mval) Mg(OH)2 with a titrated in vitro neutralising capacity of 272 mval of H+ was given for three weeks. Total prostaglandin formation and the prostaglandin profile as well as the degradation of PGE2 were assayed by incubating homogenates of endoscopic biopsies from antral and duodenal mucosa with the precursor (14C)arachidonic acid. Total prostaglandin synthesis in antrum (623 (110) pmol/mg protein) and duodenum (432 (72) pmol/mg) was stimulated after three weeks administration of low dose antacids by 176% (p less than 0.05) and 154% (p less than 0.05), respectively. An untreated control group exhibited no significant changes. In contrast, the prostaglandin profile showed only a small increase of the prostacyclin metabolite 6-keto PGF1a (p less than 0.05) at the expense PGD2. PGE2 catabolism was unaffected. This enhanced activity of mucosal prostaglandin cyclooxygenase might represent one possible mechanism of action of a low dose antacid treatment.

Sodium fusidate and its glycine conjugate, which have the same detergent properties as bile acids, significantly (p less than 0.05) stimulate HMG-CoA reductase of cultured intestine below the critical micellar concentration (CMC) without affecting brush border enzymes. Above CMC, both amphiphiles are cytotoxic. At concentrations between 1 and 5 mM, sodium fusidate decreased cholesterol contents of cultured mucosa (P less than 0.05), the increase in synthesis only partially compensating for the sterol loss. Oxygenated sterols, 7-keto- and 25-hydroxycholesterol, also depleted mucosal cholesterol at 0.5 mM, exerting their effect differently by inhibiting HMG-CoA reductase (p less than 0.01). In contrast to their marked effect on total mucosal cholesterol contents, brush border cholesterol was unaffected by both cholesterol and bile acid analogs.

A deficiency of locally synthesized prostaglandins has been suggested to underly gastric and duodenal ulcer disease and to mediate the mucosal lesions induced by non-steroidal anti-inflammatory drugs. The exact definition of their role is hampered by various methodological problems. First, the mucosal content of prostaglandins is affected by mechanical manipulation and homogenization and does not correspond to the rate of synthesis. Secondly, the assay of this rate in mass terms is also susceptible to these artefacts, and a steady state of prostaglandin secretion in vitro is usually not achieved. Thirdly, if prostaglandin synthesis is measured in vitro by the incorporation of labelled arachidonic acid, the possibly rate-limiting role of substrate supply is not taken into account. Thus, it is likely that a part of the disagreement in the field stems from the problems in measuring the true rates of prostaglandin synthesis in vivo.

Cholesterol is an essential constituent of all mammalian cell membranes, and its availability is therefore a prerequisite for cellular growth and other functions. To define further the role of cholesterol metabolism in the intestine both in vitro and in vivo, studies were performed. Several lines of evidence based on these studies suggest that the main purpose of local cholesterol synthesis in the gut is the support of rapid enterocyte proliferation: 1) growth was inhibited during pharmacologic suppression of cholesterol synthesis in intestinal organ or cell culture; 2) the endocrine regulation of intestinal growth was in most but not all instances accompanied by appropriate changes in cholesterol synthesis; 3) most of cholesterol synthesis and lipoprotein uptake was localized predominantly in the crypt and lower villus region; and 4) very little of the sterol synthesized by the intestinal mucosa was exported into lymph but seems rather to be incorporated into cell membranes.

Die 3-Hydroxy-3-Methylglutaryl-Coenzym-A-Reduktase (E. C. 1.1.1.34), das Schlusselenzym der Cholesterinsynthese wird in peripheren Zellen, wie z. B. Fibroblasten und glatten Muskelzellen u.a. durch die rezeptorvermittelte Aufnahme von LDL reguliert [1]. Auch fur den Dunndarm gibt es unter in vivo-Bedingungen gewonnene Hinweise, das Plasmalipoproteine in die Regulation der Cholesterinsynthese eingreifen. Eine pharmakologisch durch 4-Aminopyrazol(3,4)D-Pyrimidin induzierte Hypolipoproteinamie resultiert bei der Ratte in einem steilen Anstieg der Cholesterinsynthese im Ileum, der nach intravenoser Infusion von LDL reversibel ist [2]. Unter kontrollierten in vitro-Bedingungen konnte dieser Effekt bisher nicht bestatigt werden [3]. Daher untersuchten wir den Einflus von normalen und hypercholesterinamischen Plasmalipoproteinen auf die 3-Hydroxy-3-Methyl-Glutaryl-CoA-Reduktase der Mucosaorgankultur.

Regulation of the key enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC: 1.1.1.34), by heterologous human lipoproteins and hormones was studied in a maintenance culture of rat hepatocytes. The liver cells were cultured under hormone and serum free conditions and maintained differentiated morphology and specific function. Under control conditions total HMG-CoA reductase increased by 50% after 24 h culture compared to 0 h values immediately after isolation. Thereafter a plateau of enzyme activity was reached lasting until 48 h, with a slight decline at 72 h. Concomitantly the "expressed" enzyme activity increased steadily, probably through dephosphorylation of latent reductase, the activation was largely complete at 48 h. During the steady state period of total reductase VLDL added to the medium at concentrations up to 50 microgram/ml protein had no effect o HMG-CoA reductase activity. In contrast, LDL suppressed the enzyme in a dose-dependent fashion to 40% of controls at 100 microgram/ml. On the other hand, HDL had the opposite effect with a significant induction up to 252% of controls at 50 microgram/ml. Insulin also caused a comparable dose-dependent stimulation of enzyme activity at 10(-8) and 10(-7)M, whereas glucagon inhibited reductase activity. Compared to the insulin action, triiodothyronine and triamcinolone prompted a minor, but still significant increase of reductase activity. Insulin and triamcinolone acted synergistically, but the combination of triamcinolone and tri-iodothyronine was only additive. All hormonal inductions of reductase could be blocked by cycloheximide. The present data establish that HMG-CoA reductase of maintenance cultured hepatocytes is subject to a complex regulation by heterologous lipoproteins as well as pancreatic, adrenal and thyroid hormones.

A decreased PG E2 content in gastric mucosa of humans receiving a longterm antirheumatic therapy has been reported to be partially reversed after a one week treatment with an antacid (Reimann et al., Fortschr Med 102 [1984], 25-26). Therefore the effect of an Aspirin treatment of healthy volunteers with or without an antacid on the prostaglandin synthesis in gastric or duodenal mucosa was investigated. 14C-labelled arachidonic acid was used as substrate during in vitro incubation of the mucosal homogenate for determination of the endogenous formation of prostaglandins. Aspirin suppressed the total prostaglandin synthesis to less than 10% of control after one week treatment. The addition of a high dose antacid did not influence this inhibition, and no significant effect on the prostaglandin profile was detectable. It is concluded that antacids do not influence the suppression of the endogenous prostaglandin synthesis by NOSAC's, however another effect, eg a prolonged stability of PG E2 in a less acidic environment is more likely.

The effect of bile acids and bile acid/cholesterol micelles on 3-hydroxy-3-methylglutaryl coenzyme A reductase, the key enzyme of cholesterol synthesis, was investigated in cultured intestine. Glycocholic and glycodeoxycholic acid both suppressed total (fully activated) reductase activity after 3 h culture. The portion of expressed reductase, determined in the presence of NaF, was unaffected at 3 h, but decreased after 24 h of bile acid treatment. In contrast, total enzyme activity was stimulated up to 2.5-fold at 24 h; this bile acid effect was blocked by additional cholesterol. These results suggest that bile acids modulate both total reductase activity and the activation state of the enzyme in cultured intestine.

Prostaglandins are involved in many physiological functions of the gastrointestinal tract, e.g. the secretion of acid, mucus and bicarbonate, the motility, the microcirculation and cytoprotection. The diverse prostaglandins as well as prostacyclin and thromboxane are synthesized by a complex enzymatic system, which is affected by a multitude of possibly regulatory influences. Such mechanisms are the availability of dietary essential fatty acids, the calcium, dependent activation of the phospholipase A2, the self-inactivation of the prostaglandin cyclooxygenase, the availability of cofactors, the catabolism of the prostanoids and others. A minireview concerning these potentially regulatory mechanisms in the upper gastrointestinal tract is presented.

In vitro regulation of the key enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.34), was studied in 24-h organ culture of rabbit ileum. Preincubation of mucosal homogenate in phosphate buffer increased apparent reductase activity more than 5-fold. The activation was blocked in the presence of 150 mM NaF, suggesting interconversion of latent reductase by dephosphorylation. No significant further activation was achieved by potato phosphatase treatment. During culture total reductase activity was stimulated by 125% in lipoprotein-free medium. Addition of low density lipoprotein to the medium resulted in a dose-dependent suppression of reductase activity between 0.2 and 1.0 mM lipoprotein cholesterol. At these concentrations LDL inhibition reached 51 and 75% of control, respectively. The reductase response to very low density and high density lipoproteins was biphasic, with a 2- to 3-fold stimulation at 0.1–0.3 mM and a suppression at higher levels. No such stimulation was observed with high density lipoproteins obtained from cholesterol fed animals. Similarly, ‘hypercholesterolemic’ very low density lipoproteins enhanced reductase activity only slightly. It is concluded that lipoproteins are potent regulators of cholesterol synthesis in cultured intestine.

In vitro regulation of the key enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.34) by compactin, a competitive inhibitor of the enzyme, and mevalonate was studied in rabbit ileum organ culture. Addition of compactin suppressed ileum homogenate reductase activity by over 80% at concentrations up to 0.5 μg/ml. In contrast, compactin at the same concentrations added to the culture medium induced reductase activity up to 240% of controls. This increase was blocked by cycloheximide and mevalonolactone at 10 mM, but not by mevalonate (salt form) and cholesterol. Similarly, in contrast to ionized mevalonate, mevalonolactone significantly suppressed reductase activity of cultured intestine at 1 and 10 mM by 23 and 62%, respectively. A minor effect was also observed with preformed enzyme in fresh mucosal homogenate. When endogenous cholesterol synthesis was blocked by compactin, mucosal alkaline phosphatase activity decreased progressively, whereas medium activity from desquamated cells did not change. This distribution of the villous cell marker enzyme is characteristic of a decrease in crypt cell renewal and/or villous cell differentiation. This effect of compactin was also reversible with mevalonolactone. The reductase enzyme induced by compactin was probably latent intracellularly, since tissue cholesterol contents dropped sharply after blockade of endogenous sterol synthesis.